UTAH MEDICAID DUR REPORT JUNE 2015 ANDROGENIC AGENTS: TESTOSTERONE (UPDATE)

Transcription

1 UTAH MEDICAID DUR REPORT JUNE 2015 ANDROGENIC AGENTS: TESTOSTERONE (UPDATE) AVEED (testosterone undecanoate) intramuscular injection CIII Natesto (testosterone) nasal gel CIII VOGELXO (testosterone) topical gel CIII Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Melissa Archer, PharmD, Clinical Pharmacist Gary M. Oderda Pharm D, M.P.H, Professor Bryan S. Larson, Pharm D, BCPS, Clinical Pharmacist Devin H. Stock Pharm D student University of Utah College of Pharmacy Copyright 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

2 Contents Introduction... 3 Background... 3 Methodology... 5 Testosterone products... 5 Indications... 6 Diagnosing hypogonadism... 7 Guidelines for Hypogonadism in Men... 8 Guideline(s) for androgen therapy in women Use in special populations Clinical Efficacy FDA update Safety Place in therapy / Factors to consider for potential criteria Utah Medicaid Utilization Data Conclusions Potential clinical criteria Appendix 1 Drug information Appendix 2 Systematic Reviews Appendix 3 FDA data summary Appendix 4 - Utilization Data References

3 Introduction In September 2011, the P&T Committee reviewed the Androgenic agents (fluoxymesterone, methyltestosterone, oxandrolone, and testosterone), followed by a DUR Board review in October/November Indications for androgens include male hypogonadism, delayed puberty, an adjunct to promote weight gain or offset protein catabolism, and in the palliative treatment of metastatic breast cancer. During the P&T meeting, utilization data was also examined and questions entertained about how the drug is monitored. 3 It was reported that blood draws are not routinely done and that it is mostly monitored through symptoms. In the previous DUR review and report, the guidelines were reviewed, and it is recommended to obtain serum testosterone concentrations for diagnosis of hypogonadism and throughout testosterone therapy, to monitor for safety and efficacy. 3,4 According to the 2012 DUR review, utilization increased dramatically over the previous two years, testosterone blood levels were not done as recommended, and several safety and monitoring issues were identified including misuse, abuse, screening for conditions, monitoring of testosterone levels, adverse effects, risk of virilization in children and safety in specific populations. In November 2012 the DUR Board decided to accept the prior authorization criteria recommended by the University of Utah. The topical/transdermal products criteria require that the patient be male, >18 years old, diagnosis codes for primary or secondary hypogonadism (ICD or 253.4), and evidence of low testosterone symptoms and signs (two morning total testosterone levels below the reference range). The injectable testosterone products criteria require a valid diagnosis code for breast cancer submitted by an oncologist for women. The American Urological Association (AUA) states in their 2014 position statement that the increased awareness about hypogonadism has been stimulated by an increase in availability and diversity of patient-acceptable forms of testosterone replacement options in recent years. 5 The purpose of this DUR review is to examine the appropriateness of testosterone use in the Utah Medicaid population. That is when testosterone is used for approved indications and not being misused or abused. This report contains updated information and includes information on the three new products that have been approved recently; AVEED (testosterone undecanoate) intramuscular injection CIII, Natesto (testosterone) nasal gel CIII, and VOGELXO (testosterone) topical gel CIII. Background Testosterone is known as the male sex hormone and synthetic variants of it are often referred to as anabolic steroids. 6 Endogenous testosterone is secreted in the testicles of males and the ovaries of females and small amounts are also secreted by the adrenal glands. Endogenous androgens are needed for normal growth, development and maintenance of male organs and characteristics such as deepening of the voice, male hair distribution (beard, axillary, etc.), growth of the Adam s apple, increased libido, increased muscle strength and mass, and alterations in fat distribution. 7,8 It causes the growth spurts in adolescents, but also the fusion of the epiphyseal growth center responsible for the termination of linear growth. If exogenous androgens are used for long periods in children, it may result in fusion of the epiphyseal growth centers and termination of the growth process. 7 3

4 The condition where the body does not produce enough testosterone is called male hypogonadism which may be congenital or acquired (e.g. injury, infection or aging). 9 Andropause (male menopause) is the period when hormones naturally start declining (by about 1-2% yearly) usually during men s late forties or early fifties. 10 According to the American Association of Clinical Endocrinologists as many as 30 percent of men over 75 have a testosterone level that's below normal. 9 Endogenous testosterone levels are maintained through a hypothalamus pituitary testicles axis which involves stimulating and inhibitory effects. The hypothalamus secretes gonadotrophin-releasing hormone (GnRH) which controls the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. LH regulates testosterone production by the testicles (by Leydig cells) and FSH stimulates spermatogenesis. When exogenous androgens are used, the elevated blood levels inhibit production of pituitary luteinizing hormone (LH) which blocks production of endogenous androgens by Leydig cells. 7 Figure 1. Hypothalamus pituitary testicles axis (excerpt) 8 Primary hypogonadism refers to a problem with the testicles (low testosterone production & elevated gonadotrophins). Causes include Klinefelter syndrome (chromosome abnormality), injury to the testes (including radiation or chemotherapy) and undescended testes. Secondary hypogonadism indicates a problem in the hypothalamus or the pituitary gland (failure to produce enough LH and FSH, low testosterone). This can be caused by aging, obesity, drug use (prescription and recreational use), tumors, trauma, or radiation. This condition can occur during fetal development, before puberty or during adulthood (e.g. with aging) and the signs and symptoms will therefore depend on the person s physiological age. It is also possible to have a combination of primary and secondary hypogonadism for example with aging. This may also be seen in patients with certain conditions such as cirrhosis or sickle cell disease. 9,10 Signs and symptoms of hypogonadism may include underdeveloped genitals/female genitals (fetal); decreased development of muscle, impaired growth in beard/body hair and male organs, excessive 4

5 growth of arms and legs compared to trunk, gynecomastia (puberty), erectile dysfunction or decreased sex drive, infertility, decrease in muscle mass, osteoporosis, hot flashes, and emotional and mental effects such as fatigue or difficulty concentrating (adulthood). 9 It has been estimated that 1% of the entire US population use androgens. 11 A US survey found that about 4 out of 5 users were recreational athletes and body builders. 12 Pharmaceutical marketing on the potential benefits of testosterone may have attributed to the increase in testosterone use. Commercials often use the term low T for low testosterone levels. People are lured toward testosterone use for physical and psychological wants such as big muscles and improved sexual function and/or mood. 13 However, the FDA recently issued drug safety communication that they have become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging, and that the benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man s symptoms seem related to low testosterone. 14 On 01/31/2014, the FDA issued a Drug Safety Communication that they were investigating the risk of cardiovascular events associated with testosterone products. 15 The FDA announced on 03/03/2015 that they are requiring labels to be revised to clarify the approved uses of these medications ( prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions ) and to include information about a possible increased risk of heart attacks and strokes in patients taking testosterone. 14 Methodology A Cochrane Library literature search for systematic reviews was conducted. Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), relevant society websites, the FDA website (including product labeled information), Micromedex and Lexicomp were searched for safety information, systematic reviews, clinical trials, and guidelines. As per the hierarchy of evidence, high quality systematic reviews and evidence based guidelines were searched first. Testosterone products Table 1 (Appendix 1) contains a summary of the products. Testosterone products include injectables (enanthate, cypionate, or undecanoate), a buccal patch, the nonscrotal transdermal patch, implantable pellets, transdermal gels/solutions, and the recently approved nasal gel (Natesto approved by FDA in May ). 17 The scrotal patch (Testoderm TTS) was marketed until 2002 and has been discontinued. 18 Testosterone undecanoate (Aveed) was not approved in the United States at the time of the previous report, but was approved by the FDA in March Vogelxo topical gel was approved in June Oral capsules/tablets (methyltestosterone) is not available in the US. 17 Oral alkylated androgens are not recommended due to rapid first-pass metabolism so that sufficient blood levels cannot be achieved. They are also not recommended because of adverse effects including lipid changes and hepatic effects such as hemorrhagic liver cysts, cholestasis, and hepatocellular adenoma. 4,21,22 The FDA marketing status information for testosterone propionate injections states discontinued. 23 5

6 Indications Aveed (testosterone undecanoate) injection is an androgen indicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone: o Primary hypogonadism (congenital or acquired) o Hypogonadotropic hypogonadism (congenital or acquired) Aveed should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis. Limitations of use: Safety and efficacy of Aveed in males less than 18 years old have not been established. 24 Natesto is an androgen indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired) Hypogonadotropic hypogonadism (congenital or acquired) Limitations of use: Safety and efficacy of Natesto in males less than 18 years old have not been established. 25 Vogelxo is an androgen indicated for testosterone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone: Primary hypogonadism (congenital or acquired). Hypogonadotropic hypogonadism (congenital or acquired). Limitations of Use: Safety and efficacy of Vogelxo in males less than 18 years old have not been established Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure. 1 Indications of different dosage forms (adapted from information in Lexicomp 17 ): Androgen replacement therapy in the treatment of delayed puberty Male hypogonadism (primary or hypogonadotropic) Inoperable metastatic female breast cancer Labelled indications Injection Enanthate only Enanthate only Pellet x Buccal system x x Intranasal gel x x Topical gel x x Topical solution x x Transdermal system x x Capsule (not available in US): Conditions associated with a deficiency or absence of endogenous testosterone. According to Valiant Pharmaceuticals there is a pending FDA PI revision for Android and Testred (no further information) 26 6

7 Diagnosing hypogonadism Hypogonadism was defined by the Endocrine Society s Clinical Practice Guideline for Testosterone as a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. 27 Diagnosis of testosterone deficiency is based on the patient s history (e.g. injury), symptoms and signs (physical examination) as well as morning serum testosterone levels. 27 Measuring testosterone levels: Testosterone levels vary throughout the day and the Endocrine Society therefore recommend an initial morning total testosterone level and recommend repeating the total testosterone measurement. 13,27 Transient testosterone levels could be caused by acute illness, medications and other factors and up to 30% of patients have a normal level upon repeat measurement. 27 The normal testosterone level varies for different people and at different ages. The threshold for hypogonadism has not been established, but in general a level below ng/dL is considered low (300-1,000 ng/dl is considered normal). 27 The Endocrine Society advises against making a diagnosis during acute or subacute illness and the use of questionnaires such as the Aging Male Symptom Score. 27 Possible reversible causes of hypogonadism should be ruled out, such as environmental toxins, medications, eating disorders, excessive exercise, and recreational drug use. 28 Some examples of drugs that may cause hypogonadism have been included in the table below. Potential drug causes of hypogonadism Spironolactone Chronic opiate use Estrogen and progesterone Anabolic steroids Glucocorticoid Marijuana Ketoconazole (high dose use) Heroin Methadone Alcohol 7

8 Guidelines for Hypogonadism in Men North America American Urological Association: AUA Position Statement on Testosterone Therapy (2014) 5 Contradictory evidence: Cardiovascular risk in men with hypogonadism vs. beneficial influence on cardiovascular risk. Concerned about the potential for misuse of testosterone for non-medical indications (i.e. body building or performance enhancement). Hypogonadism is defined as biochemically low testosterone levels in the setting of a cluster of symptoms which may include reduced sexual desire (libido) and activity, decreased spontaneous erections, decreased energy and depressed mood. Men with hypogonadism may also experience reduced muscle mass and strength and increased body fat. Hypogonadism may also contribute to reduced bone mineral density and anemia. Testosterone therapy is an appropriate treatment for hypogonadism after full discussion of potential adverse effects. Treatment requires follow-up and medical monitoring. Testosterone therapy in the absence of hypogonadism is not appropriate. Management of hypogonadism should start with careful evaluation by a physician experienced in diagnosing hypogonadism. Many of the symptoms are non-specific and may be multifactorial in origin. Hence, symptoms may not be necessarily linked to hypogonadism alone. This fact needs to be considered in the overall evaluation. The diagnosis and management of testosterone deficiency should be made by a physician with training in the condition and its treatments. The diagnosis should be made only after taking detailed medical history, physical examination, and obtaining appropriate blood tests. Testosterone therapy should not be offered to men with normal testosterone levels. Testosterone therapy is never a treatment for infertility. The potential adverse effects of testosterone therapy should be discussed prior to treatment. These include acne, breast swelling or tenderness, increased red blood cell count, swelling of the feet or ankles, reduced testicular size and infertility. Current evidence does not provide any definitive answers regarding the risks of testosterone therapy on prostate cancer and cardiovascular disease, and patients should be so informed. The optimal follow-up of men on testosterone therapy has not been defined, but should include measurement of testosterone level, PSA and hematocrit. Other patient-specific measures may be appropriate. The AUA recognizes and encourages the need for increased educational awareness of the benefits and risks of testosterone therapy among both patients and health care providers. 5 American Urological Association: Prostate specific antigen best practice statement (2009) 29,30 TRT USE/BENEFIT: Testosterone is not indicated for the treatment of erectile dysfunction in men with normal serum testosterone concentrations CONTRAINDICATIONS/SCREENING: Age 40: Evaluation of a prostate specific antigen (PSA) level and a digital rectal examination of the prostate PSA>0.6ng/dl should be monitored annually (less frequent otherwise) American Geriatric Society (AGS): American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults / The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. 31 TRT USE/BENEFIT & CONTRAINDICATIONS/SCREENING: The AGS guidelines recommend that testosterone and methyltestosterone be avoided in patients aged 65 and over (due to the potential for cardiac problems as well as its contraindication in men with prostate cancer) unless it is indicated for moderate to severe hypogonadism. 8

9 The Endocrine Society s Clinical Practice Guideline: Testosterone Therapy in Adult Men With Androgen Deficiency Syndromes (2010) 27 TESTOSTERONE LEVEL AND MONITORING: Measurement of morning total testosterone level as initial diagnostic test and confirmation by repeating the measurement of morning total testosterone Men in whom total testosterone is near the lower limit of normal or in whom sex hormone binding globulin (SHBG) abnormality is suspected => measure free or bioavailable testosterone level The lower limit of the normal range for healthy young men should be used. This is ng/dL in some laboratories. Aim for testosterone levels in the mid-normal range Evaluating patient 3-6 months after treatment initiation and then annually to assess response to treatment, potential adverse effects and compliance Monitoring testosterone levels 3-6 months after initiation of testosterone treatment Refer to guidelines summary for monitoring of hematocrit, bone mineral density, PSA, and formulation-specific adverse effects TRT USE/BENEFIT: Androgen deficiency diagnosis: only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. Testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. Adjunctive therapy in HIV-infected men with low testosterone levels and weight loss Men receiving high doses of glucocorticoids who have low testosterone levels Against a general policy of testosterone treatment in older men. Should be an individualized basis and include explicit discussions of the uncertainty about the risks and benefits. FORMULATIONS: Chosen on the basis of the patient s preference, consideration of pharmacokinetics, treatment burden, and cost. CONTRAINDICATIONS/SCREENING: Not in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit >50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) > 19, or uncontrolled or poorly controlled heart failure. Against screening for androgen deficiency in the general population RECOMMENDATIONS FOR INITIATION OF TESTOSTERONE THERAPY: IM testosterone enanthate or cypionate mg weekly or mg every 2 weeks, one or two 5 mg patches applied to skin nightly, 1% testosterone gel 5-10g applied daily, buccal testosterone 30mg every 12 hours, implantable testosterone pellets every 3-6 months. The American College of Physicians: Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians (2009) 32 TESTOSTERONE LEVEL AND MONITORING: No recommendations against or for routine use of hormonal blood tests Decisions to measure hormone levels should be based on the basis of clinical presentation and physical findings that suggest hormonal abnormality 9

10 TRT USE/BENEFIT: No recommendations against or for hormonal treatment (inconclusive evidence) Erectile dysfunction: Phosphodiesterase-5 (PDE-5) inhibitor (if no contraindication) Clinical benefit of PDE-5 inhibitors was demonstrated regardless of the cause (e.g. diabetes, depression, or prostate cancer)or baseline severity of ED The American Society of Andrology (ASA) (2006) 19 TESTOSTERONE LEVEL AND MONITORING: Hypogonadal below 300 ng/dl measured in the morning Periodic monitoring: 3 to 6 months after initiation of therapy and then yearly Physical examination: At 3, 6, and 12 months and then annually - including digital rectal examination of the prostate, a prostate-related symptom, assessment, prostate-specific antigen (PSA) level, and hematocrit (alter or discontinue testosterone if > 52%). TRT USE/BENEFIT: TRT in aging men: when both clinical symptoms and signs suggestive of androgen deficiency and decreased testosterone levels are present. TRT may also be warranted in older men with markedly decreased testosterone levels regardless of symptoms, but signs of androgen deficiency should be present. 19 CONTRAINDICATIONS/SCREENING: Pretreatment screening in older men 1) Medical history: a. Potential sleep apnea, congestive heart failure, symptoms consistent with lower urinary tract obstruction, and personal or family history of prostate or breast carcinoma. b. Patients counseling: testosterone therapy will affect spermatogenesis and their fertility potential during treatment and for some time following cessation of therapy. 2) Physical examination, including a digital rectal examination of the prostate. 3) Laboratory tests, including hematocrit and PSA level. Abnormal digital rectal examinations and/or consistently elevated PSA level: a urological evaluation including transrectal ultrasound and biopsy of the prostate should be performed prior to initiation of testosterone therapy. American Association of Clinical Endocrinologists: Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients (2002) 21 TESTOSTERONE LEVEL AND MONITORING: TRT should maintain testosterone levels within the physiological range ( ng/dl) Testosterone dosing should follow recommended dosing from manufacturers and the FDA. Monitoring and follow-up should be conducted every 3-4 months to assess response and side effects. TRT USE/BENEFIT: Male patients with hypogonadism who is not interested in fertility or not able to achieve fertility o Increased sexual interest and number of spontaneous erections o Improved secondary sex characteristics (i.e. increased muscle mass, beard growth, growth of pubic and axillary hair, and phallus growth) Adolescent male patients with hypogonadotropic hypogonadism: Increased bone mineral density(pre-pubertal hypogonadotropic hypogonadism: diminished bone mass my only improve marginally) Normalization of growth hormone in elderly men: No recommendations (research is needed to clarify the potential risks and benefits) Delayed puberty (late teenage male patients): o Testicular size should be monitored for evidence of onset of puberty. 10

11 o Short-term, low-dose testosterone therapy should be withdrawn to determine whether spontaneous puberty is occurring. Cardiovascular risk: effect (increases, decreases or no effect) remains uncertain FORMULATIONS: Oral testosterone not recommended (metabolized quickly and cannot achieve sufficient levels; adverse effects: lipid and hepatic) International European Association of Urology: Guidelines on Male Hypogonadism (2015) TRT USE/BENEFIT: To restore physiologic testosterone levels in men with hypogonadism. Indications for initiation of testosterone treatment included: delayed puberty, Klinefelter syndrome with hypogonadism, low testosterone accompanied by sexual dysfunction, low testosterone accompanied by low bone mass, men with consistent unresolved symptoms of hypogonadism after treatment for obesity and comorbidities, hypopituitarism, testicular dysgenesis with hypogonadism, or type 2 diabetes with hypogonadism. FORMULATIONS: The use of short acting agents over long acting agents is preferred in initial treatment of men with hypogonadism RECOMMENDATIONS FOR INITIATION OF TESTOSTERONE THERAPY: Initiation doses of therapies are similar to U.S. guidelines in frequency, however some dosage amounts and routes differ due to differences in approved drugs in the U.S. vs. Europe. International Society for the Study of Aging Male (ISSAM), International Society of Andrology (ISA), European Association of Urology (EAU), European Academy of Andrology (EAA), and American Society of Andrology (ASA): Investigation, treatment and monitoring of late-onset hypogonadism in males(2009) 33 TESTOSTERONE LEVEL AND MONITORING: Optimum serum testosterone level: Inadequate data. No evidence for or against the need to maintain the physiological circadian rhythm of serum testosterone levels. Mid-to-lower young adult male serum level seems appropriate. Response to TRT should be assessed and TRT withdrawn if no improvement within a reasonable time-frame o Libido, sexual function, muscle function, improved body fat: 3-6 months, but if the testosterone level is borderline (not low), a short (i.e. 3 months) trial may be justified o Bone mineral density: longer interval required TRT USE/BENEFIT: Late-onset hypogonadism: o Characterized by symptoms and a deficiency in serum testosterone levels o May result in significant loss in quality of life and affect multiple organ systems For men with hypogonadal testosterone values TRT: o Improves body composition (i.e. decrease of fat mass and increase of lean body mass) o Increases bone density; fracture data is not yet available (osteopenia, osteoporosis and fracture prevalence rates are greater in hypogonadal younger and older men) o Erectile dysfunction and/or diminished libido AND documented testosterone deficiency are candidates for TRT 11

12 Some evidence (but additional studies needed) for combining TRT with phosphodiesterase-5 (PDE-5) inhibitor in hypogonadal or borderline eugonadal men Combination for hypogonadal men with ED should be considered when failing to either treatment alone. It is unclear whether men should be treated with testosterone, PDE-5 inhibitors, or the combination initially. FORMULATIONS: Selection of the preparation should be a joint decision of an informed patient and physician (pharmacokinetics, advantages and disadvantages) Patients with late-onset hypogonadism: short-acting may be preferred because of the possible development of an adverse event that may require rapid discontinuation The 17-α-alkylated preparations such as methyltestosterone are obsolete because of their potential liver toxicity and should no longer be prescribed CONTRAINDICATIONS/SCREENING: Men with prostate or breast cancer Men with significant erythrocytosis, untreated obstructive sleep apnea, and untreated severe congestive heart failure should not be started on TRT without prior resolution of the comorbid condition Age is not a contraindication. Risk versus benefits and individual assessments should be considered Summary Testosterone replacement therapy is medically necessary/appropriate in hypogonadism and evidence of this is a total testosterone level below the limit used by the laboratory AND symptoms of malaise, fatigue, lethargy, muscle loss, depression, or decreased libido. 19,27,34 The threshold for hypogonadism has not been established, but in general a level below ng/dL is considered low (300-1,000 ng/dl is considered normal). 27 Andropause without evidence of hypogonadism is not considered a legitimate medical diagnosis for use of testosterone treatment in the United States because there is insufficient safety information to support such use. 7,19 Canada however covers the treatment of partial androgen deficiency of aging men (PADAM) on their insurance program. 35 According to the guidelines and prior authorization criteria used by others, testosterone replacement is considered not medically necessary if the only symptom is Erectile Dysfunction or Impotence. 34 For use in men with sexual dysfunction and low serum testosterone, underlying causes of erectile dysfunction (ED) should be evaluated and other established therapies for ED should be considered before starting testosterone. 36 Short-term testosterone use can be considered in men with HIV who have low testosterone levels and weight loss to support weight gain and support muscle strength. 36 Men with low testosterone who take high dose glucocorticoids should be considered for testosterone therapy to preserve bone mineral density and lean body mass. 36 The guidelines include conditions that are contraindications for androgen therapy and makes recommendations regarding monitoring strategies (and schedule)

13 Guideline(s) for androgen therapy in women North America The Endocrine Society s Clinical Practice Guideline: Androgen therapy in women: a reappraisal: an endocrine society clinical practice guideline. 37 PARTICIPANTS: A Task Force appointed by the Endocrine Society, American Congress of Obestricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) consisting of six experts, a methodologist, and a medical writer. EVIDENCE: The Task Force commissioned two systematic reviews of published data and considered several other existing metaanalyses and trials. The GRADE methodology was used; the strength of a recommendation is indicated by a number "1" (strong recommendation, we recommend) or "2" (weak recommendation, we suggest). CONSENSUS PROCESS: Multiple communications and conference calls determined consensus. Committees of the Endocrine Society, ASRM, ACOG, ESE, and IMS reviewed and commented on the drafts of the guidelines. CONCLUSIONS: We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general wellbeing. We recommend against the routine use of dehydroepiandrosterone due to limited data concerning its effectiveness and safety in normal women or those with adrenal insufficiency. We recommend against the routine prescription of T or dehydroepiandrosterone for the treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological glucocorticoid administration, or other conditions associated with low androgen levels because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk. Evidence supports the short-term efficacy and safety of high physiological doses of T treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder. Importantly, endogenous T levels did not predict response to therapy. At present, physiological T preparations for use in women are not available in many countries including the United States, and long-term safety data are lacking. We recommend that any woman receiving T therapy be monitored for signs and symptoms of androgen excess. We outline areas for future research. Ongoing improvement in androgen assays will allow a redefinition of normal ranges across the lifespan; this may help to clarify the impact of varying concentrations of plasma androgens on the biology, physiology, and psychology in women and lead to indications for therapeutic interventions. 37 Use in special populations Hypogonadism is a known problem in aging men, but it is also commonly seen in people with conditions such as HIV and type 2 diabetes. 13,27,38,39 The FDA information states that testosterone products are only FDA-approved for use in men who lack or have low testosterone levels in conjunction with an associated medical condition

14 a. Women Testosterone levels also decline in women as they age. 40 This is associated with postmenopausal symptoms like diminished libido. 41 However, there is insufficient data to support the use of testosterone for this indication and the Endocrine society advises against generalized use of testosterone in women. 13,27 Testosterone enanthate is indicated for use in inoperable metastatic female breast cancer, but the product label states that judgment concerning androgen therapy should be made by an oncologist with expertise in this field. 42 Injectable testosterone (Delatestryl) may be used secondarily in women with advancing metastatic (skeletal) mammary cancer who are one to five years postmenopausal. 7 In premenopausal women, it has been used for breast cancer in patients who have benefited from oophorectomy (removal of ovaries) and who have a hormone-responsive tumor. 7 It is recommended to monitor for virilization (developing male sex characteristics) and to discontinue if mild virilization is present to prevent irreversible symptoms. 17 Symptoms of virilization include excess facial and body hair, baldness, acne, deepening of the voice, increased muscularity, and an increased sex drive. 43 The other testosterone products are not indicated for use in women because they have not been evaluated in women Apart from the lack of data for this indication, safety is another important concern. Testosterone may cause fetal harm. b. Males under 18 years Only testosterone enanthate (Intramuscular solution), testosterone cypionate (Intramuscular solution), and Testopel (pellet subcutaneous implantation) are indicated for use in adolescent males (safety and efficacy have not been evaluated in males <12 years of age). 17,42 Safety and efficacy of all the other currently available testosterone products (including Natesto, Vogelxo, and Aveed) in males under 18 have not been established. 17 The DELATESTRYL (Testosterone Enanthate Injection, USP) product label states that it may be used to stimulate puberty in carefully selected males with clearly delayed puberty. These patients usually have a familial pattern of delayed puberty that is not secondary to a pathological disorder; puberty is expected to occur spontaneously at a relatively late date. Brief treatment with conservative doses may occasionally be justified in these patients if they do not respond to psychological support. The potential adverse effect on bone maturation should be discussed with the patient and parents prior to androgen administration. An X-ray of the hand and wrist to determine bone age should be obtained every six months to assess the effect of treatment on the epiphyseal centers. 42 c. Geriatric patients The BEERS Criteria recommend avoiding use in older adults except in moderate to severe hypogonadism. 17 It is important to consider that there is a potential increased risk for cardiovascular disease, and elderly patients may be at greater risk for fluid retention and transaminase elevations. 17 Also, testosterone use is contraindicated in men with prostate cancer and the elderly may be at greater risk for prostatic hyperplasia and prostate cancer

15 d. HIV disease Hypogonadism often occurs in HIV-infected men. 48 The Endocrine Society Guidelines recommend that clinicians consider short-term testosterone therapy as adjunctive therapy in HIV patients with low testosterone levels and weight loss. The aim is to improve weight maintenance and increase lean body mass and muscle strength. 27 e. Glucocorticoid-Treated Men Patients receiving long-term corticosteroid treatment may develop hypogonadism, which is associated with bone loss. 48 The Endocrine Society Guidelines recommend that clinicians offer testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone levels to promote preservation of lean body mass and bone mineral density. 27 f. Other conditions Conditions that may increase the risk of hypogonadism include type 2 diabetes, obesity, metabolic syndrome and hypertension. 50 The authors of a recent review of the metabolic effects of testosterone replacement therapy (TRT) in hypogonadal type 2 diabetic men found that TRT can improve glycemic control and decrease triglyceride levels, but that additional evidence is needed (large, well-conducted RCTs). 51 Clinical Efficacy Appendix 2 contains abstracts of systematic reviews for FDA-approved and off-label indications. FDA update Testosterone Products: Drug Safety Communication - FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack And Stroke UPDATE 04/15/2015. The testosterone product labels have been updated. The revised labels clarify the approved uses of these medications and include information about a possible increased risk of heart attacks and strokes in patients taking testosterone. [This information is an update to the FDA Drug Safety Communication: FDA Evaluating Risk of Stroke, Heart Attack, and Death with FDA-Approved Testosterone Products issued on January 31, 2014.] [Posted 03/03/2015] AUDIENCE: Health Professional, Endocrinology, Urology, Family Practice, Patient ISSUE: FDA is requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications. FDA is also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone. FDA cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions. The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man s symptoms seem related to low testosterone. 15

16 Based on the available evidence from studies and expert input from an FDA Advisory Committee meeting, FDA has concluded that there is a possible increased cardiovascular risk associated with testosterone use. These studies included aging men treated with testosterone. Some studies reported an increased risk of heart attack, stroke, or death associated with testosterone treatment, while others did not. See the Data Summary section of the FDA Drug Safety Communication for additional details. BACKGROUND: Testosterone is FDA-approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism. However, FDA has become aware that testosterone is being used extensively in attempts to relieve symptoms in men who have low testosterone for no apparent reason other than aging. The benefits and safety of this use have not been established. RECOMMENDATION: Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or slurred speech. 14 More Info for Health Care Professionals Testosterone replacement therapy is approved for use only in men with primary or secondary hypogonadism resulting from certain medical conditions. The safety and efficacy of testosterone replacement therapy for age-related hypogonadism have not been established. Before initiating testosterone replacement therapy, ensure that the diagnosis of hypogonadism has been confirmed with laboratory testing. Verify that serum testosterone concentrations have been measured on at least two separate mornings and are consistently below the normal range. Avoid measuring testosterone concentrations later in the day, when measurements can be low even in men who do not have hypogonadism. For each patient, weigh the potential increased risk of major adverse cardiovascular outcomes and other risks of testosterone replacement therapy against the potential benefits of treating hypogonadism. Inform patients of the potential increased cardiovascular risk associated with testosterone replacement therapy. Encourage patients to read the patient Medication Guide or patient information leaflet they receive with their testosterone prescriptions. Report adverse events involving testosterone treatment to the FDA MedWatch program, using the information in the Contact FDA box at the bottom of the page. 14 The FDA data summary has been included in appendix 3. Safety Appendix 2 contains abstracts of systematic reviews regarding safety of testosterone. Safety issues are also discussed on page 21 (e) Screening. Monitoring requirements have been included in the drug table in appendix 1. 16

17 Black boxed Warnings in the U.S. 17 Transdermal gel and transdermal solution testosterone preparations (including Vogelxo) carry a black boxed warning for secondary exposure risks; inadvertent transfer of the medication to other people especially children. 20,49,52 WARNING: SECONDARY EXPOSURE TO TESTOSTERONE Virilization has been reported in children who were secondarily exposed to testosterone gel Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel Healthcare providers should advise patients to strictly adhere to recommended instructions for use 1 Reported signs and symptoms have included enlargement of the penis or clitoris, premature development of pubic hair, increased erections and libido, aggressive behavior, and advanced bone age. 49 The Institute for Safe Medication Practices (ISMP) has reported that they have observed a signal for adverse events resulting from the use of the topical testosterone products, Androgel and Testim. In the first three quarters of 2009, there were 210 adverse effect reports associated with testosterone products, 155 in women (70%) and 22 in children (10%), even though it is only licensed for use in men with hypogonadism. Despite an FDA warning, it appears accidental exposure and inappropriate offlabel use continues to cause injuries. 53 Testosterone undecanoate (Aveed) carries a black boxed warning for serious pulmonary oil microembolism reactions and patients must be observed for 30 minutes following injection in a health care facility that can provide appropriate medical treatment in the case of a serious reaction or anaphylaxis. Pulmonary oil microembolism (testosterone undecanoate): Serious pulmonary oil microembolism (POME) reactions, involving urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope; and episodes of anaphylaxis, including life-threatening reactions, have been reported to occur during or immediately after the administration of testosterone undecanoate injection. These reactions can occur after any injection of testosterone undecanoate during the course of therapy, including after the first dose. Following each injection, observe patients in the health care setting for 30 minutes in order to provide appropriate medical treatment in the event of serious POME reactions or anaphylaxis. Because of the risks of serious POME reactions and anaphylaxis, testosterone undecanoate is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Aveed REMS Program. 2 17

18 Serious hepatic adverse effects (Cholestatic jaundice syndrome, liver carcinoma, neoplasm of liver, Peliosis hepatis) can result from prolonged use of high doses of orally active 17-alpha-alkyl androgens (e.g., methyltestosterone) or long-term therapy with testosterone enanthate. 47,54 Kidney impairment and cardiovascular problems (including risks of stroke and heart attack) have been associated with steroid misuse and abuse. 6 In general, side effects of androgens include 6,7,19 Males Females General gynecomastia, excessive frequency or persistent penile erections shrinkage of testicles reduced sperm count or infertility baldness menstrual irregularities clitoral enlargement hoarseness acne more facial hair (hirsutism) male-pattern baldness GI including nausea &vomiting alterations in liver function tests cholestatic jaundice (changes in skin color) pelosis hepatitis fluid and electrolyte disturbances (e.g. ankle swelling) hematologic (suppression of clotting factors, polycythemia, increased hematocrit and hemoglobin) exacerbations of sleep apnea uropathy (related to BPH) male pattern baldness. Place in therapy / Factors to consider for potential criteria Factors and limitations to consider: a. Misuse Misuse of androgens is over-prescribing for conditions without sufficient evidence, or regular medical prescribing of androgens without the patient having a valid clinical indication. As mentioned earlier, the FDA information states that testosterone products are only FDA-approved for use in men who lack or have low testosterone levels in conjunction with an associated medical condition. 14 Misuse and off-label (non-fda labeled) indications include 14,55 o Testosterone for sexual dysfunction without proven androgen deficiency o Anti-aging uses o Cognitive function o Female-to-male transsexual - Gender identity disorder o Male infertility o Osteoporosis, Male (to relieve osteoporosis-related bone pain) o o Muscle injury or repair Weight gain (after weight loss following extensive surgery, chronic infections, severe trauma, AIDS-associated wasting syndrome without hypogonadism or in patients who without definite pathological reasons fail to gain or maintain weight) 18

19 Systematic reviews identified in the Cochrane Library (abstracts included in appendix 2) include offlabel/empirical/experiential uses of testosterone such as use in postmenopausal women 56,57, poor responders undergoing in vitro fertilization (IVF) 58-60, contraception in men 61, schizophrenia 62, depression 63, lower limb atherosclerosis 64, treatment in HIV for weight loss without low testosterone levels 14,65, treatment in HIV of decreased bone mineral density without low testosterone levels 14,66, genital lichen sclerosis 67, for rehabilitation after hip fracture in older people 68, its effect on bone health, 69 use in COPD 70, and hypospadias surgery 71. Some of these reviews state that it might be beneficial for these conditions in men with hypogonadism. Use in these conditions when there is evidence of hypogonadism (as recommended by the guidelines) may be appropriate. There has been increasing advocacy of testosterone treatment for male sexual dysfunction and whether treatment is necessary for andropause is a matter of opinion. 9,72 It needs to be considered whether testosterone treatment is medically necessary vs. not medically necessary for a particular condition, and whether sufficient evidence exists for such use. Guidelines state that men with erectile dysfunction and/or diminished libido and documented testosterone deficiency are candidates for TRT. 21 Most plans do not cover testosterone for use in sexual dysfunction and require prior authorization to ensure the drugs are only being used where medically necessary. 73 The authors of a recent review concluded that testosterone supplementation plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. 74 Sufficient evidence supports the use of TRT in males with diseases of the hypothalamic-pituitarygonadal axis and in boys who have not initiated puberty by the age of 14. However, TRT in aging men or in men with chronic diseases is much more controversial. 30 It is often difficult to distinguish between real testosterone deficiency and other chronic conditions such as depression and fatigue or sometimes just the desires of patients due to environmental pressure or psychological factors. Also, there is not sufficient evidence regarding the risks associated with treatment in these patients. 30 The FDA cautions against use in men with age-related hypogonadism and the product labels state that safety and efficacy have not been established for this use. 14 The authors of a recent review concluded that testosterone may be used as monotherapy in dysthymia and minor depression or as an augmentation therapy in major depression in middle-aged hypogonadal men. 75 The transdermal testosterone products have not been tested in women and the FDA said it believed that in 2007 there were 27,000 prescriptions off label for women. 53 The Use in special populations section contains more information on use in specific populations (e.g. women) or conditions (e.g. HIV). b. Abuse Abuse is the illicit or inappropriate use of androgens without a prescription for non-clinical purposes (i.e. body building or cosmetic reasons in sport, recreational and occupational settings). The most common use of androgens in an abusive manner is for body building/ cosmetic enhancement for males and athletic performance enhancement. Androgen abuse usually consists of taking times the recommended doses of a product. Androgen stacking is common, this is using multiple 19

20 agents at a time. Abuse among athletes is typically in the elite athletic field, but has been seen in collegiate and high school sports arenas. 55,76 Testosterone-containing products are classified as controlled substances under the Anabolic Steroids Control Act of 1990 and are Schedule III substances. 7,77 Androgens and anabolic steroids have been misused and abused by athletes, bodybuilders, weight lifters, and others such as security professionals (police, security guards and bouncers) to increase muscle size and strength to enhance athletic performance or physique and to enhance occupationally useful intimidating muscularity. 6,12,76 This is also a problem in high school students. According to the Centers for Disease Control (CDC), 3.6% of high school students had used these steroids without a prescription at least once. 78 Using androgens and anabolic steroids to increase muscle size and strength to enhance athletic performance or physique is not considered to be the treatment of a disease or injury and therefore not medically necessary. 6 The FDA recommends against this practice. 4,79,80 The illicit selfadministration of androgens for non-medical purposes pose health hazards to users and the community through hazardous injection techniques 12 (such as sharing of needles) and non-intended exposure of other people. Most policies exclude coverage of steroids for performance enhancement and require Prior Authorization to prevent abuse. 73,81 According to the National Institute on Drug Abuse (NIDA), anabolic steroids are reinforcing and can lead to addiction. It does not cause the same rapid high as other drugs of abuse, but long-term use may affect similar pathways and it has a huge impact on mood and behavior. It is also associated with withdrawal symptoms such as depression, mood swings, restlessness, loss of appetite, steroid cravings and just like with other drugs, people therefore continue using it. NIDA report that evidence of addiction has been seen in studies where even animals self-administer steroids. Oral, injectable and transdermal (cream or gel) anabolic steroids are abused and often used intermittently so that it is used for periods of months or weeks followed by a break in steroid use after which it is restarted again. This cycling prevents a decrease in the body s response to the steroids and by doing this users are also hoping to reduce unwanted side effects. However, steroid abuse could cause serious and irreversible adverse effects and it involves a risk of HIV/AIDS or hepatitis. Another problem reported by NIDA is stacking whereby users combine different types of steroids and may include non-steroidal supplements in an attempt to maximize their effectiveness. Negative behavior of steroid abusers include using other drugs (e.g. opioids), spending large amounts of time and money on their addiction, violence associated with anger, impaired judgment, paranoid jealousy, and impaired social relationships. 6 Regulating this use through a PA (prior authorization) may be difficult as users may obtain drugs from other sources. However, some users may be taking more than the prescribed dose or may use drugs prescribed to others. Unusual utilization patterns may assist in identifying potential abuse. c. Adverse effects Please refer to safety section. 20

21 d. Duration of therapy The duration of treatment depend on the diagnosis and patient s response to treatment as well as age, sex, and adverse effects. 7 There are no large placebo controlled studies evaluating the longterm effects of testosterone. 13 Oral testosterone is not recommended for long-term treatment (liver problems, raised cholesterol levels and increased risk of cardiac disease). 4,21,22 e. Screening and monitoring Table 1 (Appendix 1) contains information on how doses should be titrated/adjusted based on serum concentrations. In general, the product labels recommend monitoring the following periodically: serum testosterone, PSA, hemoglobin, hematocrit, liver function test, calcium, and lipid panels. Please refer to product label information for product specific information. Some conditions could be exacerbated by testosterone and it is therefore important to screen patients and to continue monitoring patients during treatment. 28 Risk of benign prostatic hyperplasia and prostate cancer: Patients must have a baseline PSA test performed with a digital rectal exam. History of breast cancer: Avoid testosterone therapy (risk of recurrence). Testosterone (excessive levels) could cause erythrocytosis: Monitor complete blood count (CBC) at baseline and periodically thereafter. Androgens cause retention of sodium, chloride, water, potassium, phosphorus, nitrogen, and decrease urinary excretion of calcium. This could cause edema with or without congestive heart failure in patients with cardiac disease, renal or hepatic dysfunction. It may also alter cholesterol concentrations and patients with a history of myocardial infarction or coronary artery disease would be at increased risk of complications. 7 Please refer to the FDA update section on the potential increased cardiovascular risk. 21

22 Utah Medicaid Utilization Data Utilization data have been included in appendix 4 (September 1 st 2012 to April 30 th 2015). It includes products for which there was no utilization whereas the charts and tables presented in the section below only includes the products which were filled. In November 2012 the DUR Board decided to accept the prior authorization criteria recommended by the University of Utah. The number of prescriptions, patients and cost decreased since then (shown below). There were also fewer unique patients in the first year below compared to the previous report. The current claims data for the last period (only 8 months) indicates a potential slight increase in the number of patients compared to year 2. 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 RX PT COST RX PT COST RX PT COST $471, $377, $210, Estimated for 12 months $315, From the previous report: 9/1/2011-8/31/2012: 457 unique patients To date there has been no utilization of the three new products; Natesto (nasal gel), Vogelxo (gel), or Aveed (injection). A. Oral Utilization of the oral methyltestosterone capsules or tablets is very limited. 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 Rx Patients Rx Patients Rx Patients Methyltestosterone ANDROID Capsule Methyltestosterone METHITEST Tablet B. Injectable 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 Rx Patients Rx Patients Rx Patients DEPO-TESTOST INJ Oil TESTOST CYP INJ Oil TESTOST ENAN INJ Oil

23 C. Transdermal/topical Please note that the third time-frame below is not a full year. 250 Number of patients ANDRODERM ANDROGEL AXIRON FORTESTA TESTIM TESTOSTERONE 9/1/2012-8/31/ /1/2013-8/31/ /1/2014-4/30/ Number of prescriptions ANDRODERM ANDROGEL AXIRON FORTESTA TESTIM TESTOSTERONE 9/1/2012-8/31/ /1/2013-8/31/ /1/2014-4/30/ Utilization for these products were lower in year 2 compared to year 1 apart from Fortesta and testosterone gel where utilization increased. 23

24 Utilization in specific populations A. Pediatrics (<18 years old) The previous review showed limited, but an increase in utilization in the pediatric population including the topical/transdermal products which are not indicated for use in patients under 18 years old. No oral or transdermal/topical products were filled for pediatric patients during this timeframe. 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 Rx Patients Rx Patients Rx Patients Testosterone Cypionate DEPO-TESTOST INJ Oil Testosterone Cypionate TESTOST CYP INJ Oil Testosterone Enanthate TESTOST ENAN INJ Oil B. Geriatrics (>65 years old) 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 Rx Patients Rx Patients Rx Patients Testosterone ANDROGEL Gel Testosterone AXIRON Solution Testosterone TESTIM Gel Testosterone Cypionate DEPO-TESTOST INJ Oil Testosterone Cypionate TESTOST CYP INJ Oil Testosterone Enanthate TESTOST ENAN INJ Oil The previous review showed broader use of these agents in the elderly (more products) which could indicate a potential for increased use. During this timeframe utilization in the geriatric population appears to be decreasing. C. Females Utilization is limited in females. In the previous review there was some utilization of the transdermal/topical products which are not indicated in women. The prior authorization appears to have taken care of this issue (none in this time period). Methyltestosterone ANDROID Capsule Testosterone Cypionate TESTOST CYP INJ Oil

25 Patients with diagnosis codes submitted within 60 days of filling a prescription for an oral, transdermal, or injectable androgen product The diagnosis codes that were defined for inclusion included the licensed indications as well as some conditions that could have caused hypogonadism. Indications outside of guidelines were also included to identify potential misuse. It is possible that diagnosis codes may have been submitted for the approved conditions without evidence of low testosterone levels (as recommended by current guidelines). 27 9/1/2014-4/30/2015 TESTOSTERONE THERAPY AND DIAGNOSIS * ICD Hypogonadism Testicular Hypofunction All Dosing Routes Oral Products Transdermal Products Injection Products Hypogonadism Hypogonadotropic, Pituitary Other Hypopituitarism and Related Disorders 253.2, 253.7, Malignant Neoplasm of Breast Delayed Puberty 259 Congenital Anomalies of Genital Organs 752.5* * Lack of Expected Normal Physiological Development in Childhood 783.4* Klinefelter s Syndrome Cachexia HIV Disease Anemia 284*, , Trans-Sexualism 302.5* Decreased Libido without Hypogonadism and NOT or Erectile Dysfunction without Hypogonadism and NOT or Psychosexual Dysfunction without Hypogonadism 302.7* and NOT or TOTAL UNIQUE PATIENTS WITH DIAGNOSIS TOTAL UNIQUE PATIENTS ON TESTOSTERONE THERAPY Percentage of patients on testosterone therapy with a diagnosis code submitted (as defined above) 68% 0% 71% 66% Previous report (time period was for 12 months, but comparing %) 45% 25% 41% 44% * Diagnosis date within 60 days before or 60 days after receiving testosterone product. 9 patients have diagnoses for HIV disease and TESTICULAR HYPOFUNC NEC (ICD ), but 2 patients (both using transdermal products) did not have a diagnosis code for hypogonadism. During the last review it was decided to require diagnosis code submission for these products so that utilization could be monitored. The percentage has improved but diagnosis codes (as defined above) 25

26 have still not been submitted for about 30% of patients. We have attempted to include the main diagnoses, but there may be some not included. It is also possible that diagnosis codes were not submitted, or not submitted during that period (60 days within first androgen product fill), or miscoded. Prescribers Family Practice Internist Nurse Practitioner Physician Assistant Osteopath Endocrinologist Physical Medicine and Rehab Urologist Unknown /1/2014-4/30/2015 PRESCRIBER TYPE Unknown % Urologist % Physical Medicine and Rehab % Endocrinologist % Osteopath % Physician Assistant % Nurse Practitioner % Internist % Family Practice % TOTAL CLAIMS

27 Conclusions Testosterone is FDA-approved as replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism and the FDA states that the benefits and safety of use for relieve of symptoms in men who have low testosterone for no apparent reason other than aging have not been established. 14 It is also important to note that the FDA issued drug safety communication to inform of possible increased risk of heart attack and stroke with the use of testosterone. The FDA required product labels to updated with this information. 14 Even though some of the issues identified in the last review appear to have improved, there are still some issues that need to be addressed and continued monitoring of these products is necessary. Potential clinical criteria You may wish to consider: Ensuring that all androgen products require a diagnosis code so that utilization can be monitored. A. That new topical/transdermal products require the same prior authorization (PA) as the one already in place for older products: years old 2. Male 3. Use is for the FDA Approved indication: Primary (congenital or acquired) or secondary (congenital or acquired) hypogonadism with ICD-9 diagnosis code of or AND 4. Evidence of low testosterone symptoms and signs (Two morning total testosterone levels below the reference range of the laboratory used) Duration: Initial 3 months? You may also wish to add the following point to the current PA criteria: 5. Evidence that hypogonadism is due to disorders of the testicles, pituitary gland, or brain, and NOT age-related. B. That new injectable testosterone products used for women require a valid diagnosis code for breast cancer submitted by an oncologist (matching the current PA for older products) You may wish to add if it is a FDA-approved indication (only testosterone enanthate has this indication). Exclusions could include: 1. Treatment related to sex transformations OR sexual function, sexual dysfunctions or inadequacies without evidence of hypogonadism (low T levels AND signs & symptoms) 2. Age-related use 3. Treatment for HIV without diagnosis of hypogonadism 4. Other off-label/empirical uses 27

28 Appendix 1 Drug information Testosterone agents(ciii). 82,83 Drug Dosage form and dosing Striant Buccal patch: 30mg testosterone extended release 30mg BID applied to gum region above incisor tooth Androderm testosterone Transdermal patch 2 mg/24 hr, 2.5 mg/24hr, 4 mg/24 hr, 5mg/24hr applied to upper arms, thighs, or stomach. FDA approved indication Primary hypogonadism, male Primary hypogonadism, male Unlabeled indication Key monitoring parameters Monitoring serum testosterone Osteoporosis (male), weight gain. Osteoporosis (male), weight gain. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Morning serum testosterone levels; 4 to 12 weeks after initiating therapy. Early morning ST following system application previous evening ~2 weeks after starting/switching Androgel testosterone Initial: 4mg patch daily then adjust based on ST levels: >930ng/dL: use 2mg patch daily ng/dl: use 4mg patch daily <400 ng/dl: use 6mg (4mg and 2 mg patch daily) Topical gel pump: 1%, 1.62% (20.25MG/1.25GM actuation) Initial: 40.5 mg applied to upper arm, then adjusted base on ST levels: Primary hypogonadism, male Osteoporosis (male), weight gain. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium For 1%: Morning ST levels ~14 days after the start of therapy or dose adjustments. For 1.62%: Pre-dose morning ST ~14 days and 28 days after starting/switching. Regular intervals during therapy

29 Testim testosterone Fortesta testosterone Vogelxo testosterone >750 ng/dl: 20.25mg per day ng/dl: 40.5 mg per day <350 ng/dl: 60.75mg per day Topical gel: 1% Initial: 50mg applied to upper arm daily, may increase to 100mg if ST lower than normal range. Topical gel 10mg/0.5gm Initial: 40mg applied to thigh, adjust based on ST levels: >2500 ng/dl: apply 20mg daily ng/dl: apply 30mg daily ng/dl: apply 40 mg daily <500 ng/dl: apply 50mg daily. Topical gel: 50mg/5gm, 12.5mg/actuation Primary hypogonadism, male Primary hypogonadism, male Primary hypogonadism, male Osteoporosis (male), weight gain. Osteoporosis (male), weight gain. Osteoporosis (male), weight gain. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Morning serum testosterone levels; approximately 14 days after initiating therapy Dose adjustment: 2 hrs post application. Titrated based on ST from a single blood draw 2 hours after applying & at about 14 days and 35 days after starting treatment or following dose adjustment. Measure ST levels ~14 days after initiation of therapy prior to morning application. Axiron testosterone Initial: apply 50mg to upper arm daily. If ST level is below normal apply 100mg daily. Topical solution 30mg/1.5mL Primary hypogonadism, male Osteoporosis (male), weight gain. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium ST from a single blood draw 2-8 hrs after applying and at least 14 days after starting/adjustment 29

30 Natesto testosterone Aveed testosterone undecanoate Testosterone cypionate or enanthate Apply 60mg to axilla same time every morning, adjust based on ST levels: >1050 ng/dl: apply 30mg daily; discontinue if ST level is >1050 after reduction. <300 ng/dl: apply 90 daily; increase to 120 mg daily if level remains <300 after increase. Nasal gel: 5.5mg/ actuation Use 1 actuation in each nostril TID (6-8 hours apart) IM solution 250mg/mL Initial: 750mg, then 750mg 4 weeks later, then 750mg every 10 weeks. 100 mg/ml or 200 mg/ml IM solution mg IM every 2-4 weeks. Primary hypogonadism, male Primary hypogonadism, male. Primary hypogonadism, male Osteoporosis (male), weight gain. None Osteoporosis (male), weight gain. Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Periodic monitoring of PSA, lipids, LFTs, hemoglobin, hematocrit, calcium Measure ST periodically, starting 1 month after initiating treatment. Discontinue therapy if ST exceeds 1050 ng/dl. If ST level is consistently <300 ng/dl consider another treatment. Measure ST levels just prior to each injection and adjust as necessary. Measure ST levels midway between injections. 30

31 Other androgen-containing products 77 Drug Dosage forms Methyltestosterone 10mg Android capsule Testred capsule Methitest tablet FDA approved indication Male: hypogonadism, delayed puberty Female: Palliative treatment of metastatic breast cancer Unlabeled indication Male: Impotence and climacteric symptoms Key Monitoring Parameters Hgb, HCT periodically (high dose patients); hepatic function; serum and urine calcium in women with disseminated breast carcinoma; signs and symptoms of virilization in women; signs and symptoms of prostatic hypertrophy, carcinoma in geriatric patients Fluoxymesterone Androxy Oxandrolone Oxandrin 10 mg tablet mg tablet Male: hypogonadism, delayed puberty; Female: Palliative treatment of breast cancer Weight gain or offset protein catabolism and relief of bone pain associated with osteoporosis Alcoholic hepatitis, severe burn (adjunct), Cachexia associated with AIDS, Turner syndrome x-ray and determination of bone age of the wrist and hand every 6 months; frequent urine and serum calcium levels in women with disseminated breast cancer; hemoglobin and hematocrit in long term therapy; liver function tests; lipid panel; signs of virilization in women Hepatic function, lipid panel, Hgb, HCT periodically (high dose patients), serum and urine calcium in women with disseminated breast carcinoma, signs and symptoms of virilization (women) Capsule (not available in US): Conditions associated with a deficiency or absence of endogenous testosterone. According to Valiant Pharmaceuticals there is a pending FDA PI revision for Android and Testred (no further information) 26 31

32 Appendix 2 Systematic Reviews More recent reviews were included where possible, but for safety/adverse effects/risks older reviews were included as well. A. USE IN OLDER MEN Please refer to FDA caution Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Testosterone supplementation therapy for older men: potential benefits and risks (Structured Abstract) 84 Original article: Gruenewald D A, Matsumoto A M. Testosterone supplementation therapy for older men: potential benefits and risks. Journal of the American Geriatrics Society.2003;51(1): Centre for Reviews and Dissemination (CRD) summary This review assessed the effects of testosterone supplementation for men older than 60 without severe illness. The authors concluded that supplementation may be helpful for men with low testosterone levels with or without hypogonadism. The review found only a few studies and the stated inclusion criteria were not consistently followed; hence, the conclusions should be interpreted with caution. Authors' objectives To assess the effect of testosterone supplementation therapy in older men. Searching MEDLINE was searched from 1966 to October 2001; the search terms were stated and reports published in any language were eligible. The reference lists of reviews and identified studies were checked. Manual searches of the Proceedings of the Endocrine Society and the American Society of Andrology Annual Meetings (1992 to 2001), and the American College of Cardiology Annual Meetings (1999 to 2001), were also conducted. Duplicate reports were excluded and only the latest updates were included. Study selection: study designs Randomised controlled trials (RCTs) published as either peer reviewed studies or abstracts were excluded if the Jadad quality score was less than 2. Trials published as abstracts or letters were only included if they were clearly double blind and placebo controlled. Non randomised trials and trials without a placebo control group that were published in peer reviewed journals were excluded. Peer reviewed, published crossover studies and studies that were not described as randomised were included. Dose finding studies were excluded. The included studies were double and single blind RCTs, double and single blind crossover studies, double blind studies with an unknown method of treatment allocation and non randomised studies. Study selection: specific interventions Studies that compared any testosterone preparation with placebo were eligible for inclusion. In the included studies, testosterone was administered over variable periods of time, ranging from a single dose to 3 years' treatment. The studies used different preparations of testosterone: transdermal, topical and scrotal testosterone; oral testosterone undecanoate; intramuscular preparations of testosterone, testosterone enanthate, testosterone cypionate and testosterone propionate; and intravenous testosterone. Study selection: participants Studies of men aged 60 years and over were eligible for inclusion. Studies in which the mean age of the participants was 50 years or less were excluded. Studies of men with severe or unstable systemic illness, and studies of men with hormone deficiencies due to specific disease (other than normal aging), were excluded. The included studies were of men whose baseline testosterone levels varied from normal to moderately below the lower limit of the normal range for young men. Some studies only recruited men with a baseline testosterone value below a specified value, while others recruited men with a range of baseline testosterone values. The included studies were of the following groups (non testosterone level characteristics): healthy men; men with abdominal obesity; men with low bone mineral density; nursing home residents; men with mild to moderate obesity; men with erectile dysfunction; healthy and cognitively normal men; admissions to geriatric evaluation and management unit for rehabilitation; men with coronary artery disease; men with post exercise ST depression; men undergoing knee or hip replacement; men with angina. Study selection: outcomes The inclusion criteria were not explicitly defined in terms of outcomes. The review assessed body composition, bone mineral density, muscle strength and functional ability, sexual function, mood and well being, cognitive function, lipids and cholesterol, coronary heart disease, effect on prostate gland and erythrocytosis. Study selection: how were decisions on the relevance of primary studies made?

33 Any disagreements about study selection were resolved through discussion. The authors did not explicitly state how many reviewers performed the selection. Validity assessment Validity was assessed using the Jadad scale, which considers randomisation, blinding and the handling of withdrawals and drop outs (see Other Publications of Related Interest). Three reviewers independently assessed validity and resolved any disagreements through discussion. Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. The results from individual studies were classified as showing an increase, no change, or a decrease in the outcome measure for the treatment compared with placebo. Methods of synthesis: how were the studies combined? The studies were grouped by the outcome assessed and a narrative synthesis was undertaken. Methods of synthesis: how were differences between studies investigated? The studies were grouped in the data extraction tables and in the text according to the baseline testosterone levels of the participants (baseline level below specified level versus no upper limit for testosterone levels) and the duration of treatment (single dose, 1 week to 3 months, and more than 3 months). Studies classified by the authors as high or lower quality were reported to have been analysed separately, but no details were reported. Results of the review Twenty nine studies were included. There were 18 RCTs (613 men), 7 double blind crossover studies (89 men), 1 single blind crossover study (6 men), 1 double blind study with an unknown method of treatment allocation (36 men) and 2 nonrandomised studies (67 men). Testosterone supplementation increased lean body mass (5 out of 7 studies) and decreased fat mass (7 out of 9 studies assessing some measure of body fat) in healthy men with low to slightly decreased testosterone levels. However, these changes were not significant in all cases. For all studies, testosterone supplementation was associated with either an improvement or no change in lower body strength (5 studies: all reported no change), upper body strength (5 studies: 3 reported no change and 2 reported an improvement), function (7 studies: 4 reported no change and 3 reported improvements in some measures), sexual function (5 studies: 4 reported no change and 1 reported improvements in some measures), and mood (10 studies: 6 reported no change and 4 reported improved mood or energy). Testosterone supplementation had mixed effects on cognitive function (5 studies). Improvement was found on some measures: spatial and verbal memory, spatial ability and spatial cognition improved in 2 studies, while working memory improved in 1 study. No improvement was found on other measures, i.e. memory recall and verbal fluency (1 study). In addition, verbal fluency failed to improve with practice (1 study). Testosterone supplementation improved exercise induced coronary ischaemia seen on electrocardiography (4 studies), but the results for angina were mixed (4 studies: 2 reported reduced angina and 2 reported no change). A few studies found that men with low testosterone levels were more likely to show improvements in the following outcomes than men with a lesser degree of testosterone deficiency: lumbar bone mineral density (2 studies reported an increase for low testosterone men; no unrestricted studies assessed this outcome), self reported functional status (4 studies reported no change for low testosterone men; 3 unrestricted studies reported an improvement), libido (3 studies reported an improvement for low testosterone men; 1 unrestricted study reported an improvement), erectile function (1 low testosterone study reported an improvement; 2 unrestricted studies reported no improvement), and exercise induced coronary ischaemia (2 studies reported a benefit for low normal testosterone men; 1 study reported a benefit for markedly reduced testosterone). Testosterone supplementation had no major adverse effects on lipids: 4 studies reported that low density lipoprotein cholesterol levels were reduced or unchanged, while 6 studies reported that high density lipoprotein levels were unchanged. Most of the studies reported that the mean haematocrit increased from baseline by 2.5 to 5%. Between 6 and 25% of men developed haematocrit levels above the normal range. Nine studies found no increase in voiding symptoms, abnormal findings on examination of the prostate, or postvoid residual urine during treatment. One study found that the prostate increased in size by 12%. The results for prostate specific antigen were mixed: 5 studies reported no effect, while 4 studies reported a significant increase even after 6 weeks' treatment. 33

34 One study reported no change in sleep apnoea with testosterone supplementation. Authors' conclusions Testosterone supplementation cannot be recommended for older healthy men with normal or low normal testosterone levels. There was evidence that testosterone supplementation may be useful in men with reduced testosterone levels and clinical hypogonadism. Supplementation many also be helpful in older men with low testosterone levels, regardless of symptoms. The longer term (beyond 3 years) efficacy and safety are unknown. CRD commentary The review question was clear in terms of the intervention and participants. The inclusion criteria were defined in terms of the study design, but the criteria were not clearly stated or implemented. Several relevant sources were searched, the search terms were stated, and studies in any language were eligible. The methods used to select the studies and extract the data were not described, so it is not known whether any efforts were made to reduce errors and bias. Three reviewers independently assessed validity, which reduces the potential for bias and errors. The validity of all the studies was assessed using criteria validated for the reporting of RCTs, but methodological problems in the individual studies were not reported. Some relevant information on the studies was tabulated. However, the tools used to measure the outcomes were not described for all outcomes, hence the validity of some outcome measures was unknown. The results from the individual studies were classified as increased, unchanged or reduced, but it was unclear whether these categories were based on statistically significant changes or not. A narrative synthesis was appropriate given the small number of studies, but the studies were combined without highlighting the better quality evidence and without taking account of the number of participants on which the evidence was based. However, the authors did analyse higher and lower quality studies separately, but these categories were not defined and the data were not reported. The authors discussed some of the limitations of the review. In view of those highlighted above and the small number of men reported in a few trials, the evidence presented in the review was limited and the conclusions must be interpreted with caution. Implications of the review for practice and research Practice: The authors stated that evidence from the review did not support the use of testosterone supplementation in healthy older asymptomatic men with normal to low testosterone levels. They further stated that testosterone may be helpful for symptomatic men with symptoms due to low testosterone levels, and that a trial of testosterone in such men is reasonable unless there are contraindications. In addition, testosterone may help older men with marked reductions in their testosterone level, whether or not they have symptoms. The authors also stated that close monitoring is required in men receiving testosterone supplementation. Research: The authors stated that well designed, long term placebo controlled RCTs are required to determine the effectiveness of testosterone supplementation and its effects on function and quality of life. Funding Department of Veterans Affairs Medical Research Funds 84 B. MOOD WITH HYPOGONADISM Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Impact of exogenous testosterone on mood: a systematic review and meta analysis of randomized placebo controlled trials (Provisional abstract) Centre for Reviews and Dissemination Original article: Amanatkar HR, Chibnall JT, Seo BW, Manepalli JN, Grossberg GT. Impact of exogenous testosterone on mood: a systematic review and meta analysis of randomized placebo controlled trials. Annals of Clinical Psychiatry.2014;26(1): BACKGROUND: In the last decade, there has been a surge of new clinical trials studying the impact of exogenous testosterone on mood. The results of these studies have been inconsistent. METHODS: Meta-analysis of controlled clinical trials using common depression rating scales was performed. RESULTS: Sixteen trials with a total of 944 subjects met selection criteria. Meta-analysis of data showed a significant positive impact of testosterone on mood (z=4.592; P<.0001). Subgroup analysis showed a significant effect size of (P<.0001) in the trials with a mean age of <60 years. However, the effect size was not statistically significant in those trials with a mean age of >60 years. The effect size in hypogonadal men was (P<.0001), whereas the result was not statistically significant in 34

35 eugonadal men. In addition, the effect size was larger in subthreshold depression compared with major depression. Oral testosterone compared with oral dehydroepiandrosterone, testosterone gel, and intramuscular testosterone did not show a significant result. Larger CONCLUSIONS: Testosterone may be used as a monotherapy in dysthymia and minor depression or as an augmentation therapy in major depression in middle-aged hypogonadal men. 75 C. SEXUAL DYSFUNCTION Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Synergetic effect of testosterone and phosphodiesterase 5 inhibitors in hypogonadal men with erectile dysfunction: a systematic review (Provisional abstract) Centre for Reviews and Dissemination Original article:alhathal N, Elshal AM, Carrier S. Synergetic effect of testosterone and phosphodiesterase 5 inhibitors in hypogonadal men with erectile dysfunction: a systematic review. Canadian Urological Association Journal.2012;6(4): Abstract Testosterone deficiency seems to impair the clinical response to phophodiesterase-5 (PDE-5) inhibitors in patients with erectile dysfunction (ED). In hypogonadal men, testosterone repletion was associated with enhanced sexual function in patients who failed initial treatment with sildenafil or tadalafil. We conducted a systematic review of studies that evaluated combination therapy of testosterone and PDE-5 inhibitors in patients with ED and low, low-normal testosterone levels who failed monotherapy. The studies we examine are heterogeneous with several methodological drawbacks and that, overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone <300 ng/dl (10.4 nmol/l) who failed monotherapy. Further studies, with a randomized placebo-controlled and double blind design, are needed to describe the appropriate target patient group, testosterone cut-off and to define the optimal dose and duration of combination therapy. 85 Testosterone supplementation and sexual function: a meta analysis study (Provisional abstract) Centre for Reviews and Dissemination Original article: Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, Rochira V, Sforza A, Lenzi A, Mannucci E, Maggi M. Testosterone supplementation and sexual function: a meta analysis study. Journal of Sexual Medicine.2014;11(6): Introduction The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. Aim The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). Methods An extensive Medline, Embase, and Cochrane search was performed. Main Outcome Measures All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). Results Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying trim and fill method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [ ] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. Conclusions TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable

36 D. HYPOGONADAL WITH DIABETES / METABOLIC EFFECTS Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta analysis of randomized controlled trials (Provisional abstract) Centre for Reviews and Dissemination Original article: Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and meta analysis of randomized controlled trials. Asian Journal of Andrology.2014;16(1): This systematic review was aimed at assessing the metabolic effects of testosterone replacement therapy (TRT) on hypogonadal men with type 2 diabetes mellitus (T2DM). A literature search was performed using the Cochrane Library, EMBASE and PubMed. Only randomized controlled trials (RCTs) were included in the meta-analysis. Two reviewers retrieved articles and evaluated the study quality using an appropriate scoring method. Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity. We used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis. Five RCTs including 351 participants with a mean follow-up time of 6.5-months were identified that strictly met our eligibility criteria. A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): 1.10; 95% confidence interval (CI) ( 1.88, 0.31)), fasting serum insulin levels (MD: 2.73; 95% CI ( 3.62, 1.84)), HbA1c % (MD: 0.87; 95% CI ( 1.32, 0.42)) and triglyceride levels (MD: 0.35; 95% CI ( 0.62, 0.07)). The testosterone and control groups demonstrated no significant difference for other outcomes. In conclusion, we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM. Considering the limited number of participants and the confounding factors in our systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM. 51 Effects of testosterone substitution on metabolic syndrome related factors in hypogonadal males: a meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article:wan ZH, Wen YB, Ding QF, Xu TY. Effects of testosterone substitution on metabolic syndrome related factors in hypogonadal males: a meta analysis. National Journal of Andrology.2010;16(6): OBJECTIVE: To conduct a meta-analysis on the effects of testosterone on the related factors of metabolic syndrome in hypogonadal males. METHODS: Based on the principles and methods of Cochrane systematic reviews, we searched the PubMed (1980 to August 2009), Embase (1980 to August 2009), the Cochrane Central Register of Controlled Trials and CNKI (1995 to August 2009), and handsearched some relevant journals and conference proceedings as well. We also identified randomized controlled trials addressing the use of testosterone for the treatment of hypogonadism, screened the retrieved studies according to the predefined inclusion and exclusion criteria, evaluated the quality of the included studies, and performed a meta-analysis on the results of homogeneous studies using the Cochrane Collaboration's RevMan 5.0 software. RESULTS: Six randomized controlled trials were included. The results of analysis indicated that testosterone substitution could significantly ameliorate fasting blood glucose, total cholesterol and insulin resistance in hypogonadism patients, and it could also reduce LDL, HDL, triglyceride and systolic blood pressure, though with no significant difference from the controls. However, there was insufficient evidence to show the effects of testosterone on waist circumference, waist-hip ratio and diastolic blood pressure. CONCLUSION: Existing clinical evidence has demonstrated the positive effects of testosterone substitution on the improvement of insulin resistance, blood glucose and lipids, but due to the heterogeneity and high risk of bias in the included studies, the evidence might be insufficient to give full support to the demonstration. Further large-scale trials are required to define the metabolic effects of testosterone in the treatment of hypogonadism. 86 E. PATIENTS WITH HIV Cochrane Systematic Reviews Johns K, et al. (2005) Anabolic Steroids for the treatment of weight loss in HIV-infected individuals 65 Background Individuals with HIV infection often lose weight during the course of their disease. Furthermore, low serum concentrations of testosterone are common in individuals with HIV infection, particularly those with weight loss. Treatment of weight loss with anabolic steroids in HIV-infected individuals may be beneficial. Objectives Our objectives were to assess the efficacy and safety of anabolic steroids for the treatment of weight loss in adults with HIV infection. Search methods We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, AIDSLINE, AIDSearch, EMBASE, CINAHL, Current Contents, and the National Library of Medicine Gateway Abstracts for controlled trials 36

37 up to April We also searched the bibliographies of the identified studies and review the articles. In addition, pharmaceutical manufacturers of anabolic steroids were contacted. Selection criteria Randomized controlled trials that compared the use of an anabolic steroid to placebo to treat weight loss in adults with HIV were included. Randomized controlled trials that compared the use of anabolic steroids to placebo for the treatment of weight loss in adults with HIV were selected. Change from baseline in lean body mass or in body weight was reported as on outcome measure. Data collection and analysis Two reviewers independently assessed the trials for quality of randomization, blinding, withdrawals, and adequacy of allocation concealment. For continuous data, weighted mean differences (WMD) were calculated. For dichotomous outcomes, risk differences, were calculated. Because of uncertainty as to whether consistent true effects exist in such different populations and treatments, the authors decided a priori to use random effects models for all outcomes. Main results Thirteen trials met the inclusion criteria. Two hundred ninety-four individuals randomized to anabolic steroid therapy and 238 individuals randomized to placebo were included in the analysis of efficacy for change from baseline in lean body mass. Three hundred forty-three individuals randomized to anabolic steroid and 286 randomized to placebo were included in the analysis of efficacy for change from baseline in body weight. The mean methodologic quality of the included studies was 4.1, of a maximum 5 points. Although significant heterogeneity was present for both outcomes, the average change in lean body mass was 1.3 kg (95% CI: 0.6, 2.0), while the average change in total body weight was 1.1 kg (95% CI: 0.3, 2.0). A total of eight deaths occurred during the treatment period; four in the anabolic steroid treatment groups and four in the placebotreatment groups (risk difference 0.00, 95% CI -0.03, 0.03). The risk difference for withdrawals or discontinuations of study medication due to adverse events was 0.00 (95% CI: -0.02, 0.03). Authors' conclusions Although the results of the trials were heterogeneous, on average, the administration of anabolic steroids appeared to result in a small increase in both lean body mass and body weight as compared with placebo. While these results suggest that anabolic steroids may be useful in the treatment of weight loss in HIV infected individuals, due to limitations, treatment recommendations cannot be made. Further information is required regarding the long-term benefit and adverse effects of anabolic steroid use, the specific populations for which anabolic steroid therapy may be most beneficial, and the optimal regime. In addition, the correlation of improvement in lean body mass with more clinically relevant endpoints, such as physical functioning and survival, needs to be determined. Plain language summary Anabolic steroids may be beneficial in the treatment of weight loss in HIV-infected individuals. Anabolic steroids include testosterone and its derivatives. One of the functions of testosterone is to help build muscle. Testosterone has been demonstrated to increase muscle mass and lean body mass in testosterone-deficient but otherwise healthy men. Individuals with HIV infection often lose weight and have low blood levels of testosterone; thus, the use of anabolic steroids in the treatment of weight loss in individuals with HIV infection may be beneficial. The purpose of this review was to evaluate anabolic steroids as a means of treatment of weight loss in individuals with HIV infection. The review includes 13 randomized clinical trials in the primary analysis. The results suggested that anabolic steroids increased both lean body mass and body weight. However, the results were not consistent among individual trials and the average increase was small and may not be clinically relevant. Furthermore, the results need to be interpreted with caution as this meta-analysis was limited due to small sample sizes; short duration of treatment and of follow-up; and heterogeneity of the study populations, the anabolic interventions, and concomitant therapies. 65 Lin, D. and Rieder, M. J. (2007) Interventions for the treatment of decreased bone mineral density associated with HIV infection 66 Background Decreased bone mineral density (BMD) occurs more commonly in patients with HIV than in the general population, making this group more susceptible to fragility fractures. However, bone loss is under-treated in patients with HIV. Objectives To assess the effects of interventions aimed at increasing bone mineral density in HIV-infected adults. Search methods We searched MEDLINE, EMBASE, LILACS, The Cochrane Library, Meeting Abstracts, AIDSTRIALS, ACTIS, Current Controlled Trials, National Institutes of Health Clinical Trials Registry, and CenterWatch (search date July 2006). Selection criteria Randomised trials comparing any pharmacological or non-pharmacological therapy with placebo, no treatment, or an alternative therapy, with the goal of increasing bone mineral density in adult (age 18 years or over) patients with HIV. Data collection and analysis Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details. 37

38 Main results Three completed randomised-controlled studies examined the role of alendronate in patients with HIV and osteopenia or osteoporosis. When all three studies were combined, much heterogeneity was seen (p<0.0001), most likely due to different populations and interventions. A sensitivity analysis showed that in two studies without heterogeneity (p=0.11), alendronate, calcium and vitamin D improved lumbar BMD after one year when compared with calcium and vitamin D (weighted mean difference % confidence interval (CI) 0.80, 4.51 percent). However the alendronate group did not have less fragility fractures, relative risk (RR) 1.28 (95% CI 0.20, 8.21), or osteoporosis, RR 0.50 (95% CI 0.24, 1.01). Adverse events were not significantly different between groups, RR 1.28 (95% 0.20, 8.21). One randomised-controlled study done in patients with AIDS wasting found that after three months, testosterone enanthane improved lumbar BMD compared to placebo by (95% CI 0.48, 6.92) percent, but progressive resistance training did not improve lumbar BMD ( % CI -2.81, 3.61 percent). No group in this study had any adverse effects. Authors' conclusions The very limited data reviewed showed that bisphosphonate therapy and in those with AIDS wasting syndrome, testosterone may be safe and possibly effective methods to improve bone mineral density in HIV patients. The available studies are small, of short duration, and not powered to detect changes in WHO categories and fracture rates. Larger studies using bisphosphonates are currently underway. The role of colecalciferol, androgen replacement in women, and growth hormone are also under investigation. 66 F. OTHER OFF-LABEL/INVESTIGATIONAL USES Cochrane Systematic Reviews Grimes, D. A. et al. (2012) Steroid hormones for contraception in men 61 Background Male hormonal contraception has been an elusive goal. Administration of sex steroids to men can shut off sperm production through effects on the pituitary and hypothalamus. However, this approach also decreases production of testosterone, so 'add-back' therapy is needed. Objectives To summarize all randomized controlled trials (RCTs) of male hormonal contraception. Search methods In January and February 2012, we searched the computerized databases CENTRAL, MEDLINE, POPLINE, and LILACS. We also searched for recent trials in ClinicalTrials.gov and ICTRP. Previous searches included EMBASE. We wrote to authors of identified trials to seek additional unpublished or published trials. Selection criteria We included all RCTs that compared a steroid hormone with another contraceptive. We excluded non-steroidal male contraceptives, such as gossypol. We included both placebo and active-regimen control groups. Data collection and analysis The primary outcome measure was the absence of spermatozoa on semen examination, often called azoospermia. Data were insufficient to examine pregnancy rates and side effects. Main results We found 33 trials that met our inclusion criteria. The proportion of men who reportedly achieved azoospermia or had no detectable sperm varied widely. A few important differences emerged. 1) Levonorgestrel implants (160 μg daily) combined with injectable testosterone enanthate (TE) were more effective than levonorgestrel 125 µg daily combined with testosterone patches. 2) Levonorgestrel 500 μg daily improved the effectiveness of TE 100 mg injected weekly. 3) Levonorgestrel 250 μg daily improved the effectiveness of testosterone undecanoate (TU) 1000 mg injection plus TU 500 mg injected at 6 and 12 weeks. 4) Desogestrel 150 μg was less effective than desogestrel 300 μg (with testosterone pellets). 5) TU 500 mg was less likely to produce azoospermia than TU 1000 mg (with levonorgestrel implants). 6) Norethisterone enanthate 200 mg with TU 1000 mg led to more azoospermia when given every 8 weeks versus 12 weeks. 7) Four implants of 7-alpha-methyl-19-nortestosterone (MENT) were more effective than two MENT implants. We did not conduct any metaanalysis due to intervention differences. Several trials showed promising efficacy in percentages with azoospermia. Three examined desogestrel and testosterone preparations or etonogestrel and testosterone, and two examined levonorgestrel and testosterone. Authors' conclusions No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition, assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful

39 Elias A and Kumar A. (2007) Testosterone for schizophrenia 62 Background Recently, sex hormones such as estrogens and testosterone or its derivatives have been the focus of interest for treatment of persistent symptoms associated with schizophrenia. Objectives To review the effects of dehydroepiandrosterone (DHEA)/testosterone as adjunctive therapy to standard antipsychotic drugs. Search methods We searched the Cochrane Schizophrenia Group Trials Register (January 2007). Selection criteria We included all clinical randomised trials comparing DHEA/testosterone plus standard antipsychotic treatment with standard treatment alone. Data collection and analysis We independently selected studies and extracted data. For dichotomous data we calculated the relative risk (RR) and its 95% confidence interval (CI) on an intention to treat basis, using a fixed effects model. We presented continuous data using the weighted mean difference statistic, with a 95% confidence interval using a fixed effects model. Main results We found three relevant small, short trials (total n=126). Clinical Global Impression data were equivocal (n=27, 1 RCT, WMD CI -0.9 to 0.1). Average total PANSS scores were not significantly different between the DHEA plus antipsychotic group and those given antipsychotic drugs and placebo (n=82, 2 RCTs, WMD CI to 5.5). PANSS positive scores were equivocal (n=55, 1 RCT, WMD CI -3.8 to 1.8). For negative symptoms binary SANS scale data favoured the DHEA plus antipsychotic group (n=30, 1 RCT, RR 0.23 CI 0.1 to 0.6, NNT 2 CI 2 to 3) but PANSS negative scores were not significantly different between comparison groups (n=55, 1 RCT, WMD CI -6.4 to 1.8). About 17% of people left both groups early (n=64, 2 RCTs, RR 0.80 CI 0.3 to 2.4). St Hans Rating Scale data for extrapyramidal symptoms favoured the DHEA plus antipsychotic group (n=30, 1 RCT, WMD CI -8.8 to -1.2) but akathisia ratings were equivocal (n=34, 1 RCT, RR 2.67 CI 0.3 to 23.1). Ratings of parkinsonian movement disorder differed within the same trial depending of the outcome scale used. Quality of life seemed unaffected by use of DHEA (n=55, 1 RCT, WMD 6.20 CI -1.4 to 13.8). Authors' conclusions Results are inconclusive with most outcomes being either non-significant or producing contradictory findings. Currently, adjunctive DHEA should remain an experimental treatment for people with schizophrenia. Price, J. and Leng, G. C. (2012) Steroid sex hormones for lower limb atherosclerosis 64 Background There is accumulating evidence that steroid sex hormones have a beneficial effect on a number of risk factors for peripheral arterial disease. Objectives The objective of this review was to determine whether exogenous steroid sex hormones are an effective treatment for patients with lower limb atherosclerosis. Search methods For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched August 2012) and CENTRAL 2012, Issue 7. There were no language restrictions. Selection criteria We selected randomised or quasi-randomised controlled trials of steroid sex hormones in patients with lower limb atherosclerosis. Data collection and analysis Both authors extracted data and assessed trial quality independently. Whenever possible investigators were contacted to obtain information needed for the review that could not be found in published reports. Main results Four trials appeared to meet the inclusion criteria, but one was excluded because of poor methodology. The three remaining trials compared testosterone treatment with placebo in a total of 109 subjects with intermittent claudication or critical leg ischaemia. The most recent trial to meet the inclusion criteria dated from No trials were available which investigated the potentially beneficial effects of oestrogenic hormones in women with lower limb atherosclerosis. Testosterone therapy produced no significant improvement in tests of walking distance or in a variety of other objective tests for peripheral arterial disease, including venous filling time, muscle blood flow and plethysmography. The relative risk for subjective improvement in symptoms using the combined trial results was also non-significant (relative risk (RR) 1.10, 95% confidence interval (CI) 0.81 to 1.48). Authors' conclusions There is no evidence to date that short-term testosterone treatment is beneficial in subjects with lower limb atherosclerosis. However, this might reflect limited data rather than the lack of a real effect

40 Chi, C. C. et al. (2011) Topical interventions for genital lichen sclerosus 67 Background Lichen sclerosus is a chronic, inflammatory skin condition that most commonly occurs in adult women, although it may also be seen in men and children. It primarily affects the genital area and around the anus, where it causes persistent itching and soreness. Scarring after inflammation may lead to severe damage by fusion of the vulval lips (labia); narrowing of the vaginal opening; and burying of the clitoris in women and girls, as well as tightening of the foreskin in men and boys, if treatments are not started early. Affected people have an increased risk of genital cancers. Objectives To assess the effects of topical interventions for genital lichen sclerosus and adverse effects reported in included trials. Search methods We searched the following databases up to 16 September 2011: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2007), LILACS (from 1982), CINAHL (from 1981), British Nursing Index and Archive (from 1985), Science Citation Index Expanded (from 1945), BIOSIS Previews (from 1926), Conference Papers Index (from 1982), and Conference Proceedings Citation Index - Science (from 1990). We also searched ongoing trial registries and scanned the bibliographies of included studies, published reviews, and papers that had cited the included studies. Selection criteria Randomised controlled trials (RCTs) of topical interventions in genital lichen sclerosus. Data collection and analysis Two authors independently selected trials, extracted data, and assessed the risk of bias. A third author was available for resolving differences of opinion. Main results We included 7 RCTs, with a total of 249 participants, covering 6 treatments. Six of these RCTs tested the efficacy of one active intervention against placebo or another active intervention, while the other trial tested three active interventions against placebo. When compared to placebo in one trial, clobetasol propionate 0.05% was effective in treating genital lichen sclerosus in relation to the following outcomes: 'participant-rated improvement or remission of symptoms' (risk ratio (RR) 2.85, 95% confidence interval (CI) 1.45 to 5.61) and 'investigator-rated global degree of improvement' (standardised mean difference (SMD) 5.74, 95% CI 4.26 to 7.23). When mometasone furoate 0.05% was compared to placebo in another trial, there was a significant improvement in the 'investigator-rated change in clinical grade of phimosis' (SMD -1.04, 95% CI to -0.31). Both trials found no significant differences in reported adverse drug reactions between the corticosteroid and placebo groups. The data from four trials found no significant benefit for topical testosterone, dihydrotestosterone, and progesterone. When used as maintenance therapy after an initial treatment with topical clobetasol propionate in another trial, topical testosterone worsened the symptoms (P < 0.05), but the placebo did not. One trial found no differences between pimecrolimus and clobetasol propionate in relieving symptoms through change in pruritus (itching) (SMD -0.33, 95% CI to 0.33) and burning/pain (SMD 0.03, 95% CI to 0.69). However, pimecrolimus was less effective than clobetasol propionate with regard to the 'investigator-rated global degree of improvement' (SMD -1.64, 95% CI to -0.87). This trial found no significant differences in reported adverse drug reactions between the pimecrolimus and placebo groups. Authors' conclusions The current limited evidence demonstrates the efficacy of clobetasol propionate, mometasone furoate, and pimecrolimus in treating genital lichen sclerosus. Further RCTs are needed to determine the optimal potency and regimen of topical corticosteroids, examine other topical interventions, assess the duration of remission or prevention of flares, evaluate the reduction in the risk of genital squamous cell carcinoma or genital intraepithelial neoplasia, and examine the efficacy in improving the quality of the sex lives of people with this condition. 67 Farooqi, V. et al. (2014) Anabolic steroids for rehabilitation after hip fracture in older people 68 Background Hip fracture occurs predominantly in older people, many of whom are frail and undernourished. After hip fracture surgery and rehabilitation, most patients experience a decline in mobility and function. Anabolic steroids, the synthetic derivatives of the male hormone testosterone, have been used in combination with exercise to improve muscle mass and strength in athletes. They may have similar effects in older people who are recovering from hip fracture. Objectives To examine the effects (primarily in terms of functional outcome and adverse events) of anabolic steroids after surgical treatment of hip fracture in older people. 40

41 Search methods We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (10 September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013 Issue 8), MEDLINE (1946 to August Week ), EMBASE (1974 to 2013 Week 36), trial registers, conference proceedings, and reference lists of relevant articles. The search was run in September Selection criteria Randomised controlled trials of anabolic steroids given after hip fracture surgery, in inpatient or outpatient settings, to improve physical functioning in older patients with hip fracture. Data collection and analysis Two review authors independently selected trials (based on predefined inclusion criteria), extracted data and assessed each study's risk of bias. A third review author moderated disagreements. Only very limited pooling of data was possible. The primary outcomes were function (for example, independence in mobility and activities of daily living) and adverse events, including mortality. Main results We screened 1290 records and found only three trials involving 154 female participants, all of whom were aged above 65 years and had had hip fracture surgery. All studies had methodological shortcomings that placed them at high or unclear risk of bias. Because of this high risk of bias, imprecise results and likelihood of publication bias, we judged the quality of the evidence for all primary outcomes to be very low. These trials tested two comparisons. One trial had three groups and contributed data to both comparisons. None of the trials reported on patient acceptability of the intervention. Two very different trials compared anabolic steroid versus control (no anabolic steroid or placebo). One trial compared anabolic steroid injections (given weekly until discharge from hospital or four weeks, whichever came first) versus placebo injections in 29 "frail elderly females". This found very low quality evidence of little difference between the two groups in the numbers discharged to a higher level of care or dead (one person in the control group died) (8/15 versus 10/14; risk ratio (RR) 0.75, 95% confidence interval (CI) 0.42 to 1.33; P = 0.32), time to independent mobilisation or individual adverse events. The second trial compared anabolic steroid injections (every three weeks for six months) and daily protein supplementation versus daily protein supplementation alone in 40 "lean elderly women" who were followed up for one year after surgery. This trial provided very low quality evidence that anabolic steroid may result in less dependency, assessed in terms of being either dependent in at least two functions or dead (one person in the control group died) at six and 12 months, but the result was also compatible with no difference or an increase in dependency (dependent in at least two levels of function or dead at 12 months: 1/17 versus 5/19; RR 0.22, 95% CI 0.03 to 1.73; P = 0.15). The trial found no evidence of between-group differences in individual adverse events. Two trials compared anabolic steroids combined with another nutritional intervention ('steroid plus') versus control (no 'steroid plus'). One trial compared anabolic steroid injections every three weeks for 12 months in combination with daily supplement of vitamin D and calcium versus calcium only in 63 women who were living independently at home. The other trial compared anabolic steroid injections every three weeks for six months and daily protein supplementation versus control in 40 "lean elderly women". Both trials found some evidence of better function in the steroid plus group. One trial reported greater independence, higher Harris hip scores and gait speeds in the steroid plus group at 12 months. The second trial found fewer participants in the anabolic steroid group were either dependent in at least two functions, including bathing, or dead at six and 12 months (one person in the control group died) (1/17 versus 7/18; RR 0.15, 95% CI 0.02 to 1.10; P = 0.06). Pooled mortality data (2/51 versus 3/51) from the two trials showed no evidence of a difference between the two groups at one year. Similarly, there was no evidence of between-group differences in individual adverse events. Three participants in the steroid group of one trial reported side effects of hoarseness and increased facial hair. The other trial reported better quality of life in the steroid plus group. Authors' conclusions The available evidence is insufficient to draw conclusions on the effects, primarily in terms of functional outcome and adverse events, of anabolic steroids, either separately or in combination with nutritional supplements, after surgical treatment of hip fracture in older people. Given that the available data points to the potential for more promising outcomes with a combined anabolic steroid and nutritional supplement intervention, we suggest that future research should focus on evaluating this combination. 68 Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Testosterone use in men and its effects on bone health: a systematic review and meta-analysis of randomized placebocontrolled trials (Structured abstract) 69 Original article:tracz M J, Sideras K, Bolona E R, Haddad R M, Kennedy C C, Uraga M V, Caples S M, Erwin P J, Montori V M. Testosterone use in men and its effects on bone health: a systematic review and meta analysis of randomized placebocontrolled trials. Journal of Clinical Endocrinology and Metabolism.2006;91(6): Centre for Review and Dissemination (CRD) summary 41

42 This review assessed the effects of testosterone on bone mineral density in men. The authors concluded that intramuscular testosterone moderately increased lumbar bone spine density, but the effects on femoral neck density were uncertain. Overall, this was a well conducted review and the authors' conclusions are likely to be reliable. Authors' objectives To evaluate the effects of testosterone on measures of bone health in men. Searching MEDLINE, EMBASE and the Cochrane CENTRAL Register were searched from inception to March 2005; the search terms were not reported. The reference lists of primary studies and reviews identified from a search of MEDLINE were screened. In addition, experts who were members of the Endocrine Society Task Force were contacted. [A: No language restrictions were applied.] Study selection: study designs Randomised controlled trials (RCTs) were eligible for inclusion. The duration of the included studies ranged from 3 to 36 months; only two studies lasted more than 12 months. Study selection: specific interventions Studies that compared any available preparation of testosterone with placebo were eligible for inclusion. In the included studies, testosterone was given intramuscularly or transdermally. Intramuscular interventions were testosterone enanthate 200 mg every week, 2 weeks or month, or testosterone mixed esters 200 mg every 2 weeks or 250 mg monthly. Transdermal interventions were a 2.5 mg patch, 5 mg Androderm patch, or 6 mg scrotal patch per day. Study selection: participants Studies of men with any level of androgen deficiency were eligible for inclusion. The mean age of the participants in the included studies ranged from 36 to 75 years, and the mean baseline total testosterone levels ranged from 291 to 646 nanog/dl. Where reported, the included studies were in men with different characteristics, including chronic glucocorticoid use, wasting due to acquired immune deficiency syndrome, and Leydig cell dysfunction. One study included men with known osteoporotic fractures. Study selection: outcomes Studies that assessed bone fractures, or lumbar or femoral neck bone mineral density (BMD), were eligible for inclusion. Studies that only assessed changes in biomarkers of bone turnover were excluded. Study selection: how were decisions on the relevance of primary studies made? Teams of two reviewers independently selected the studies. Any disagreements on inclusions were resolved through recourse to a third reviewer. Validity assessment Two reviewers independently assessed the validity of each study. The studies were assessed for adequacy of randomisation, concealment of allocation, blinding of the patients, health care providers and collectors of data, and losses to follow up. [A: The authors assumed that studies described as double blind were blinded.] Data extraction Two reviewers independently extracted the data onto a standardised form. For each study, data on the BMD (either end point or change from baseline) were extracted for the longest follow up period with sufficiently complete data whilst patients were still taking testosterone or placebo. This was then used to calculate the effect size (ES) and 95% confidence interval (CI) of the difference in BMD between treatments. Authors of the primary studies were contacted for missing outcomes data. The studies were classified according to the mean testosterone level at baseline; a low testosterone level was defined as a total testosterone level of 300 nanog/dl or lower. Men in studies that did not report previous osteoporotic fractures were assumed to have not experienced previous fractures. Methods of synthesis: how were the studies combined? Pooled standardised mean differences with 95% CIs were calculated using a random effects model for BMD at lumbar spine and femoral neck separately. Pooled percentage changes in BMD were also reported with 95% CIs. Methods of synthesis: how were differences between studies investigated? Statistical heterogeneity was assessed using the I squared statistic. Pre planned subgroup analyses were used to evaluate the effects of study quality, patient characteristics (age >60 years, primary or secondary prevention, level of androgen deficiency and previous glucocorticoid use), interventions (route of administration) and duration of follow up. Results of the review Eight RCTs (n=365) were included: seven parallel group RCTs and one crossover RCT. In terms of study quality, one study reported allocation concealment, while the reporting and use of blinding varied between studies. Losses to follow up ranged from 6 to 34% (median 14). None of the included studies assessed bone fractures. The meta analysis showed a small significant increase in lumbar spine BMD in men taking testosterone compared with placebo; the ES was 0.31 (95% CI: 0.02, 0.61), corresponding to a 4% (95% CI: 0.3, 8) gain in lumbar BMD. Moderate heterogeneity was found (I squared 46%). 42

43 There was a small but non significant increase in femoral BMD with testosterone compared with placebo; the ES was 0.17 (95% CI: 0.11, 0.45). Moderate heterogeneity was found (I squared 26%). The subgroup analysis showed that intramuscular testosterone significantly increased lumbar spine BMD in men taking testosterone compared with placebo; the ES was 0.62 (95% CI: 0.32, 0.92), corresponding to an 8% (95% CI: 4, 13) gain in lumbar BMD. This effect was significantly greater than the effect of transdermal testosterone on lumbar BMD (p=0.009). No significant heterogeneity was found in this subgroup analysis (I squared 0%). The review authors stated that this explained the heterogeneity among studies evaluating lumbar spine BMD (no data were presented). There was no difference between i.m. testosterone and transdermal testosterone for femoral neck BMD. Subgroup analyses showed no significant interaction between treatment and use of glucocorticoids, testosterone level at baseline, age, duration of follow up and losses to follow up. Authors' conclusions Intramuscular testosterone moderately increased lumbar bone spine density in men, but the effects on femoral neck density were uncertain. CRD commentary The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Several relevant sources were searched and attempts were made to minimise language bias. However, the search terms were not reported and only published studies were eligible; this raised the possibility of publication bias, as the authors acknowledged. Two reviewers independently selected studies, assessed validity and extracted the data, thereby reducing the potential for reviewer bias and errors. Validity was assessed using defined criteria, but the results were only partially reported. The review authors appear to have presumed that blinding was used in several studies but the justification for this was not clear. The data were combined in a meta analysis, statistical heterogeneity was assessed, and pre planned subgroup analyses were used to examine potential sources of heterogeneity. Where the authors were unable to identify factors responsible for the heterogeneity this was stated. However, high drop out rates might indicate that there were problems with the treatments and reasons for drop outs were not reported. Overall, this was a well conducted review and the authors' conclusions are likely to be reliable. Implications of the review for practice and research Practice: The authors stated that patients and clinicians need to take the potential benefits and side effects (see Other Publications of Related Interest) of testosterone into account when making treatment choices, and that clinicians who are uncertain about whether or not to recommend testosterone to their patients should instead enrol patients in future RCTs. Research: The authors stated that large RCTs are required to assess the long term (3 years or more) effects of testosterone plus adequate calcium and vitamin D on bone fractures in men with and without previous osteoporotic fractures. There is also a need to compare testosterone with other therapies such as bisphosphonates. Funding Department of Medicine, Mayo Clinic College of Medicine. 69 Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Atlantis E, Fahey P, Cochrane B, Wittert G, Smith S. 70 Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta analysis. BMJ Open.2013;3(8):e OBJECTIVE: Low testosterone level may be a reversible risk factor for functional disability and deterioration in patients with chronic obstructive pulmonary disease (COPD). We sought to systematically assess the endogenous testosterone levels and effect of testosterone therapy on exercise capacity and health-related quality of life (HRQoL) outcomes in COPD patients, as well as to inform guidelines and practice. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Scopus, Cochrane Library, CINAHL, Health Source Nursing and PsychINFO and the reference lists of retrieved articles published before May INCLUSION CRITERIA: Observational studies on endogenous testosterone levels in people with chronic lung disease compared with controls, or randomised controlled trials (RCTs) on testosterone therapy for exercise capacity and/or HRQoL outcomes in COPD patients were eligible. 43

44 DATA EXTRACTION AND ANALYSIS: Data on the mean difference in endogenous total testosterone (TT) values, and the mean difference in exercise capacity and HRQoL values were extracted and pooled using random effects meta-analysis. RESULTS: Nine observational studies in 2918 men with COPD reported consistently lower levels of TT compared with controls (weighted mean difference was nmol/l (95% CI to -1.23)). Six RCTs in 287 participants yielded five studies on peak muscle strength and peak cardiorespiratory fitness outcomes (peak oxygen uptake (VO2) and workload) and three studies on HRQoL outcomes. Testosterone therapies significantly improved peak muscle strength (standardised mean difference (SMD) was 0.31 (95% CI 0.05 to 0.56)) and peak workload (SMD was 0.27 (95% CI 0.01 to 0.52)) compared with control conditions (all but one used placebo), but not peak VO2 (SMD was 0.21 (95% CI to 0.56)) or HRQoL (SMD was (95% CI to 0.25)). CONCLUSIONS: Men with COPD have clinically relevant lower than normal TT levels. Insufficient evidence from short-term studies in predominately male COPD patients suggests that testosterone therapy improves exercise capacity outcomes, namely peak muscle strength and peak workload. 70 Hormone therapy in hypospadias surgery: a systematic review (Provisional abstract) Centre for Reviews and Dissemination Original article: Netto JM, Ferrarez CE, Schindler Leal AA, Tucci S, Gomes CA, Barroso U. Hormone therapy in hypospadias surgery: a systematic review. Journal of Pediatric Urology.2013;9(6 Part B): Surgical correction of hypospadias is proposed to improve the aesthetic and functional quality of the penis. Hormone therapy preceding surgical correction is indicated to obtain better surgical conditions. However, there is divergence in the literature regarding the hormone therapy of choice, time of its use before surgery, appropriate dose, and route of application. To try to elucidate this matter, an electronic survey of the databases PubMed and Cochrane Central Library was conducted, limited to articles in English published since Search strategy identified 14 clinical trials that matched the inclusion criteria. Analysis was made in terms of study design, classification of hypospadias, association with chordee and cryptorchidism, type of hormone, route of application, dose and duration of treatment, penile length before and after hormone therapy, glans circumference before and after hormone therapy, adverse effects, and surgical complications. From the trials evaluated it was not possible to determine the ideal neoadjuvant treatment. A preference for use of testosterone was observed. Intramuscular administration seems to have fewer adverse effects than topical treatment. Side effects were seldom described, and treated patients were not followed on a long-term basis. The scarcity of randomized and controlled clinical trials regarding the topic impairs the establishment of a protocol. In conclusion, although preoperative hormone therapy is currently used before hypospadias surgery, its real benefit in terms of improvement of the penis and surgical results has not been defined. 71 Testosterone and depression: systematic review and meta analysis (Structured abstract) Centre for Reviews and Dissemination Original article: Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and metaanalysis. Journal of Psychiatric Practice.2009;15(4): CRD summary This review concluded that testosterone replacement therapy may have an antidepressant effect, especially for patients who also have hypogonadism or HIV infection. Limitations in the review methods and the evidence base suggest that the conclusions should be treated with caution. The conclusions are unlikely to be applicable to the general population of patients with depression. Authors' objectives To evaluate the effect of testosterone administration on depression. Searching The authors searched MEDLINE, the Clinical Trials Registry and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to February The search was limited to English language publications. Search terms were reported. Reference lists were scanned to identify additional studies. Study selection Randomised controlled trials (RCTs) comparing testosterone based treatment with placebo were eligible for the review. Participants had to be diagnosed with a depressive disorder based on diagnostic and statistical manual of mental disorders (DSM) criteria. The primary outcome was depression response, defined as a 50% or greater decrease in Hamilton Rating Scale for Depression (HAM D) score compared with baseline. Studies that used other scales to assess depression were excluded.included trials used a range of different doses and forms of testosterone therapy. Treatment duration ranged from six to 12 weeks. All except one included trial recruited patients with hypogonadism and/or patients who were human immunodeficiency virus (HIV) positive in addition to being depressed. Two trials included patients with normal testosterone levels at baseline.two reviewers independently selected studies for inclusion. Disagreements were resolved by discussion or by consensus of all reviewers. 44

45 Validity assessment The authors did not state that they assessed validity. Data extraction Data on numbers of participants and outcomes in each group were used to derive the risk ratio and odds ratio (OR) and associated 95% confidence intervals (95% CIs) for depression response. Trial authors were contacted for additional data if necessary.the authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Methods of synthesis Trials were pooled by meta analysis using a fixed effect (Mantel Haenszel) model. Statistical heterogeneity was assessed using the χ2 test and I2 statistic. Subgroup analyses were performed for patients with and without hypogonadism, those with and without HIV infection, and for different methods of testosterone administration (injection or gel). Publication bias was assessed using the Begg rank correlation method, Egger weighted regression method, calculation of a 'fail safe N' and examination of funnel plots. Results of the review Seven RCTs (n=355 patients) were included in the meta analysis. Across all trials, testosterone significantly improved depression response compared with placebo (OR 0.40, 95% CI 0.26 to 0.63).In subgroup analyses, testosterone had a positive effect for patients with hypogonadism and for those with and without HIV infection, but not for those with eugonadism. Testosterone gels were significantly superior to placebo (OR 0.18, 95% CI 0.04 to 0.77, two RCTs) but injections were not (OR 0.54, 95% CI 0.28 to 1.03, four RCTs).No evidence of significant publication bias was found. Cost information The review had clear inclusion criteria for participants, intervention, study design and outcomes. Outcomes had to be evaluated using a particular scale, which meant that relevant studies using other scales would have been excluded. The authors searched a number of relevant sources, but limiting the search to English language studies meant that relevant studies could have been missed (language bias). Unpublished studies were not sought, but publication bias was assessed using standard methods. Two reviewers independently selected studies for the review, but it was unclear whether similar methods to reduce errors and bias were used in data extraction.the authors did not assess validity of the included trials, which meant that the reliability of the included trials and the synthesis based on them was uncertain. Trials were combined in a meta analysis; statistical heterogeneity was assessed and differences between trials were investigated using subgroup analyses.the authors' conclusions reflected the evidence presented, but the lack of validity assessment and small numbers of trials and participants (particularly in the subgroup analyses), suggest that the conclusions should be treated with caution. A high proportion of patients in the included trials had comorbid conditions, such as hypogonadism or HIV infection, and the conclusions are unlikely to be applicable to the general population of patients with depression. Authors' conclusions Testosterone may have an antidepressant effect, especially for patients who also have hypogonadism or HIV infection. The route of administration may also affect treatment response. CRD commentary The review had clear inclusion criteria for participants, intervention, study design and outcomes. Outcomes had to be evaluated using a particular scale, which meant that relevant studies using other scales would have been excluded. The authors searched a number of relevant sources, but limiting the search to English language studies meant that relevant studies could have been missed (language bias). Unpublished studies were not sought, but publication bias was assessed using standard methods. Two reviewers independently selected studies for the review, but it was unclear whether similar methods to reduce errors and bias were used in data extraction.the authors did not assess validity of the included trials, which meant that the reliability of the included trials and the synthesis based on them was uncertain. Trials were combined in a meta analysis; statistical heterogeneity was assessed and differences between trials were investigated using subgroup analyses.the authors' conclusions reflected the evidence presented, but the lack of validity assessment and small numbers of trials and participants (particularly in the subgroup analyses), suggest that the conclusions should be treated with caution. A high proportion of patients in the included trials had comorbid conditions, such as hypogonadism or HIV infection, and the conclusions are unlikely to be applicable to the general population of patients with depression. Implications of the review for practice and research Practice: The authors stated that clinicians may consider evaluating testosterone levels in depressed patients; any testosterone replacement therapy should only be initiated after a thorough discussion of the potential benefits and disadvantages, and the monitoring required.research: The authors stated that further trials are required to compare different routes of testosterone administration. Funding Charleston Area Medical Center (CAMC) Health Education and Research Institute; CAMC Foundation, Inc., West Virginia

46 G. USE IN WOMEN (Also: Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. 37 ) Cochrane Systematic Reviews Somboonporn, W. et al. (2005) Testosterone for peri and postmenopausal women 56 Background The question of whether adding testosterone therapy to conventional postmenopausal hormone therapy (HT) is effective or safe is unresolved. Therefore, we aimed to determine the efficacy and safety of testosterone therapy for postmenopausal women using HT. Objectives To determine the benefits and risks of testosterone therapy for postmenopausal women taking HT. Search methods We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched 21 July, November 2008), The Cochrane Library (2008, Issue 3), MEDLINE (1966 to July 2008), EMBASE (1980 to July 2008), Biological Abstracts (1969 to 2008), PsycINFO (1972 to July 2008), CINAHL (1982 to July 2008), and reference lists of articles. We also contacted pharmaceutical companies and researchers in the field. Selection criteria Studies included randomised comparisons of testosterone plus HT versus HT alone in peri or postmenopausal women. Data collection and analysis Two review authors independently assessed the quality of the trials and extracted data. For dichotomous outcomes, a Peto odds ratio (OR) and its 95% confidence interval (CI) were calculated. For continuous outcomes, non-skewed data from valid scales were synthesized using a weighted mean difference or standardized mean difference. If statistical heterogeneity was found, a random-effects model was used and reasons for the heterogeneity were explored and discussed. Main results Thirty-five trials with a total of 4768 participants were included in the review. The median study duration was six months (range 1.5 to 24 months). Most of the trials were of adequate quality with regard to randomisation and concealment of allocation sequence. The major methodological limitations were attrition bias and lack of a washout period in the crossover studies. The pooled estimate suggested that the addition of testosterone to HT regimens improved sexual function scores and number of satisfying sexual episodes for postmenopausal women. Significant adverse effects were decreased highdensity lipoprotein (HDL) cholesterol levels and an increased incidence of hair growth and acne. The discontinuation rate was not significantly greater with the addition of testosterone therapy (OR 0.99, 95% CI 0.83 to 1.19). Authors' conclusions There is good evidence that adding testosterone to HT has a beneficial effect on sexual function in post-menopausal women. However, the combined therapy is associated with a higher incidence of hair growth and acne and a reduction in HDL cholesterol. These adverse events may differ by the different doses and route of testosterone administration. There is insufficient evidence to determine the effect of testosterone in long term use. Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Gonzalez Comadran M, Duran M, Sola I, Fabregues F, Carreras R, Checa MA. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta analysis. Reproductive BioMedicine Online.2012;25(5): A systematic review and meta-analysis was performed to evaluate the effect of transdermal testosterone preceding ovarian stimulation in women with poor ovarian response undergoing IVF. Studies comparing pretreatment with transdermal testosterone versus standard ovarian stimulation among poor responders were included. The main outcome assessed was live birth. Three trials were included (113 women in the testosterone group, 112 in the control group). Testosterone-treated women achieved significantly higher live birth rate (risk ratio, RR, 1.91, 95% CI 1.01 to 3.63), clinical pregnancy rate (RR 2.07, 95% CI 1.13 to 3.78) and required significantly lower doses of FSH (RR , 95% CI to ). However, differences observed in clinical pregnancy per embryo transferred were not statistically significant (RR 1.72, 95% CI 0.91 to 3.26). No differences were observed regarding number and quality of the oocytes retrieved. In conclusion, transdermal testosterone significantly increases live birth and reduces the doses of FSH required. These findings support the theoretical synergistic role of androgens and FSH on folliculogenesis. The present data should be interpreted with caution because of the small number of trials and clinical heterogeneity. The identification of poor responders that could especially benefit from testosterone treatment should be addressed in further studies. The poor response to ovarian stimulation among women undergoing IVF is of great concern in reproductive medicine. Certain modalities have been tested to improve this response to gonadotrophin stimulation, although results from some studies have shown conflicting results. Hence, a systematic 46

47 review and meta-analysis was performed in order to evaluate the effect of transdermal testosterone prior to ovarian stimulation among these women with poor ovarian response. The main outcome assessed was live birth rate. In all, three trials were included, which comprehended 113 women in the testosterone group and 112 in the control group. Women that were pretreated with transdermal testosterone achieved significantly higher live birth rate and clinical pregnancy rate and required significantly lower doses of exogenous FSH as compared with controls. However, when clinical pregnancy rate was adjusted per embryo transferred differences observed were not statistically significant. No differences were observed in the number and quality of the oocytes retrieved. In conclusion, transdermal testosterone prior to ovarian stimulation significantly increases live birth and reduces the doses of FSH required among poor responders. In addition, the identification of poor responders that could especially benefit from testosterone treatment should be addressed in further studies. 58 The benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Firwana B, Altayar O, Prokop L, Montori VM, Murad MH. The benefits and harms of systemic testosterone therapy in postmenopausal women with normal adrenal function: a systematic review and meta analysis. Journal of Clinical Endocrinology and Metabolism.2014;99(10): T use was associated with statistically significant improvement in various domains of sexual function and personal distress in postmenopausal women, although the majority of the trials did not have specific or contemporary diagnostic criteria for androgen deficiency in women. T use was also associated with a reduction in total cholesterol, triglyceride, and high-density lipoprotein and an increase in low-density lipoprotein and in the incidence of acne and hirsutism. No significant effect was noted on anthropometric measures and bone density. Long-term safety data were sparse, and the quality of such evidence was low. 57 Effect of pretreatment with transdermal testosterone on poor ovarian responders undergoing IVF/ICSI: a meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Luo S, Li SW, Li XH, Qin L, Jin S. Effect of pretreatment with transdermal testosterone on poor ovarian responders undergoing IVF/ICSI: a meta analysis. Experimental and Therapeutic Medicine.2014;8(1): In order to identify and describe the effectiveness of transdermal testosterone pretreatment on poor ovarian responders, MEDLINE, EMBASE, the Cochrane library and the Chinese biomedical database were searched for randomized controlled trials (RCTs). Three RCTs, which compared the outcomes of female pretreatment with transdermal testosterone prior to in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with those of control groups, were included in the present review. The three RCTs enrolled a total of 221 randomized subjects. The meta-analysis revealed that females who received transdermal testosterone treatment prior to their IVF/ICSI cycle had a two-fold increase in live birth rate [risk ratio (RR)=2.01, 95% confidence interval (CI) ], clinical pregnancy rate (RR=2.09, 95% CI ) and a significantly more oocyte retrieved [mean difference (MD)=1.36, 95% CI ]. The current findings provide evidence that pretreatment with transdermal testosterone may improve the clinical outcomes for poor ovarian responders undergoing IVF/ICSI. However, the results should be interpreted with caution due to the small sample size of the studies used and the heterogeneities. Further good quality RCTs would be needed to reach further conclusions. 59 The use of androgens or androgen modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Bosdou JK, Venetis CA, Kolibianakis EM, Toulis KA, Goulis DG, Zepiridis L, Tarlatzis BC. The use of androgens or androgen modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta analysis. Human Reproduction Update.2012;18(2): BACKGROUND: The aim of this meta-analysis was to evaluate the role of androgens or androgen-modulating agents on the probability of pregnancy achievement in poor responders undergoing IVF. METHODS: Medline, EMBASE, CENTRAL, Scopus and Web of Science databases were searched for the identification of randomized controlled trials evaluating the administration of testosterone, dehydroepiandrosterone (DHEA), aromatase inhibitors, recombinant luteinizing hormone (rlh) and recombinant human chorionic gonadotrophin (rhcg) before or during ovarian stimulation of poor responders. RESULTS: In two trials involving 163 patients, pretreatment with transdermal testosterone was associated with an increase in clinical pregnancy [risk difference (RD): +15%, 95% confidence interval (CI): +3 to +26%] and live birth rates (RD: +11%, 95% CI: +0.3 to +22%) in poor responders undergoing ovarian stimulation for IVF. No significant differences in clinical pregnancy and live birth rates were observed between patients who received DHEA and those who did not. Similarly, (i) the use of aromatase inhibitors, (ii) addition of rlh and (iii) addition of rhcg in poor responders stimulated with rfsh for IVF were not associated with increased clinical pregnancy rates. In the only eligible study that provided data, live birth rate was increased in patients who received rlh when compared with those who did not (RD: +19%, 95% CI:+1 to +36%). CONCLUSIONS: Based on the limited available evidence, transdermal testosterone pretreatment seems to increase clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF. There is insufficient data to 47

48 support a beneficial role of rlh, hcg, DHEA or letrozole administration in the probability of pregnancy in poor responders undergoing ovarian stimulation for IVF. 60 H. SAFETY ISSUES Other reviews in the Cochrane Library (Reviews that met the criteria for inclusion in DARE) Testosterone therapy and cardiovascular events among men: a systematic review and meta analysis of placebo controlled randomized trials (Provisional abstract) Centre for Reviews and Dissemination Original article: Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta analysis of placebo controlled randomized trials. BMC Medicine.2013;11(1): Background: Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods: A systematic review and meta-analysis was conducted of placebocontrolled randomized trials oftestosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using "("testosterone" or "androgen") and trial and ("random*")" with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results: Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions: The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosteroneincreased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy. 87 Cardiovascular risk associated with testosterone boosting medications: a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M. Cardiovascular risk associated with testosterone boosting medications: a systematic review and meta analysis. Expert Opinion on Drug Safety.2014;13(10): INTRODUCTION: Recent reports have significantly halted the enthusiasm regarding androgen-boosting; suggesting that testosterone supplementation (TS) increases cardiovascular (CV) events. AREAS COVERED: In order to overcome some of the limitations of the current evidence, the authors performed an updated systematic review and meta-analysis of all placebo-controlled randomized clinical trials (RCTs) on the effect of TS on CV-related problems. Out of 2747 retrieved articles, 75 were analyzed, including 3016 and 2448 patients in TS and placebo groups, respectively, and a mean duration of 34 weeks. Our analyses, performed on the largest number of studies collected so far, indicate that TS is not related to any increase in CV risk, even when composite or single adverse events were considered. In RCTs performed in subjects with metabolic derangements a protective effect of TS on CV risk was observed. EXPERT OPINION: The present systematic review and meta-analysis does not support a causal role between TS and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient's metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease. 88 Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Borst SE, Shuster JJ, Zou B, Ye F, Jia H, Wokhlu A, Yarrow JF. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta analysis. BMC Medicine.2014;12: Background Potential cardiovascular (CV) risks of testosterone replacement therapy (TRT) are currently a topic of intense interest. However, no studies have addressed CV risk as a function of the route of administration of TRT. Methods 48

49 Two meta-analyses were conducted, one of CV adverse events (AEs) in 35 randomized controlled trials (RCTs) of TRT lasting 12 weeks or more, and one of 32 studies reporting the effect of TRT on serum testosterone and dihydrotestosterone (DHT). Results CV risks of TRT: Of 2,313 studies identified, 35 were eligible and included 3,703 mostly older men who experienced 218 CVrelated AEs. No significant risk for CV AEs was present when all TRT administration routes were grouped (relative risk (RR) = 1.28, 95% confidence interval (CI): 0.76 to 2.13, P = 0.34). When analyzed separately, oral TRT produced significant CV risk (RR = 2.20, 95% CI: 1.45 to 3.55, P = 0.015), while neither intramuscular (RR = 0.66, 95% CI: 0.28 to 1.56, P = 0.32) nor transdermal (gel or patch) TRT (RR = 1.27, 95% CI: 0.62 to 2.62, P = 0.48) significantly altered CV risk. Serum testosterone/dht following TRT: Of 419 studies identified, 32 were eligible which included 1,152 men receiving TRT. No significant difference in the elevation of serum testosterone was present between intramuscular or transdermal TRT. However, transdermal TRT elevated serum DHT (5.46-fold, 95% CI: 4.51 to 6.60) to a greater magnitude than intramuscular TRT (2.20-fold, 95% CI: 1.74 to 2.77). Conclusions Oral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies. 89 Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized controlled trials. Haddad R, et al. (2007) 90 Objective: To conduct a systematic review and meta-analysis of randomized trials that assessed the effect of testosterone use on cardiovascular events and risk factors in men with different degrees of androgen deficiency. Methods: Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The database search was performed again in March We also reviewed reference lists from included studies and content expert files. Eligible studies were randomized trials that compared any formulation of commercially available testosterone with placebo and that assessed cardiovascular risk factors (lipid fractions, blood pressure, blood glucose), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, angina or claudication, revascularization, stroke), and cardiovascular surrogate end points (ie, laboratory tests indicative of cardiac or vascular disease). Using a standardized data extraction form, we collected data on participants, testosterone administration, and outcome measures. We assessed study quality with attention to allocation concealment, blinding, and loss to follow-up. Results: The 30 trials included 1642 men, 808 of whom were treated with testosterone. Overall, the trials had limited reporting of methodological features that prevent biased results (only 6 trials reported allocation concealment), enrolled few patients, and were of brief duration (only 4 trials followed up patients for > 1 year). The median loss to follow-up across all 30 trials was 9%. Testosterone use in men with low testosterone levels led to inconsequential changes in blood pressure and glycemia and in all lipid fractions (total cholesterol: odds ratio [OR], -0.22; 95% confidence interval [CI], to 0.27; high-density lipoprotein cholesterol: OR, -0.04; 95% CI, to 0.30; low-density lipoprotein cholesterol: OR, 0.06; 95% CI, to 0.42; and triglycerides: OR, -0.27; 95% CI, to 0.08); results were similar in patients with low-normal to normal testosterone levels. The OR between testosterone use and any cardiovascular event pooled across trials that reported these events (n = 6) was 1.82 (95% CI, 0.78 to 4.23). Several trials failed to report data on measured outcomes. For reasons we could not explain statistically, the results were inconsistent across trials. Conclusion: Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects. Patients and clinicians need large randomized trials of men at risk for cardiovascular disease to better inform the safety of long-term testosterone use. 90 Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review (Structured Abstract) 91 Original article: Shabsigh R, Crawford E D, Nehra A, Slawin K M. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. International Journal of Impotence Research.2009;21(1):9 23 Centre for Review and Dissemination (CRD) summary The authors concluded that there was no evidence that testosterone treatment in men with hypogonadism increased the risk of prostate cancer. The authors conclusions appeared to reflect review findings, but the lack of reporting of review methods and study quality and reliance upon generally small short term studies meant that they may not be robust. Authors' objectives To determine if testosterone therapy for hypogonadism in men increases the risk of prostate cancer. Searching MEDLINE and EMBASE were searched from 1970 through 2008 for studies published in English. Search terms were reported. References in journal articles, conference proceedings and books were screened and study investigators contacted for further references. Study selection 49

50 Studies of any design that evaluated the effects of monotherapy with testosterone therapy for signs and symptoms of hypogonadism or an abnormally low or low normal testosterone level of any aetiology in adult men were eligible for inclusion. Studies had to assess prostate cancer confirmed histologically. Studies could be in men with or without a history of prostate cancer. The included studies evaluated different formulations, modes of administration and doses of testosterone (details were reported). The age of patients ranged from 18 to 86 years. Outcomes reported were the incidence of prostate cancer during testosterone therapy, changes in levels of prostate specific antigen and Gleason grade of cancer. The duration of follow up ranged from two months to 10 years. The authors stated neither how papers were selected for the review nor how many reviewers performed the selection. Validity assessment The authors did not state that they assessed validity. Data extraction For each study, numbers of patients with outcomes of interest were presented. The authors stated neither how data were extracted for the review nor how many reviewers performed the data extraction. Methods of synthesis The studies were grouped by study design and the presence or absence of a history of prostate cancer and combined in a narrative synthesis. Results of the review Forty four studies were included.men without a history of prostate cancer were assessed in 11 placebo controlled RCTs (n=893) and 29 non placebo controlled studies (n=1,732, which comprised: one case series n=20; 15 prospective studies n=1,354; five retrospective studies n=349; and eight case reports n=9).men with a history of prostate cancer were assessed in four studies: one prospective (n=5) and three retrospective case series (n=48). Men without a history of prostate cancer: Randomised placebo controlled trials (11 studies, nine with follow up of one year or less): rates of prostate cancer were similar for testosterone and placebo treated groups (1.3% versus 1.5%; overall seven out of 542 testosterone treated men developed prostate cancer). The incidence across studies ranged from 0% in both groups to 9.5% in a testosterone group versus 21% for a placebo group in one study; this study was the only one that routinely performed end of study prostate biopsies. Non placebo controlled studies (21 studies): seven studies reported a total of 12 cases of prostate cancer; the incidence per study ranged from 1.2% to 4.5%. One retrospective study examined 20 cases of prostate cancer in men who received testosterone; 11 cancers were detected in the first two years of testosterone therapy and nine were detected 28 months to eight years after the start of treatment. Men with a history of prostate cancer:the four studies (n=53) found no evidence of a recurrence of prostate cancer over follow up that ranged from 0.5 to 12 years. Following treatment, prostatespecific antigen levels were less than 1ng/mL after 8.5 years in one retrospective study and undetectable for up to 12 years in two other retrospective studies. Cost information The review question was clearly stated. Inclusion criteria were defined for intervention, participants and outcomes; criteria for study design were broad. Only two relevant sources were searched. No attempts were made to minimise language bias and it was unclear whether attempts were made to minimise publication bias. Methods used to select studies and extract data were not described, so it was unknown whether efforts were made to reduce reviewer errors and bias. A narrative synthesis was appropriate. In placebo controlled trials, the overall cancer rate in each group was reported and prostatespecific antigen results were reported as changes from baseline in each treatment group, rather than as differences between treatment groups; this plus a lack of clarity in the number of cancer cases made it difficult to interpret the results. The authors acknowledged some limitations of the evidence, such as short term follow up. In addition, evidence about men with previous prostate cancer was based on only 53 men. Small short term studies provide only limited evidence. The authors conclusions appeared to reflect review findings, but the lack of reporting of review methods and study quality and reliance upon generally small short term studies meant that they may not be robust. Authors' conclusions There was no evidence that testosterone treatment in men with hypogonadism increased the risk of prostate cancer. CRD commentary The review question was clearly stated. Inclusion criteria were defined for intervention, participants and outcomes; criteria for study design were broad. Only two relevant sources were searched. No attempts were made to minimise language bias and it was unclear whether attempts were made to minimise publication bias. Methods used to select studies and extract data were not described, so it was unknown whether efforts were made to reduce reviewer errors and bias. A narrative synthesis was appropriate. In placebo controlled trials, the overall cancer rate in each group was reported and prostatespecific antigen results were reported as changes from baseline in each treatment group, rather than as differences between treatment groups; this plus a lack of clarity in the number of cancer cases made it difficult to interpret the results. The authors acknowledged some limitations of the evidence, such as short term follow up. In addition, evidence about men with previous prostate cancer was based on only 53 men. Small short term studies provide only limited evidence. The authors conclusions appeared to reflect review findings, but the lack of reporting of review methods and study quality and reliance upon generally small short term studies meant that they may not be robust. 50

51 Implications of the review for practice and research Practice: The authors stated that before starting testosterone treatment in men with hypogonadism, a prostate biopsy should be performed in men with higher prostate specific antigen levels. Patients who receive testosterone therapy should be closely and regularly monitored and should be referred if prostate specific antigen levels increased or an abnormality was found on digital rectal examination. Research: The authors did not state any implications for future research. Funding Funding source not stated. Several of the authors had links to pharmaceutical companies. 91 The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta analysis (Provisional abstract) Centre for Reviews and Dissemination Original article: Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta analysis. Prostate Cancer and Prostatic Diseases.2014;17(2): BACKGROUND: Testosterone replacement therapy (TRT) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of TRT causing prostate cancer. The aim of this study was to assess the relationship between TRT and prostate cancer. METHODS: A literature review was performed to identify all published, randomized controlled trials (RCTs) of testosterone treatment for hypogonadism. The search included the MEDLINE, Embase and the Cochrane Controlled Trials Register databases. Fixed-effect model was chosen for homogeneous studies; otherwise, a random-effect model was used. Inconsistency was quantified by using the I2 statistic, which tests the proportion of heterogeneity across studies. RESULTS: Results of 22 RCTs involving a total of 2351 patients were analyzed. Eleven RCTs were short-term (<12 months) and 11 were long-term (12-36 months) comparisons of TRT with a placebo; TRT was administered transdermally, orally or by injection. Respective odds ratio (OR) and 95% confidence interval (CI) values for injection, transdermal administration and oral administration of short-term TRT were as follows: prostate cancer: 0.39 ( ), 1.10 ( ) and no oral; biopsy: 5.28 ( ), 2.11 ( ) and no oral; and prostate nodule: 1.01 ( ), no injection and oral. Respective OR and 95% CI values for injection, transdermal administration and oral administration of long-term TRT were as follows: prostate cancer: 2.09 ( ), 3.06 ( ) and 0.19 ( ); biopsy: 2.09 ( ), 3.65 ( ) and 0.97 ( ); and prostate nodule: 3.13 ( ), 1.00 ( ) and 0.97 ( ). Though for some routes of administration and some end points, the OR associated with testosterone administration were >1 indicating increased risk, none of these reached or even approached statistical significance (all P>0.10), which was consistent with the results of subgroup analyses and sensitivity analysis. Besides, sensitivity analysis indicated that short-term TRT was more likely to increase PSA levels than treatment with placebo (P< ). CONCLUSIONS: This meta-analysis shows that regardless of the administration method, TRT is the short-term safety and does not promote prostate cancer development or progression but long-term data are warranted with justifiable end points. 92 Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis (Structured Abstract) 93 Original article: Fernandez Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM. Adverse effects of testosterone therapy in adult men: a systematic review and meta analysis. Journal of Clinical Endocrinology and Metabolism.2010;95(6): Centre for Review and Dissemination (CRD) summary This review concluded that although haemoglobin and haematocrit increased and high density lipoprotein cholesterol decreased in men who received testosterone therapy, the clinical significance of these findings was unclear and the evidence base was deficient. The review had some limitations, but the authors were appropriately cautious regarding the reliability of the results given the limitations of the original studies. Authors' objectives To determine the adverse events associated with testosterone therapy in adult men. Searching MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from 2003 to August 2008 without language restrictions. Studies published prior to 2003 were obtained from two existing systematic reviews (see Other Publications of Related Interest) augmented with a search to include previously excluded patients with HIV/AIDS. Reference lists and relevant experts were utilised as additional sources of information. Search terms were not reported but the search strategy was available on request from the authors. Study selection Comparative studies (randomised and non randomised) of adult men with low or low normal testosterone levels treated with any testosterone formulation were eligible for inclusion. Studies needed to be for at least three months and include a non testosterone control group. Studies where testosterone was a cointervention with other hormones or drugs were ineligible. Outcomes were specified in three categories: prostate outcomes (four measures and a composite outcome), cardiovascular events and cardiometabolic risk factors (12 outcomes) and indices of red cell mass (three outcomes). There was wide variation in patient setting, age, type and duration of intervention and length of follow up across the studies. Details of the control interventions used were not provided for most studies.two reviewers independently assessed study 51

52 eligibility. Discrepancies were resolved by consensus or arbitration. Validity assessment The study quality assessment evaluated randomisation sequence generation, allocation concealment, baseline imbalance, blinding, attrition, intention to treat and imputation methods.assessment was performed by two independent reviewers. Discrepancies were resolved by consensus or through arbitration. Data extraction Event rates and sample sizes were extracted in duplicate. Risk ratios and associated 95% confidence intervals were calculated. Mean values, sample sizes and standard deviations were extracted to calculate weighted mean differences (WMD) for continuous outcomes. Data were extracted from the longest time point where multiple time points were presented. Study authors were contacted for clarification of methods and for missing data. Methods of synthesis Studies were pooled using meta analysis (DerSimonian and Laird random effects model). Heterogeneity was measured with Ι². Subgroup analyses were performed on patient age, testosterone level, formulation, route of administration and dose, duration of follow up, loss to follow up, concealment of allocation and blinding. Peto odds ratio and different continuity correction factors were analysed to assess sensitivity. Results of the review Fifty one randomised controlled trials (2,701 patients, range 10 to 406) were included. Treatment duration ranged from three months to three years. Studies had high to medium risk of bias. Losses to follow up ranged from zero to 45%. Allocation concealment was not reported in more than half of the included studies. Three trials had no blinding. Results for baseline imbalance and intention to treat were not reported. Five additional studies were relevant but did not report outcomes sufficiently for inclusion in meta analyses. Testosterone treatment was associated with an increase in haemoglobin (WMD 0.80g/dL, 95% CI 0.45 to 1.14), haematocrit (WMD 3.18%, 95% CI 1.35 to 5.01) and erythrocytosis (RR 3.15, 95% CI 1.56 to 6.35) and a decrease in high density lipoprotein cholesterol (WMD 0.49mg/dL, 95% CI 0.85 to 0.13). There was no significant effect on mortality, prostate or cardiovascular outcomes. Heterogeneity was generally high and was explained partly by dose and route of testosterone administration. Cost information This review used appropriate methods to minimise bias when identifying, selecting and synthesising studies. Study quality, inadequate follow up and potential reporting bias all introduced uncertainty. Numerous subgroup analyses were performed to explore the high heterogeneity. Judicious interpretation suggested that dose and route of testosterone administration merited further investigation as reasons for variation in adverse events. Results for some of the study quality criteria were not reported and there was a lack of reporting of control interventions, which made interpretation of the data more difficult. The review had some limitations, but the authors were appropriately cautious about the reliability of the results given the limitations of the original studies. Authors' conclusions Adverse events associated with testosterone therapy were increases in haemoglobin and haematocrit and a small decrease in high density lipoprotein cholesterol. The clinical significance of these findings was unclear. The evidence base was deficient because of low quality studies with inadequate duration. CRD commentary This review used appropriate methods to minimise bias when identifying, selecting and synthesising studies. Study quality, inadequate follow up and potential reporting bias all introduced uncertainty. Numerous subgroup analyses were performed to explore the high heterogeneity. Judicious interpretation suggested that dose and route of testosterone administration merited further investigation as reasons for variation in adverse events. Results for some of the study quality criteria were not reported and there was a lack of reporting of control interventions, which made interpretation of the data more difficult. The review had some limitations, but the authors were appropriately cautious about the reliability of the results given the limitations of the original studies. Implications of the review for practice and research Practice: The results supported guidance that haemoglobin and haematocrit should be monitored in androgen deficient men receiving testosterone therapy. Research: Studies were needed to assess patient important outcomes of longer duration and follow up as the available evidence was insufficient to weigh up the relative benefits and harms of testosterone treatment. Funding The Endocrine Society, USA; Instituto de Salud Carlos III, Spain. 93 Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized placebo controlled trials (Structured abstract) 94 Original article: Calof O M, Singh A B, Lee M L, Kenny A M, Urban R J, Tenover J L, Bhasin S. Adverse events associated with testosterone replacement in middle aged and older men: a meta analysis of randomized, placebo controlled trials.journals of Gerontology Series A Biological Sciences and Medical Sciences.2005;60(11):

53 Centre for review and Dissemination (CRD) summary This review evaluated the risk of adverse events associated with testosterone replacement in older men. The authors concluded that testosterone replacement is associated with a significantly higher risk of prostate events and of a haematocrit of more than 50% relative to placebo. A limited search, unclear review methodology, and the unknown quality of the primary studies limit the reliability of the conclusions. Authors' objectives To determine the risk of adverse events associated with testosterone replacement in older men. Searching The authors searched MEDLINE from 1966 to April 2004 for both English and non English articles; the search terms were stated. In addition, experts searched publications for further relevant papers and letters were sent to authors to clarify information provided in the publications. Study selection: study designs Double blind, randomised controlled trials (RCTs) lasting at least 90 days were eligible for inclusion. The mean duration of the included studies was 10 months (range: 90 days to 3 years). Study selection: specific interventions Studies that investigated the use of testosterone or its esters in replacement doses were included in the review. Studies that used androgens other than testosterone, or that used supraphysiologic doses of testosterone, were excluded. Studies that included medications other than testosterone were also excluded, unless they had a clearly defined testosterone only arm. Testosterone dose and formulation varied across studies: formulations included testosterone patch, injectable testosterone esters, testosterone gel and oral testosterone undecanoate. Study selection: participants Men aged 45 years or older with low or low normal testosterone levels, and without an acute illness, were included in the review. Studies of participants who had unstable disease conditions, or who were infected with the human immunodeficiency virus, were excluded. Where stated, the mean age of the participants in the included studies ranged from 51.9 to 81.0 years. One study that included both younger and older men, but where the majority of the population was over 45 years, was also included in the review. Most studies were in asymptomatic men selected by level of testosterone. Study selection: outcomes The primary review outcome measure was the all cause prostate event rate. Prostate events included prostate biopsies, prostate cancers, increase in International Prostate Symptom Score (IPSS) of greater than 4, prostate specific antigen (PSA) of greater than 4 ng/ml or a PSA increment of at least 1.5 ng/ml during treatment, and acute urinary retention. Cardiovascular outcomes included all cardiovascular events, myocardial infarction, chest pain or ischaemia, coronary procedure or coronary artery bypass graft, and vascular events or cerebrovascular accidents. Other categories of adverse events that were assessed were haematological, lipids, respiratory and/or sleep apnoea, other adverse events and death. Study selection: how were decisions on the relevance of primary studies made? The authors did not state how the papers were selected for the review, or how many reviewers performed the selection. Validity assessment Study quality was assessed according to randomisation, concealment, blinding, and whether the control group was placebotreated or not. The authors did not state how the papers were assessed for quality, or how many reviewers performed the quality assessment. Data extraction Three reviewers extracted the data. The rates of each of the seven categories of adverse event were extracted from each study. Methods of synthesis: how were the studies combined? A pooled event rate per 1,000 patient years was calculated for each outcome for each treatment group, based on an average study duration of 10 months. Odds ratios (ORs) were pooled using a random effects model, weighted for sample size. The Clopper Pearson method was used to calculate 95% confidence intervals (CIs). Methods of synthesis: how were differences between studies investigated? Differences between the studies were discussed in the text and forest plots were presented for some meta analyses. A sensitivity analysis was carried out after excluding 6 studies. Studies were excluded because two did not use a placebocontrol, three included participants receiving glucocorticoids, and one included participants with chronic angina pectoris. Results of the review Nineteen RCTs (n=1,084) were included in the review. There were significantly more prostate events in men receiving testosterone than in men receiving placebo (OR 1.78, 95% CI: 1.07, 2.95). There was no statistically significant difference between treatment groups in terms of rates of prostate cancer, increases in PSA levels, prostate biopsies, or increase in IPSS scores. There was no statistically significant difference between treatment groups in the rate for all cardiovascular events. An increase in haematocrit over 50% was the most common testosterone related adverse event. There was a significantly higher number of participants with haematocrit over 50% in the testosterone group than in the placebo group (OR 3.69, 95% 53

54 CI: 1.82, 7.51). Of the 11 studies that reported plasma lipid values, four reported a significant decrease and seven reported no significant change in high density lipoprotein cholesterol levels, four found a decrease in total cholesterol levels, and two found a decrease in low density lipoprotein cholesterol level in men receiving testosterone. The 4 studies that used a testosterone patch reported a high frequency of skin irritation at the application site (range: 17 to 40%). The frequency of men with a new diagnosis of sleep apnoea during treatment was not statistically significantly different between treatment groups. No deaths were reported in the testosterone treated group, while two were reported in the placebo treated group. Other adverse events were reported. The exclusion of 6 studies from the sensitivity analysis did not change the findings. Authors' conclusions Testosterone replacement in older men is associated with a significantly higher risk of identifying prostate events and a haematocrit of more than 50% relative to placebo. The increase in haematocrit was the most common adverse event associated with testosterone replacement. The data confirm the need to monitor haematocrit and PSA, and for digital examination of the prostate during testosterone replacement in older men. CRD commentary The authors set out a clear question at the beginning of the review, with inclusion criteria clearly defined in terms of the participants, interventions, outcomes and study design. Only one database was searched, which increased the possibility that relevant studies might have been missed. In addition, publication bias was not assessed. However, the search was not restricted to English language papers, which helps to reduce the risk of language bias. It was unclear whether measures were taken to reduce bias in the study selection and quality assessment processes. Although three reviewers extracted data, it was not clear whether the extraction was carried out in duplicate or independently. The quality of the studies was assessed on appropriate criteria; however, the results of the assessment were not reported. Although only double blind studies were eligible for inclusion in the review, it was unclear whether all included studies met this criterion. Statistical heterogeneity was not assessed and, although forest plots were presented for some meta analyses, no comments about statistical heterogeneity were made. In addition, the authors pointed out several sources of clinical heterogeneity and bias, which suggested that statistical pooling of the studies might not have been appropriate. The limited search, incomplete reporting of review methods, and lack of reporting of a quality assessment mean that the reliability of the authors' conclusions is unclear. Implications of the review for practice and research Practice: The authors stated that older men who decide to receive testosterone treatment should be warned about the increased risk of prostate events and increased haematocrit, and should be monitored by periodic evaluation of haematocrit and PSA and by digital rectal examination of the prostate. Research: The authors stated that sources of bias that could contribute to the observed frequency of prostate events in testosterone treated men should be taken into account, and strategies for minimising bias should be incorporated in the design of testosterone trials. The authors stated that studies of longer duration would be needed to determine the effects of testosterone on prostate and cardiovascular risk

55 Appendix 3 FDA data summary Data Summary FDA reviewed five observational studies 4-8 and two meta-analyses of placebo-controlled trials 9,10 to examine the risk of cardiovascular events associated with testosterone replacement therapy (TRT). The five observational studies were retrospective cohort studies that reported conflicting results. Two of these studies found statistically significant cardiovascular harm with TRT (Vigen and Finkle), 4-5 two studies found a statistically significant mortality benefit with TRT (Shores and Muraleedharan), 6-7 and one study was inconclusive (Baillargeon). 8 The Vigen study evaluated male veterans who underwent angiography and had low testosterone concentrations. On average, testosterone-treated men were 64 years old and untreated men were 61 years old. This study found an increased risk with TRT compared to no TRT for the composite cardiovascular outcome of myocardial infarction, stroke, and death (Hazard Ratio [HR]=1.29, 95% Confidence Interval [CI]: ). 4 The Finkle study evaluated TRT users in a large claims database. The men included in this study were on average 54 years old. This study found an increased risk of non-fatal myocardial infarction during the 90 days following an initial prescription for TRT compared to the pre-trt period (Relative Risk [RR]=1.36, 95% CI: ). 5 The Shores study evaluated a population of male veterans older than 40 years of age with low testosterone and found a decreased risk of all-cause mortality with TRT compared to no TRT (HR=0.61, 95% CI: ). 6 The Muraleedharan study evaluated men with type 2 diabetes in the United Kingdom. The main analysis assessed mortality in men with low serum testosterone concentrations compared to men with normal serum testosterone concentrations. Mortality was also assessed in a subgroup analysis of treated and untreated men with low serum testosterone; an increased risk of allcause mortality in men with no TRT compared to those on TRT was found (HR=2.30, 95% CI: ). 7 Finally, the Baillargeon study evaluated men older than 65 years of age enrolled in Medicare and found no overall increase in risk of hospitalization for myocardial infarction when comparing those treated with TRT to those receiving no TRT (HR=0.84, 95% CI: ). 8 The Xu meta-analysis involved 27 published, randomized, placebo-controlled trials representing 2,994 mostly middle-aged and older male participants (1,773 treated with testosterone and 1,261 treated with placebo) who reported 180 cardiovascularrelated adverse events. 9 This study found that testosterone therapy was associated with an increased risk of adverse cardiovascular events (Odds Ratio [OR]=1.5, 95% CI: ); however, methodological issues limit conclusions. These limitations include inconsistent and incomplete reporting of adverse events; substantial clinical heterogeneity in the design and conduct of the component trials and the types of cardiovascular outcomes included in the analyses; potential bias resulting from selection of component trials; and variable quality of the trials, particularly with regard to ascertainment of cardiovascular safety outcomes and balance in cardiovascular risk factors and discontinuation rates across study arms. The Corona meta-analysis involved 26 published, randomized, controlled trials, 20 of which were also included in the Xu metaanalysis. The included studies represented 3,236 men (1,895 men treated with testosterone, 1,341 men treated with placebo) who reported 51 major adverse cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction or stroke, and serious acute coronary syndromes or heart failure. 10 This study did not find a statistically significant increased risk of these cardiovascular events associated with testosterone treatment. Similar to the first meta-analysis, this study had methodological issues that limit conclusions. These issues include incomplete adverse event reporting in the published trials, clinical trial heterogeneity, possible treatment arm imbalances in cardiac risk factors, high or unbalanced discontinuation rates in some component trials, and the potential for bias in trial selection and interpretation of reported adverse events. The five observational studies and the Xu meta-analysis were discussed at a joint meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on September 17, Based on these findings, the advisory committee members were in general agreement that the signal of cardiovascular risk is weak and that only a prospective, well-controlled clinical trial could determine whether testosterone causes cardiovascular harm. The Corona study was recently published and could not be reviewed in time to be presented at the Advisory Committee meeting; however, we have reviewed the study and factored its findings into our overall assessment. For complete reviews, background information, and minutes of the September 17, 2014, Advisory Committee meeting, click here

56 Appendix 4 - Utilization Data ALL PATIENTS 9/1/2012-8/31/2013 9/1/2013-8/31/2014 9/1/2014-4/30/2015 GENERIC BRAND FORM RX PT COST RX PT COST RX PT COST Fluoxymesterone ANDROXY Tablet 0 0 $ $ $ - Methyltestosterone ANDROID Capsule 5 3 $ 1, $ $ Methyltestosterone METHITEST Tablet 1 1 $ $ $ - Methyltestosterone TESTRED Capsule 0 0 $ $ $ - Testosterone ANDRODERM Patch $ 31, $ 16, $ 9, Testosterone ANDROGEL Gel $314, $241, $137, Testosterone AXIRON Solution $ 40, $ 19, $ 5, Testosterone FORTESTA Gel 29 9 $ 9, $ 24, $ 5, Testosterone NATESTO Gel 0 0 $ $ $ - Testosterone TESTIM Gel $ 46, $ 49, $ 21, $ Testosterone TESTOSTERONE Gel 0 0 $ , $ 14, Testosterone VOGELXO Gel 0 0 $ $ $ - Testosterone Cypionate DEPO-TESTOST INJ Oil $ 6, $ 5, $ 1, Testosterone Cypionate TESTOST CYP INJ Oil $ 19, $ 16, $ 15, Testosterone Enanthate DELATESTRYL INJ Oil 0 0 $ $ $ - Testosterone Enanthate TESTOST ENAN INJ Oil $ 2, $ 1, $ Testosterone Propionate FIRST-TESTOS Cream 0 0 $ $ $ - Testosterone Undecanoate AVEED INJ Solution 0 0 $ $ $ * $471, * $377, * $210, *Number of unique patients (it is possible that some patients had fills for two (or more) different drugs and/or brands in the same dosing form category so the count of unique patients may be less than the sum of the patient counts for each generic/brand)

57 References 1. VOGELXO (testosterone) gel - Product label (Label approved 06/04/2014) Aveed FDA label and approval history. provalhistory#apphist. 3. STATE MEDICAID P&T COMMITTEE MEETING. THURSDAY, October 20, Archer M OG. Medicaid Drug Class Review: Androgenic Agents.October American Urological Association (AUA) Position Statement on Testosterone Therapy (2014) Anabolic Steroids. In: Services USDoHaH, edjuly Endo Pharm. DELATESTRYL (Testosterone Enanthate Injection, USP) Drug Label Testosterone. Accessed 30 August Mayoclinic. Male hypogonadism Quallich S. Determining when men need testosterone. The Clinical Adviser July 2009; Accessed 19 September Sjoqvist F, Garle M, Rane A. Use of doping agents, particularly anabolic steroids, in sports and society. Lancet. 2008;371(9627): Parkinson AB, Evans NA. Anabolic androgenic steroids: a survey of 500 users. Med Sci Sports Exerc. Apr 2006;38(4): Coplan B, Spiegel J, Bleaman I, Roch J. Testosterone replacement therapy: take an informed, individualized approach. JAAPA. Jan 2011;24(1): Testosterone Products: Drug Safety Communication - FDA Cautions About Using Testosterone Products for Low Testosterone Due to Aging; Requires Labeling Change to Inform of Possible Increased Risk of Heart Attack And Stroke UPDATE 04/15/ cts/ucm htm. 15. Testosterone Products: Drug Safety Communication - FDA Investigating Risk of Cardiovascular Events [Posted 01/31/2014]. 16. Natesto FDA information. ails. 17. Lexicomp Online Tenover JL. The androgen-deficient aging male: current treatment options. Rev Urol. 2003;5 Suppl 1:S Testosterone replacement therapy for male aging: ASA position statement. J Androl. Mar-Apr 2006;27(2): Vogelxo FDA information. 21. Petak SM, Nankin HR, Spark RF, Swerdloff RS, Rodriguez-Rigau LJ. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and

58 treatment of hypogonadism in adult male patients update. Endocr Pract. Nov-Dec 2002;8(6): UMASS Therapeutics Class Overview - Topical Androgens. Accessed 4 September Testosterone Propionate. &DrugName=TESTOSTERONE%20PROPIONATE&CFID= &CFTOKEN=fed59d53fa4f876a- 8275C2C B-8AE6F38C786F0E AVEED (testosterone undecanoate) injection, for intramuscular use - Product label (label approved 3/3/2015) Natesto (testosterone) nasal gel - Product label (Label approved 5/28/2014) Customer service Valiant Pharmaceuticals - Called 6/3/2015 and spoke to Tammy (Medical Information) who transferred me to Cheryl (Customer service). 27. Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline. 2010; Androgens-in-Men-Standalone.pdf. Accessed 7 August Sexson EK, J. Male Hypogonadism: A Review of the Disease and Its Treatment. U.S. Pharmacist. 2010;35(6):HS7-HS Greene KL, Albertsen PC, Babaian RJ, et al. Prostate specific antigen best practice statement: 2009 update. J Urol. Nov 2009;182(5): Cunningham GR, Toma SM. Clinical review: Why is androgen replacement in males controversial? The Journal of clinical endocrinology and metabolism. 2011;96(1): Beers Criteria Potentially Inappropriate Medications for Geriatrics (Geriatric Lexi-Drugs). Accessed 7 May Qaseem A, Snow V, Denberg TD, et al. Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians. Ann Intern Med. Nov ;151(9): Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male. Mar 2009;12(1): BlueCross BlueShield of Mississippi. 7 August Kryger. Women and Testosterone 6. Accessed 29 August Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. Jun 2010;95(6): Wierman ME, Arlt W, Basson R, et al. Androgen therapy in women: a reappraisal: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. Oct 2014;99(10): Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab. Nov 2004;89(11):

59 39. Salehian B, Jacobson D, Swerdloff RS, Grafe MR, Sinha-Hikim I, McCutchan JA. Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection. Endocr Pract. Jan-Feb 1999;5(1): Bachmann GA, Leiblum SR, Sandler B, et al. Correlates of sexual desire in post-menopausal women. Maturitas. Sep 1985;7(3): Margo K, Winn R. Testosterone treatments: why, when, and how? Am Fam Physician. May ;73(9): Delatestryl (testosterone enanthate) injection Virilization (Adrenogenital Syndrome) Watson Pharma. Androderm (testosterone) transdermal system prescribing information. Corona, CA2001 Jun. 45. Unimed Pharmaceuticals. AndroGel 1% (testosterone) gel prescribing information. Marietta, GA Aug. 46. Auxilium. Testim (testosterone gel) prescribing information. Malvern, PA.2005 Jul. 47. Columbia. Striant (testosterone buccal system) mucoadhesive prescribing information. Revised: 11/ Testosterone, Testosterone Cypionate, Testosterone Enanthate, Testosterone Propionate (AHFS DI (Adult and Pediatric)) Abbott Laboratories. AndroGel (testosterone gel) 1% Drug Label Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. Jan ;350(5): Cai X, Tian Y, Wu T, Cao CX, Li H, Wang KJ. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: a systematic review and metaanalysis of randomized controlled trials. Asian Journal of Andrology.2014;16(1): ELI LILLY AND CO. AXIRON (testosterone) topical solution Drug Label. 53. The Institute for Safe Medication Practices (ISMP) QuarterWatch: 2009 Quarters1-3. February 25, Testosterone and Methyltestosterone. atedsearch. Accessed 7 August Handelsman DJ. Androgen misuse and abuse. Best practice & research. Clinical endocrinology & metabolism. Apr 2011;25(2): Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women. The Cochrane database of systematic reviews. 2005(4):CD Gonzalez-Comadran M, Duran M, Sola I, Fabregues F, Carreras R, Checa MA. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and metaanalysis. Reprod Biomed Online. Nov 2012;25(5): Effect of pretreatment with transdermal testosterone on poor ovarian responders undergoing IVF/ICSI: a meta-analysis. Experimental and Therapeutic Medicine. 59

60 60. Bosdou JK, Venetis CA, Kolibianakis EM, et al. The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and metaanalysis. Hum Reprod Update. Mar-Apr 2012;18(2): Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF. Steroid hormones for contraception in men. The Cochrane database of systematic reviews. 2012;3:CD Elias A, Kumar A. Testosterone for schizophrenia. The Cochrane database of systematic reviews. 2007(3):CD Testosterone and depression: systematic review and meta-analysis (Structured abstract) Centre for Reviews and Dissemination Original article: Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta analysis. Journal of Psychiatric Practice.2009;15(4): Price J, Leng GC. Steroid sex hormones for lower limb atherosclerosis. The Cochrane database of systematic reviews. 2012;10:CD Johns K, Beddall MJ, Corrin RC. Anabolic steroids for the treatment of weight loss in HIV-infected individuals. The Cochrane database of systematic reviews. 2005(4):Cd Lin D, Rieder MJ. Interventions for the treatment of decreased bone mineral density associated with HIV infection. The Cochrane database of systematic reviews. 2007(2):CD Chi CC, Kirtschig G, Baldo M, Brackenbury F, Lewis F, Wojnarowska F. Topical interventions for genital lichen sclerosus. The Cochrane database of systematic reviews. 2011(12):CD Farooqi V, van den Berg ME, Cameron ID, Crotty M. Anabolic steroids for rehabilitation after hip fracture in older people. The Cochrane database of systematic reviews. 2014;10:CD Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. Jun 2006;91(6): Atlantis E, Fahey P, Cochrane B, Wittert G, Smith S. Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. BMJ Open. 2013;3(8). 71. Netto JM, Ferrarez CE, Schindler Leal AA, Tucci S, Jr., Gomes CA, Barroso U, Jr. Hormone therapy in hypospadias surgery: a systematic review. J Pediatr Urol. Dec 2013;9(6 Pt B): Shabsigh R. Testosterone therapy in erectile dysfunction. Aging Male. Dec 2004;7(4): ConnectiCare Prior Authorization Criteria: Testosterone Replacement Therapy. Accessed 4 September Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a metaanalysis study. The journal of sexual medicine. Jun 2014;11(6): Amanatkar HR, Chibnall JT, Seo BW, Manepalli JN, Grossberg GT. Impact of exogenous testosterone on mood: a systematic review and meta-analysis of randomized placebo-controlled trials. Ann Clin Psychiatry. Feb 2014;26(1): Handelsman DJ. Testosterone: use, misuse and abuse. Med J Aust. Oct ;185(8): Testosterone [P&T Notes] (University of Utah Formulary) Eaton DK, L; Kinchen, S; et al. Youth risk behavior surveillance - United States, MMWR Surveill Summ : Lacy CF AL, Goldman MP, Lance LL, eds. Drug Information Handbook. 12th ed ed: Hudson, OH: Lexi-Comp; McEvoy GK SE, Kester L, Litvak K, Miller J, Welsh OH, eds. AHFS 2009 Drug Information: Bethesda, MD: American Society of Health System Pharmacists;

61 81. Aetna Clinical Policy Bulletin: Androgens and Anabolic Steroids. Accessed 4 September Lexi Drugs. Lexi-Comp Inc.; Accessed April 22, Testoserone Accessed April 22, Gruenewald DA, Matsumoto AM. Testosterone supplementation therapy for older men: potential benefits and risks. Journal of the American Geriatrics Society. Jan 2003;51(1): ; discussion Alhathal N, Elshal AM, Carrier S. Synergetic effect of testosterone and phophodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review. Can Urol Assoc J. Aug 2012;6(4): Wan ZH, Wen YB, Ding QF, Xu TY. [Effects of testosterone substitution on metabolic syndromerelated factors in hypogonadal males: a meta-analysis]. Zhonghua Nan Ke Xue. Jun 2010;16(6): Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC medicine. 2013;11: Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosteroneboosting medications: a systematic review and meta-analysis. Expert Opinion on Drug Safety. Oct 2014;13(10): Borst SE, Shuster JJ, Zou B, Ye F, Jia H, Wokhlu A, Yarrow JF. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Medicine.2014;12: Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clinic proceedings. Jan 2007;82(1): Shabsigh R, Crawford ED, Nehra A, Slawin KM. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. International journal of impotence research. Jan-Feb 2009;21(1): Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer and Prostatic Diseases.2014;17(2): Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. Jun 2010;95(6): Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. The journals of gerontology. Series A, Biological sciences and medical sciences. Nov 2005;60(11):