Southern Derbyshire Shared Care Pathology Guidelines Primary and Secondary Hypogonadism in Adult Males (Biochemical Investigation of Erectile Dysfunction) Purpose of Guideline The purpose of this document is to provide outline guidelines for the initial investigation of adult males with problems with suspected hypogonadism. It has been produced by the Southern Derbyshire Shared Care Pathology Group in conjunction with the RDH s Chemical Pathology, Endocrinology, Urology Departments. As with any guidelines they are for guidance only, and are not necessarily proscriptive. Background Gonadotrophin releasing hormone (GnRH) is secreted in a pulsatile manner from the hypothalamus. GnRH causes the release of Lutinising Hormone (LH) and Follicular stimulating hormone (FSH) from the anterior pituitary. In the testis, FSH acts on the Sertoli cells causing maturation of the germ cells to increase spermatogenesis. The Sertoli cells produce Inhibin B which feeds back on the pituitary to reduce FSH production. LH stimulates the secretion of testosterone from the Leydig cells of the testis. Testosterone feeds back on the hypothalamus and pituitary decreasing GnRH and LH production. Peak adult testosterone occurs around 9.00 am, whilst the lowest values (up to 60% lower) are found in the evening. 60% of plasma testosterone is bound to Sex Hormone Binding Globulin (SHBG), 38% loosely bound to albumin and other binding proteins whilst the rest is free or unbound. This free testosterone is the active form in the body, i.e. it is the physiologically active form, and will obviously be dependent on the total amount of SHBG present. Factors that decrease SHBG include androgens, obesity, hyperinsulinism, hypothyroidism and Glucocorticoids. Raised SHBG levels can be found in hyperthyroidism. Measurement of free testosterone is technically difficult to achieve and therefore calculations using total testosterone/shbg have been used. At present RDH report the Free Androgen Index (FAI) as an assessment of free testosterone. Reference Ranges for Adult Males Testosterone (aged > 40y) 8.3 27.8 nmol/l Testosterone (aged < 40y) 9.9 27.8 nmol/l LH 1.7 8.6 IU/L FSH 1.5 12.4 IU/L SHBG 14.5 48.4 nmol/l Free Androgen Index 34 106 % 1
Definition of hypogonadism Inadequate functioning of the testes as manifested by deficiencies in gametogenesis or the secretion of gonadal hormones. Initial investigations. The initial investigations should also be assessing common contributing factors which may affect male fertility/libido as well as the assessment of testosterone levels. Since there is a degree of diurnal variation in hormones (including testosterone), samples should be always taken around 9.00am (between 8-11am). First line If >28 nmol/l: Just Measure Serum Testosterone Androgen excess possible. Consider anabolic steroids as cause of erectile dysfunction, gynaecomastia, testicular atrophy. Hyperthyroidism may elevate SHBG. Repeat with request for LH/FSH, SHBG, Thyroid function tests and contact Duty Biochemist. If 12 but 28 nmol/l: Adequate function. further testing is usually required. Guidance states that offering testosterone replacement therapy to men with total testosterone >12 is not indicated. If 7 but <12 nmol/l: If 3 but <7 nmol/l: If <3 nmol/l: Inadequate function possible Inadequate function likely Inadequate function very likely Unless already measured the laboratory will assay SHBG (to calculate the Free Androgen Index) TSH, LH, FSH & prolactin on all samples where the testosterone is <12 nmol/l. All patients with an early morning testosterone of <3 nmol/l and some patients with values between 3 and 7 nmol/l will need referral to a Consultant Endocrinologist for further assessment. Many patients with testosterone concentrations between 7 and 12 nmol/l will not have hypogonadism and do not need to be referred at all. 2
Interpreting borderline-low and low testosterone levels Ensure that the sample was definitely taken in the morning, if not repeat on 9 am sample. Apart from erectile dysfunction and/or loss of libido are there any other symptoms of hypogonadism present? o Decrease in beard or body hair growth o Decrease in muscle mass o Gynaecomastia o Osteoporosis Obviously the lower the testosterone the more likely the patient has hypogonadism. If the patients does have hypogonadism, is this primary or secondary (pituitarydependent)? Does the patient have any of the following? o Hypotension o Weight Loss o Hypoglycaemia o Secondary hypothyroidism The following flow chart summarises the interpretation of low and borderline low testosterone results. The Chemical Pathology department will advise on the correct action to be taken with the results. In cases where secondary hypogonadism is possible, Free T4 and cortisol will also be measured. Further Pathology Testing When assessing patients with potential hypogonadism you may wish to undertake some extra testing when assessing these patients. Quite frequently these tests have already been undertaken, but if not they can help in deciding on patient care and treatment. Glucose/HbA1c LFT s U & E s Full Blood Count PSA 3
When Testosterone < 12 nmol/l on 9 am sample If 7 but <12 nmol/l: Inadequate function possible If 3 but <7 nmol/l: Inadequate function likely If <3 nmol/l: Inadequate function very likely LH > 8.6 IU/L LH = 1.7 8.6 IU/L LH < 1.7 IU/L Primary Hypogonadism Possible Primary Hypogonadism Unlikely Secondary Hypogonadism Likely ( IF FSH also < 1.5 IU/L) Is FAI < 34%? Is FAI < 34%? Is FAI < 34%? Patient May Still Be Hypogonadal Contact Duty Biochemist Hypogonadism Unlikely Repeat tests in 3-6 months Consider Treatment Options Any other Symptoms of Pituitary Impairment? Consider Consultant Referral Consider Consultant Referral Please te Consultant referral is usually required to establish the cause of any hypogonadism All patients with testosterone < 3 nmol/l should be referred for further assessment All patients with unexplained extra symptoms of hypogonadism and/or pituitary impairment should be referred Obviously the lower the FAI & Testosterone the more likely there will be significant pathology 4
When to refer? Testosterone < 7 nmol/l, FAI < 34% & unequivocally abnormal LH/FSH. It is recommended that all patients with results which strongly suggest secondary or primary hypogonadism should be referred to a specialist to elucidate the cause, assess the potential associated pituitary or testicular pathology and establish the appropriate replacement therapy. Long-term follow up and monitoring of treatment can be done in Primary Care. In borderline cases it is recommended that the tests are repeated. Patients with total testosterone <7 nmol/l and/or free androgen index <34 on two consecutive occasions require investigation of the cause of their hypogonadism and are likely to benefit from testosterone replacement therapy. Testosterone 7-12 nmol/l, FAI, LH and FSH variable. Most patients with total a testosterone between 7 and 12 nmol/l will not be hypogonadal, and will not need further investigation and treatment, however some may require further assessment. It is important to confirm symptomatic benefit with adequate testosterone replacement in these individuals. If no benefit is demonstrated cessation of treatment should be considered. Testosterone > 12 nmol/l Patients with two consecutive total testosterone >12 nmol/l and/or free androgen index >34 do not warrant treatment. Retesting after 6-12 months may be considered in some cases. What to do with a diabetes, renal disease or other comorbidites patient with a low testosterone? There are a large number of co-morbid conditions which can be associated with low serum testosterone. There is some evidence that testosterone can have beneficial effects in some of these conditions such as diabetes, heart failure and vascular disease. The relevance of this to clinical practice remains controversial. The primary indication for testosterone replacement remains symptoms of hypogonadism and treatment should be planned and monitored on that basis. Co-morbid patients with low testosterone should be considered for testosterone replacement and symptoms monitored in order to demonstrate benefit. 5
Treatment What about safety monitoring before testosterone replacement therapy? All patients must have polycythaemia excluded before treatment. All men over 50 should have a PSA and prostate examination before commencing therapy. Consider what the physical effects of testosterone replacement will be on the patient such as increased aggression and sexual behaviour Monitoring patients on testosterone Aim to normalise testosterone to 15 nmol/ L or above and within the normal range if treated with testosterone gel. Patients treated with long acting testosterone intramuscular injections (Nebido) should have trough testosterone levels in the lower normal range.(greater than 10-12 depending on symptoms. Check PSA/ FBC/Testosterone at 3, 6, 9 and 12 months after commencing testosterone. Annually thereafter. A raised or significantly increasing PSA should warrant discussion with consultant urologist. A final point Low testosterone in men is not uncommon. It is important to check symptomatic males on two separate occasions before considering further investigations or treatment. If the cause is not apparent consider endocrine/urological referral for complete imaging and pathology investigations. Contacts Duty Biochemist 01332 789383 (8.0 am to 7.0 pm) On Call Consultant Biochemist Via RDH switchboard, 01332 340131 ( 24/7) Endocrinology Advice 01332 783284 Urology Advice 01332 789178 Patient Information website http://www.patient.co.uk/medicine/testosterone.htm References 1. Diver MJ. Ann Clin Biochem 2006; 43: 3 12 2. Vermeulen A et al. J Clin Endo Metab 2007;84(10): 3666-3672 3. Ly LP et al. Eur J Endo 2005;152: 471-478 4. Morris PD et al. Eur J Endo 2004;151: 241-249 5. Sacks SS Clin Biochem Rev 2005; 26: 43-45 6. Bandolier. http://jr2.ox.ac.uk/bandolier/booth/sexhkth/testo.html 7. AACE Hypogonadism guidelines, Endocrine practice. 2002; 8(6): 439-454 8. Erectile Dysfunction Alliance. Erectile dysfunction. 1999. http://www.bashh.org/committees/sig/dys_sig/edguidelines.pdf 9. Islam N et al The hormonal assessment of the infertile male. 1998; 82: 69-75 10. Ho C et al. Ann Clin Biochem 2006; 43: 389 397 11. Nieschlag et al. ISA,ISSAM and EAU recommendations Int J Andrology, 28:125 127 (2005) 12. Vermeulen A. Envirn. Health Perspectives Suppl.1993, 101 (S2), 91-100. 13. Website http://pubs.niaaa.nih.gov/publications/arh25-4/282-287.htm accessed 09/08/2011 6