Topical Progesterone Studies Author Subjects Design Preparation Results. Randomized, placebocontrolled. (28 days)

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1 Topical Progesterone Studies Author Subjects Design Preparation Results Leonetti et al, 2003: Fertil Steril,79(1), Wren et al, 2003: Menopause, 10(1), Vashisht et al, 2005, Gynecol Endocrinol, 21(2), ; Vashisht et al, 2005, BJOG, 112(10), PMP women (32 analyzed) 27 PMP women (23 completed) 54 PMP women (41 completed) controlled trial (28 days) cross-over study (12 weeks) 48 week openlabel study Progesterone cream (1.5% or 4% - dosed by weight); Placebo cream; both used BID; all subjects received conjugated estrogens (0.625 mg/d) starting 2 weeks before ProFemme Cream (16, 32, or 64 mg micronized ), used for the latter 2 weeks of each 4 week period (3 cycles). 17Bestradiol patch worn continuously. Progestelle (6% cream containing 40 mg /d) Topical estradiol gel (1 mg/d) throughout study Endometrial biopsies = significant decrease in endometrial proliferation scores in both treatment groups compared to group. Baseline biopsies taken 2 weeks after estrogen treatment. Serum levels rose to ng/ml but none of the 21 endometrial biopsies obtained late in cycle indicated secretory endometrium Endometrial biopsy indicated endometrial thick-ness increased significantly (3.3->5.5mm) by 48 wks. 2/39 biopsies indicated endometrial hyperplasia; 8/39 = endometrial proliferation

2 Herman et al, 2005, J Clin Pharmacol, 45, Lewis et al, 2002, Maturitas, 41, 1-6 Carey et al, 2000, BJOG, 107(6), O Leary et al, 2000, Clin Endocrin-ology, 53, PMP women controlled, cross-over trial (24 d) 22 PMP women Randomized double-blind, controlled trial (8 weeks) 24 PMP women (19 completed) 12 women: 6 pre-menopausal, 6 postmenopausal Open-label study (42 days) Open-label study (single dose) Pro-Gest Cream (40 mg BID); Prometrium 200 mg po q D, each for 12 days Compounded cream (20 mg/g) 1-2 g dose vs Compounded cream (40 mg/g) 1-2 g dose vs Placebo (cream applied BID x 3 weeks with a 1 week wash-out) Progestelle cream (containing 40 mg q D or 20 mg BID) ProFemme cream (containing 64 mg ) In a whole blood assay, levels increase in both groups; no significant differences between groups found. Plasma levels increased slightly but significantly in both TX groups vs (range nmol/l in 20 mg grp & nmol/L in 40 mg grp). Salivary levels were high and did not correlate to serum levels. Serum levels increased to nmol/l (with wide variation). No difference between single and divided dose. No change in baseline serum level in either group at 3 hrs. after treatment. Salivary levels rose significantly in both groups within 1 hour.

3 Burry et al, 1999, Am J Obstet Gynecol, 180 (6, Pt 1), Cooper et al, 1998, Lancet, 351(9111), PMP women Open-label study (4 weeks) 20 surgically menopausal women controlled crossover study (33 days) Pro-Gest Cream (containing 30 mg daily) x 2 weeks; then 30 mg BID x 2 weeks; Transdermal estradiol patch 0.05 mg worn throughout study 1 tsp. Pro-Gest cream or each applied BID x 10 days with a 4 day wash-out period Each subject then took Uterogestan/oral 100 mg q AM and 200 mg q PM x 5 days Mean serum levels rose to ng/ml Median plasma levels after 10 days were 2.9 nmol/l after Pro-Gest, compared to 9.5 nmol/l with oral DHEA studies Authors Subjects Design Preparation Results Jankow-ski, Gozan-ski, & Schwartz (2006). J Clin Endocrinol Metab, 91(8), older men and 70 postmenopausal women controlled trial lasting one year 50 mg DHEA/day or ALL subjects demonstrated improved hip BMD (both treatment AND control); no change in fat-free mass noted

4 Panjari, Bell, Jane, et al (2009). J Sex Med, 6(9), post-menopausal women with low libido and not taking estrogen control-led trial x 26 weeks 50 mg/day DHEA or No improvement in sexual function was found; women using DHEA were more likely to experience acne and unwanted facial and body hair growth. Labrie, Archer, Bou-chard, et al (2009). Menopause, 16(5), women controlled, double-blind 1% DHEA or vaginally daily Treatment group reported 65% improvement in arousal and/or sensation (P=.006), 39% improvement in arousal and/or lubrication (P=.0014), 75% improvement in orgasm (P=.047), and 57% improvement in dryness with intercourse (P=.0001) Calvo, Luu-The, Morissette, et al (2008). J Steroid Biochem Mol Biol, 112(4-5), post-menopausal women control-led trial 0.3%, 1%, or 2% DHEA cream or applied to the skin tice daily Treatment groups demonstrated decreased expression of genes associated with differentiation of keratinocytes, suggesting value for its use as an anti-aging topical treatment.

5 Panjari, Bell, Jane, Adams, Morrow, & Davis (2009). Maturitas, 63(3), postmenopausal women were studied for 52 weeks to evaluate the long term safety of DHEA. control-led trial 50 mg/day oral DHEA or No effects were found on blood lipid levels, insulin resistance, or endometrium Testosterone studies Authors Subjects Design Preparation Results Davis, Moreau, Kroll et al (2008). New Eng J Med, 359(19), women with hypoactive sexual desire disorder studied over a 52 week period Patch containing 150 ug/d, 300 ug/d, or Ness, Albano, McTiernan, & Cauley (2009). Arch Int Med, 169(1), controlled trial largest efficacy trial to date for testosterone and HSSD. None of the women were taking estrogen. WHI dataset RCT CEE CEE and MPA Testosterone at both doses increased desire and decreased distress; the number of satisfying sexual episodes was greatest in women using the 300 ug patch. Most common adverse event was unwanted hair growth. 4 women in the treatment group were diagnosed with breast cancer vs none in the group (CI, ) No difference in breast cancer risk when testosterone was used with CEE.

6 Tamimi, Hankinson, Chen, Rosner, & Colditz (2006). Arch Int Med, 166(14), ,342 postmenopausal women from the Nurse health Study (18,754 never users of hormones vs 587 users of E+T) Prospective, cohort study over 24 years of follow-up ( ) Estrogen plus testosterone in any form Risk of breast cancer among nurses taking estrogen plus testosterone was 2.5 times statistically significantly greater than nurses not using hormones, and even higher in nurses using estrogen alone. Position Statements Author Statement Source North American Menopause Society American Society for Reproductive Medicine (ASRM) Prescription of custom-compounded HT is not advised due to lack of quality control and regulatory oversight of these products, with concerns regarding product efficacy and safety The use of serum or salivary hormone levels is not recommended to assist in the management of HT as these levels are of no value in either selecting initial medication dosages or monitoring therapy for menopausal symptoms women requesting custom compounded HT should be encouraged to use FDA approved HT products (eg, estradiol and ) that are biochemically identical to the hormones naturally produced by the ovary during reproductive life Evidence is lacking to support superiority claims of CBHT over conventional HT; Customized CBHT pose additional risks Under-dosage and over-dosage are possible Conventional HT is preferred given available data Evidence is inadequate to support the efficacy or safety of individualized HT regimens based on salivary, serum, or urinary testing Shifren, J.L., Gass, M.L.S. (2014). The North American Menopause Society recommendations for clinical care of midlife women. Menopause, 21(10), ACOG Committee on Gynecologic Practice and American Society for Reproductive Medicine Practice Committee. (2012). Compounded bioidentical menopausal

7 American College of Obstetrics and Gynecology (ACOG) Recommendations American College of Clinical Pharmacy Global Consensus Statement on Menopausal Health Endocrine Society Evidence is lacking to support superiority claims of CBHT over conventional HT; Customized CBHT pose additional risks Under-dosage and over-dosage are possible Conventional HT is preferred given available data Evidence is inadequate to support the efficacy or safety of individualized HT regimens based on salivary, serum, or urinary testing No data are currently available to support claims that compounded bioidentical hormone therapy is a safer or more efficacious option compared with manufactured hormone therapy; the ACCP recommends against the consistent use of compounded bioidentical hormones as a safer option compared with manufactured therapy and supports the statements of other key organizations The use of custom compounded bioidentical hormone therapy is not recommended No evidence supports the safety or efficacy of compounded BHT. hormone therapy. Fertility and Sterility, 98(2), American College of Obstetrics and Gynecology. (2012). ACOG Committee Opinion #532, Obstetrics & Gynecology, 120(2), McBane, SE, Borgelt, LM, Barnes, KN, Westberg, SM, Lodise, NM, & Stassinos, M. (2014). Use of compounded bioidentical hormone therapy in menopausal women: An opinion statement of the Women s Health Practice and Research Network of the American College of Clinical Pharmacy. Phamacotherapy, 34(4), devilliers, TJ, Gass, ML, Haynes, CJ, et al (2013). Global consensus statement on menopausal health. Climacteric, 16, Santern, RJ, Allred, DC,

8 American Medical Society American Cancer Society Menopause Website USPSTF: No statement on CBHT; Summary Patients may be receiving erroneous or misleading information about CBHT. FDA regulation and oversight of all menopausal therapy (CBHT and HT) is needed No evidence supports the safety or efficacy of CBHT. Additional concerns exist about the purity, potency, and quality of CBHT No position statement No study has shown that bioidentical hormones are any safer than other forms of these hormones Bioidentical hormones should be assumed to have the same health risks as any other type of hormone therapy Recommends against the use of hormone therapy (E+P for non-hysterectomized; E only for Ardoin, SP, et al. (2010). Postmenopausal hormone therapy: An Endocrine Society scientific statement. J Clin Endocrinol Metab, 95, s1-66. AMA House of Delegates (2009). Resolution 706: FDA oversight of bioidentical hormone preparations. As cited by McBane, et al (2014). Use of compounded bioidentical hormone therapy in menopausal women: An opinion statement of the Women s Health Practice and Research Network of the American College of Clinical Pharmacy. Phamacotherapy, 34(4), org/cancer/cancerc auses/ othercarcinogens/ medicaltreatments/ menopausalhormonereplacementtherapy-andcancer-risk entiveservicestaskf orce.org

9 of recommendations for postmenopausal women using conventional hormone therapy hysterectomized women) for the prevention of chronic conditions /Page/Document/R ecommendationsta tementfinal/ menopausalhormone-therapypreventivemedication