Cyclic progesterone and spironolactone treatment for androgenic polycystic ovary syndrome

"Phase II 6-month Cyclic Progesterone/Spironolactone pilot Therapy Trial in Polycystic Ovary Syndrome : pre-post, single-arm feasibility study"

Prior JC et al., 2021·Open Collections

Androgenic Polycystic Ovary Syndrome (PCOS) creates physical/emotional burdens in 4-20% of premenopausal women living with PCOS (WLWP) few menstruations per year, subfertility, hirsutism/acne and low quality of life by validated PCOS Questionnaire (PCOSQ). Combined hormonal contraceptives (CHC), the current standard-of-care, improve PCOSQ only 16%; with stopping CHC, benefits disappear within 6-months. We hypothesize too-fast brain/luteinizing hormone (LH) pulses cause PCOS. Progesterone (P4) slows LH when testosterone (FreeT) is normal. Combining two approved medications, Cyclic P4 with anti-androgen, Spironolactone (Sp), will likely provide effective, durable benefits. WLWP lit-review suggested significant P4 7-14-day benefits. A 6-month prospective feasibility study of CyclicP4/Sp is necessary. Perform a pilot study in 40 WLWP on Cyclic P4 (300 mg/bedtime, 14 days/month) plus Spironolactone (Sp, 200 mg/d). Assess longitudinal within-WLWP 6-month 1) PCOSQ; 2) FreeT, HbA1c, and LH; plus 3) WLWP's acceptance of CyclicP4/Sp. Single-centre, prospective, longitudinal single cohort study. Recruit \~7-8 WLWP/month over 4-6 months; 85% retention. Eligible WLWP have physician-diagnosed PCOS, are 1-month off CHC/metformin, ages 19-35 (avoiding adolescence/perimenopause), HbA1c <6.4% (no diabetes) and commit to non-hormonal contraception, if needed. Recruitment uses online, internet, strategic ads and tear-tab posters. Measures at 0 and 6 as above plus K+ (safety assessment). Menstrual Cycle Diary monitoring (flow, adherence), 2 visits, monthly telephone/emails for support and assessment of any adverse effects. changes by paired T-test. A feasibility 6-month study of CyclicP4/Sp will facilitate a CIHR-funded RCT of CHC versus this innovative and likely beneficial treatment for WLWP.

MON-LB9 Cyclic Progesterone Therapy in Androgenic Polycystic Ovary Syndrome (PCOS) - Person-Related 6-Month Experience Changes

Shirin S et al., 2020·J Endocr Soc

Endometrial cancer1 and oligomenorrhea2 are common risks for women living with androgenic PCOS (WLWP); cyclic progesterone therapy could prevent both. Cyclic oral micronized progesterone therapy (Cyclic OMP; 300 mg at hs/14 days/cycle) also corrects the neuroendocrine origins of PCOS3. Although vaginal progesterone is used in PCOS ovulation induction 4, and short Cyclic OMP decreases LH and/or Testosterone 5,6, no WLWP person-level prospective data with Cyclic OMP therapy are published. A WLWP, aged 31, BMI 20.1, with heavy flow and slightly irregular \~35-day cycles, was unable to tolerate birth control pills. She was prescribed Cyclic OMP (300 mg/h.s. cycle days 14-27)7. She began keeping the Menstrual Cycle Diary© (Diary), a 19-item tool (scored 0-4), during her 1st Cyclic OMP cycle and took no other therapy. This pilot study was designed to understand Cyclic OMP-related 1) by documenting experience changes on the 1st to the 6th complete Diary; and 2) by assessing follicular phase changes in baseline data (no Rx) vs. cycles 3 and 6. We entered data from six consecutive Diaries into an SPSS (Version 24) database. Analysis #1 used Wilcoxon Signed Ranks Tests (for within-person ordinal data) and #2 repeated measures ANOVA. What Cyclic OMP-related experience changes occurred for a WLWP? On Cyclic OMP, she spontaneously reported improvements in aching joints, sleep and GI problems. We assessed selected, potentially E2-related flow, fluid retention, breast tenderness, stretchy cervical mucus and anxiety. Cyclic OMP was associated with shorter cycle lengths of 28.17+/-0.8 days. Fluid retention (P=0.000), mucus (P=0.048), and breast tenderness (P=0.000) all decreased, but anxiety and flow were unchanged. Follicular phase only fluid retention significantly decreased (F (1.2, 14.7) = 6.7, P =0.017). Although open-label, these prospective analyses suggest that Cyclic OMP, alone, is related to short-term benefits in androgenic PCOS. Prospective studies and controlled comparative trials of this innovative “luteal phase replacement” PCOS therapy are needed. 1Barry J Hum Reprod Update 2014 20:748. 2Azziz R Nat Rev Dis Primers 2016;2:16057. 3Blank S Hum Reprod Update 2006;12:351. 4Montville C Fertil Steril 2010;94:678. 5Livadas S Fertil Steril 2010;94:242. 6Bagis T J Clin Endocr Met 2002;87:4536. 7Prior J //hellocluecom/articles/cycle-a-z/the-case-for-a-new-pcos-therapy 2018

MON-LB010 Cyclic Progesterone Therapy for Androgenic Polycystic Ovary Syndrome (PCOS) - A Systematic Review of the Literature

Shirin S et al., 2020·J Endocr Soc

Women living with androgenic PCOS (WLWP) experience unpredictable oligomenorrhea1 and are at increased risk for endometrial cancer2. Oral micronized progesterone (OMP) given cyclically (14 days/cycle or 4 weeks, Cyclic OMP), in luteal phase doses3 (300 mg at bedtime) as a “luteal phase replacement” therapy would be likely to effectively treat both. In addition, evidence suggests PCOS is causally related to rapid pulsing of GnRH and LH 4; OMP normalizes LH pulsatility if androgen levels are not elevated 4. Previous searches did not find progesterone therapy for PCOS 5. Does the peer-reviewed literature provide evidence for prescribing cyclic progesterone therapy in PCOS? Literature search methods used Medline (Ovid) and PubMed for published articles. “polycystic ovary syndrome”, “androgenic PCOS”, and, “micronized progesterone.” We sought publications with eligible women participants having androgenic PCOS, drug exposures (cyclic OMP, vaginal progesterone, and in varying doses and durations) and specific outcomes (biochemical or patient-reported data or both) in all languages. We excluded reviews and practice guidelines but searched bibliographies for missed citations. Results discovered 18 articles in combined Medline (n=6) and PubMed (12) searches. After excluding duplicates, articles on estradiol (E2) alone E2 with OMP therapy, five eligible articles remained. We read all in full detail. Progesterone therapy was beneficial for WLWP as, even in sub-therapeutic doses (<300 mg at bedtime) and in cycles of too short durations (<14 days), it decreased luteinizing hormone (LH) 6,7 and total testosterone 7 levels. Vaginal progesterone (200 mg, b.i.d for 2 to 12 weeks) added to letrozole ovulation induction increased the pregnancy rate from 0 to 21% 8. Although present data suggest Cyclic OMP withdrawal predictively causes flow, we found no evidence it improved women’s cycle-related experiences nor decreased acne and hirsutism. Women-reported data on Cyclic OMP for improving androgenic PCOS cycle regularity, daily experiences and risks for endometrial cancer are needed. 1Azziz R Nat Rev Dis Primers 2016;2:16057. 2Barry J Hum Reprod Update 2014; 20:748. 3Simon J Fertil Steril 1993;60:26. 4Blank S Hum Reprod Update 2006;12:351. 5Teede H Clin Endocrinol (Oxf) 2018;89:251. 6Livadas S Fertil Steril 2010;94:242. 7Bagis T J Clin Endocr Met 2002;87:4536. 8Montville C Fertil Steril. 2010;94:678.

The central role of ovulatory disturbances in the etiology of androgenic polycystic ovary syndrome (PCOS)—Evidence for treatment with cyclic progesterone

Lara Briden et al., 2020·Drug Discovery Today: Disease Models