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Menstrual cycle suppression; an endocrine treatment

Menstrual cycle suppression; an endocrine treatment Leslie Miller, M.D. Associate Professor OBGYN University of Washington lmiller@u.washington.edu www.noperiod.com Is it more “natural” to have periods? 100 years ago, menarche later More gestations and lactation years

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Menstrual cycle suppression; an endocrine treatment

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  1. Menstrual cycle suppression; an endocrine treatment Leslie Miller, M.D. Associate Professor OBGYN University of Washington lmiller@u.washington.edu www.noperiod.com

  2. Is it more “natural” to have periods? • 100 years ago, menarche later • More gestations and lactation years • historically women 50 to 150 cycles • modern lifestyle up to 450 cycles

  3. RV Short. The evolution of human reproduction. Proc Royal Soc London 1976; 195:3-24.

  4. “Excessive menstruation is an iatrogenic disorder of communities practicing any form of contraception.” • RV Short. Why menstruate? Healthright 1985;4:9-12 • .

  5. Is Menstruation Necessary? • for successful human pregnancy • to prepare for implantation • NOT for contraception

  6. Hormones control bleeding • If progestin dose high enough then ovarian suppression, atrophy=amenorrhea • Lower progestin dose=irregular bleeding • Progestin thins endometrium • Estrogen drives proliferation of lining • Estrogen added to produce cyclic bleeds • Cyclic withdrawal= regular bleeding

  7. An extended cycle is still a cycle • 90 women randomized to 28 vs 49 day • Monophasic 30 mcg EE2/300 NG • 12 study cycles • Bleeding less but... • Spotting days similar even at end of year • Miller L, Notter K. Menstrual reduction with extended use of combination oral contraceptive pills: randomized controlled trial. Obstet Gynecol 2001;98:771-8.

  8. Why every “season”? • 30 mcg EE2/ 150 mcg Lng • 84 days active, 7 spacers or 84-day cycle • 456 women • 40.6% dropped (35 quit because of bleeding) • 4th pill pack (end of year) still 58.5% BTB/spotting and half reported more than 4 days Anderson FD, Hait H, the Seasonale 301 Study Group. A multicenter, randomized study of an extended cycle oral contraceptive. Contraception 2003;68:89-96.

  9. Trying not to cycle • 30 EE/ 150 LNG 84-days or 91-day cycle • New patent “Seasonique” • Added 10 mcg of EE to the 7 spacer pills • 1006 enrolled…50.3% quit early • Unscheduled bleed/spot 11 to 4 days/ cycle • Too much estrogen, LNG withdrawal= bleed Anderson etal. Safety and efficacy of an extended regimen oral contraceptive utilizing low dose ethinyl estradiol. Contraception 2006;73:229-234.

  10. Cycles= bleeding • To induce bleeding withdrawal of hormones • subsequent reintroduction of these hormones to suppress the ovary and regenerate blood lining. • Takes set time to bleed and then stop bleeding • Likely it requires a higher dose to come back without irregular bleeding after 7 days off. • Likely there will not be a “perfect” withdrawal bleed of 2 days every few months.

  11. Cycles= ovarian follicular activity • 36 women took 1 of 3 OC brands for 3 mos • 47% developed a dominant follicle • 86% of this occurred during pill free week • Associated with estradiol elevation • But no ovulation (compliant use) Baerwald AR etal. Ovarian follicular development is initiated during the pill free interval of OC use. Contraception 2004;70:371-7.

  12. Reducing the pill free interval • Pill free interval of 4 days • 20 mcg 24-day products, more ovarian suppression, but more irregular bleeding unless weak progestin…but why cycle? • Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral contraceptive regimens contraining gestodene (60 mcg) and ethinyl estradiol (15 mcg) on ovarian activity. Fertil steril 1999;72:115-20. Fruzzetti F et al. A 12 month clinical investigation with a 24 day regimen containing 15 mcg EE2 plus 60 mcg gestodene with respect to hemostasis and cycle control. Contraception 2001;63:303-7.Contraception 2006;73:30-33.

  13. Beware of PMS advertising • 450 women with PMDD • Placebo vs OC (24-day 20 EE/3 DSP) • 3 treatment cycles • 50% reduction of daily Sx scores in 48% of women on OC vs 36% response with placebo = FDA indication • No comparison to other OC or continuous Yonkers etal. Efficacy of a new low dose OC with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol 2005;106:492-501. Barbosa etal. Minesse cycle control. Contraception 2006;73:30-33.

  14. Continuous OC suppresses ovary • Open label comparison of 4 OC doses (all 30-35mcg of ethinyl estradiol with use continuous for 3 months vs cyclic • Fewer follicles > 4 mm with daily use • No follicle ≥ 10 mm with daily use Birtch etal. Ovarian follicular dynamics during conventional vs continuous OC use. Contraception 2006;73:235-43.

  15. Continuous HRT • Originally cyclic prescribed for HRT too • Continuous HRT biopsy=less proliferative compared to cyclic progestin=safer • By 6 months 70-80% amenorrhea • Sturdee DW, et al. The endometrial response to sequential and continuous combined oestrogen progestogen replacement therapy. British J Obstet and Gyn 2000;107:1392-1400. Raudaskoski et al. Intrauterine 10 mcg and 20 mcg IUS in postmenopausal women on ERT compared to cyclic oral provera. BJOG 2002;109:136-44.

  16. Continuous OC for endometriosis • Enovid used in 1959 to induce “pseudo-pregnancy” up to 3 yrs, Robert Kistner • Continuous 20 mcg EE2/DSG effective for up to 2 years in endometriosis patients Vercellini P, etal. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fert Steril 2003;80:560-3.

  17. Eliminate the pill free interval • RCT daily vs cyclic vaginal 50mcg OCP • 70% amenorrhea by 3 months, 90% by 1 yr • No pregnancies with daily OC use • 4 pregnancies with cyclic use Coutinho EM et al. Comparative study on intermittent versus continuous use of a contraceptive pill administered by vaginal route. Contraception 1995;51:355-58.

  18. Continuous OCP RCT • 79 randomized to either daily 20 mcg EE2/100 mcg Lng or 28 day cycle • For one year • 32 continuous and 28 cyclic completed • Discontinuation rates similar (p=0.6) Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial. Obstet Gynecol 2003;101:653-61.

  19. Percent not bleeding

  20. To get Amenorrhea, takes time… • Overall spotting days no difference • But days 1-21 spotting  until cycle 6 • 22% with a bleeding episode >10 days • 16% amenorrhea cycles 1-3 • 72% amenorrhea cycles 10-12 Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate withdrawal bleeding: a randomized trial. Obstet Gynecol 2003;101:653-61.

  21. What is the best daily “recipe”? • monophasic formulation • lower estrogen dose=less proliferation • daily 20 mcg EE2 < cyclic 30 mcg EE2 • Lng and NETA, old favorites, safer, generic • What we really need are pills in bottle • Could be like thyroid medication

  22. Progestin type may matter • 139 women randomized • All cyclic OC switchers • 4 doses (20 vs 30 EE/LNG vs NETA) • 6 months; 38% to 72% completed study Edelman etal. Continuous oral contraceptives. Are bleeding patterns dependent on the hormones given? Obstet Gynecol 2006;107:657-65.

  23. ↑Amenorrhea with ↓EE and NETA

  24. Desogestrel=more bleeding • 177 OC switchers after 2 run-in cycles • 126 days of 30 EE/3 DSG (80.8% completed) • Median day to 1st bleed day=99 (51, 127) • 10.7% quit for unacceptable bleeding • Median bleed/spot days 17.0 (5.0, 32.0) • 45.2% bled for ≥ 20 days Foidart etal. The use of an OC containing ethinyl estradiol and drospirenone in an extended regimen over 126 days. Contraception 2006;73:34-40.

  25. Cardiovascular risk increased with “third generation” progestins • WHO study on inflammatory markers • Higher c-reactive protein, fibrinogen, and blood viscosity with DSG or gestodene • Doubles risk and worse for smokers Doring A, etal. Third generation oral contraceptive use and cardiovascular risk factors. Atherosclerosis 2004;172:281-6.

  26. If a progestin is not “androgenic” then it can increase estrogen effects • Lng vs Desogestrel 30 mcg EE COC • Significant differences in SHBG • ↑60% with Lng and ↑280% with DSG • Associated with prothrombotic changes too • Drospirenone…could have risks too Van Rooijen M, Silvera A, Hamsten A, Bremme K. Sex hormone binding globulin. A surrogate marker for the prothrombotic effects of combined oral contraceptives. Am J Obstet Gynecol 2004;190:332-7.

  27. Estrogen increases SHBG...Perhaps not great for the libido • “chronic SHBG elevation led to low levels of bioavailable testosterone/androgen insufficiency” • 62 women on OC, 39 stopped OC, 23 never OC • SHBG levels 4 fold higher with OC • Even 6 months off OC better but still elevated Panzer etal. Impact of OC on SHBG and androgen levels. A retrospective study in women with sexual dysfunction. J Sex Med 2006;3:104-113.

  28. 12 weeks (84 days) of patch use • 155 women randomized to extended • Compared to 80 women to 28-day cycle • only 12% reported amenorrhea over 84-days • Half did not bleed until after day 54 • 3x more breast tenderness/nausea if extend • Headache (18% if extend vs 3%) but extension does decrease headaches in patch free week Stewart etal. Extended use of transdermal norelgestromin/ethinyl estradiol. Obstet Gynecol 2005;105:1389-96. Fertil Steril 2005;83:1875-77.

  29. Pills…only a few hours of elevated EE Pregnancy is also a time of continuous estrogen exposure= ↑ thrombosis Contraception 2005;72:168-74 Contraception 2006;73:223-8 Tmax versus AUC

  30. Comparison of 4 ring schedules • 429 women randomized, 67% finished year • 28-day, 49-day, 91-day, 364-day • Longer cycles more unscheduled bleeding • 20 women quit 364-day vs only 5 in 49-day arm for unacceptable bleeding Miller etal. Extended regimens of the contraceptive vaginal ring. Obstet Gynecol 2005;106:473-82.

  31. What about Pregnancy? • Many other methods change the period • Pregnancy tests cheap and easy to do • Daily pill use very unlikely to get pregnant • Needed pill free week and missed pills to ovulate • And the modern OCP is not a teratogen except spironolactone is and perhaps drospirenone is • Letterie G, Chow G. Effect of missed pills on oral contraceptive pill effectiveness. Obstet Gynecol 1992;79:979-82.Bracken MB. Oral contraception and congenital malformations in offspring: a review and metaanalysis of the prospective studies. Obstet Gynecol 1990;76:552-7.

  32. Return to fertility • Reversible • Little prospective data • Could be a rebound effect in FSH? • Ovulate before bleed!

  33. Possible risk of higher EE2 with the loss of hormone free week • No reversal of hepatic changes • Dose accumulation • 42 day cycles increased SHBG/HDL • Lower EE2 prudent and ↓ side-effects? McGurgan P, O’Donovan P, Duffy S, rogerson L. Should menstruation be optional for women? Lancet 2000;355:1730. Oral contraceptive and hemostasis study group. The effects of seven monophasic OC regimens on hemostatic variables. Contraception 2003;67:173-185. Cachrimanidou AC et al. Hemostasis profile and lipid metabolism with long interval use of desogestrel containing oral contraceptive. Contraception 1994;50:153-65.

  34. Bone density • Little natural estradiol production • Exogenous EE2 important • Proven no loss unlike DMPA • But will peak bone density be reached? Cromer BA etal. A prospective comparison of bone density in adolescent girls receiving DMPA, norplant, or OC. J Pediatr 1996;129:671-6. Berenson AB etal. A prospective, controlled study of the effects of hormonal contraception on bone mineral density. Obstet Gynecol 2001;98:576-82. Polatti F etal. Bone Mass and longterm monophasic OC treatment in young women. Contraception 1995;51:221-4.

  35. Chemoprevention of cancer • Ovulation suppression likely important • But also progestin induced apoptosis • Is it dose or regimen? • Could continuous OC also prevent breast cancer? Schildkraut JM etal. Impact of progestin and estrogen potency in oral contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002;94:32-8. Pike MC, Spicer DV. Hormonal contraception and chemoprevention of female cancers. Endocrine Related Cancer 2000;7:73-83. Ursin G etal. Mammographic density changes during the menstrual cycle. Cancer epidemiology biomarkers and prevention 2001;10:141-2.

  36. Could anemia be protective? • Hemochromatosis, Polycythemia vera ↑ males • ↑ Thrombosis  with ↑ viscosity • Atherosclerosis↑ with ↑ ferritin • Could check ferritin and CBC • And donate blood Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F, the Bruneck Study Group. Body iron stores and the risk of carotid atherosclerosis. Circulation 1997;96:3300-7. Sullivan JL. The iron paradigm of ischemic heart disease. American Heart Journal 1989;117:1177-1188.

  37. Counseling Women • Introduce the idea but don’t over sell it • She must want this • To expect irregular bleeding and spotting • Keep a menstrual diary • See regularly to help problem solve • Emphasize the other benefits • Ask about her partner’s concerns

  38. Irregular bleeding…expect it • Withdraw first if history of irregular menses? • Atrophy after one cycle of progestin likely • Stop “to have a period” counter productive? • More estrogen = fuel on the fire? • 6 months to suppress ovarian hormones? • Various things to try…vit C, NSAIDS, BID doses • A progestin switch can work, why? Time? • Remember to check HCG, US, even EMB…

  39. Change the paradigm • Avoid brand names • Think “what hormones” “what dose” • Imagine like other endocrine conditions • Monitor response…adjust dose as needed to treat “ovulation” and “menses” • We don’t need new patents… • Why not just 31 pills in a bottle?

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