Menstrual cycle suppression; an endocrine treatment

Leslie Miller, M.D.Associate Professor OBGYN University of Washingtonlmiller@u.washington.eduwww.noperiod.com

Is it more natural to have periods?100 years ago, menarche laterMore gestations and lactation yearshistorically women 50 to 150 cyclesmodern lifestyle up to 450 cycles

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

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

Is Menstruation Necessary?

for successful human pregnancyto prepare for implantationNOT for contraception

Hormones control bleedingIf progestin dose high enough then ovarian suppression, atrophy=amenorrhea Lower progestin dose=irregular bleedingProgestin thins endometriumEstrogen drives proliferation of liningEstrogen added to produce cyclic bleedsCyclic withdrawal= regular bleeding

An extended cycle is still a cycle90 women randomized to 28 vs 49 day Monophasic 30 mcg EE2/300 NG12 study cycles Bleeding less but...Spotting days similar even at end of yearMiller L, Notter K. Menstrual reduction with extended use of combination oral contraceptive pills: randomized controlled trial. Obstet Gynecol 2001;98:771-8.

Why every season?30 mcg EE2/ 150 mcg Lng 84 days active, 7 spacers or 84-day cycle456 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.

Trying not to cycle 30 EE/ 150 LNG 84-days or 91-day cycleNew patent SeasoniqueAdded 10 mcg of EE to the 7 spacer pills1006 enrolled50.3% quit earlyUnscheduled bleed/spot 11 to 4 days/ cycleToo much estrogen, LNG withdrawal= bleedAnderson etal. Safety and efficacy of an extended regimen oral contraceptive utilizing low dose ethinyl estradiol. Contraception 2006;73:229-234.

Cycles= bleedingTo induce bleeding withdrawal of hormonessubsequent reintroduction of these hormones to suppress the ovary and regenerate blood lining. Takes set time to bleed and then stop bleedingLikely 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.

Cycles= ovarian follicular activity 36 women took 1 of 3 OC brands for 3 mos47% developed a dominant follicle 86% of this occurred during pill free weekAssociated with estradiol elevationBut 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.

Reducing the pill free intervalPill free interval of 4 days20 mcg 24-day products, more ovarian suppression, but more irregular bleeding unless weak progestinbut 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.

Beware of PMS advertising450 women with PMDDPlacebo vs OC (24-day 20 EE/3 DSP)3 treatment cycles50% reduction of daily Sx scores in 48% of women on OC vs 36% response with placebo = FDA indicationNo comparison to other OC or continuousYonkers 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.

Continuous OC suppresses ovaryOpen label comparison of 4 OC doses (all 30-35mcg of ethinyl estradiol with use continuous for 3 months vs cyclicFewer follicles > 4 mm with daily useNo follicle 10 mm with daily useBirtch etal. Ovarian follicular dynamics during conventional vs continuous OC use. Contraception 2006;73:235-43.

Continuous HRT Originally cyclic prescribed for HRT tooContinuous HRT biopsy=less proliferative compared to cyclic progestin=saferBy 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.

Continuous OC for endometriosisEnovid used in 1959 to induce pseudo-pregnancy up to 3 yrs, Robert KistnerContinuous 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.

Eliminate the pill free intervalRCT daily vs cyclic vaginal 50mcg OCP 70% amenorrhea by 3 months, 90% by 1 yrNo pregnancies with daily OC use4 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.

Continuous OCP RCT79 randomized to either daily 20 mcg EE2/100 mcg Lng or 28 day cycleFor one year32 continuous and 28 cyclic completedDiscontinuation 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.

Percent not bleeding

To get Amenorrhea, takes timeOverall spotting days no differenceBut days 1-21 spotting until cycle 622% with a bleeding episode >10 days 16% amenorrhea cycles 1-372% 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.

What is the best daily recipe?monophasic formulationlower estrogen dose=less proliferationdaily 20 mcg EE2 < cyclic 30 mcg EE2Lng and NETA, old favorites, safer, genericWhat we really need are pills in bottleCould be like thyroid medication

Progestin type may matter139 women randomizedAll cyclic OC switchers4 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.

Amenorrhea with EE and NETA

Desogestrel=more bleeding177 OC switchers after 2 run-in cycles126 days of 30 EE/3 DSG (80.8% completed)Median day to 1st bleed day=99 (51, 127)10.7% quit for unacceptable bleedingMedian bleed/spot days 17.0 (5.0, 32.0)45.2% bled for 20 daysFoidart etal. The use of an OC containing ethinyl estradiol and drospirenone in an extended regimen over 126 days. Contraception 2006;73:34-40.

Cardiovascular risk increased with third generation progestinsWHO study on inflammatory markersHigher c-reactive protein, fibrinogen, and blood viscosity with DSG or gestodeneDoubles risk and worse for smokers

Doring A, etal. Third generation oral contraceptive use and cardiovascular risk factors. Atherosclerosis 2004;172:281-6.

If a progestin is not androgenic then it can increase estrogen effectsLng vs Desogestrel 30 mcg EE COC Significant differences in SHBG 60% with Lng and 280% with DSGAssociated with prothrombotic changes tooDrospirenonecould 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.

Estrogen increases SHBG...Perhaps not great for the libidochronic SHBG elevation led to low levels of bioavailable testosterone/androgen insufficiency62 women on OC, 39 stopped OC, 23 never OCSHBG 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.

12 weeks (84 days) of patch use155 women randomized to extendedCompared to 80 women to 28-day cycleonly 12% reported amenorrhea over 84-days Half did not bleed until after day 543x more breast tenderness/nausea if extendHeadache (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.

Tmax versus AUCPillsonly a few hours of elevated EEPregnancy is also a time of continuous estrogen exposure= thrombosis

Contraception 2005;72:168-74Contraception 2006;73:223-8

Comparison of 4 ring schedules 429 women randomized, 67% finished year28-day, 49-day, 91-day, 364-dayLonger cycles more unscheduled bleeding20 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.

What about Pregnancy?Many other methods change the periodPregnancy tests cheap and easy to doDaily pill use very unlikely to get pregnantNeeded pill free week and missed pills to ovulateAnd 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.

Return to fertilityReversibleLittle prospective dataCould be a rebound effect in FSH? Ovulate before bleed!

Possible risk of higher EE2 with the loss of hormone free weekNo reversal of hepatic changesDose accumulation42 day cycles increased SHBG/HDLLower EE2 prudent and side-effects?

McGurgan P, ODonovan 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.

Bone densityLittle natural estradiol productionExogenous EE2 importantProven no loss unlike DMPABut 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.

Chemoprevention of cancerOvulation suppression likely importantBut also progestin induced apoptosisIs 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.

Could anemia be protective?Hemochromatosis, Polycythemia vera males Thrombosis with viscosityAtherosclerosis with ferritin Could check ferritin and CBCAnd donate bloodKiechl 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.

Counseling WomenIntroduce the idea but dont over sell itShe must want thisTo expect irregular bleeding and spottingKeep a menstrual diarySee regularly to help problem solveEmphasize the other benefits Ask about her partners concerns

Irregular bleedingexpect itWithdraw first if history of irregular menses?Atrophy after one cycle of progestin likelyStop to have a period counter productive?More estrogen = fuel on the fire?6 months to suppress ovarian hormones? Various things to tryvit C, NSAIDS, BID dosesA progestin switch can work, why? Time?Remember to check HCG, US, even EMB

Change the paradigmAvoid brand namesThink what hormones what doseImagine like other endocrine conditionsMonitor responseadjust dose as needed to treat ovulation and menses We dont need new patentsWhy not just 31 pills in a bottle?