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Menstrual cycle suppression; an endocrine treatment

Leslie Miller, M.D.Associate Professor OBGYN University of Washington

lmiller@u.washington.eduwww.noperiod.com

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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

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

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“Excessive menstruation is an iatrogenic disorder of communities practicing any form of contraception.”

RV Short. Why menstruate? Healthright 1985;4:9-12 .

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Is Menstruation Necessary?

• for successful human pregnancy

• to prepare for implantation• NOT for contraception

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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

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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.

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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.

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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= bleedAnderson etal. Safety and efficacy of an extended regimen oral

contraceptive utilizing low dose ethinyl estradiol. Contraception 2006;73:229-234.

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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.

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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.

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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.

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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 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.

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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 useBirtch etal. Ovarian follicular dynamics during conventional vs

continuous OC use. Contraception 2006;73:235-43.

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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.

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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.

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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.

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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.

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Percent not bleeding

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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.

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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

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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.

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↑Amenorrhea with ↓EE and NETA

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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 daysFoidart etal. The use of an OC containing ethinyl estradiol and

drospirenone in an extended regimen over 126 days. Contraception

2006;73:34-40.

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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.

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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.

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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.

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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.

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Tmax versus AUC

• 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

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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.

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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.

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Return to fertility

• Reversible• Little prospective data• Could be a rebound

effect in FSH? • Ovulate before bleed!

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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.

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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.

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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.

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Could anemia be protective?

• Hemochromatosis, Polycythemia vera ↑ males• ↑ Thrombosis with ↑ viscosity• Atherosclerosis↑ with ↑ ferritin • Could check ferritin and CBC• And 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.

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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

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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…

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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?