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Menstrual cycle suppression; an endocrine treatment Leslie Miller, M.D. Associate Professor OBGYN University of Washington [email protected] 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 l.jpg

Menstrual cycle suppression; an endocrine treatment

Leslie Miller, M.D.

Associate Professor OBGYN University of Washington

[email protected]

www.noperiod.com


Is it more natural to have periods l.jpg
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



Slide4 l.jpg

“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 l.jpg
Is Menstruation Necessary? communities practicing any form of contraception.”

  • for successful human pregnancy

  • to prepare for implantation

  • NOT for contraception


Hormones control bleeding l.jpg
Hormones control bleeding communities practicing any form of contraception.”

  • 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


An extended cycle is still a cycle l.jpg
An extended cycle is still a cycle communities practicing any form of contraception.”

  • 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.


Why every season l.jpg
Why every “season”? communities practicing any form of contraception.”

  • 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.


Trying not to cycle l.jpg
Trying not to cycle communities practicing any form of contraception.”

  • 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.


Cycles bleeding l.jpg
Cycles= bleeding communities practicing any form of contraception.”

  • 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.


Cycles ovarian follicular activity l.jpg
Cycles= ovarian follicular activity communities practicing any form of contraception.”

  • 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.


Reducing the pill free interval l.jpg
Reducing the pill free interval communities practicing any form of contraception.”

  • 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.


Beware of pms advertising l.jpg
Beware of PMS advertising communities practicing any form of contraception.”

  • 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.


Continuous oc suppresses ovary l.jpg
Continuous OC suppresses ovary communities practicing any form of contraception.”

  • 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.


Continuous hrt l.jpg
Continuous HRT communities practicing any form of contraception.”

  • 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.


Continuous oc for endometriosis l.jpg
Continuous OC for endometriosis communities practicing any form of contraception.”

  • 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.


Eliminate the pill free interval l.jpg
Eliminate the pill free interval communities practicing any form of contraception.”

  • 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.


Continuous ocp rct l.jpg
Continuous OCP RCT communities practicing any form of contraception.”

  • 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.


Percent not bleeding l.jpg
Percent not bleeding communities practicing any form of contraception.”


To get amenorrhea takes time l.jpg
To get Amenorrhea, takes time… communities practicing any form of contraception.”

  • 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.


What is the best daily recipe l.jpg
What is the best daily “recipe”? communities practicing any form of contraception.”

  • 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


Progestin type may matter l.jpg
Progestin type may matter communities practicing any form of contraception.”

  • 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.


Amenorrhea with ee and neta l.jpg
communities practicing any form of contraception.”Amenorrhea with ↓EE and NETA


Desogestrel more bleeding l.jpg
Desogestrel=more bleeding communities practicing any form of contraception.”

  • 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.


Cardiovascular risk increased with third generation progestins l.jpg
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.


If a progestin is not androgenic then it can increase estrogen effects l.jpg
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.


Estrogen increases shbg perhaps not great for the libido l.jpg
Estrogen increases SHBG... estrogen effectsPerhaps 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.


12 weeks 84 days of patch use l.jpg
12 weeks (84 days) of patch use estrogen effects

  • 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.


Tmax versus auc l.jpg

Pills…only a few hours of elevated EE estrogen effects

Pregnancy is also a time of continuous estrogen exposure= ↑ thrombosis

Contraception 2005;72:168-74

Contraception 2006;73:223-8

Tmax versus AUC


Comparison of 4 ring schedules l.jpg
Comparison of 4 ring schedules estrogen effects

  • 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.


What about pregnancy l.jpg
What about Pregnancy? estrogen effects

  • 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.


Return to fertility l.jpg
Return to fertility estrogen effects

  • Reversible

  • Little prospective data

  • Could be a rebound effect in FSH?

  • Ovulate before bleed!


Possible risk of higher ee2 with the loss of hormone free week l.jpg
Possible risk of higher EE2 estrogen effectswith 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.


Bone density l.jpg
Bone density estrogen effects

  • 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.


Chemoprevention of cancer l.jpg
Chemoprevention of cancer estrogen effects

  • 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.


Could anemia be protective l.jpg
Could anemia be protective? estrogen effects

  • 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.


Counseling women l.jpg
Counseling Women estrogen effects

  • 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


Irregular bleeding expect it l.jpg
Irregular bleeding…expect it estrogen effects

  • 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…


Change the paradigm l.jpg
Change the paradigm estrogen effects

  • 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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