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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

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
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
“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
Is Menstruation Necessary?
  • for successful human pregnancy
  • to prepare for implantation
  • NOT for contraception
hormones control bleeding
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
an extended cycle is still a cycle
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.
why every season
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.

trying not to cycle
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.

cycles bleeding
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.
cycles ovarian follicular activity
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.

reducing the pill free interval
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.
beware of pms advertising
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.

continuous oc suppresses ovary
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.

continuous hrt
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.
continuous oc for endometriosis
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.

eliminate the pill free interval
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.

continuous ocp rct
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.

to get amenorrhea takes time
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.

what is the best daily recipe
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
progestin type may matter
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.

desogestrel more bleeding
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.

cardiovascular risk increased with third generation progestins
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
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
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.

12 weeks 84 days of patch use
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.

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

Tmax versus AUC
comparison of 4 ring schedules
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.

what about pregnancy
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.
return to fertility
Return to fertility
  • 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
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.

bone density
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.

chemoprevention of cancer
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.

could anemia be protective
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.

counseling women
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
irregular bleeding expect it
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…
change the paradigm
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?