Menstrual cycle suppression; an endocrine treatment

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Menstrual cycle suppression an endocrine
treatment

• Leslie Miller, M.D.
• Associate Professor OBGYN University of
  Washington
• lmiller_at_u.washington.edu
• www.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 1953-24.

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• Excessive menstruation is an iatrogenic
  disorder of communities practicing any form of
  contraception.
• RV Short. Why menstruate? Healthright 198549-12
• .

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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, atrophyamenorrhea
• Lower progestin doseirregular 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 200198771-8.

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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
  20036889-96.

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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 enrolled50.3 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 200673229-234.

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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 200470371-7.

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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
  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 199972115-20. 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 200163303-7.Contraception
  20067330-33.

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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 continuous
• Yonkers etal. Efficacy of a new low dose OC with
  drospirenone in premenstrual dysphoric disorder.
  Obstet Gynecol 2005106492-501. Barbosa etal.
  Minesse cycle control. Contraception
  20067330-33.

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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 gt 4 mm with daily use
• No follicle 10 mm with daily use
• Birtch etal. Ovarian follicular dynamics during
  conventional vs continuous OC use. Contraception
  200673235-43.

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Continuous HRT

• Originally cyclic prescribed for HRT too
• Continuous HRT biopsyless proliferative compared
  to cyclic progestinsafer
• 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 20001071392-1400. Raudaskoski et al.
  Intrauterine 10 mcg and 20 mcg IUS in
  postmenopausal women on ERT compared to cyclic
  oral provera. BJOG 2002109136-44.

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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 200380560-3.

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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 199551355-58.

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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 (p0.6)
• Miller L, Hughes JP. Continuous combination oral
  contraceptive pills to eliminate withdrawal
  bleeding a randomized trial. Obstet Gynecol
  2003101653-61.

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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 gt10 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
  2003101653-61.

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What is the best daily recipe?

• monophasic formulation
• lower estrogen doseless proliferation
• daily 20 mcg EE2 lt 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 2006107657-65.

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?Amenorrhea with ?EE and NETA
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Desogestrelmore bleeding

• 177 OC switchers after 2 run-in cycles
• 126 days of 30 EE/3 DSG (80.8 completed)
• Median day to 1st bleed day99 (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 20067334-40.

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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 2004172281-6.

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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
• Drospirenonecould 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
  2004190332-7.

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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 20063104-113.

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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
  20051051389-96. Fertil Steril 2005831875-77.

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Tmax versus AUC

• Pillsonly a few hours of elevated EE
• Pregnancy is also a time of continuous estrogen
  exposure ? thrombosis
• Contraception 200572168-74
• Contraception 200673223-8

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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
  2005106473-82.

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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 199279979-82.Bracken MB. Oral
  contraception and congenital malformations in
  offspring a review and metaanalysis of the
  prospective studies. Obstet Gynecol
  199076552-7.

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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, ODonovan P, Duffy S, rogerson L.
  Should menstruation be optional for women? Lancet
  20003551730. Oral contraceptive and hemostasis
  study group. The effects of seven monophasic OC
  regimens on hemostatic variables. Contraception
  200367173-185. Cachrimanidou AC et al.
  Hemostasis profile and lipid metabolism with long
  interval use of desogestrel containing oral
  contraceptive. Contraception 199450153-65.

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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 1996129671-6.
  Berenson AB etal. A prospective, controlled study
  of the effects of hormonal contraception on bone
  mineral density. Obstet Gynecol 200198576-82.
  Polatti F etal. Bone Mass and longterm monophasic
  OC treatment in young women. Contraception
  199551221-4.

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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
  20029432-8. Pike MC, Spicer DV. Hormonal
  contraception and chemoprevention of female
  cancers. Endocrine Related Cancer 2000773-83.
  Ursin G etal. Mammographic density changes during
  the menstrual cycle. Cancer epidemiology
  biomarkers and prevention 200110141-2.

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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 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 1997963300-7.
  Sullivan JL. The iron paradigm of ischemic heart
  disease. American Heart Journal
  19891171177-1188.

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Counseling Women

• Introduce the idea but dont 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 partners concerns

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Irregular bleedingexpect 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 tryvit 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 responseadjust dose as needed to treat
  ovulation and menses
• We dont need new patents
• Why not just 31 pills in a bottle?