Physiology of the Menopausal Transition: The Hormonal Milieu

Nanette Santoro, MD Professor and E Stewart Taylor Chair of Obstetrics and Gynecology University of Colorado School of Medicine  Advisory Board and Stock Options: Menogenix, Inc  Consultant: Ansh Laboratories, Astellas/Ogeda

Disclosures Learning Objectives

At the conclusion of this lecture, the listener is expected to: Enumerate the patterns of hormones and symptoms that occur during the menopause transition Apply this information to anticipate how hormone changes may relate to symptoms STRAW Stages of Reproductive Aging Surrounding the MT

-3b/-3a Late -2b -2a Late Peri +1a/1b Reproductive: Early Peri Cycles >=60 days Menses have ended Cycles regular/slightly apart irregular Cycles variable* FSH high FSH high Normal to variable FSH Variable FSH Ovarian reserve very Ovarian reserve low low to undetectable Ovarian reserve low Ovarian reserve low

*Early perimenopausal cycles may be defined as either >7 days difference in cycle length or duration of amenorrhea <60 days. Adapted from Harlow,et al: Menopause 2012; 19: The Road to Menopause

Pre-MT Early MT Late MT

Menses • reserve 3-11 Regular Normal Skipped •>1 Prolonged mos ovarian cycles period/3 Amenorrhea reserve mos apart

Median Age 47 Median Age 49 Early Transition

Low ovarian reserve results in: Lowered AMH Lowered inhibin B and A (luteal phase) Intermittent increases in FSH Erratic hormone patterns The MT is the Tipping Point for Disruption of Negative Feedback Loops

Estradiol Negative producing feedback upon FSH Preovulatory FSH dependent follicle Inhibin producing Antral follicles AMH producing Pre-antral follicles FSH independent

Primordial follicles (true ovarian reserve) Probable Sequence of Events

Lowered ovarian reserve (clinically silent), leads to: Less AMH, inhibin B and inhibin A, which leads to: Less restraint on FSH, which leads to: ’Rapid’ cycles, short follicular phases, and follicle maturation that begins before the next menses Estradiol feedback may be of lesser importance at this time in the transition E2 and Inhibin Changes in Relation to FMP

Burger, H. G. et al. J Clin Endocrinol Metab 1999;84:4025-4030

Copyright ©1999 The Endocrine Society LOOP (Luteal Out Of Phase) Cycles

©2009The North American Menopause Society. Published by Lippincott Williams & Wilkins, Inc. 2 Hale, Georgina; Menopause. 16(1):50-59, January 2009. Transition Hormone Patterns Individual Perimenopausal Woman The Net Result of Early MT Changes

More frequent menses Longer luteal phases relative to follicular phase (prolonged PMDD) Wider hormone excursions that in midreproductive life= Worse migraines Greater ‘menstrual magnification’ of pre-existing conditions that were tolerable in mid-reproductive life Late MT

60-364 days of amenorrhea More prolonged stretches of low estradiol, failure to produce progesterone Hot spot for acceleration of ‘typical’ menopausal symptoms (hot flashes, vaginal dryness, adverse mood, sleep changes) Predicted Menstrual Cycle Length By Luteal Activity

ELA cycles=solid lines non-ELA cycles=dashed lines

The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 7, 1 July 2017, Pages 2218– 2229, https://doi.org/10.1210/jc.2016-4017 The content of this slide may be subject to copyright: please see the slide notes for details. Whole Cycle Hormones by Cycle Type

The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 7, 1 July 2017, Pages 2218–2229, https://doi.org/10.1210/jc.2016-4017 The content of this slide may be subject to copyright: please see the slide notes for details. Ovulatory Type Cycles Get Rarer— But Only Towards the End of the Transition

From: Menstrual Cycle Hormone Changes in Women Traversing Menopause: Study of Women’s Health Across the Nation J Clin Endocrinol Metab. 2017;102(7):2218-2229. doi:10.1210/jc.2016-4017 J Clin Endocrinol Metab | Copyright © 2017 Endocrine Society What We Have Learned

Hormone patterns don’t really become ‘estrogen deficient’ until the late transition Instability of overall day-to-day and month-to-month patterns may cause symptoms starting in the early transition Earlier onset of the MT = a longer, more symptomatic process

Paramsothy P, Menopause 2017; 24: 142 Can we use a blood test to predict menopause?

Antimullerian hormone (AMH) produced by granulosa cells of primary and growing follicles Provides a direct measurement of ovarian reserve If sufficiently sensitive, should theoretically predict the time to menopause (FMP) Cross Sectional AMH in Women Aged 24-50

Seifer D, Fertil Steril 2011; 95: 747 SWAN AMH Project

• Pre- or early perimenopausal and age 42- 52 when enrolled in SWAN • At least 1 blood sample available while pre- or early perimenopausal for initial AMH • AMH measured annually until 12 months after the FMP Results

• AMH was measured on 7714 blood samples from 1536 women (average 5 samples/woman) • African-American – 2177 samples • Caucasian – 3494 samples • Chinese -- 781 samples • Japanese --975 samples • Hispanic – 287 samples Mean age at time of 1st AMH measurement = 47.5 Serum AMH vs Time to FMP

What we learned

A sensitive and specific AMH assay CAN predict time to menopause…and can also predict when imminent menopause is unlikely Clinical Lessons Learned from SWAN

Why do migraine headaches worsen during the menopausal transition? Pavlovic J, Neurology 2016; 87:49

Luteal Estrogen Declines More Rapidly in Perimenopausal Migraineurs Clinical Lessons Learned from SWAN

When do women lose bone density in association with menopause? Are we screening the right people at the right time? What We Thought We Knew

Bone loss begins in the late 40’s/early 50’s It’s associated with menopause, somehow… Bone Loss Is Not Evident Until the Late MT

Finkelstein JCEM 2008; 93: 861 Lumbar Spine BMD Loss in Relation to FMP

Greendale J Bone Miner Res 2012; 27: 111 A New Model For Bone Loss Emerges

Shieh, A, Clin NA Ob Gyn 2018 Summary

The menopause transition is NOT a gradual process of hormone withdrawal Initial loss of negative feedback restraint on the HPO axis causes acceleration of folliculogenesis, asynchronous cycles, and destabilizing hormone fluctuations for some Later transition changes more closely mimic those associated with classic estrogen deficiency models Clinicians need to appreciate how these differing phases of the transition will influence the symptom experience for women