Hot Issues in Women’s Health: Hormones,

Menopause and Metabolism Nanette Santoro, MD

Professor and E Stewart Taylor Chair of Obstetrics and Gynecology

University of Colorado School of Medicine

Learning Objectives

At the end of this session, the learner is expected to be able to:

Recite the stages of the menopausal transition and relate these stages to specific hormone alterations.

Predict the hormonal changes associated with changes in metabolism

Understand how common menopausal symptoms influence metabolism apart from hormones

Provide patients with evidence based guidelines to promote metabolic health in midlife

The Road to Menopause

Norma l ova rian reserve

Regular •Reduced

reserve•At lea st 1

period/3mos

Skipped cycles

Menses 3 -11 months apa rtProlonged

Amenorrhea

Pre-­MT Early MT Late MT

Median Age 47 Median Age 49

Hormone Changes in the Pre- and Early Menopause Transition

‘Monotropic’ rise in FSH: first described in 1976 (Sherman)

Erratic estradiol patterns (Santoro, 1996)

Reduced progesterone production across the transition (Prior, Santoro, 2008)

Shorter menstrual cycles (Klein, 2002)

Less frequent ovulationSherman BM JCEM 1976; 42:629; Santoro JCEM 1996; 81: 1495; Santoro JCEM

2008; 93:1711; Prior JC Nov Found Symp 2002; 242:172; Klein JCEM 2002; 87: 5746

Transition Hormone Patterns

Breakdown of Usual Patterns

Short cycles due to low inhibin and high FSH

Follicle recruitment occurs in luteal phase

New dominant follicles are ready to ovulate at menses

Aberrant patterns appear to be associated with lower luteal P production

Outcome=hormone roller coaster!

Individual Perimenopausal Woman

The Early Transition

At least 1 menstrual period every 3 months

Not an ‘estrogen deficient’ state

Metabolic changes in the early MT likely due to: Age related change in metabolism

Disruption of sleep

The Role of Sleep

Experimental sleep restriction leads to: Consumption of app 500 more calories/day Gravitation to high salt/sugar/fat

Physiologic sleep restriction may cause the same types of issues

Midlife women susceptible to sleep apnea, snoring spouse, anxiety

And hot flashes make all of that worse!

Spaeth, Am J Clin Nutr 2014; 100: 559

Copyr ight r est r ict ions m ay apply.

Kravitz , H. M. et a l. Arch Intern Med 2005;;165:2370-­2376.

% women with trouble sleeping by cycle day (n = 630)

Sleep Duration and BMI

Applehans, BM, Obesity 2013; 21:77

Mean (±SEM) Daily Caloric Intake During Baseline and Sleep

Restriction.

Andrea M Spaeth et a l. Am J Clin Nutr 2014;;100:559-­566

©2014 by American Society for Nutri tion

The Late Menopause Transition

60+ days of amenorrhea

Estrogen deficiency predominates Sleep gets even worse! Hot flashes get worse—up to 85% of

women affected SHBG and androgen metabolism shifts Changes in cardiometabolic markers

become evident

Hot Flashes Across the Transition: SWAN

Gold, Am J Pub Health 2006; 96: 1226

Adventitial Diameter in Relation to FSH/E2 in the MT

El Khoudary Atherosclerosis, 2012; 225:180

Changes in IMT and AD Across the MT

El Khoudary Menopause 2013; 20:8

Testosterone, Estrogen and SHBG—It Gets Complicated

Decreasing estrogen>>>lower SHBG

Increased Free Androgen Index

More, not less bioavailable androgen

Testosterone/estradiol molar ratio predicts incident metabolic syndrome (Torrens)

FAI related to visceral fat (Janssen)

Relationships persist after adjusting for HOMA and insulin resistance

Torrens JI Menopause2009; 16:257; Janssen I, Obesity 2010: 18: 604

Are Today’s Women with PCOS Tomorrow’s Metabolic Train Wrecks?

Women from SWAN who were hyperandrogenic and oligomenorrheic at baseline (Polotsky 2014 JCEM 99:2120): 12 years follow up Incident Metabolic Syndrome HR 1.4 [0.9-2.2]

no higher than eumenorrheic normoandrogenicwomen

No increased risk in hyperandrogenic, eumenorrheic or normoandrogenic, oligomenorrheic women

Do Hormones Drive Metabolism or Vice Versa?

SWAN cohort analyzed sequentially over 9 years and looked for lagged relationships between waist circumference and FSH Estradiol Testosterone SHBG

Wildman JCEM 2012; 97:E1695

Sequential Relationships Between Waist Circumference and FSH Using Standardized

Estimates

Wildman R P et a l. JCEM 2012;;97:E1695-­E1704

©2012 by Endocrine Soc iety

Sequential Relationships Between Waist Circumference and Estradiol, Stratified by Menopausal Status Using

Standardized Estimates

Wildman R P et a l. JCEM 2012;;97:E1695-­E1704©2012 by Endocrine Soc iety

Sequential Relationships Between Waist Circumference and Testosterone Using

Standardized Estimates

Wildman R P et a l. JCEM 2012;;97:E1695-­E1704

©2012 by Endocrine Soc iety

Sequential Relationships Between Waist Circumference and SHBG Using

Standardized Estimates

Wildman R P et a l. JCEM 2012;;97:E1695-­E1704

©2012 by Endocrine Soc iety

Changes in Metabolism Associated with Menopause

Decreased energy expenditure (mostly due to decreased physical activity)

No change in insulin-stimulated glucose disposal

Changes in BMR controversial

Women aged 55-65 lose less weight (7kg) after bariatric surgery than women aged 20-45

Duval, Eur J Clin Nutr2013; 67:407-11; Toth, Diab Care 2000, 23: 801; Ochner, Obese Surg 2013; 23: 1650

The Role of Mood

Adverse mood is a common menopausal symptom

Risk for new onset major depression increases (16% prevalence)

Anxiety follows a similar pattern

Depression and Anxiety

Adverse mood most likely in the LATE transition

Women with minimal pre-existing symptoms are most vulnerable (Soares, Drugs Aging 2013; 30:677)

Experimental induction of perimenopausewith VCD decreases P and DHT and produces anxiety symptoms in animal model (Reis, Psychoneuroendocrinology 2014: 49:130)

Adjusted OR for CES-­‐D > 16 Across Visits 00-­‐05 by Menopausal Status (p=.005)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Pre Early Peri Late Peri Post HT Users

Premenopause=reference group. *95% CI does not include 1 (Bromberger, J Affect Disord 2007)

***

*

Predicting First Major Depression Onset(n=42) Among 266 Women without Past MDD

at BaselineHR

J.T. Bromberger et al, Psychological Medicine, 41:2238, 2011.

* **

*95% CI not included

Mood and Metabolism

Anhedonia, apathy>>>decreased activity

Disrupted sleep patterns

Loss of diurnal cortisol rhythm Increased visceral fat Increased consumption of ‘comfort foods’

Emotional eating

Tomlayama, Psychoneuroendocrinology. 2011;36:1513; Ibrahim, Eat Behav 2016; 21:214;

What Can the Clinician Do?

Treat key menopausal symptoms Hot flashes Poor sleep

Detect and treat metabolic syndrome/weight management Metformin Lifestyle

Detect and treat mood disorders

Exercise: An Essential Modifier

Maintains weight

Maintains endothelial function

Improves insulin sensitivity

Raises HDL

Mindfulness: An Essential Modifier

May reduce BP

Reduces stress

Improves chronic pain

Improves sleep (mindfulness CBT)

Abbot J Psychosom Res 2014; 76:361; Cherkin, JAMA 2016; 315: 1240; Schramm PJ, Sleep Med 2016; 17:57

Hormones

Reduce/eliminate hot flashes

May improve sleep, vaginal symptoms, mood

Reduces incident diabetes by 7% per year

Summary

Midlife introduces a set of age and menopause related challenges that affect a woman’s homeostasis

Sleep, mood and physical activity may all be altered by the menopausal transition

Hormones may play a role in affecting metabolism directly but more likely indirectly

Clinicians can help their patients adapt