MenopauseMS II

Joanna Wilson, D.O.Internal Medicine,

HerCare at Amarillo Diagnostic ClinicCommunity Associate Professor of Internal Medicine

Texas Tech, Amarillo

Proportion of average female lifespan spent in menopause years: 1/3 to 1/2

• Objectives:• To recognize the physiology of the menopause• To review the natural experiences of menopause• To appreciate the challenges of symptom treatment

Stages: -5 -4 -3 -2 -1 +1 +2

Terminology:

Reproductive Menopausal Transition Postmenopause

Early Peak Late Early Late* Early* Late

  Perimenopause  

Duration of Stage:

variable variable1yr

4 yrsuntil

demise

Menstrual Cycles:variable

toregular

regular

variable cycle length

(>7 days different from

normal)

2 skipped cycles and an

interval of amenorrhea

Amen x 12 mos none

Endocrine: normal FSH FSH FSH FSH

0

* Stages most likely to be characterized by vasomotor symptoms¥ STages of Reproductive Aging Workshop

Final Menstrual Period(FMP)

STRAW¥ Staging System

Adapted from Soules et al., Fertility and Sterility, VOL. 76, NO. 5, November 2001, p. 875

Determinants of Age at Menopause (Average Age =51 years)

Unaffected by:– Race – Socioeconomic status– Number of pregnancies– Oral contraceptive use– Education– Physical characteristics– Age of menarche– Age of last pregnancy

Affected by:– Smoking– Family pattern– Chemotherapy– Nulliparity– Hysterectomy*– Excessive alcohol intake*

– *=possible assn

Can We Predict Menopause? No

• Antimullerian hormone• Synthesized in the granulosa cells of preantral and small

antral follicles• Inhibits the transition from primordial into primary follicles

preventing excessive follicular recruitment by FSH– Correlates strongly to antral follicle count =

“functional ovarian reserve”• Peak level at age 30• Undetectable about 5 years prior to final menstrual period

– Potential predictor of menopause• Less useful for younger (<41 years) and older (>57 years)

FSH >30 Suggests Cessation of Ovulation

Hypothalamus

Hypothalamic-PituitaryCirculation

GnRHAnterior Pituitary Gland

Estrogen

Progesterone

FSHLH

Hypothalamic-Pituitary Circulation:Prior to Menopause

Hypothalamus

Hypothalamic-PituitaryCirculation

GnRH Anterior Pituitary Gland

Estrogen

Progesterone

FSHLH

Hypothalamic-Pituitary Circulation:Peri-Menopause (anovulatory cycle)

X

Cycle 1

AnovulationIrregularBleeding

Cycle 2

AnovulationIrregularBleeding

Cycle 3

OvulationShort

Follicular Phase

300

200

100

0

20

10

0

Estradiol(pg/mL)

Progesterone(ng/mL)

Perimenopause: Intermittent Ovulation and Irregular Cycles

Clinical Issues of Menopause: Change in Uterine Bleeding

• Most common symptom of menopause• Irregular bleeding occurs from 10 years prior

to final menstrual period (FMP)– Decreased frequency of ovulation (anovulatory

cycles)• Pregnancy is possible until ALL ovulation ceases

• Uterine bleeding after menopause is always cause for concern if the patient is not taking hormones

Estrogen Receptors Are In Almost Every Cell!

Clinical Issues of Menopause: Vasomotor Symptoms

• Second most common symptom of menopause• Primary reason women seek medical

treatment• 1-5 minutes with increased skin temp. 1-7˚C• More frequent and severe after

premenopausal oophorectomy

Years Before Years After

Menopause

Prevalence of Hot Flashes

3 2 1 1 2 3

Prevalence of Vasomotor Symptoms• > 75% of women report hot flashes within the

2-year period surrounding their menopause• 25% remain symptomatic for > 5 years• 5% of women have hot flashes or night sweats forever

Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.

Clinical Issues of Menopause: Sleep Disturbances

• Trouble getting and staying asleep• Triggers may be joint pain, flashes, stress

• Usually cause fatigue, poor focus, and irritability

• Often associated with underlying sleep disorder

• Melatonin, Trazodone, non-BZD’s, BZD’s, sleep hygiene, meditation• Progesterone may help

Clinical Issues of Menopause: Cognition (“Menopause Fog”)

• Forgetfulness, “cloudy” thinking• Due to variations in estrogen

– Exacerbated by multi-tasking, depression, anxiety

• Treatment includes daily physical exercise and adequate sleep

• Refer for neurocognitive testing for dementia or ADHD if severe– Alzheimer’s Dementia is more common in older

women

Clinical Issues of Menopause: Psychological Symptoms

• Menopause does not cause depression– Depression is more likely to resurface if present

prior to menopause

• Anxiety is frequent– Stressors: children leaving, ill parents, job

changes, financial, marriage, physical changes

• Counseling, cognitive behavioral therapy, antidepressants, BZD’s, exercise, estrogen

Clinical Issues of Menopause: Urinary Health

• Ureteral thickening recurrent cystitis, frequency

• pH rises alters vaginal flora balance• Loss of pelvic organ support cystocele,

rectocele• Loss of pelvic floor tone incontinence,

muscle spasms • Overactive Bladder (wet or dry)

Clinical Issues of Menopause: Sexual Function

• Majority of women state their sexual relationships did not change during menopause

• Most common complaints: low libido, vaginal dryness

• Barrier methods of prevention should be encouraged for sexually active women with a new partner

Clinical Issues of Menopause:Hair Changes

• Female pattern hair loss (FPHL): thinning on the crown– Hypoestrogenemic and relative

hyperandrogenic state• Estrogen prolongs anagen phase• Testosterone shortens anagen

phase with progressive miniaturization of susceptible hair follicles

– Off-label treatment may include antiandrogens (spironolactone) or topical minoxidil, biotin, finasteride

Clinical Issues of Menopause:Dental Health

• Hormone receptors exist in the basal and spinous layers of the epithelium and connective tissue

• Fluctuations of sex hormones around menopause have been implicated in inflammatory changes in gingiva– Atrophy of bony tooth

sockets leading to gum retraction, periodontal pocket development, bacterial invasion, and periodontitis

• Rate of systemic bone loss is a predictor of tooth loss– For each 1%/year

decrease in BMD, the risk for tooth loss more than quadruples

Clinical Issues of Menopause:Bone Loss

Clinical Issues of Menopause: Bone Loss

• First 5 years after menopause is time of more accelerated bone loss

• DXA indicated for patients with risk factors, and for those whom treatment would be initiated– http://www.shef.ac.uk/FRAX/tool– NOF Clinician’s Guidelines

Clinical Issues of Menopause: Body Composition Change

• Average weight gain = 5 lbs.– Increased central fat

distribution• Weight gain assd with

– Metabolic Syndrome– Hot flashes– Sleep deprivation– Sedentary lifestyle

• Decrease in muscle mass– Resistance training most

beneficial

Hypertension: Gender and Age Effects

Age Men (%) Women (%)

20-34 11.1 6.8

35-44 25.1 19.0

45-54 37.1 35.2

55-64 54.0 53.3

65-74 64.0 69.3

75 and older 66.7 78.5

All 34.1 32.7

LDL Cholesterol Levels After Menopause

90

100

110

-24 -18 -12 -6 0 6Months

% o

f le

vel a

t -6

mo

nth

s b

efo

re m

eno

pau

se Menopause

Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31

HDL Cholesterol Levels After Menopause

90

100

110

-24 -18 -12 -6 0 6Months

% o

f le

vel a

t -6

mo

nth

s b

efo

re m

eno

pau

se

Menopause

Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31

Endothelial Cell Layers in Healthy Postmenopausal and Premenopausal Women

• Postmenopausal cells show evidence of endothelial cell death, denudation, and RBC, platelet, and protein attachment, as well as fractured basal membranes, and loss of intercellular junctions

• Premenopausal cells show tight connections, a continuous layer of endothelial cells, and thick plasma membranes

Compounded “Bioidentical” Hormones

• Dosing schedule mimics premenopausal state in postmenopausal women

• Plant derived hormones modified to be identical to human molecules

• Not regulated for purity of modification process• Saliva levels do not accurately measure tissue

levels• Progestogen skin cream has not been proven

effective to prevent endometrial cancer

Hormone Therapy (HT)

• Estrogen (E) treats:– Hot flashes– Night sweats– Mood– Vaginal dryness– Cognitive slowing

• Progesterone (P) treats:– Endometrial

proliferation from estrogen stimulation

HT Regimen Choices: Cyclic: daily E with cycles of P vs. Continuous

CombinedCyclicAdvantages• Predictable withdrawal

bleeding every monthDisadvantages• 2-pill dosing may

discourage compliance• Withdrawal bleeding

persists indefinitely

Continuous CombinedAdvantages• Most women will achieve

amenorrhea in time• Convenient 1-pill dosing

enhances compliance and ensures appropriate progestin treatment

• Lower risk of endometrial hyperplasia compared with cyclic regimen

Disadvantages• Unpredictable spotting• Daily progesterone exposure

and side effects

The Women’s Health Initiative in Women With Uteri

The Women’s Health Initiative in Women Without Uteri

Estrogen and Progestin Risks

• Venous thromboembolism (DVT, PE) risk is increased with both E and P use– Risk appears reduced in transdermal estrogen vs

oral– Risk appears reduced in first and second

generation progestins vs newer

• Arterial clot risk is higher in smokers, and women with HTN, DM, and high cholesterol

• Risks of both types increase with age

“The Timing Hypothesis”(Early exposure to HT might be good!)• Sex steroid hormones alter the biology of

vessel wall cells and the inflammatory cells that accumulate differently according to the stage of the disease– It is likely that early physiological sex hormone

replacement can improve or reverse early endothelial dysfunction

– HT given in advanced atherosclerotic lesions likely predisposes the lesion to inflammatory and hemostatic abnormalities

Assess Your Patient’s Risk Before Starting HT

Next Studies to Evaluate Type and Exposure Age

• Elite: Early Versus Late Intervention Trial With Estradiol– Oral E2 vs. placebo– Measuring Carotid intimal medial thickness

• KEEPS: Kronos Early Estrogen Prevention Study– CEE vs transdermal E2 with micronized

progesterone– Measuring carotid IMT

Non-Estrogen Symptom Therapies

• Selective Serotonin Reuptake Inhibitors• Serotonin Norepinephrine Reuptake Inhibitors• Gabapentin• Clonidine• OTC Vaginal moisturizers and lubes• Vitamin E, coconut oil, olive oil• Phytoestrogens (soy, black cohosh, flax)

Variable Stimulation of the Estrogen Receptor Results in Tissue Specific

Responses

Creating the Perfect Estrogen Replacement

Newest Menopause Therapies

• Duavee (CEE + bazedoxifene)– FDA-approved for vasomotor symptoms and

prevention of postmenopausal osteoporosis

• Osphena (Ospemiphene)– FDA-approved for painful intercourse due to

vulvovaginal atrophy

Menopause Summary

• The sex hormone deficiency of menopause affects nearly every cell of the body

• Vascular disease, osteoporosis, genitourinary, dental, and skin changes increase in prevalence after menopause

• Estrogen and non-estrogen treatments are available for symptom management

• Hormone therapy given near the age of menopause has many benefits, but the safety data is inconclusive

Thank You!

Questions?

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