MenopauseUNC School of Medicine

Obstetrics and Gynecology ClerkshipCase Based Seminar Series

Objectives for Menopause

Define menopause and describe changes in the hypothalamic-pituitary-ovarian axis associated with perimenopause and menopause

Recognize symptoms and physical exam findings related to perimenopause and menopause

Discuss management options for patients with perimenopausal and menopausal symptoms

Counsel patients regarding the menopausal transition

Discuss long-term changes associated with menopause

Average age is 51.4 years 95% confidence interval of Bell Curve gives a range of 45-55

years. Less than 2% occur before age 40. Factors associated with early menopause

Cigarette smoking (1.5 yrs earlier) History of short intermenstrual interval Family history Chemo / Radiation / Genetic factors

Unrelated to number of prior ovulations, pregnancies, use of OCPs, height, weight, age at menarche, race, class or education

Epidemiology

In 2000, life expectancy Women 79.7 years Men 72.9 years

Once you reach 65 Women expect to live until 84.3 years old Men expect to live until 80.5 years old

Therefore, more than 1/4 of a woman’s life is spent in menopause

Elderly Population

Peri-menopause Transitional period

Hallmark is menstrual irregularities Shortened cycle length Skipped cycles 10% of women will have abrupt cessation of menses

Median length of 4-5 years

Median age of onset is 47.5 years

Peri-Menopause

Definition No menses for 12 consecutive months

No other identifiable cause

Depletion of follicles with loss of granulosa and thecal cell function 6-7 million oocytes at 20 weeks fetal age

1 million oocytes at birth drop to 400,000 at puberty

300-400 ovulatory events over lifetime

Accelerated follicular loss 2-8 yrs before menopause

Physiology

Depletion of follicles with loss of granulosa and thecal cell function Granulosa cells produce less inhibin, which provides negative

feedback for FSH secretion by the pituitary gland Increase in FSH levels After menopause, LH levels are also elevated Would you check a FSH or LH level to diagnose menopause?

Physiology

Menstrual irregularities Primary reason women seek medical attention!

Cycles shorten as increased FSH triggers early ovulation

Skipped cycles due to anovulation

Long periods of anovulation can lead to Excessive estrogen states

Irregular, unexpected menses

Symptoms

• What can women expect?– Discuss expected age of onset (51.5 years)– Discuss possible symptoms to expect– Discuss treatment options

Patient Counseling

Do you think the perimenopausal women can get pregnant? YES

Guinness World Record = 57 yrs & 120 days

So, remember to recommend contraception. Low-dose oral contraceptives may be used in women without contraindications (i.e. non-smokers).

Symptoms

Hot Flushes Subjective feeling of intense heat followed by skin

flushing and diaphoresis. Sudden dilation of peripheral vasculature secondary to

abrupt estrogen withdrawal. Skin temperature increases and core temperature drops.

Usually, occurs for a few seconds to minutes. Duration is about 1-2 years. 25% for > 5 years.

Symptoms

Genitourinary atrophy A variety of symptoms

Atrophic vaginitis, urethritis, recurrent UTIs, dyspareunia

Pelvic organ prolapse is NOT caused by estrogen deficiency

Symptoms

Urinary Incontinence Atrophy of estrogen-dependant tissues such as the

urethra may contribute to existing causes for urinary incontinence

Typically addressed with local application of estrogen cream

Symptoms

Sexual Disturbances Decreased interest in sexual activity

May be related to decreased testosterone levels

May be related to psychosocial stressors

Anatomic changes secondary to estrogen deficiency Atrophy of vaginal mucosa and lower urethra

Thinning of vaginal mucosa with decreased lubrication and elasticity, leading to dyspareunia

Symptoms

Sleep Disturbances Estrogen appears related to producing restful,

deep-stage sleep

Hot flushes more common at night Wakening or disruption of deep-stage sleep

Contributes to feeling of overall fatigue

Symptoms

Mood Swings / Irritability / Depression NOT associated with menopausal hormone changes

alone

Stage of life associated with multiple changes (e.g., children leaving home, parents aging, retirement)

Hot flushes and fatigue can lead to emotional lability

Symptoms

Cognitive Function Some types of memory and brain function may be

influenced by estrogen

Some evidence suggests that Alzheimer’s disease is less frequent in estrogen users and the effect was greater with increasing dose and duration of use.

Symptoms

Cardiovascular Disease Leading cause of death in US women (Ahead of cancer,

cerebrovascular disease and MVAs) Death rate for CV disease is 3X the rate for breast cancer

and lung cancer. Changes in lipid profile in menopause

Increased LDL Decreased HDL ? Decrease in triglycerides

Adverse Health Effects

Osteoporosis Spinal bone density peaks at 20 years, while cortical bone

density peaks in late 20s

Rate of loss of 0.5%/year prior to age 40, then anywhere from 2-9%/year for first 10-15 years after menopause

Primary loss is trabecular bone, leading to compression fractures, loss of height, kyphosis

Adverse Health Effects

Osteoporosis Osteopenia = BMD between -1 and -2.5 SD of a young, white

adult woman. Osteoporosis = BMD -2.5 or greater SD 25-50% of women will have spinal compression fractures by

age 70 20% of Caucasian women age 80 will have hip fractures, with

15-20% mortality. Annual incidence is 1.3% after age 65

Adverse Health Effects

Osteoporosis High risk:

Caucasian, Asian Thin, inactive, smokers High caffeine/alcohol intake, low dietary calcium, high dietary

protein and phosphates H/o oligomenorrhea, excessive exercise, eating disorder Medical conditions – hyperthyroid, cancer, myeloproliferative

disorders Low Risk:

African American Obese, active

Adverse Health Effects

Osteoporosis Protection:

Ca supplements (1200mg, 1500mg) Weight-bearing exercise HRT: estrogen increases

Intestinal calcium absorption Renal conservation of calcium Increases 1,25-dihydroxyvitamin D (active form)

Vitamin D (400-800IU)

Adverse Health Effects

Types of hormone replacement Estrogen alone (for women without a uterus) Estrogen and progesterone

Sequential Continuous

Local estrogen SERM’s (Selective Estrogen Receptor Modulators)

Hormone Replacement

Relief of vasomotor symptoms HRT is effective in reduces the number of hot flashes

6-8 weeks to see maximal effect

Combination HRT (0.625mg estrogen/2.5mg MPA)

What about lower doses of HRT? For combination HRT, all doses resulted in similar relief of

symptoms

For estrogen alone, most relief with higher doses

HRT: Advantages

Vaginal atrophy Menopause thins the vaginal epithelium and increases

the vaginal pH (> 6.0).

Estrogen decreases the vaginal pH, thickens the vaginal epithelium and reverses vaginal atrophy.

Less atrophic changes with higher doses of HRT

HRT: Advantages

Bone protection Reduction of bone loss

Prevents OP-related hip fractures

Protects the spine and the small bones

WHI: 5 fewer hip fractures per 10,000 person-yrs

HRT: Advantages

Colon cancer Some observational studies have suggested a reduced

risk.

WHI: 6 fewer cases / 10,000 person-yrs

HRT: Advantages

Endometrial cancer 8-10 fold increased risk with unopposed estrogen.

PEPI: unopposed estrogen x 3 yrs = 24% with atypical hyperplasia (vs 1% women on placebo)

Risk is increased with: Increased duration and dose Continuous versus cyclic therapy Absence of a progestin

HRT: Disadvantages

Breast cancer Meta-analysis of 51 case-controlled & cohort studies

showed no increased risk with short-term use.

After 5 years of use, risk increased by 35%.

WHI: 8 more invasive cases / 10,000 person-yrs

Women diagnosed with breast cancer while using HRT have been shown to have better survival

HRT: Disadvantages

Thromboembolic disease Increases risk for DVT 2 – 3.5 fold

Strokes: 8 more / 10,000 person-yrs

PEs: 8 more / 10,000 person-yrs

HRT: Disadvantages

Cardiovascular disease Traditionally, HRT was thought to provide protection

against coronary heart disease (CHD) Observational studies found lower rates of CHD in

postmenopausal women on HRT. The consensus was that CHD was about 35-50% lower in

women using HRT. Many studies showed that HRT improved lipid profiles.

HRT: Disadvantages

Cardiovascular disease What about secondary prevention? i.e. women who

have a h/o coronary heart disease, does HRT help? Heart and Estrogen/Progestin Replacement Study

(HERS) was a RCT, double-blinded study of 2,763 PM women with intact uteri and a h/o CHD

52% higher rate of major coronary events in the 1st year Then there was a reduction in the risk with longer use –

i.e. 33% lower risk in the 4th and 5th years

HRT: Disadvantages

Cardiovascular disease What about primary prevention? i.e. in healthy women,

does HRT prevent CHD? Women’s Health Initiative (WHI) RCT of 16,608 postmenopausal women aged 50-79

years old with an intact uterus 40 different US centers Combination HRT – 0.625mg CEE and MPA 2.5mg vs

placebo

HRT: Disadvantages

Cardiovascular disease (WHI) 7 more CHD events 8 more strokes 8 more PEs 8 more invasive cancers

Study stopped after 5.2 yrs (planned 8.5yrs) because of cases of breast cancer

HRT: Disadvantages

SERMs

Selective estrogen receptor modulators

Work as agonists and antagonists depending on the tissue

Raloxifene and tamoxifen

Hormone Alternatives

Estrogen Raloxifene TamoxifenPrevent OP ↑ ↑ ↑ ↑ ↑ ↑

Risk Breast ↑ ↑ ↓ ↓ ↓ ↓Cancer

Hot Flashes ↓ ↓ ↓ ↑ ↑

Endometrial ↑ ↑ no effect ↑ Cancer

Venous ↑ ↑ ↑ ↑ ↑ ↑ Thrombosis

SERMs

SERMs Overall, SERMs can help to prevent OP and breast cancer

However, they aggravate hot flashes, the most common indication for estrogen therapy

Tamoxifen stimulates the endometrium

Hormone Alternatives

Limited studies with relatively short duration of therapy and follow-up.

Soy and isoflavones may be helpful in the short-term (< 2 yrs) for vasomotor sx and may protect against osteoporosis. Large amounts needed: 35-75mg qd isoflavones/day

Black cohosh may be helpful in the short-term (< 6 mos) for vasomotor symptoms.

Alternative Medicine

Benefits Detriments Vasomotor sx

Vaginal atrophy

Osteoporosis

Colon cancer

Endometrial ca

Breast ca

VTE

CHD

Summary: Hormone Replacement

Bottom Line Concepts Menopause is the natural course aging of the female reproductive

system, driven by loss of oocytes Symptoms of menopause include

Menstrual irregularities Hot flushes Sleep disturbances Mood changes Sexual disturbances Urinary incontinence Cognitive function Hair growth

Health risks of menopause include osteoporosis, lipid abnormalities, cardiovascular disease, and cancer.

Treatment options include HRT, SERMs, soy, isoflavones, black cohosh Risks/benefits of HRT and SERMs need to be discussed

A 44-year old woman presents for evaluation of abnormal menstrual bleeding. Her periods have been regular in the past but for the last 6 months she has had a period every 35-56 days, lasting 7-9 days. The bleeding is heavier than usual and she feels tired all the time. She has gained 15 lbs over the last 2 years, which she believes is due to lack of exercise and increased eating/sleeping. She complains that her skin is dry. Exam is unremarkable. What would your recommend next? Check pregnancy test Discuss exercise / eating patterns Check TSH, PRL Consider endometrial biopsy Expectant management versus hormonal management

Case: Abnormal Bleeding

58 year old postmenopausal woman referred to you by a friend. She has no known medical problems and is on no medications. Her social history is remarkable for an 80-pack/year history of tobacco use. Her physical exam is unremarkable. What are the important health maintenance aspects of the exam to focus on? Blood pressure Pelvic exam Breast exam / mammography Fecal occult blood Smoking cessation Flu shot Osteoporosis

Case: Health Maintenance

A 47 year old woman, G2P2, presents with menstrual cycles varying in length from 20 to 40 days. Until 9 months ago she had regular 28 day cycles. She reports frequent hot flushes. She recently resumed sexual activity and uses no contraception, but she does not desire pregnancy. She does not smoke and has no other medical problems. Her physical exam is unremarkable. What are her options for cycle control? Low dose combination oral contraceptive Continuous low dose estrogen and progestin menopause regimen Cyclic progestin therapy for 12 days a month Continuous low dose estrogen (0.625mg conj EE) Estradiol vaginal ring

Case: Abnormal Bleeding

A menopausal patient with osteoporosis has been reading information on the Internet about different treatment modalities for osteoporosis. She wishes to know more about what therapies are actually available and how they work? Estrogen: Reduces osteoclast activity SERMs: Reduces osteoclast activity Bisphosphonates: Reduces osteoclast activity

Take on empty stomach, first thing in AM with 8oz water and no food for 30 minutes

Take sitting up due to esophagitis risk Calcium supplementation within 4 hours

Calcium / Vitamin D supplements

Case: Osteoporosis

References and Resources

APGO Medical Student Educational Objectives, 9th edition, (2009), Educational Topic 47 (p100-101).

Beckman & Ling: Obstetrics and Gynecology, 6th edition, (2010), Charles RB Beckmann, Frank W Ling, Barabara M Barzansky, William NP Herbert, Douglas W Laube, Roger P Smith. Chapter 37 (p329-336).

Hacker & Moore: Hacker and Moore's Essentials of Obstetrics and Gynecology, 5th edition (2009), Neville F Hacker, Joseph C Gambone, Calvin J Hobel. Chapter 35 (p379-385).