Menopause

Division of Urogynecology and Reconstructive Pelvic Surgery

Department of OB/GYN

Epidemiology

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

Elderly Population

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

Peri-menopause

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

Physiology

General feature is 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

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?

Symptoms

Menstrual irregularities is the 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 and irregular, unexpected menses

Symptoms

Do you think the perimenopausal women can get pregnant?

– YES

– Guinness World Record = 57 yrs & 120 days

– So, remember to recommend contraception. Low does oral contraceptives may be used in women without contraindications (i.e. smoking).

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.

Adverse Health Effects

Cardiovascular Disease– Leading cause of death in US women (f/b

malignancies, 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)

Hormone Replacement

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

Sequential Continuous

– Local estrogen– SERM’s (Selective Estrogen Receptor Modulators)

HRT - Advantages

1. Relief of vasomotor symptomsHRT 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

2. 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

3. 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

4. Colon cancer

– Some observational studies have suggested a reduced risk.

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

HRT - Disadvantages

1. 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

2. 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

3. 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

4. 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

4. 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

4. 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

4. 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

SERMs

Selective estrogen receptor modulators

Work as agonists and antagonists depending on the tissue

Raloxifene and tamoxifen

SERMs

Estrogen Raloxifene TamoxifenPrevent OP ↑ ↑ ↑ ↑ ↑ ↑

Risk Breast ↑ ↑ ↓ ↓ ↓ ↓Cancer

Hot Flashes ↓ ↓ ↓ ↑ ↑

Endometrial ↑ ↑ no effect ↑ Cancer

Venous ↑ ↑ ↑ ↑ ↑ ↑ Thrombosis

SERMs

Overall, SERMs can help to prevent OP and breast cancer

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

Also, tamoxifen stimulates the endometrium.

Alternative Medicine

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.

35-75mg qd isoflavones / day

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

Summary

Health Risks– Osteoporosis– Lipid abnormalities– Cardiovascular disease– Cancer

Summary

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

Hormone Replacement

Benefits Detriments

Vasomotor sx

Vaginal atrophy

Osteoporosis

Colon cancer

Endometrial ca

Breast ca

VTE

CHD

Abnormal Bleeding

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

Health Maintenance

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

Abnormal Bleeding

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

Osteoporosis

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