Obstetrics and Gynecology Clerkship Case Based Seminar Series Menopause UNC School of Medicine Obstetrics and Gynecology Clerkship Case 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

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 Once you reach 65 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 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?

Symptoms 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

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

Symptoms 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. Hot flush mechanism is likely due to unstable hypothalamic control of heat regulation mechanism caused by estrogen withdrawl

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 (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)

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 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: Disadvantages 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

Hormone Alternatives SERMs Selective estrogen receptor modulators Work as agonists and antagonists depending on the tissue Raloxifene and tamoxifen

SERMs Estrogen Raloxifene Tamoxifen Prevent OP ↑ ↑ ↑ ↑ ↑ ↑ Risk Breast ↑ ↑ ↓ ↓ ↓ ↓ Cancer Hot Flashes ↓ ↓ ↓ ↑ ↑ Endometrial ↑ ↑ no effect ↑ Venous ↑ ↑ ↑ ↑ ↑ ↑ Thrombosis

Hormone Alternatives 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

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. Large amounts needed: 35-75mg qd isoflavones/day Black cohosh may be helpful in the short-term (< 6 mos) for vasomotor symptoms.

Summary: Hormone Replacement Benefits Detriments Vasomotor sx Vaginal atrophy Osteoporosis Colon cancer Endometrial ca Breast ca VTE CHD

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

Case: 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

Case: 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

Case: 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

Case: 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

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).