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

2. 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

3. Epidemiology Average age is 51.4 years
95% confidence interval of Bell Curve gives a range of 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

4. Elderly Population In 2000, life expectancy Once you reach 65
Women years
Men 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

5. 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

6. 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
ovulatory events over lifetime
Accelerated follicular loss 2-8 yrs before menopause

7. 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?

8. 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

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

10. 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).

11. 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

12. Symptoms Genitourinary atrophy A variety of symptoms
Atrophic vaginitis, urethritis, recurrent UTIs, dyspareunia
Pelvic organ prolapse is NOT caused by estrogen deficiency

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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

19. 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 years after menopause
Primary loss is trabecular bone, leading to compression fractures, loss of height, kyphosis

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

21. 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

22. 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 ( IU)

23. 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)

24. 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

25. 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

26. 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

27. HRT: Advantages Colon cancer
Some observational studies have suggested a reduced risk.
WHI: 6 fewer cases / 10,000 person-yrs

28. 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

29. 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

30. 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

31. 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.

32. 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

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

34. 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

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

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

37. 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

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

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

40. 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

41. 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 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

42. 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

43. 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

44. 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

45. References and Resources
APGO Medical Student Educational Objectives, 9th edition, (2009), Educational Topic 47 (p ).
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 (p ).
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 (p ).