Menopause

1. Menopause Author: Beatrice Hong, MD Editor: Amy Shaheen, MD, Assistant Professor of Clinical Medicine Duke University Medical Center

2. Menopause Mrs. P is a 49 year old woman with a history of hypertension who presents to your clinic for routine follow up. She states, “I am generally very healthy and I’m having irregular periods and feeling irritable. I’m either dying or could I be going through menopause?

3. Menopause: Statistics • WHO definition of menopause: “the permanent cessation of menstruation determined retrospectively after 12 consecutive months of amenorrhea without any other pathological or physiological cause” • Perimenopause: year before the final menstrual period through the first year after the final menstrual period • Irregular menstruation is due to fluctuations in the hormones of the hypothalamic-pituitary –ovarian axis.

4. The STRAW Staging System 2001- Panel of experts from Stages of Reproductive Aging Workshop created a staging system to classify reproductive aging. Consists of 7 stages based on menstrual cycles and FSH levels. Not validated in research settings. Adapted from: Soules MR, Sherman S, Parrott E, Rebar R, Santoro N, Utian W, Woods N. Executive summary: Stages of Reproductive Aging Workshop (STRAW).FertilSteril 2001 Nov;76(5):874-8.

5. Menopause • Brambilla et al found 3-11 months of amenorrhea or irregular periods among women age 45-55 were most predictive of menopause within the following 3 years (sensitivity rate 72%; specificity 76%) • Treloar (30 year study of women through lifetime until menopause) found mean age of onset of perimenopause as 45.5 years • ·McKinlay in Massachusettes Women’s Health Study (1992) reported median age of onset as 47.5 years • Age 45: 40% have started or completed the transition • Age 50: 75% have started or completed the transition • Age 55: 98% have started or completed the transition • Mean age of 51 • Late menopause is defined by menopause after age 55 • Probability of menstruating spontaneously after 12 months of amenorrhea is less than 2%

6. Factors that influence earlier menopause • Factors that influence earlier menopause • Smokers- 1-2 years earlier • Reduces bioavailability of estrogen by inc hepatic metabolism, dec production of estrogen, increase circulation of estrogens • Women who never had children • Women with more regular cycles • Family History- OR 6.1 of early menopause if family history (Maturitas. 1995;22:79-87) • H/o type 1 diabetes • Galactose consumption • Shorter cycle length during adolescence • History of hysterectomy with ovarian preservation- also more severe sx, unknown etiology

7. Menopause Mrs. P says, “ Okay that’s great. So maybe I have menopause. My last period was 3 months ago. Can you run some test to diagnose menopause?” You scratch your head and think….

8. Diagnosis • Clinical diagnosis- amenorrhea for 6-12 months with symptoms of menopause • Serum clarification- High serum FSH (above upper limit of normal for reproductive women) • High LH, less marked than FSH (FSH:LH ratio >1); less useful as LH concentrations are very high during preovulatory gonadotropin surge in normal cycles

9. Menopause – diagnosis (continued) This question was addressed in a Rational Clinical Exam paper, “Is this woman perimenopausal?” – Summary of Results: JAMA Feb 19,2003 Vol 293 No7

10. Menopause – diagnosis (conclusion) • Conclusion: Hot flashes, nights sweats and vaginal dryness have the highest positive likelihood ratio. However, the absences of these findings are not effective at ruling out perimenopause. High FSH also suggest evidence for a perimenopausal state (LR+ 3.06) but it’s absence is poor at ruling it out. • Therefore, no single element of the history of clinical exam can confirm or rule out menopause. FSH levels do not help confirm the diagnosis.

11. Menopause Mrs. P says “Well, you’re a lot of help! What can I expect when I do develop menopause? I’ve heard that hot flashes are horrible.”

12. Menopause: Short term Effects of Estrogen Deficiency • Hot flashes- occurs in 75% of women • Centrally mediated, correlated with pulses of LH secretion • Self limited: 30-50% gave improvement in several months and 50-75% women have cessation within 5 years • Defined as sudden sensation of heat centered on face and upper chest that generalizes, lasts 2-4 minutes, assoc with profuse perspiration and occasionally palpitations, followed by chills and shivering • Occurs several times a day, with a wide range of frequency • Considered thermoregulatory dysfunction with inappropriate peripheral vasodilatation with increased blood flow and perspiration with rapid heat loss and decrease in core body temp resulting in shivering • Cultural differences • North American, European and Australian: 50-85% • Indonesian and Chinese 10-25%

13. Menopause: Short term Effects of Estrogen Deficiency • Sleep disturbance/Depression • Sleep disturbance often occurs from hot flashes • Results in fatigue, irritability, depression • Unclear relationship between menopause and depression, conflicting longitudinal population studies show absence or relationship. • Sexual Function- prevalence18-21% • Decrease in blood flow to the vagina and vulva resulting in decrease in vaginal lubrication and sexual function • Decreased sensation in clitoral and vulvar area • Vaginal atrophy results in: • Pale vagina lacking normal rugae • Atrophic cervix • Decreased elasticity of vaginal wall: becomes shorter or narrower • May result in dyspaurenia • Androgen production declines as well; potential for decrease in libido: usually thought to be secondary to vaginal dryness, decreased sleep etc

14. Menopause: Short term Effects of Estrogen Deficiency • Urinary incontinence- prevalence 26-55% • Atrophy of urethral epithelium: atrophic urethritis, diminished urethral mucosal seal, increased irritation; predisposes to both urge and stress incontinence • Urinary tract infection • Mucosal atrophy predisposes to infection • Estrogen deficiency increases vaginal pH and alter the vaginal flora, predisposing to infection • Connective tissue changes- reduced collagen content of skin and bones • Results in increased aging and wrinkling • Imbalance- thought to be central effect • Associated with forearm fractures in women: incidence of Colles’ fractures increases markedly in women at age 50; evidence of increased postural sway in patient’s with Colles’ fractures( Age Ageing 1987 May;16(3):133-8).

15. Long Term Effects of Estrogen Deficiency • Long Term Effects of Estrogen Deficiency • Osteoporosis • Cardiovascular disease • Dementia

16. Menopause “That all doesn’t sound too good to me” worries Mrs. P. “ I’ve had friends take estrogen for these problems and they tell me that they feel like young women again. Do you think that’s a good idea for me?”

17. Menopause: Replacement Therapy Estrogen replacement therapy has been the gold standard therapy known to be the most effective in the relief of menopausal symptoms including hot flashes, vaginal dryness and urinary symptoms. However, several well known studies have pushed away from recommended use of estrogen replacement therapy.

18. Menopause: Women’s Health Initiative (NEJM 2003 349:523) RCT examining primary prevention of coronary heart disease in healthy postmenopausal women aged 50 to 79 years. One of the trials (enrolling 16,000 women) using continuous estrogen-progestin therapy was discontinued early due to an increased risk of CHD, stroke, venous thromboembolism, and breast cancer over an average follow-up of 5.2 years The rate of CHD events (nonfatal myocardial infarction or death due to CHD) increased by 24 percent (39 versus 33 events per 10,000 person years) mostly in nonfatal myocardial infarction. The increase in risk was greatest in year one (HR 1.81; CI 1.09 to 3.01). A smaller increase in risk was seen in years two through five (with a significant trend toward a decline in excess risk over time)

19. Menopause: Estimates of CHD Figure 2. Kaplan–Meier Estimates of Cumulative Hazard Rates of CHD.

20. Menopause: HERS trial (Heart and Estrogen/Progestin Replacement Study) • HERS trial (Heart and Estrogen/Progestin Replacement Study) • A randomized, blinded, placebo-controlled secondary prevention trial enrolling 2763 postmenopausal women under the age of 80 with a history of CHD were randomly assigned to receive the same regimen used in the WHI (0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily) or placebo for an average of four years • Among women with CHD who were followed for a total of 6.8 years, there was no reduction in risk in women in the treatment group as compared with women in the placebo group

21. Menopause: HERS Trial (Summary of Results) NEJM 348;7 Feb 13, 2003

22. Menopause: Recommendations • USPSTF (The U.S. Preventive Services Task Force): Recommends against the routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women. • The American College of Obstetricians and Gynecologists: recommend against the use of HRT for the primary or secondary prevention of cardiovascular disease • North American Menopause Society: recommend against the use of HRT for the primary or secondary prevention of cardiovascular disease. • American Heart Association: recommends against the use of HRT for primary or secondary prevention of cardiovascular disease

23. Menopause: Recommendations • FDA- recommends using ERT for moderate to severe vasomotor symptoms at lowest possible dose • Also topical estrogens are recommended for vaginal complaints. • Contraindications to using estrogen: abnormal genital bleeding, breast cancer, h/o of thrombotic events, liver disease • Generally, the sentiment about ERT use in light of current evidence is to limit postmenopausal estrogen use. For selective symptomatic women, short term use may have a favorable benefit-harm ratio. This will need to be discussed the patient for an individualized decision.

24. Menopause: Alternative Treatment Options • Alternative Treatment Options • Isoflavones (soy/red clover)- • RCT revealed that 60g of soy protein daily reduced hot flashes by 45% • This is a lot of soy! Consider the caloric implications. • Megestrol, clonidine, SSRI have been shown to reduce hot flashes by 40-80%, but less effective than estrogen • Exercise- observational studies show that regular exercise reduces the incidence of severe hot flashes • Black cohash- implicated in symptomatic benefit, no good evidence to support this • Dong Quai- RCT in 1997 revealed no significant benefit • Evening Primrose Oil- no evidence to support any benefit

25. References • Nelson, HD MD. Post menopausal Estrogen for Treatment of Hot Flashes. JAMA 2004 291;13:1621-1625. • Diagnosis and clinical manifestations of menopause. UpToDate 2005 • Bastian, LA et al. Is this Woman Perimenopausal? JAMA 2003 289;7:895-902. • Grodstein F et al. Understanding the Divergent Data on Postmenopausal Hormone Therapy. NEJM 2003 348;7 645-650. • Morelli V and Naquin C. Alternative Therapies for Traditional Disease States: Menopause. America Family Physician. 2002 66;1 129-134.