1. By 2010, 45% of American women will be over age 50 Natl Center for Health Statistics

2. Perimenopausal Transition Years 100 75 50 25 0 30 35 40 45 50 55 60 Age (years) Postmenopause Reproductive Years Women (%)

3. Changes Prior to Menopause  Anovulatory cycles  or  Menstrual cycle length  FSH level (day 3)  Inhibin B

4. 1. Klein NA, Soules MR. Clin Obstet Gynecol. 1998;41:912-920. 2. Munster K et al. Br J Obstet Gynaecol. 1992;99:422-429. Perimenopause Time of transition characterized by unstable endocrine physiology and highly variable, unpredictable hormone profiles 1 Although cycle length begins to shorten, potential for ovulation and pregnancy is preserved for a number of years 1,2

5. The Perimenopausal Transition: Endocrine Changes Mean Circulating Hormone Levels Adapted from Speroff, Glass, and Kase. Clinical Gynecology and Endocrinology. 6th ed. Williams & Wilkins;1999:653. 80 70 60 50 40 30 20 10 0 FSH & LH IU/L Estradiol Estrone pg/mL 200 160 120 80 40 0 4446485052545658 Age (years) Menopause FSH LH Estradiol

6. Changes Associated With Declining Estrogen Concentrations Hot flushes Urogenital atrophy Mood changes Changes in cognitive function Bone loss Changes in skin appearance Increase in risk of cardiovascular disease Physiologic changes of the eye

7. Symptoms Early phase –Breast tenderness –Irregular menstruation –Irritability –Loss of sense of wellness –Hot flashes/night sweats –Sleep disturbance Late phase –Cognitive dysfunction –Irregular and abnormal flow –Sexual dysfunction –Somatic symptoms increase

8. When Does Perimenopause Occur? Average 1 Range* Age of Onset (y)4639-51 Duration (y)3.8 2 2-8 *95% of women. 1 Adapted from Speroff, Glass, and Kase. In: Clinical Gynecology and Endocrinology. 6th ed. Williams & Wilkins;1999:653. 2 McKinley Maturitas 1992; 14: 103-115

9. Age of Menopause Median age of natural menopause (y) 1,2 Overall51.1-51.4 Smokers1 to 2 years younger Likelihood of being menopausal by 1,2 Age 50 y~30% Age 55 y*  80% *May be more appropriate than age 50 for OC discontinuation. 1. Stanford JL et al. J Chron Dis. 1987;40:995-1002. 2. McKinlay SM et al. Ann Intern Med. 1985;103:350-356.

10. Menstrual Cycle Changes: Hallmark of Perimenopause

11. Changes in Cycle Length During Perimenopause Menstrual Cycle Length Shortens 35 30 25 15202530354045 Age (years) Mean 5th, 25th, 50th, 75th, and 95th centile values Cycle Length (days) Adapted from Munster K et al. Br J Obstet Gynaecol. 1992;99:422-429.

12. Menstrual Cycle Changes: Hallmark of Perimenopause Usually shorter cycle length (eg, by 2 to 7 days) –longer or irregular less common Changes in quality –Heavier initially, then lighter –Spotting prior to menses Adapted from Nachtigall LE. Clin Obstet Gynecol. 1998;41:921-927.

13. Vasomotor Instability During Perimenopause “Hot flashes are one of the chief menopausal complaints for which women in Western societies seek medical treatment.” 1 1. Kronenberg F. Ann N Y Acad Sci. 1990:592:52-86.

14. Vasomotor Instability During Perimenopause ~ 85% of perimenopausal women experience vasomotor instability –hot flushes, night sweats, sleep disturbances Intensity, duration, and frequency highly variable –1-2 to 40 flushes/day Nachtigall LE. Clin Obstet Gynecol. 1998;41:921-927.

15. Menstrual Status % Reporting Hot Flashes Premenopausal * ~10 Perimenopausal † ~30 – 85% Recently postmenopausal ~20 – 90% 4 years postmenopause ~20 – 60% Vasomotor Instability During Perimenopause * Menstruation within the 3 prior months with no change in regularity of cycle. † 3 to 11 months of amenorrhea or increased menstrual irregularity. 1.McKinlay SM et al. Maturitas. 1992;14:103-115. 2. Kronenberg F. Ann N Y Acad Sci. 1990:592:52-86. 3. Nachtigall LE. Clin Obstet Gynecol. 1998;41:921-927

16. Serum Concentrations of Ovarian Hormones Premenopause (mean)Postmenopause (mean) Estradiol (pg/mL)50-400 8-35 (<25) Estrone (pg/mL)30-30020-60 Testosterone (ng/dL)20-50 (35) 30 Androstenedione (ng/dL)~130~50 Ovaries produce more androgen than estrogen.

17. Consequences of Menopausal Hormone Deficiency Last period Age (year) Bone loss/osteopenia 4090+45 5550606570758085 Menopause symptoms Sexual complaints Urogenital atrophy and symptoms Vascular and heart disease Osteoporosis

18. Hot flushes/night sweats Palpitations Sleep disturbance Chest pressure Shortness of breath Headaches Numbness Fatigue Weakness Joint pain Decreased sexual desire Vaginal dryness and painful intercourse Loss of urinary control Memory loss Anxiety Depression The Menopausal Syndrome

19. Prevalence of Vasomotor Complaints Oldenhave A, et al. Am J Obstet Gynecol. 1993;168:772-780. Severity 0 Absence 1 2 3-4 5-6 Moderate/Severe 100 75 50 25 0 Regular menstrual bleeding Pre/perimenopause (months since last menstrual bleeding) Postmenopause (years since last menstrual bleeding) <11-33-66-12124356-78-10>10 Reporting Complaints (%)

20. Genitourinary Symptoms Associated With Menopause Genital Irritation, burning, pruritus Leukorrhea Dyspareunia Decreased vaginal secretions Shortening/lessening of vaginal distensibility Urinary Frequency, urgency Dysuria Nocturia Incontinence* *Controversial.

21. Vaginal Cytology PremenopausePostmenopause

22. Effect of Estrogen on Vaginal Symptoms E 2 = 17 ß-estradiol; CEE = conjugated equine estrogens. Rioux JE, et al. Menopause. 2000;7:156-161. Vaginal symptoms score: 0 = none, 1 = mild, 2 = moderate, 3 = severe 0.0 0.5 1.0 1.5 2.0 02 1224 Mean Composite Scores Weeks of Treatment Vaginal tablets E 2 25  g (n = 80) Vaginal cream CEE 1.25 mg (n = 79)