Menopause Update: From the Menopausal Transition to Healthy Aging

1. Menopause Update: From the Menopausal Transition to Healthy Aging Nancy Fugate Woods, RN, PhD, FAAN University of Washington School of Nursing

2. Purposes • Review the historical development of research support for women’s health with particular emphasis on menopause • Identify breakthroughs in menopause research over the past twenty years • Challenge researchers and clinicians regarding needs for future research efforts related to menopause and healthy aging

3. Aging of the Baby Boomers extended our focus from menopause to healthy aging as part of the first NIH Women’s Health Research Agenda (1991)

4. In 1991 the first Women’s Health Initiative study sites were funded Launch of the tri-part study: clinical trial of hormone therapy, calcium and Vitamin D, low fat/high fiber diet; the observational study; and the community prevention studies led by the CDC

5. March 1993 – first National Institutes of Health working conference on Menopause: Current Knowledge and Recommen-dations for Research

6. 1999 –2nd NIH Women’s Health Research Agenda • Included attention to diverse populations of women

7. Agenda for Research on Women’s Health for the 21st Century: The Menopausal Process (1999) • Clarify and define the various stages comprising the transition from premenopause to perimenopause to postmenopause • Characterize the normal antecedents and sequellae of the menopause transition, distinguishing the influence of menopause from disease processes and the aging processes • Behavioral aspects of menopause • Pharmacologic issues related to menopause

8. Breakthroughs in Menopause Research • Staging the Menopausal Transition • Characterizing Women’s Physiology during the Menopausal Transition • Identifying Symptoms associated with the Menopausal Transition and their Correlates: Basis for Symptom Management • Identifying the Consequences of Menopause for Healthy Aging

9. Staging Reproductive Aging Workshop (STRAW) • Workshop sponsored by the National Institute on Aging, National Institute of Child Health and Human Development, North American Menopause Society and American Society for Reproductive Medicine – 2001 • Purposes • Develop preliminary staging system for the menopause transition • Re-evaluate existing nomenclature • Identify knowledge gaps and future research opportunities

10. Benefits of a Staging System • Researchers and clinicians would be able to compare cases and compare data across studies • Women would understand the timing and duration of the transition to menopause, the consequences for their fertility, and whether their bleeding patterns were normative • Clinicians and women time could time decisions about assessment and prevention, e.g. osteoporosis screening (Mitchell, Woods & Mariella, 2000)

11. Proposed Staging System for the Menopausal Transition (STRAW Conference Soules et al 2001)

12. The Seattle Midlife Women’s Health Study

13. Study Design – Seattle Midlife Women’s Health Study • Longitudinal study with 508 women interviewed between 1990-1992 • Annual follow-up since enrollment with 344 women starting longitudinal study in 1992 • Cohort included 220 participants in 1996 when monthly urine samples were added to study and and 193 in 2000 when DNA samples were obtained • Women had 16 years of education, 85-91% employed, 75-89% white, and 68-69% partnered

14. MENSTRUAL CYCLE CALENDAREarly Transition (SWMHS-Mitchell et al 2000)Late Reproductive (STRAW-Soules et al 2001)

15. MENSTRUAL CYCLE CALENDARMiddle Transition (SWMHS)Early Transition (STRAW)

16. MENSTRUAL CYCLE CALENDARLate Transition

17. Age of Onset and Duration of Menopausal Transition Stages (Mitchell, Woods, and Mariella, 2000;2006 update)

18. Study of Women’s Health Across the Nation (SWAN) began in September,1994 with funding from the National Institute on Aging, and additional support from the National Institute of Nursing Research and the Office of Research on Women’s Health.

19. Goals of SWAN • To describe the chronology of the biological and psychosocial characteristics of the menopausal transition • To describe the effects of this transition on subsequent health and risk factors for age-related chronic conditions • Emphasis placed on: • Multi-ethnic samples • Community or population-based sample

20. Characterizing Women’s Physiology during the Menopausal Transition • SWAN Study included Daily Hormone Study over multiple years as well as annual blood draws, interviews, clinical exams, and questionnaires • Representation of multiple American ethnic groups of women: African-, Chinese-, Japanese-, Hispanic and White-Americans • Women ages 42-52 at entry to study, still being followed

21. SWAN Cohort Composition New Jersey Pittsburgh Michigan UC Davis Boston Chicago UCLA 162 199 281 250 248 286 325 934 281 250 286 1550 301 African Am 253 Japanese 208 215 209 Chinese 146 218 Hispanic Caucasian 452 463 456 543 496 459 432 3301 Total

22. Model for Ovarian Aging (Santoro 2005) FMP Stable Ovarian Function Critical Level of Follicle Depletion Subsequent Progress: Multiple Modifying Factors Santoro 2005

23. Comparison of Reproductive Age and Perimenopausal Women’s Cycles Santoro 1999

24. Increased E2 as ovary overshoots response to FSH – Santoro 1999

25. Mechanisms Initiating Menopause • Does central nervous system aging or clocks control the onset of menopause, e.g. by altering sensitivity to ovarian steroids? Increasing the elaboration of FSH? • Does ovarian aging control the onset of menopause, e.g. by follicular depletion? Producing less estrogen? Anovulatory cycles?

26. Presence of Luteal Activity by Age: SWAN Data (Santoro 2003)

27. Hypothalamic-pituitary Sensitivity to Estrogen (Weiss et al 2005) • SWAN Participants were studied in a daily urinary hormone study (n=848) • Three groups of women were studied who had: • estrogen increases and an LH surge • estrogen increases without an LH surge • neither estrogen increases nor an LH surge

28. Decrease in Estrogen Sensitivity • Anovulatory cycles with estrogen peaks were frequent in older reproductive age women; in these women there is evidence of failure of the estrogen-positive feedback on LH secretion to trigger ovulation • In anovulatory cycles follicular estrogen levels did not lower LH secretion as occurs in younger reproductive age women; there is decreased estrogen-negative feedback on LH secretion • (Weiss et al, 2005)

29. Melbourne Midlife Women’s Health Project • Charted the course of the natural transition to menopause for a population based sample of Australian white women (N=453) (begun 1990) • Compared women who remained in the late reproductive stage or in the menopausal transition with those who became postmenopausal over an 8 year period

30. Burger et al 2000

32. DHEAS by FMP and Age (Burger 2000)

33. The Seattle Midlife Women’s Health Study

34. FSH by Menopause Transition Stages: Middle – Post: Seattle Midlife Women’s Health Study

37. Estrone (E1G) by Menopause Transition Stages: Middle to Postmenopause:

42. Estrone and FSH Levels (Urinary) by Menopausal Transition Stages: Seattle Midlife Women’s Health Study Di Julio et al, in press Maturitas

43. Understanding Symptoms and their Correlates: Menopausal Transition • National Institute on Aging proposed that the NIH office of Medical Applications of Research (OMAR) Consensus Development Program convene an NIH State of the Science Conference on Management of Menopause-Related Symptoms (March 2005) • Proceedings published in special Issue of the American Journal of Medicine (vol 118, no 12B, 2005)

44. Which symptoms do women report during the perimenopause? • Vasomotor symptoms – hot flashes and night sweats • Dysphoric Mood – e.g depressed mood, irritable, tense • Sleep disruption • Sexual concerns or problems • Cognitive changes – e. g. forgetful • Vaginal dryness • Urinary incontinence • Somatic/bodily pain symptoms • Breast pain • Bleeding symptoms

45. Seattle Midlife Women’s Health Study • Charting the course of the natural transition to menopause for a population based sample of 35-55 year old white, Asian, and African American women (n=375) in longitudinal study begun in 1990 and followed until 2006 • Women were in late reproductive stage or early menopausal transition stage at recruitment • Women provide daily health diary recordings for 3 days per month, monthly early am urine sample for endocrine analyses, and annual health update • Symptoms rated from 0 (absent) to 4 (extreme)