PERIMENOPAUSE Patricia J. Sulak, MD Founder, Living WELL Aware LLC Author, Should I Fire My Doctor? Author, Living WELL Aware: Eleven Essential Elements to Health and Happiness Endowed Professor Texas A&M College of Medicine Department of Obstetrics and Gynecology Baylor Scott & White Health, Temple Texas Objectives Define the menopausal transition. Describe the hormonal changes and their consequences and bleeding patterns. Discuss evaluation of the perimenopausal patient. List therapies for perimenopausal women. Disclosure I am Founder of Living WELL Aware LLC I will be discussing off label uses of contraceptives. Percent 1 9 8 7 6 5 4 3 2 1 The Menopause 47.5 51.3 45 46 47 48 49 5 51 52 53 54 55 Age (Years) Perimenopausal Postmenopausal McKinlay et al. Maturitas 1992. Epidemiology Age 6 (Years) 4 Age of Menopause and Life Expectancy 8 2 Definitions of Menopausal Transition: STRAW 185 19 195 2 Date Anderson RN. National Vital Statistics Reports. Hyattsville, 1999;47(28) 1
STages of Reproductive Aging Workshop Definition: STRAW Stages: Terminology: Variable Menstrual to Cycles: regular Menopause Terminology: STRAW* Staging System -5-4 -3 Reproductive Regular Endocrine: Normal FSH FSH -2 Menopausal Transition FSH Final Menstrual Period Variable cycle length (>7 days different from normal) -1 ³2 skipped cycles and an interval of amenorrhea (³6 days) +1 +2 Postmenopause None FSH *STRAW = Stages of Reproductive Aging Workshop Soules, MR et al. Fertil Steril. 21;76:875-878 Defining Hormonal Status Premenopause Menses in previous 3 months with no change in menstrual regularity in preceding year Early Menses in previous 3 months and changes in regularity in past year Late No menses in previous 3 months, but menses in previous 11 months Menopause 12 or greater months of amenorrhea Menopause 29; 16: 86-869 Study Women s Health Across the Nation SWAN Study of Women s Health Across the Nation: SWAN Prospective, longitudinal multiethnic study of over 3 women aged 42 to 52 at 7 U.S. sites from 1995-22 seen annually x 6 yrs Eligibility: uterus present, at least one ovary, not using hormones, menses in last 3 months Numerous variables evaluated and reported in several publications 2
Change in HRQL in menopausal transition in a multiethnic cohort of middle-aged women: SWAN Menopause 29; 16: 86-69 Ethnic groups: 48% white, 27% black, Hispanic 7.5%, Chinese 8%, Japanese 9% Reduced physical functioning was sign. greater at late peri- and post menopause; muscle / joint pain Changes in HRQL over the menopausal transition are largely explained by symptoms related to menopause and or aging Depressive symptoms during the menopausal transition: SWAN J Affect Disord 27; 13: 267-72 Most midlife women do not experience high depressive symptoms but those that do more likely to occur during peri- or postmenopause Health and psychosocial factors increased the odds of having a high depression score and in some cases were more important than menopausal status (ex. difficulty paying for basics, negative attitudes, poor perceived health, stressful events) Findings in Numerous SWAN Publications Findings in Numerous SWAN Publications Higher % of body fat assoc. with increasing odds of VMS Am J Epidemiol 28; 167: 78-85 VMS higher in: Blacks, increasing BMI, smokers, h/o anxiety, less educated, and particularly in late perimenopause Am J Public Health 26; 96: 1226-35 Higher testosterone level sign. assoc. with higher depression scores during menopausal transition but no assoc. with other hormones (estradiol, FSH, DHEA-S) Arch Gen Psychiatry 21; 67: 598-67 While Blacks reported more VMS, Whites reported more psychosomatic symptoms. Soc Sci Med 21; 52: 345-56 Odds of developing metabolic syndrome increased during the menopausal transition. Increase in testosterone or a decrease in SHBG increased the odds. Arch Intern Med 28; 168: 1568-75 Bone loss accelerates with menopause (~1%-2% per year) Age-related bone loss (~.5%-1.% per year) Symptoms/Sequele of 6 5 1 AGE in YEARS Menstrual changes Vasomotor symptoms Mood alterations Decreased HRQL Infertility Declining bone mass Increased risk CVD Physical decline 3
Physiology of the Progressive follicular depletion (quantity/quality) Birth: 1 million follicles Constant rate of atresia,? accelerated in late 3s secondary to elevated FSH Menopause: approx. 1 follicles remaining Genetic factors: family history Environmental factors: smoking Characterization of Reproductive Hormonal Dynamics in the Study comparing the hormonal dynamics of cycling women aged 47 and older, compared to women aged 43 to 47, and women aged 19-38. Measured LH, FSH, estrone conjugates, and pregnanediol glucuronide Santoro et al. J Clin Endocrinol Metab 81:1495-151, 1996 Physiology of Reduced quality / quantity of aging follicles Reduced secretion of inhibin (granulosa cells); exerts negative feedback on FSH Increase in FSH: increased follicular response Increase in estrogen levels and inadequate luteal progesterone production Eventually ovarian follicular depletion and a hypoestrogenic state Perimenopausal Hormonal Dynamics Shorter follicular phase of menstrual cycle Greater estrone conjugate excretion: hyperestrogenism Elevated FSH and LH levels Decreased luteal phase progesterone excretion Santoro et al. J Clin Endocrinol Metab 81:1495-151, 1996 Perimenopausal Menstrual Patterns Shortened follicular phase of menstrual cycle (from an average 14 days to 11 days); cycles every 24 days or less, instead of 28 to 3 Increased estrogen throughout ovulatory cycles with decreased luteal progesterone leading to AUB Eventually, anovulatory cycles: AUB-O Finally, hypoestrogenic cycles with elevated gonadotropins; menses further apart and lighter 4
Perimenopausal Transition Hyperestrogenic Hypoprogestagenic State } Endometrial hyperplasia Growth of fibroids Menorrhagia Dysfunctional bleeding Hormone Transition In the early phase, most perimenopauseal cycles are ovulatory but shortened follicular phase Cycles of hyperestrogenism with luteal phase hypoprogesterone state Progression to tonically elevated gonadotropin (FSH) secretion and persistently low estrone excretion as approach menopause -- NOT AN ORDERLY PROGRESSION -- Premenopause Menopause Discontinuous, erratic, unpredictable process Can begin in late 3s Each cycle is an independent event FSH is constantly fluctuating and does not help predict when menopause will occur FSH (mlu/mgcr) 1 8 6 4 2 FSH and E 1 Variability in a Perimenopausal Woman 25 2 4 6 8 9 11 13 16 17 266 FSH E 1 Days FSH variability makes diagnosing menopause using a single FSH value unreliable Estrogen variability may account for perimenopausal menstrual irregularities 15 1 5 E 1 (ng/mgcr) Santoro N et al. J Clin Endocrinol Metab. 1996;81:1495-151 Hormonal Roller Coaster Hormonal Changes in Perimenopausal and Postmenopausal Women After Last Menses Mean concentrations of estradiol (E 2 ), FSH, and testosterone (T) stratified by months from last menses Anovulation E 2 and T Concentrations (pg/ml) 25 2 15 1 5 25 2 15 1 5 FSH Concentration (miu/ml) E 2 FSH T -- Constantly fluctuating hormonal state -- <3 3 to 9 9 to 12 12 to 24 >24 Months From Last Menses Longcope C, et al. Maturitas. 1986;8:189-196 5
Factors To Consider in Management of Management of the PERIMENOPAUSE What is the hormonal status of the patient? What are the patient s concerns? What are our concerns? What are the options for mgt of the hormonal issues? What is the Hormonal Status? Progesterone deficient only (estrogen excess) Estrogen deficient only Estrogen and progesterone deficient What are the patient s concerns / our concerns? Symptoms: hot flashes, vaginal dryness, mood alterations, abnormal bleeding. Risk Factors: osteoporosis, heart disease, endometrial cancer, general well-being : Preventive Healthcare : Screening Tests Smoke cessation Maintenance of IBW Exercise Healthy eating Calcium supplements HRQL Pap Smear Mammogram Lipid profile DM screening TSH Colon CA screening If risk factors: Bone mineral density 6
? What are options? Estrogen only -- how much? Progestin only -- how much/when? Estrogen & Progestin: cyclic vs. combined HRT; combination Ocs Non-hormonal mgt Hormonal Management of Treat Menorrhagia Treat Anovulatory Bleeding Contraception Prevention of bone loss Treat vasomotor symptoms Increased risk DVT/PE OCs HRT ü ü ü ü ü ü ü ü ü Beneficial Effects of Perimenopausal Oral Contraceptive Use Contraception Menstrual cycle control Cancer protection Prevention of bone loss Treat vasomotor symptoms Beneficial effects on breast Beneficial Effects of Perimenopausal Oral Contraceptive Use Reduced Need for Surgical Procedures Endometrial Biopsy Possible decrease in fibroid growth, endometriosis, and ovarian cysts HORMONE THERAPY 7