1. Menopause MS II Joanna Wilson, D.O. Internal Medicine, HerCare at Amarillo Diagnostic Clinic Community Associate Professor of Internal Medicine Texas Tech, Amarillo

2. Proportion of average female lifespan spent in menopause years: 1/3 to 1/2 Objectives: To recognize the physiology of the menopause To review the natural experiences of menopause To appreciate the challenges of symptom treatment

3. Stages: -5-4-3-2+1+2 Terminology: ReproductiveMenopausal TransitionPostmenopause EarlyPeakLateEarlyLate * Early * Late Perimenopause Duration of Stage: variable 1 yr 4 yrs until demise Menstrual Cycles: variable to regular regular variable cycle length (>7 days different from normal)  2 skipped cycles and an interval of amenorrhea Amen x 12 mos none Endocrine: normal FSH  FSH 0 * Stages most likely to be characterized by vasomotor symptoms ¥ STages of Reproductive Aging Workshop Final Menstrual Period (FMP) STRAW ¥ Staging System Adapted from Soules et al., Fertility and Sterility, VOL. 76, NO. 5, November 2001, p. 875

5. Determinants of Age at Menopause (Average Age =51 years) Unaffected by: – Race – Socioeconomic status – Number of pregnancies – Oral contraceptive use – Education – Physical characteristics – Age of menarche – Age of last pregnancy Affected by: – Smoking – Family pattern – Chemotherapy – Nulliparity – Hysterectomy* – Excessive alcohol intake* – *=possible assn

6. Can We Predict Menopause? No Antimullerian hormone Synthesized in the granulosa cells of preantral and small antral follicles Inhibits the transition from primordial into primary follicles preventing excessive follicular recruitment by FSH – Correlates strongly to antral follicle count = “functional ovarian reserve” Peak level at age 30 Undetectable about 5 years prior to final menstrual period – Potential predictor of menopause Less useful for younger ( 57 years)

8. FSH >30 Suggests Cessation of Ovulation

9. Hypothalamus Hypothalamic-Pituitary Circulation GnRH Anterior Pituitary Gland Estrogen Progesterone FSH LH Hypothalamic-Pituitary Circulation: Prior to Menopause

10. Hypothalamus Hypothalamic-Pituitary Circulation GnRH Anterior Pituitary Gland Estrogen Progesterone FSHLH Hypothalamic-Pituitary Circulation: Peri-Menopause (anovulatory cycle) X

11. Cycle 1 Anovulation Irregular Bleeding Cycle 2 Anovulation Irregular Bleeding Cycle 3 Ovulation Short Follicular Phase 300 200 100 0 20 10 0 Estradiol (pg/mL) Progesterone (ng/mL) Perimenopause: Intermittent Ovulation and Irregular Cycles

12. Clinical Issues of Menopause: Change in Uterine Bleeding Most common symptom of menopause Irregular bleeding occurs from 10 years prior to final menstrual period (FMP) – Decreased frequency of ovulation (anovulatory cycles) Pregnancy is possible until ALL ovulation ceases Uterine bleeding after menopause is always cause for concern if the patient is not taking hormones

13. Estrogen Receptors Are In Almost Every Cell!

14. Clinical Issues of Menopause: Vasomotor Symptoms Second most common symptom of menopause Primary reason women seek medical treatment 1-5 minutes with increased skin temp. 1-7˚C More frequent and severe after premenopausal oophorectomy

15. Years BeforeYears After Menopause Prevalence of Hot Flashes 321123 Prevalence of Vasomotor Symptoms > 75% of women report hot flashes within the 2-year period surrounding their menopause 25% remain symptomatic for > 5 years 5% of women have hot flashes or night sweats forever Kronenberg F. Ann N Y Acad Sci. 1990;592:52-86.

16. Clinical Issues of Menopause: Sleep Disturbances Trouble getting and staying asleep Triggers may be joint pain, flashes, stress Usually cause fatigue, poor focus, and irritability Often associated with underlying sleep disorder Melatonin, Trazodone, non-BZD’s, BZD’s, sleep hygiene, meditation Progesterone may help

17. Clinical Issues of Menopause: Cognition (“Menopause Fog”) Forgetfulness, “cloudy” thinking Due to variations in estrogen – Exacerbated by multi-tasking, depression, anxiety Treatment includes daily physical exercise and adequate sleep Refer for neurocognitive testing for dementia or ADHD if severe – Alzheimer’s Dementia is more common in older women

18. Clinical Issues of Menopause: Psychological Symptoms Menopause does not cause depression – Depression is more likely to resurface if present prior to menopause Anxiety is frequent – Stressors: children leaving, ill parents, job changes, financial, marriage, physical changes Counseling, cognitive behavioral therapy, antidepressants, BZD’s, exercise, estrogen

19. Clinical Issues of Menopause: Urinary Health Ureteral thickening recurrent cystitis, frequency pH rises alters vaginal flora balance Loss of pelvic organ support cystocele, rectocele Loss of pelvic floor tone incontinence, muscle spasms Overactive Bladder (wet or dry)

21. Clinical Issues of Menopause: Sexual Function Majority of women state their sexual relationships did not change during menopause Most common complaints: low libido, vaginal dryness Barrier methods of prevention should be encouraged for sexually active women with a new partner

22. Clinical Issues of Menopause: Hair Changes Female pattern hair loss (FPHL): thinning on the crown – Hypoestrogenemic and relative hyperandrogenic state Estrogen prolongs anagen phase Testosterone shortens anagen phase with progressive miniaturization of susceptible hair follicles – Off-label treatment may include antiandrogens (spironolactone) or topical minoxidil, biotin, finasteride

23. Clinical Issues of Menopause: Dental Health Hormone receptors exist in the basal and spinous layers of the epithelium and connective tissue Fluctuations of sex hormones around menopause have been implicated in inflammatory changes in gingiva – Atrophy of bony tooth sockets leading to gum retraction, periodontal pocket development, bacterial invasion, and periodontitis Rate of systemic bone loss is a predictor of tooth loss – For each 1%/year decrease in BMD, the risk for tooth loss more than quadruples

24. Clinical Issues of Menopause: Bone Loss

25. First 5 years after menopause is time of more accelerated bone loss DXA indicated for patients with risk factors, and for those whom treatment would be initiated – http://www.shef.ac.uk/FRAX/tool http://www.shef.ac.uk/FRAX/tool – NOF Clinician’s Guidelines

26. Clinical Issues of Menopause: Body Composition Change Average weight gain = 5 lbs. – Increased central fat distribution Weight gain assd with – Metabolic Syndrome – Hot flashes – Sleep deprivation – Sedentary lifestyle Decrease in muscle mass – Resistance training most beneficial

27. Hypertension: Gender and Age Effects AgeMen (%)Women (%) 20-3411.16.8 35-4425.119.0 45-5437.135.2 55-6454.053.3 65-7464.069.3 75 and older66.778.5 All34.132.7

28. LDL Cholesterol Levels After Menopause Menopause Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31

29. HDL Cholesterol Levels After Menopause Menopause Jensen J, et al. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12:321-31

31. Endothelial Cell Layers in Healthy Postmenopausal and Premenopausal Women Postmenopausal cells show evidence of endothelial cell death, denudation, and RBC, platelet, and protein attachment, as well as fractured basal membranes, and loss of intercellular junctions Premenopausal cells show tight connections, a continuous layer of endothelial cells, and thick plasma membranes

32. Compounded “Bioidentical” Hormones Dosing schedule mimics premenopausal state in postmenopausal women Plant derived hormones modified to be identical to human molecules Not regulated for purity of modification process Saliva levels do not accurately measure tissue levels Progestogen skin cream has not been proven effective to prevent endometrial cancer

33. Hormone Therapy (HT) Estrogen (E) treats: – Hot flashes – Night sweats – Mood – Vaginal dryness – Cognitive slowing Progesterone (P) treats: – Endometrial proliferation from estrogen stimulation

34. HT Regimen Choices: Cyclic: daily E with cycles of P vs. Continuous Combined Cyclic Advantages Predictable withdrawal bleeding every month Disadvantages 2-pill dosing may discourage compliance Withdrawal bleeding persists indefinitely Continuous Combined Advantages Most women will achieve amenorrhea in time Convenient 1-pill dosing enhances compliance and ensures appropriate progestin treatment Lower risk of endometrial hyperplasia compared with cyclic regimen Disadvantages Unpredictable spotting Daily progesterone exposure and side effects

35. The Women’s Health Initiative in Women With Uteri

36. The Women’s Health Initiative in Women Without Uteri

37. Estrogen and Progestin Risks Venous thromboembolism (DVT, PE) risk is increased with both E and P use – Risk appears reduced in transdermal estrogen vs oral – Risk appears reduced in first and second generation progestins vs newer Arterial clot risk is higher in smokers, and women with HTN, DM, and high cholesterol Risks of both types increase with age

39. “The Timing Hypothesis” (Early exposure to HT might be good!) Sex steroid hormones alter the biology of vessel wall cells and the inflammatory cells that accumulate differently according to the stage of the disease – It is likely that early physiological sex hormone replacement can improve or reverse early endothelial dysfunction – HT given in advanced atherosclerotic lesions likely predisposes the lesion to inflammatory and hemostatic abnormalities

40. Assess Your Patient’s Risk Before Starting HT Safety of Hormone Treatment Time Since Menopause High Blood Pressure Diabetes Smoking Heart Attack Stroke Breast Cancer Blood Clot

41. Next Studies to Evaluate Type and Exposure Age Elite: Early Versus Late Intervention Trial With Estradiol – Oral E2 vs. placebo – Measuring Carotid intimal medial thickness KEEPS: Kronos Early Estrogen Prevention Study – CEE vs transdermal E2 with micronized progesterone – Measuring carotid IMT

42. Non-Estrogen Symptom Therapies Selective Serotonin Reuptake Inhibitors Serotonin Norepinephrine Reuptake Inhibitors Gabapentin Clonidine OTC Vaginal moisturizers and lubes Vitamin E, coconut oil, olive oil Phytoestrogens (soy, black cohosh, flax)

43. Variable Stimulation of the Estrogen Receptor Results in Tissue Specific Responses

44. Creating the Perfect Estrogen Replacement

45. Newest Menopause Therapies Duavee (CEE + bazedoxifene) – FDA-approved for vasomotor symptoms and prevention of postmenopausal osteoporosis Osphena (Ospemiphene) – FDA-approved for painful intercourse due to vulvovaginal atrophy

46. Menopause Summary The sex hormone deficiency of menopause affects nearly every cell of the body Vascular disease, osteoporosis, genitourinary, dental, and skin changes increase in prevalence after menopause Estrogen and non-estrogen treatments are available for symptom management Hormone therapy given near the age of menopause has many benefits, but the safety data is inconclusive

47. Thank You! Questions? Arrange for a 4 th -year rotation in Women’s Health in my clinic!