Menopause

1. Menopause Permanent cessation of menses for at least 1 year FSH > or = 40 IU/ml Signs of hypoestrogenism

2. Perimenopause • The Period surrounding menopause: • Before, during, and after • Mean age of onset: 46 yrs. • Mean duration: 5 yrs. (2-8 yrs.) • Only one marker: Menstrual irregularity • In only 10% of women, menstuation ceased abruptly with no period of prolonged irregularity.

3. What Happens •  follicular quality and/or quality •  INHIBIN Level   FSH Levels with normal or even increased estradiol levels until 6 mo. to 1 yr

4. Initial Evaluations • Medical History and Physical Examination • Breast and Pelvic Examination • Pap Smear (repeat every 1 yrs) • Mammography if >40 yrs (repeat every 1 yrs) • Evaluation of General Medical Conditions • Detection of common medical problems as early as possible: Hypertention, Heart diseases, Diabetes Mellitus, Cancer • STD screening • TSH screening at 40 yrs and q 2 yrs after 60 yrs of age • Occult blood after 50 yrs of age • Evaluation of vision, hearing, and teeth impairments

5. Hormonal Levels •  FSH (10-20) >  LH (3) • FSH (T1/2 = 3-4 hr)has longer halflife than LH (T1/2 = 20 min) • There is no negative feedback system like Estrogen for LH • Changes in circulating hormone levels at menopause

6. Age Of Menopause • The most important determinant factor is genetics. • Mothers and daughters tend to experience menopause at the same age • Factors that cause slightly earlier menopause • Tobacco use (about 1.5 yrs) • Nulliparity • Living in high altitude • Heavy physical exercise • Undernurishment and thinness • Vegetarrian diet • IUGR in late gestation • Previous Hx. Of TAH or endometrial ablation • Irregular menses at early 40s

7. Age Of Menopause • These factors don’t affect the age of menopause • Use of OCPs • Socioeconomic states • Marital status • Age of menarche • Parity • Race • Height • Premature ovarian failure: Spontaneous menopause before 40 yrs of age

8. Problems • Unopposed Estrogen • AUB •  risk of endometrial cancer • Hypoestrogenism • Vasomotor, emotional, atrophic, cognitive, cardiovascular, and musculoskeletal impacts • Estrogen-Progestin Therapy

9. Indications of ERT • Menopause • Hot Flashes • Vaginal Atrophy • Urinary Tract Symptoms • High risk for osteoporosis (Family Hx., Cigarette smoking, Low body weight) • High risk for cardiovascular disease (Previous myocardial infarction, Hypertention, Family Hx., Cigarette smoking)

10. Contraindications for ERT • Absolute • Pregnancy • Undiagnosed uterine bleeding • Active thrombophlebitis • Current gallbladder diseases • Liver diseases • Neuro-ophthalmologic eye diseases • Relative • Hx. of breast cancer • Hx. Of recurrent thrombophlebitis or thromboembolic disease • Migraine headache ? • Epilepsy ?

11. Indications for • Pretreatment Endometrial Biopsy: • Characteristics associated with high risk endometrial pathology • Hx. of unopposed estrogen therapy • During-treatment Endometrial Biopsy • Clinician’s anxiety • Patient’s anxiety • Treatment with unopposed estrogen • AUB during treatment • Endometrial thickness > 4 mm • D & C • Cervical stenosis • Abnormal pelvic exam • Suspicious endometrail biopsy results • Patient’s pain intolerance

12. Complex hyperplasia or malignancy Hystero- scopy and fractional curettage Atypical hyperplasia or malignancy Hysterec-tomy (or other definitive therapy) Abnormal Normal or simple hyperplasia Abnormal Bleeding Endometrial Biopsy Tissue insufficient for diagnosis Ultrasound and/or office hystero-scopy Normal Group therapy (repeat endo. Biop. In 6 mo) Simple hyperplasia or normal pathology Abnormal Uterine Bleeding • Management of postmenopausal AUB

13. Biopsy Results • Endometrial biopsy results in post-menopausal period: • 1-2% Cancer • 50% Normal • 3% Polyps • The rest atrophic • Plans for Treatment: • Cancer and/or Atypical Hyperplasia  HYSTERECTOMY • Simple hyperplasia  Med. Prog. Acetate 10 mg/day for 12-14 days per month • Nonresponders (6-7%)  Re-evaluate after 3-4 months • If persistant AUB or Hyperplasia again  D&C • If hyperplasia regressed  conyinue progestrone therapy until vasomotor symptoms begin and/or no withdrawal bleeding anymore. Evaluate for ERT. • Conterception

14. Menopause • The Hot Flashes

15. High cholestrol High LDL LDL entry into endothelium Monocyte adherence, entry, and conversion to macrephages Foam cells Fatty streak Smooth muscle cell proliferation and migration LDL oxidation Endothelial injury and dysfunction Vaso-constriction Thrombus Athero-sclerotic fibrous plaque Menopause • Menopause and the Perimenopausal transition

16. Consequences • Cardiovascular • The optimal cholestrol/lipoprotein profile • Total cholestrol: Less than 200 mg/dl • HDL cholestrol: Greater than 50 mg/dl • LDL cholestrol: Less than 130 mg/dl • Triglycerides: Less than 250 mg/dl •  Risk of MI • Total cholestrol > 256 mg/dl • Triglycerides > 400 mg/dl • HDL cholestrol < 50 mg/dl • Risk of Heart diseases based on Chol/HDL ratio • < 2.5 Lowest risk • 2.5-3.7 Below average risk • 3.8-5.6 Average risk • 5.7-8.3 High risk • > 8.3 Dangerrous

17. Excess alcohol Excess caffeine & low calcium Low Vit D Low calcium Diet Age Heparin OSTEOPOROSIS Race Anticonvulsants Environmental factors Pathophysio-logic factors Drugs Lack of estrogen Corticosteroids Body weight Thyroxine Diseases Lifestyle Sedentary Smoking Consequences • Osteoporosis

18. Consequences • Osteoporosis • Commonly associated injuries: • Femoral Head Fx. • Hip Fx. • Vertebral Fx. • Colles’ Fx • Teeth Loss • Specific causes

19. Consequences • Osteoporosis • Laboratory Exams • Ca, Phos, ALP, PTH • RFT • CBC, ESR, Protein Electrophoresis • TFT • Alternative Treatments: • Calcium-Vit D Supplements • Bisphosphonate: ETIDRONATE 400 mg for 2 weeks then 12 weeks drug free OR ALENDRONATE (FOSAMAX Tabs) 5-10 mg/day • Calcitonin: 100 IU/day SQ OR 200 IU/day Intranasal • Raloxifen (EVISTA 60 mg Tabs):  Hot flashes,  risk of breast cancer • Tibolon: 2.5 mg/day

20. Hormone Replacement Therapy • The Sequential Program for Oral Postmenopausal Hormone Therapy • Daily Estrogen 0.625 mg conjugated estrogens, or 1.25 mg estropipate, or 1.0 mg micronized estradiol or equivalent doses of other estrogens • Monthly progestin 0.7 mg norethindrone, or 200 mg micronized progestrone, or 5 mg medroxyprogestrone acetate, or equivalent doses of other progestins given daily for 2 weeks every month • Combined with daily calcium supplementation (500mg with a meal), and vitamin D (400 IU in winter months and 800 IU for women over age 70).

21. Hormone Replacement Therapy • The Continuous Combination Program for Oral Postmenopausal Hormone Therapy • Daily Estrogen 0.625 mg conjugated estrogens, or 1.25 mg estropipate, or 1.0 mg micronized estradiol or equivalent doses of other estrogens • Monthly progestin 0.35 mg norethindrone, or 100 mg micronized progestrone, or 2.5 mg medroxyprogestrone acetate, or equivalent doses of other progestins • Combined with daily calcium supplementation (500 mg with a meal), and vitamin D (400 IU in winter months and 800 IU for women over age 70).

22. Hormone Replacement Therapy • Relative estrogen potencies

23. Hormone Replacement Therapy • Usual initial dosages of estrogens used for HRT • Oral • Conjugated equine estrogens 0.625-1.25 mg daily Synthetic conjugated estrogens 0.625-1.25 mg daily Micronized estradiol 1-2 mg daily Esterified estrogens 0.625-1.25 mg daily Estropipate 0.625-1.25 mg daily Ethinyl estradiol 0.02 mg daily • Topical Patch • 17 b-Estradiol 0.025-0.1 mg patch once or twice weekly • Vaginal • Conjugated equine estrogens 0.2-0.625 mg, 2-7 times per week 17 b-Estradiol 1 mg, 1-3 times/week • Injectable • Estrone 0.1-1.0 mg weekly Estradiol cypionate in oil 1-5 mg IM weekly3-4 Estradiol valerate in oil 10-20 mg IM / 4 weeks

24. Effects of HRT • Cardiovascular • A favorable impact on the circulating lipid and lipoprotein profile, especially a  in total cholestrol and LDL-cholestrol and  in HDL-cholestrol • A direct antiatherosclerotic effect in arteries • Augmentation of vasodilating and antiplatelet aggregation factors, specifically nitric oxide and prostacyclin (endothelium-dependent mechanisms) • Vasodilation by means of endothelium-independent mechanisms • Direct inotropic actions on the heart and large blood vessels • Improvement of peripheral glucose metabolism with a subsequent decrease in circulating insulin levels • Antioxidant activity • Favorable impact on fibrinolysis, at least partially mediated by endothelial nitric oxide and prostacyclin synthesis

25. Effects of HRT • Cardiovascular • Inhibition of vascular smooth muscle growth and migration – intimal thickening • Protection of endothelial cells from injury • Inhibition of macrophage foam cell formation • Reduced levels of angiotensin-converting enzyme and renin • Reduction of P-selection levels • Reduction of homocystein levels

26. Effects of HRT • Cardiovascular •  50% risk of coronary artery disease •  45% risk of myocardial infarction •  risk and extension of stroke even in hypertension or smoking •  basal insulin levels and  Insulin resistance • Effect of estrogen on BP •  epinephrin associated BP •  BP with idiosyncratic effect • HRT in hypertensive patient: • Control BP q 6 mo. • If BP variability  control BP q 3 mo.