1. Doç. Dr. Gazi YILDIRIM Yeditepe Üniversitesi Hastanesi Kadın Hastalıkları ve Doğum AD

2. Reproductive Aging Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1.5-2 million follicles At menarche - 300,000- 400,000 follicles Follicular atresia continues throughout life. Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs. Oocytes and Follicles

3. Menopause Facts Average age at menopause: 51 years (1% at age 40, 5% after age 55) Factors impacting age at menopause Maternal age at menopause Tobacco use SES/ Education Alcohol use Body Mass Index Factors that probably don’t impact on age at menopause OCP use Parity Race Height

4. Age (years) Date Age At Menapause And Expected Life *Projected estimate. Federal Interagency Forum on Aging-Related Statistics. Indicator 2: Life Expectancy. Available at: http://www.agingstats.gov/tables%202001/tables-healthstatus.html. Accessed 1/3/02. US Department of Health and Human Services. Healthy People 2010. Washington DC: January 2000. 18501900195020002050* Age at menopause

5. Stages of Reproductive Aging

6. Reproductive Stage Age in years 25% 12% 20 30 37 40 45 Miscarriage Rate / month Pregnancy Rate / month

7. FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Reproductive Aging Hormonal Changes

8. FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Reproductive Aging Hormonal Changes

9. FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Reproductive Aging Hormonal Changes

10. Diagnosing Perimenopause Clinical diagnosis based on menstrual cycle pattern. Early follicular phase FSH and symptoms may help solidify diagnosis. Rule out hypothyroidism, depression etc.

11. Perimenopause -- Symptoms: Vasomotor instability (85%) Sleep disturbances Mood disturbances. Somatic symptoms: Fatigue, palpitations, headache, increased migraine, breast pain and enlargement. Oligo-  Anovulation heavier or irregular cycles. Highly Variable

12. Age (years) Estrogen Secretion 40 45 50 55 60 65 70  75 Development of subclinical disease Estrogen Deprivation Related Problems Urogenital symptoms Cardiovascular disease Short-term Symptoms Long-term Diseases Cognitive decline (Alzheimer’s disease) Hot flushes Mood, sleep, and/or acute cognitive changes Osteoporosis

13. Menopausal Symptom Prevalence of Hot Flushes

14. Sleep Disturbance in Peri/Postmenopausal Women ↑ reports of difficulty sleeping 1 2 Kravitz, Sleep 2008 Falling asleep Waking up repeatedly 1 Kravitz, Menopause 2003

15. Managing Perimenopause Goals: Patient education Prevention of endometrial cancer Individualized symptomatic relief Menstrual control Minimizing hot flashes Mood disturbances

16. Managing Perimenopause Symptom Relief Menstrual Cycle Control Birth Control Endometrial Cancer Prevention Hormonal contraceptives (oral or ring) +++ Cyclic progestin therapy +/- -++ Progesterone IUD-+/-+++ EPT++--+++

17. Risks Benefits Weighing Risks vs Benefits Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333. Stroke Breast Cancer VTE Symptom Control Skeletal Benefit QOL CVD Risk Cognition

18. WHI Hormone Trials

19. Menopause Hormone Therapy (MHT)…lessons learnt from WHI Is NOT risk free NOT cardioprotective CAN harm Aged Remote from last menstrual period Overweight/obese Existing pre morbidities

20. MHT & Breast Cancer Risk Current Understanding: Estrogen alone Rx in hysterectomized population is deemed relatively safe for breast tissue Type of progesterone (natural progesterone preferred over synthetic) and regimen (cyclic preferred over continuous) merit consideration.

21. MHT & VTE Risk AgeBody Mass Current Understanding: Advancing age, obesity and individualized profile should be considered when assessing risks for TE in patient being considered for HT

22. VTE Risk: Drug & Route Route of HT & Progestin Oral vs. Transdermal E Current Understanding: Choice of progestin (progesterone preferred to synthetic progestins) and both dose & route of E (low dose transdermal preferred over oral route) can confer risk reduction against TE.

23. MHT Decision Should Be Based upon Individualized Assessment Risks Benefit Underlying atherosclerosis? Stroke/MI VTE? Breast cancer? … does she have a uterus and therefore will need E+P Symptoms Severity Nature Skeletal perspective THERE IS NO ROLE OF HORMONE THERAPY FOR CARDIAC PROTECTION OR COGNITIVE BENEFIT

24. TANIMLAR

25. Conclusions with Level of Evidence A Hot flashes “Standard-dose” estrogen with or without a progestogen markedly lowers the frequency and severity of hot flashes, and lower doses of estrogen are also effective in many women. Tibolone (a hormonal alternative widely available worldwide but not in the United States) alleviates postmenopausal vasomotor symptoms.

26. Urogenital system Very low doses of vaginal estradiol relieve symptoms and normalize vaginal atrophy. Estrogen used vaginally or systemically reduces the symptoms of overactive bladder. Vaginal estrogen reduces the incidence of recurrent urinary tract infections. Tibolone improves urogenital atrophy. Conclusions with Level of Evidence A

27. Bone Estrogen with or without a progestogen prevents early postmenopausal bone loss and augments bone mass in late postmenopause as effectively as the bisphosphonates. Estrogen alone and estrogen plus a progestogen prevent hip and vertebral fractures. Tibolone significantly reduces vertebral and nonvertebral fractures in osteoporotic women over the age of 60 yr. Raloxifene, a selective estrogen receptor modulator, improves bone mineral density and reduces vertebral but not hip fractures.

28. Conclusions with Level of Evidence A Colon cancer MHT with estrogen plus a progestogen decreases colon cancer risk. Breast Raloxifene decreases breast cancer risk. Estrogen and estrogen plus a progestogen increase mammographic density. Tibolone increases risk of breast cancer recurrence.

29. Conclusions with Level of Evidence A Sexual function Physiological amounts of transdermal testosterone increase the number of self-reported, sexually satisfying events per month as well as desire, arousal, responsiveness,and orgasm. DHEA does not significantly improve sexual function. Venothrombotic episodes MHT increases the risk of venothrombotic episodes approximately 2-fold and is multiplicative with baseline risk factors including age, higher body mass index, thrombophilias, surgery, and immobilization. Raloxifene increases the incidence of venothrombotic episodes.

30. Conclusions with Level of Evidence A Stroke Tibolone increases risk of stroke in older but not in younger women. No increase in stroke occurs with raloxifene. Hormone use does not reduce stroke incidence in older women with preexisting vascular disease. Endometrium Estrogen alone without a progestogen causes an increase in endometrial cancer. Continuous estrogen plus a progestogen does not cause endometrial cancer. Tibolone does not induce endometrial hyperplasia or carcinoma

31. Conclusions with Level of Evidence A Gallbladder Estrogen alone and estrogen plus a progestogen increase the risk of gallbladder disease. Cognition MHT initiated after age 60 yr does not improve memory

32. Selected Conclusions with Level of Evidence B Metabolism Use of estrogen alone and estrogen plus a progestogen in theWHI was associated with a decrease in the risk for type 2 diabetes. Initiation of MHTis associated with lesser accumulation of weight, fat mass, and/or centrally located fat mass. Joints Estrogen exerts a protective effect on osteoarthritis. Estrogen alone reduces total arthroplasty rate. Addition of a progestogen to estrogen appears to counteract the beneficial effects of estrogen on arthroplasty rate.

33. Quality of life MHTproduces an improvement in health-related quality of life through decreased symptoms, sleep enhancement, and, possibly, mood enhancement. Sexual function Tibolone improves sexual well-being in postmenopausal women presenting with low libido, with greater improvements in desire, arousal, satisfaction, and receptiveness than seen with transdermal estrogen- progestogen therapy. Selected Conclusions with Level of Evidence B

34. Endometrium Sequential estrogen plus a progestogen reduces the risk of endometrial carcinoma compared to estrogen but not as effectively as continuous estrogen plus a progestogen. Vaginal estrogen in doses of 7.5 to 25 g twice weekly does not stimulate the endometrium. Raloxifene reduces the incidence of endometrial carcinoma. Selected Conclusions with Level of Evidence B

35. Premature menopause Women with bilateral oophorectomy prior to age 45 are at increased risk of negative effects on the cardiovascular system, bone, cognition, mood, and sexuality. Overall mortality MHT was associated with a 40% reduction in mortality in women in trials in which participants had a mean age below 60 yr or were within 10 yr of menopause onset. Selected Conclusions with Level of Evidence B

36. Coronary heart disease (CHD) Basic science, animal models, and observational studies support the hypothesis that MHT may prevent atherosclerosis and reduce CHD events. Subgroup analyses suggest that the lack of benefit or increase in CHD risk observed in the overall analysis of the WHI resulted from harmful effects of MHT in older women starting therapy many years after onset of menopause. Tibolone does not increase the risk of CHD events. Selected Conclusions with Level of Evidence B

37. Use of estrogen alone for less than 5 yr may reduce the risk of breast cancer in patients starting therapy many years after the onset of menopause. Tibolone reduces the risk of developing breast cancer. Estrogens increase the risk of breast cancer after more than 5 yr of use, particularly in recently menopausal women. Combined estrogen and progestogen therapy increases the risk of invasive breast cancer, which may occur within 3 to 5 yr of initiation and rises progressively beyond that time. Selected Conclusions with Level of Evidence B

38. TargetE+PSERMsTSECs Breast Uterus Hot Flush Vagina Bone Future of MHT

40. SERM Clomiphene Tamoxifen Toremifene Droloxifene Iodoxifene Raloxifene Basedoxifene Ormeloxifene-NEAREST TO IDEAL 40

41. Raloxifene Mechanism of Action: selective estrogen-receptor modulator Benefits Increases BMD of hip and spine in women 1 Females: approved for treatment and prevention of osteoporosis in women. Not approved in males 2 Narrow study contexts 3,5 Was not shown to significantly impact BMD in males 4

42. TSEC A TSEC is the partnering of a SERM and other estrogens to achieve clinical results based on their blended tissue selective activity profiles. One option for a TSEC is the pairing of a SERM(Bazedoxifene) with CEE. 42

43. Tissue Selective Estrogen Complex Bazedoxifine/Conjugated Estrogen (Duavee) Mechanism of Action: SERM that selectively stimulates lipid metabolism and bone, however, has no effect on the uterus and breast. Benefits FDA approved for postmenopausal moderate/severe vasomotor symptoms prevention of postmenopausal osteoporosis. Increased hip and lumbar BMD

44. Bazedoxifene/Conjugated Estrogen (Cont’d) Approved in Women for 2 prevention of osteoporosis osteopenia post menopausal vasomotor and sleep disturbances Men: None of the three major clinical trials included men, despite that estrogen has been demonstrated to play a significant role in bone formation 3,4,5.

45. SPRM Pure agonistProgesterone J 1042 J 867 J 956 Mifepristone (RU486) Pure antagonist Onapristone Asoprisnil (J867) abortifacienttreshold

46. prevention of postmenopausal osteoporosis PRIMARY PREVENTION 1. HRT 2. SERMS 3. TIBOLONE 4. Biophosphonate SECONDARY PREVENTION 1. Biophosphonates 2. Calcitonin (>5 yrs menopause) 3. Teriparatide 46

47. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action First line treatment for osteoporosis in both men and post- menopausal women 1 Application Approved in both sexes for the prevention and treatment of osteoporosis Aledronate 2, Risedronate 3 and Zoledronic Acid 4

48. DrugVertebral Fracture RR Hip Fracture RR Non- vertebral RR Route/ Frequency Indicated for which gender AlendronatePO/QDay, QWeek Women Men RisedronatePO/QDay, QWeek, QMonth Women Men IbandronateNE PO/QMonth IV/Q3Mont h Women Zoledronic Acid IV/QYearWomen Men RR = Risk ReductionNE = No effect demonstrated Bisphosphonates