Menopause

1. Menopause N.Cem FIÇICIOĞLU, M.D., Ph.D. Professor and Director Department of Gynecology & Obstetrics and IVF Center Yeditepe University, School of Medicine İstanbul

2. Menopause; is that point in time when permanent cessation of menstruation occurs following the loss of ovarian activity. • Perimenopause;is the period immediately before and after the menopause. • Climacteric is the more encompasing word, indicating the period of time when a women passesthrough a transition from the reproductive stagesof life to postmenopausal years .

3. The median age of onset of perimenopause is 47.5 years • The age of menopause is 48-55 years

4. Hormone production after menopause • Menstrual cycle changes prior to menopause is marked by elevated FSH levels and decreased levels of inhibin, AMH but normal levels of estradiol and LH. • FSH higher than LH ; LH is cleared from blood so much faster “half life is 30 minutes for LH and 4 hours for FSH!” • FSH can not be used clinically to titer estrogen dosage “ it can be effected not only estrogen but INHIBİN also”

5. Androstenedion production is reduced by one half before menopause • Testesteron production are increased in postmenopausal ovarion stroma by İncreased FSH/LH levels but overall are same as conversion is reduced peripherically. • The circulating estradiol is 10-20pg/ml most of which derived from peripheral conversion estrone

6. Hormonal problems • Relative estrogen excess uch as dysfunctional bleeding, endometrial hyperplasia, endometrial cancer • Estrogen deprivation such as flushes, atrophic changes, osteoporosis • Problems with estrogen-progestin therapy.

7. Estrogen excess • ANOVULATION • Increased androgen “ stress, endocrine tumors • İncreased aromotization “ obesity,hyperthyroism” • Direct secretion of estrogen, ovarian tm • Decreased levels of SHBG,,leading to increased free estrogen • ENDOMETRİAL PATHOLOGY

8. Even with the lowest estrogen dose Oral conraceptive , the estrogen dosage is four fold greater tha the standard postmenopausal dose !! • At Pill free period day 5-7 ...FSH is greater than 30 IU/L than changed to HRT program.

9. Vazomotor symptoms Atrophic changes Psychophysiologic effects Osteoporosis “ the critical blood of estradiol that is necessary to maintain bone is 40-50 pg/ml CVD > Estrogen deprivation

10. “CVD >”Possible benefical actions of estrogens • Total cholesterol and LDL <, HDL > • Antiatherosclerotic effects • Nitric oxide and prostacycline “vazodilating and Antiplatelet aggregation fac.” > • İnotropic effect • Improvement of peripheral glucose metabolizm.,insuline levels <.

11. HORMONE REPLACEMENT THERAPY (HRT)Evidence-based Guidelines N.Cem FIÇICIOĞLU, M.D., Ph.D. Professor and Director Department of Gynecology and Obstetrics Yeditepe University, School of Medicine İstanbul

12. Introduction • HRT does not suit everyone. • Each woman needs to be aware of the benefits and potential risks of HRT (pros and cons) so that she can make an informed decision. • Our duty as clinicians is to ensure that women are provided with consistent and up-to-date information

13. HRT and Menopausal Symptoms

14. VASOMOTOR HOT FLUSHES includes night sweats Grade A • HRT is an effective treatment for hot flushes • Tibolone is effective for alleviating the severity and reducing the frequency of hot flushes N.Z Guidelines May 2001 N.Z Guidelines May 2001

15. VASOMOTOR HOT FLUSHES (includes night sweats) Grade B • Unopposed estrogen may be effective for reducing the waking episodes that are associated with sleep disruption. • There is no evidence that HRT is effective for vasomotor symptoms such as headaches and dizziness. N.Z Guidelines May 2001

16. Vaginal atrophy Grade A • Low dose topical estrogen is an effective treatment • E3 (estriol) therapy is also effective but requires either the addition of progestogen or close monitoring of the endometrium • Tibolone has been shown to be effective for vaginal atrophy N.Z Guidelines May 2001

17. PSYCHOLOGICAL SYMPTOMS • These include depression, mood changes, anxiety, irritability, loss of libido, lack of energy and memory loss.

18. PSYCHOLOGICAL SYMPTOMS Grade A • Estrogen is not an effective treatment in elderly women with established Alzheimer's disease • The addition of low doses of androgens to HRT provides relief in women with either a premature or surgical menopause who suffer from low libido ( for <2 years). N.Z Guidelines May 2001

19. PSYCHOLOGICALSYMPTOMS Grade A • Tibolone is effective in providing relief from low libido in postmenopausal women • Estrogen replacement therapy is not an effective treatment for loss of libido in postmenopausal women. N.Z Guidelines May 2001

20. PSYCHOLOGICAL SYMPTOMS There is insufficient or inconsistent evidence that HRT • Improves measures of cognition 2-Prevents or delays the onset of Alzheimer's disease 3-Elevates mood or relieves depression

21. HRT and risk of cancer

22. RISK OF BREAST CANCER • Continuous combined HRT was associated with an increased breast cancer risk if used for four years or more • However this increased risk dissipates quickly once use is discontinued. (NICHD) study November 29,2002. (WHI) July 2002

23. RISK OF BREAST CANCER • Inspite of an increased risk of breast cancer diagnosis, the mortality from breast cancer is unchanged .(WHI) July 2002

24. RISK OF ENDOMETRIAL CANCER Grade A • Unopposed estrogen therapy should not be used in women with a uterus because of an increased risk of endometrial cancer. • Women who have had a hysterectomy may take unopposed estrogen therapy

25. RISK OF ENDOMETRIAL CANCER A • Combined continuous regimens offer better protection of the endometrium than sequential regimens. N.Z Guidelines May 2001

26. RISK OF OVARIAN CANCER Grade A • There is no conclusive evidence that combined regimens HRT either increases or decreases the risk of developing ovarian cancer. N.Z Guidelines May 2001

27. RISK OF OVARIAN CANCER • Researchers from the National Cancer Institute (NCI) have found that women in a large study more than 44000 women who used estrogen replacement therapy after menopause were at increased risk for ovarian cancer. July 2002 JAMA

28. HRT and Osteoporosis The silent killer

29. HRT and Osteoporosis Grade A • HRT and Bisphosphonates has positive effects on bone density in postmenopausal women whether or not they have osteoporosis N.Z Guidelines May 2001

30. HRT and Osteoporosis Grade B • Maintaining HRT use decreases the risk of vertebral and non-vertebral fractures in women after surgical menopause ,early postmenopausal women and in women with established osteoporosis

31. HRT and Osteoporosis Grade B • Selective Estrogen Receptor Modulators (SERMs) may be useful in the prevention of vertebral fractures in women who cannot use HRT or bisphosphonates. N.Z Guidelines May 2001

32. ACOG issues New Recommendations On SERMS • ACOG recommends Raloxifene in the prevention of osteoporosis in women at risk for the disease, and in the prevention of bone fractures in women who already have osteoporosis • ACOG recommends that SERMS can not be used in women with a history of blood clots. • SERMS increase vaginal dryness and hot flashes. ACOG. October,2002

33. HRT and cardiac risk

34. HRT and cardiac risk • Unlike earlier observational studies that suggested the possibility of some protection against heart disease, recent studies showed a small but significant increased risk of non-fatal heart attacks

35. HRT and cardiac risk • The Heart and Estrogen Replacement Study (HERS) is the first published randomized placebo controlled study of HRT in 2763 women with established coronary artery disease (HERS I1998) • (HERS II) is follow up study of HERS I the report was published in the July 2002 issue of The Journal of the American Medical Association (JAMA).

36. HRT and cardiac risk HERS II trial results confirm the initial findings of HERS I • increased risk of coronary events in the early years of treatment • increase in thromboembolic events in the HRT group compared with placebo mainly seen in the first year of use

37. HRT and cardiac risk Grade B • HRT is contraindicated for secondary prevention of further coronary disease because of lack of documented efficacy and a possible early excess mortality.

38. the Women's Health Initiative (WHI)study • This randomized controlled trial examined the risks and benefits of long-term combined HRT use in 16.608 asymptomatic postmenopausal women compared to the placebo group • The trial has been halted prematurely, after 5. years of an 8-year study, due to an increased risk of invasive breast cancer. . July 2002 JAMA

39. The Women's Health Initiative (WHI) Study • The another WHI trial on estrogen use alone is continuing, because of no increased risk for breast cancer in this study. • The report was published in the July, 2002, issue of JAMA

40. The Women's Health Initiative (WHI) Study The key findings after five years / 10,000 women per year • Breast cancer increased from 30 to 38 cases ( did not appear in the first four years of use). • Coronary heart disease increased from 30 to 37 cases (appeared in first year of use ) • Stroke increased from 21 to 29 cases (were greatest during the first 2 years ) • Blood Clots: increased from16 to 34 cases July 2002 JAMA

41. The Women's Health Initiative (WHI) Study The benefits were • A reduction in colorectal cancer from 16 to 10 cases The reduced risk of colorectal cancer emerged after 3 years • Hip fracture (reduced from 15 to 10) July 2002 JAMA

42. New Study of the National Institute of Child Health and Human Development (NICHD) November 29, 2002 • Unlike the WHI, this study looked at pill and patch hormone users as well as several types of hormone regimens in 3,823 postmenopausal women ACOG. November 29,2002

43. New Study of the National Institute of Child Health and Human Development (NICHD) Results were consistent with the recent Women's Health Initiative • Continuous combined HRT was associated with an increased breast cancer risk if used for five or more years. • no association between breast cancer risk and the regimens of either estrogen-alone or sequential HRT . • However, the study found this increased risk dissipates quickly once use is discontinued. ACOG. November 29,2002

44. Should progestins be adminestered to histeroctomized patients? • Stage 1 adenocarsinoma “Ib gr1-2” • Previously treated endometrioid tumor of ovary • Past history of endometriosis • At high risk of osteoporosis • Elevated triglycerid levels

45. Conclusion An Important Note: Research Continues, Recommendations May Change 1-HRT is not recommended for routine use in the menopause. 2-HRT must be used for as short a time as possible with lowest effective dose . ACOG. August,2002

46. Conclusion (cont.) 3- The results of the WHI study confirm what is already known about the long-term risks of HRT, including breast cancer and venous thromboembolism. 4-HRT has not been proven to be beneficial in primary and secondary prevention of coronary heart disease in fact may result in a small increased rate of CHD.

47. Conclusion (cont.) 5-ACOG continues to recommend that decisions regarding HRT therapy must be made between the woman and her physician on an individual basis. 6- HRT is the most effective treatment of menopausal symptoms . ACOG. July, 2002

48. Conclusion (cont.) 7-For patients with osteoporosis, other preventive therapies such as bisphosphonates and SERM are available. However, for women at risk of osteoporosis who also have vasomotor menopausal symptoms, HRT can be of benefit . . ACOG. August,2002

49. ِAlternatives to HRT

50. In 1997, 42% of Americans had used 1 of 16 different alternative therapies (Gass & Rebar, 2001)