DR. Alaa Mosbah M.D OBS GYN Lecturer of OBSGYN Mansoura Faculty of Medicine 2008

1.  DR. Alaa Mosbah M.D OBS & GYN Lecturer of OBS&GYN Mansoura Faculty of Medicine (2008) One-year treatment with hormone replacement therapy influenced favorably a number of prognostic cardiovascular risk factors in healthy women. The most important effect was the lowering of fibrinogen. Furthermore, in this study the effect of hormone replacement therapy on hemostasis did not deviate between a cyclic estrogen/sequential progestogen regimen and a continuous estrogen/sequential progestogen regimen. (Am J Obstet Gynecol 1999;180:283-9.)  One-year treatment with hormone replacement therapy influenced favorably a number of prognostic cardiovascular risk factors in healthy women. The most important effect was the lowering of fibrinogen. Furthermore, in this study the effect of hormone replacement therapy on hemostasis did not deviate between a cyclic estrogen/sequential progestogen regimen and a continuous estrogen/sequential progestogen regimen. (Am J Obstet Gynecol 1999;180:283-9.)

2. Introduction With a marked increase in longevity, women now spend third of their lives in the post-menopausal period. Third of total female population are in menopause. Therefore they would have to cope with the post menopausal syndrome and face the consequences .

3. Life expectancy and age of menopause

4. HRT does not suit everyone. Each woman needs to be aware of the benefits and potential risks of HRT (pros and cons).

5. HRT: Pros and Cons Pros Cons Excellent symptom management Decreased rates of: Colon Cancer Osteoporosis ? UTI ? Depression Preservation of joints, teeth, skin CHD: doesn�t help, might hurt Increased risk of stroke and PE Increased rates of breast Ca Increased GB disease Increased rates of lupus Vaginal bleeding

6. INDICATIONS MENOPAUSE CLIMECTERIC OSTEOPOROSIS PRE MATURE MENOPAUSE

7. MENOPAUSAL SYMPTOMS PHYSICAL PSYCHOLOGICAL

8. PSYCHOLOGICAL SYMPTOMS DEPRESSION IRRITABILITY TIREDNESS / POOR SLEEP ANXIETY LOSS OF LIBIDO FORGETFULNESS LOSS OF CONCENTRATION

10. PHYSICAL SYMPTOMS Hot Flushes Night Sweats Palpitations Sexual Changes Skin & Hair Changes Joint Pains Urinary Symptoms Weight Gain Headache

12. LONG TERM MENOPAUSAL EFFECTS

13. HORMONES/DRUGS INHRT ESTROGENS PROGESTOGENS TIBOLONE (STEAR) RALOXIFENE (SERM )

14. Alternatives to HRT Lifestyle Exercise Diet-fiber Reduce exposure to Xenohormones Nutritional Supplementation Adrenal Support Liver Support Omega 3 Herbal supplements Black Cohosh Dong Quai Chaste Berry Evening Primrose Oil Bioidentical hormones

15. ROUTS OF T/M ORAL TRANSDERMAL IMPLANTS Vaginal Creams & Pessaries & Hormone Releasing Intra Uterine System (Mirena)

16. Terminology and Definitions Hormone therapy (HT) :treatment with one of several available estrogens, with or without a progestin, and without reference to its route of delivery Estrogen therapy (ET): estrogen-only therapy Estrogen/progestin therapy (EPT): combination estrogen/ progestin therapy Hormone replacement therapy (HRT): older term, usually denoting combination estrogen/progestin therapy.

17. Estrogen replacement therapy (ERT): also an older term, denoting estrogen-only therapy Progestin: any of a group of steroid hormones, including synthetic forms, that have the effect of progesterone Progestogin: any of a group of steroid hormones that have the effect of progesterone Progesterone: the naturally occurring progestin, produced in the corpus luteum of the ovary

18. New developments in HRT Low-dose therapy :0.3 mg CEE +1.5 mg MPA Traditionally, doses of 0.625�1.25 mg conjugated equine oestrogens were considered necessary for adequate symptom control and bone protection. Now much lower doses have been shown to be effective and progestogen has been shown to have a further additive effect.

19. The Mirena intrauterine system Merina delivers LNG at a rate of 20 micrograms/24 hours initially . A smaller version, the menopause levonorgestrel system (MLS) has been developed, which releases 10 micrograms LNG/24 hours initially .

21. HRT Guidelines

22. The Million Women Study A national study of women's health, involving 1.3 million UK women aged 50 and over( between 1996 and 2001). The study is looking at how HRT affects a woman's breasts and other aspects of her health. 66 National Health Service Breast Screening Centres were involved.

23. Women's Health Initiative (WHI) study WHI Study in the United States began in 1997 and was scheduled to be completed in 2005. However, researchers halted the study on May, 2002 because they felt that the health risks for participants taking HRT outweighed the possible benefits of HRT.

24. HRT and Menopausal Symptoms

25. VASOMOTOR HOT FLUSHES HRT is an effective treatment for hot flushes (Grade A). Tibolone is effective for alleviating the severity and reducing the frequency of hot flushes (Grade A).

26. Unopposed estrogen may be effective for reducing sleep disruption (Grade B). There is no evidence that HRT is effective for vasomotor symptoms such as headaches and dizziness (Grade B).

27. UROGENITAL SYMPTOMS  Low dose topical estrogen or Oral Estriol is an effective treatment for vaginal dryness (Grade A). Tibolone has been shown to be effective for vaginal dryness (Grade A). Topical ERT for 6 months decreases the incidence of recurrent UTIs (Grade A).

28. PSYCHOLOGICAL SYMPTOMS Estrogen is not an effective treatment in elderly women with established Alzheimer's disease (Grade A) . 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) (Grade A).

29. Tibolone is effective in providing relief from low libido in post-menopausal women (Grade A). ERT is not an effective treatment for loss of libido in post-menopausal women (Grade A). Combined HRT does not improve cognitive function in women aged 65 or more (Grade A)

30. HRT and risk of cancer

31. RISK OF BREAST CANCER

32. Continuous combined HRT was associated with an increased breast cancer risk if used for four years or more (Grade A). However this increased risk disappears within 5 years once use is discontinued (Grade C). Use of Tibolone is associated with an increased risk of invasive breast cancer (Grade C) . (Women's Health Initiative study 2002 ), (The Million Women Study 2003 )

35. RISK OF ENDOMETRIAL CANCER Unopposed estrogen therapy should not be used in women with a uterus because of an increased risk of endometrial cancer (Grade A) . Women who have had a hysterectomy may take unopposed estrogen therapy (The Million Women Study 2005 ).

36. Combined continuous regimens offer better protection of the endometrium than sequential regimen (Grade A) . Continuous combined (oestrogen plus progestogen) HRT decrease the risk of endometrial cancer compared to the risk in women who have never used HRT. (The Million Women Study 2005 )

37. The synthetic HRT product, tibolone , increased the risk of endometrial cancer when used for more than 3 years. compared to the risk in women who have never used HRT. (The Million Women Study 2005 )

40. RISK OF OVARIAN CANCER Incidence of ovarian cancer increased with increasing duration of use of HRT(estimated duration of use at time of diagnosis, 7.7 years) (The Million Women Study April 24, 2007 )

41. RISK OF COLORECTAL CANCER Combined HRT use is associated with decreased risk of colorectal cancer (Grade B).

42. HRT AND VENOUSTHROMBOEMBOLISMRCOG 2004 It is recommended that, in women with a previous VTE, with or without an underlying heritable thrombophilia, oral HRT should usually be avoided (Grade A).

43. It is recommended that, when a woman who is on HRT develops a VTE, HRT should be discontinued (Grade A). In high risk women with an underlying thrombophilic trait HRT is not recommended (Grade B). SERMs should be considered to carry the same risk of thrombosis as oestrogen-containing HRT (Grade B).

44. Prior to commencing HRT, a personal history and a family history assessing the presence of VTE in a first- or second-degree relative should be obtained (Grade C). HRT should be avoided in women with multiple pre-existing risk factors for VTE (Grade C) .

45. It is recommended that, if a woman requires to continue on HRT after a VTE, long-term anticoagulation should be considered (Grade C).

46. Coronary heart disease (CHD) HRT is contraindicated for secondary prevention of further coronary disease because of lack of documented efficacy and a possible early excess mortality (Grade A)

47. Heart and Estrogen/progestin Replacement Study (HERS) reported that standard doses of EPT increased the risk of CHD in the first year of therapy (Grady D et al. JAMA. 2002)

48.  Randomised controlled trials have found an increased risk of CHD in women who started combined oestrogen-progestogen therapy more than 10 years after menopause. Newly menopausal women, have a lower relative risk compared with older women (Rossouw JE. JAMA 2007)

49. Stroke In randomised controlled trials, oestrogen-only and combined HRT increased the risk of stroke (mostly ischaemic) compared with placebo. Hendrix SL, et al. Circulation 2006

50. In Tibolone users; The LIFT(long term intervention on fractures with tibolone) study identified a significantly (2�2-times) increased risk of stroke, mostly ischaemic, risk increased from the first year of treatment (Cummings SR. BMJ 2006)

51. HRT and Osteoporosis HRT and Bisphosphonates has positive effects on bone density in postmenopausal women whether or not they have osteoporosis (Grade A)

52. 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 (Grade B).

53. Selective Estrogen Receptor Modulators (SERMs) may be useful in the prevention of vertebral fractures in women who cannot use HRT or bisphosphonates (Grade A)

56. HRT AND GALLBLADDER DISEASE Combined HRT is associated with increased risk of gallbladder disease and biliary tract surgery (Grade B)

58. Conclusion Research Continues, Recommendations May Change 1-Decisions regarding HRT therapy must be made between the woman and her physician on an individual basis. 2-HRT must be used for as short a time as possible with lowest effective dose .

59. 3- HRT has long-term risks 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.

60. 5- The low dose hormone replacement therapy is as effective as the standard dose HRT, and may have a favorable side effect profile 6- HRT is the most effective treatment of menopausal symptoms .

61. 7-For patients at risk of 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 .

62. 8-The decision to prescribe HRT should be based on a thorough evaluation of the potential benefits and potential risks of treatment

63. 9-Evidence for the risks of HRT in women who had premature menopause is limited and the balance of benefits and risks may be more favourable than in older women . It is uncertain whether the results of WHI and MWS can be applied to younger postmenopausal women taking appropriate doses and regimens (British Menopause Society Council 12 February 2008)

64. 10-There is a lack of evidence to confirm benefits or to highlight possible adverse effects of HRT alternative therapies