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Menopause: When to use HRT?


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Management of menopause, to use Estrogen therapy or not. Management of aging.

Menopause: When to use HRT?

  1. 1. MENOPAUSE: HRT or NO HRT ? <ul><li>Professor Galal Lotfi, MD, MRCOG </li></ul><ul><li>Obstetrics & Gynecology </li></ul><ul><li>Suez Canal University </li></ul><ul><li>Egypt </li></ul><ul><li>Suez Canal University Conference. April 15-16, 2010 </li></ul><ul><li>Ismailia - Egypt </li></ul>
  2. 2. Egypt
  3. 3. Suez Canal University Hospital
  4. 4. Starts as a date and continues as a status! <ul><li>Clinically speaking, menopause is a date, the day after a woman's final period finishes. </li></ul><ul><li>In practice, &quot;menopause&quot; is usually not used to refer to one day, but to the whole of the menopause transition years. This span of time is also referred to as the change of life, the change , or the climacteric and more recently is known as &quot;perimenopause”. The word menopause is also often used in popular to mean all the years of postmenopause (Wikipedia). </li></ul>
  5. 5. This is the Change The change is not a disease
  6. 6. For a woman without a uterus? <ul><li>She is having no menstruation but does she pass through menopause!! </li></ul><ul><li>Very confusing to the patients. </li></ul>
  7. 7. Which is best name?
  8. 8. Do we deal with Menopause or Climacteric? <ul><li>We talk menopause but actually we are concerned about the changes of Climacteric. </li></ul><ul><li>Menopause is the result of Climacteric which is normal developmental process of aging. </li></ul>
  9. 9. Starts by a date that never ends? <ul><li>The age of menopause has not changed , but there is gradual increase in life expectancy. In previous centuries women were not expected to live beyond menopause, now they spend > one third of their life after menopause. </li></ul><ul><li>>31 million women are undergoing menopausal transition in USA. </li></ul><ul><li>Menopause is a normal developmental process, but the decline in E can have clinical sequelae. </li></ul><ul><ul><li>Vasomotor symptoms. </li></ul></ul><ul><ul><li>Osteoporosis. </li></ul></ul><ul><ul><li>Cardiovascular disease. </li></ul></ul><ul><ul><li>Urogenital atrophy. </li></ul></ul><ul><ul><li>Cognitive decline and Alzheimer's disease. </li></ul></ul>
  10. 10. Menopause is OK but its sequalae are not OK Hot flashes Osteo, Urogenital CVD Mood Collagen
  11. 11. Physiology <ul><li>Ovarian Decline..... Change </li></ul><ul><li>Reproduction and menopause..... Change </li></ul><ul><li>Hormonal Changes...... Change </li></ul><ul><li>Sequalae E decline... this is the problem </li></ul>
  12. 13. Ovarian Process. <ul><li>Menopause results from: </li></ul><ul><ul><li>1.Follicular depletion (&quot;natural&quot; menopause) or </li></ul></ul><ul><ul><li>2.Surgical removal of the ovaries (&quot;induced, or surgical,&quot; menopause). </li></ul></ul><ul><li>The secretion of the ovarian E & P declines. </li></ul><ul><li>Menstrual cycles seldom cease abruptly; there is an interval of &quot;perimenopause&quot; or &quot;menopausal transition,&quot; during which there are considerable hormonal fluctuations. </li></ul><ul><li>Perimenopause begins a few years before last cycle ; the cycles become irregular with symptoms suggesting a decline in E. Perimenopause also extends for a few years after the last menstrual cycle; during this time, transient and episodic bursts of ovarian activity may occur, which may result in some vaginal bleeding. </li></ul>
  13. 14. 1. Physiology of Menopause <ul><li>Age of menopause occurs at a median age of 51.4 years, with a range from 40-58 years. </li></ul><ul><li>Factors Affecting age of menopause: </li></ul><ul><ul><li>Familial factors & genetic polymorphisms of E receptor (ER). </li></ul></ul><ul><ul><li>Childhood cognitive function. </li></ul></ul><ul><ul><li>Multiparity and increased body mass index (BMI) are associated with later onset. </li></ul></ul>
  14. 15. Physiology of Menopause <ul><li>Factors causing earlier menopause: </li></ul><ul><ul><li>Smoking. </li></ul></ul><ul><ul><li>Nulliparity. </li></ul></ul><ul><ul><li>Medically treated depression. </li></ul></ul><ul><ul><li>Toxic chemical exposure. </li></ul></ul><ul><ul><li>Treatment of childhood cancer with abdominal-pelvic radiation and alkylating agents. </li></ul></ul><ul><li>Premature, or early, menopause (age < 40 years) has been linked to both familial and nonfamilial X-chromosome abnormalities. </li></ul>
  15. 16. 2. Reproduction and Meno. <ul><li>Climacteric :The time from the decline in reproductive capacity onward. </li></ul><ul><li>Reproductive aging occurs rapidly after the third decade, and fecundity is extremely low before menopause. </li></ul><ul><ul><li>Both Climacteric and reproductive aging start far before menopause. </li></ul></ul><ul><li>Follicular atresia accelerates at about 37.5 years . Thus, reproductive aging precedes menopause by 5-10 years, at a &quot;young&quot; chronologic age. This is signified by an increase in (FSH) level in the early follicular phase of regular cycles and a decrease in the circulating inhibin B level. The elevation in FSH drives the accelerated follicle depletion. </li></ul>
  16. 17. 3. Hormonal Changes <ul><li>E. Decreased </li></ul><ul><li>E1 S. Decreased </li></ul><ul><li>FSH, LH. Increased </li></ul><ul><li>AD, T. Decreased </li></ul><ul><li>In late perimenopause, levels of E2 and inhibin decrease. FSH is markedly increased. </li></ul>
  17. 18. 4. Effects of Declining Estrogen <ul><li>Two estrogen receptors exist: ER-alpha and ER-beta. Various estrogens have different affinities for ER-alpha and ER-beta, which, in turn, have different tissue distributions in the body. For example, in certain regions of the brain (eg, frontal cortex), ER-beta predominates over ER-alpha. In the cerebellum, only ER-beta is expressed. Because ERs are abundant throughout the body, the menopausal decline of estrogen potentially affects virtually all organ systems, so we get: </li></ul>
  18. 20. 1. Brain and CNS <ul><li>ER are abundant in the brain. E have a role in many brain processes, and it’s absence result in physiologic and symptomatic changes. </li></ul><ul><li>E is important for cerebral blood flow , cerebral glucose administration , synaptic activity , neuronal growth , survival of cholinergic neurons , as well as such complex functions as cognition . </li></ul><ul><li>Mood Changes and Cognitive Function </li></ul><ul><ul><li>E has a positive effect on mood and sense of well-being, which may be due to its stimulation of the adrenergic and serotoninergic systems. However:: </li></ul></ul><ul><ul><li>The role of E deficiency in postmenopausal depression, declining cognitive function, dementia, and Alzheimer's disease is not clear . </li></ul></ul>
  19. 21. Brain and CNS <ul><li>Migraine </li></ul><ul><ul><li>E and progestins affect central serotoninergic and opioid neurons, causing a change in the prevalence or intensity of headaches. </li></ul></ul><ul><ul><li>Women with a history of menstrual migraines may experience an exacerbation. </li></ul></ul>
  20. 22. 2. Hot Flushes <ul><li>Eearly and acute symptom of E deficiency. </li></ul><ul><li>Begin in the perimenopause when E levels fluctuate widely. </li></ul><ul><li>It is the rapid fall in E level that precipitates the symptoms. </li></ul><ul><li>The cause of flushes remains illusive, the episodes result from a hypothalamic response (probably mediated by catecholamines) induced by a change in E status. </li></ul>
  21. 23. Hot Flushes <ul><li>Hot flushes can cause insomnia, which contributes to fatigue, irritability, and a reduced ability to concentrate. </li></ul><ul><li>Psychological changes attributable to chronic sleep disturbance may be more than side effects of hot flushes -- a direct effect of changing hormonal status may also play a role. </li></ul>
  22. 24. 3. Vision <ul><li>Idiopathic full-thickness macular degeneration predominantly affects women > 60 years. </li></ul><ul><li>There appears to be a hormonal component, because symptoms become more severe with menopause. </li></ul>
  23. 25. 4. Collagen <ul><li>E has a positive effect on collagen, which is important for bone and skin. The loss of collagen is more rapid in the first few years after menopause, and 30% of skin collagen is lost within the first 5 years.The rate is 2% per year for the first 10 years after menopause. This statistic, is similar to that of bone loss; strongly suggests a link between skin thickness, bone loss, and osteoporosis. </li></ul><ul><li>Reductions in collagen support: </li></ul><ul><ul><li>Atrophy of the vaginal and urethral mucosa. </li></ul></ul><ul><ul><li>Uterine prolapse. </li></ul></ul><ul><ul><li>U rinary incontinence. </li></ul></ul><ul><ul><li>Skin changes. </li></ul></ul>
  24. 27. 5. Urogenital Atrophy <ul><li>E deficiency has deleterious affects on the urogenital system. </li></ul><ul><li>One third of women =>50 years has urogenital problems. </li></ul><ul><li>E deficiency results in: </li></ul><ul><ul><li>Thin and paler vaginal mucosa. </li></ul></ul><ul><ul><li>Moisture content is low. </li></ul></ul><ul><ul><li>pH increases (usually pH > 5). </li></ul></ul><ul><ul><li>Inflammation and small petechiae. </li></ul></ul><ul><ul><li>Loss in superficial cells and an increase of basal and parabasal cells. </li></ul></ul><ul><ul><li>UTI (eg, coliform bacteria), as a result of the reduced acidity. </li></ul></ul><ul><ul><li>Decrease in lactobacilli, yeast, and bacterial vaginosis-associated bacteria also may explain the lower incidence of bacterial vaginosis and yeast vaginitis than in young women. </li></ul></ul><ul><li>Dry and atrophied vaginal and urethral epithelium can cause vaginal discomfort, itching, dyspareunia, and recurrent vaginitis as well as such urinary symptoms as frequency and dysuria.. </li></ul><ul><li>E deficiency in periurethral tissues cause pelvic laxity and stress incontinence. </li></ul>
  25. 28. 6. Bone Loss <ul><li>More than one third of women > 65 years suffer from osteopenia/ osteoporosis, a disorder of low bone mass. </li></ul><ul><li>E deficiency is a dominant pathogenic factor in bone loss. </li></ul><ul><li>From 1.5 years before to 1.5 years after menopause, spine bone mineral density (BMD) decreases by 2.5% per year , compared with a premenopausal loss rate of 0.13% per year. </li></ul><ul><li>Loss of trabecular bone (spine) with E deficiency is greater than cortical bone (femoral neck) loss. E deficiency is also a risk factor for alveolar (oral) bone loss in postmenopausal women with a history of periodontitis. </li></ul>
  26. 29. Bone Loss <ul><li>There is an association between reduced BMD and both cardiovascular (CV) mortality and cognitive decline. </li></ul><ul><li>In women, peak BMD is achieved by the second decade and begins to decrease thereafter. At menopause, there is 3% reduction in bone mass per year for the first 5 years; thereafter, 1%-2% per year, increasing the risk of fracture. </li></ul>
  27. 30. Bone Loss <ul><li>E action on bone is mediated by direct effects on and by effects on collagen . The accelerated decline in bone mass is mediated by a variety of mechanisms, but the primary event is increased resorption (osteoclastic activity), which becomes uncoupled from bone formation (osteoblastic activity). </li></ul><ul><li>There are also indirect effects mediated by parathyroid hormone and cytokines, which oppose the resorptive effects . Osteoprotegin (OPG), is a soluble protein that inhibits osteoclastic bone resorption. </li></ul><ul><li>In postmenopause, the positive effects of estrogen on growth factors, calcitonin, vitamin D metabolism, and calcium absorption are also diminished. </li></ul>
  28. 31. 7. CardioVascular <ul><li>E deficiency increases the risk of (CVD). </li></ul><ul><li>CVD in postmenopausal women aged 50-59 was 4-fold higher than in premenopausal women of the same age. </li></ul><ul><li>However, the relative risk (RR) of CVD depended on the interval that age was adjusted for (ie, for a 5-year interval, the RR was1.7; for a 1-year interval, the RR was 1.2) as well as on adjustment for smoking . </li></ul><ul><li>Aging and E deficiency contribute to the increased risk of CVD in older women. </li></ul><ul><li>Premature menopause, <age 35, has 2- to 3-fold increased risk of myocardial infarction; oophorectomy (before age 35) increases the risk 7-fold. </li></ul>
  29. 32. CVD <ul><li>Cholesterol rises after menopause. </li></ul><ul><li>Increases in low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein (VLDL) and lipoprotein a (LP(a)). </li></ul><ul><li>The oxidation of LDL-C is also enhanced. </li></ul><ul><ul><li>However most of these changes occur in a variable degrees with aging </li></ul></ul>
  30. 33. CVD <ul><li>Coagulation balance is not altered. </li></ul><ul><li>Blood flow in all vascular beds decreases after menopause. </li></ul><ul><li>Estrogen and progesterone receptors have been found in vascular tissues, including coronary arteries. Overall, the direct vascular effects that occur after menopause are considered as important as, or more important than, the changes in lipid and lipoproteins in terms of CVD risk. </li></ul><ul><li>Carbohydrate tolerance decreases as a result of an increase in insulin resistance. </li></ul>
  31. 34. 7.Sexuality <ul><li>E deficiency causes urogenital atrophy, which affect sexual function. This may lead to a decline in sexual interest, but the ability to become sexually aroused may also be affected. </li></ul><ul><li>Postmenopausal women become androgen deficient; which lead to reduced libido. </li></ul><ul><li>Clinicians have proposed adding androgen to HRT for complaints relating to sexual desire and arousal and energy level. </li></ul>
  32. 35. 7.Sexuality <ul><li>DHEA is a therapeutic option in menopause. </li></ul><ul><li>10% DHEA vaginal cream have beneficial effects, without significant adverse effects, through the transformation of DHEA into androgens and/or estrogens in specific peripheral intracrine tissues. Endometrium remained atrmation. </li></ul>
  33. 36. How They Perceive Menopause <ul><li>More than half (51%) reported that they were happier and more fulfilled in their postmenopausal years than in their 20s (10%), 30s (17%), or 40s (16%). </li></ul><ul><li>They reported that many areas of their lives had improved since menopause, and almost 75% had made some health-related lifestyle change at midlife (eg, smoking cessation). </li></ul><ul><li>More than half reported that their sexual relationship was unchanged at menopause. </li></ul>
  34. 37. Women’s Perceptions of Menopause <ul><li>Cessation of menstrual cycles </li></ul><ul><li>End of reproductive ability </li></ul><ul><li>A time of hormonal changes </li></ul><ul><li>A change of life </li></ul><ul><li>A changing body </li></ul><ul><li>A time of changing emotions </li></ul><ul><li>A time of symptoms and disease </li></ul><ul><li>An aging process </li></ul>
  35. 38. If she does not have any of these, why not to leave her alone??
  36. 39. How to Manage? <ul><li>It is the approach to management of menopause that is critical. </li></ul><ul><li>Assessment of symptoms (if present), the needs of the woman, her specific risk factors , and her family history are fundamental. </li></ul><ul><ul><li>It is only in this context that the various options should be considered and choices made. </li></ul></ul><ul><li>The ultimate question:Will any of the available options improve the overall quality of life for the woman ? </li></ul>
  37. 40. Preventive measures for menopause <ul><li>How can we modify the increased mortality and morbidity rates in our older women patients? </li></ul><ul><ul><li>Smoking cessation to prevent lung cancer. </li></ul></ul><ul><ul><li>Screen for breast cancer risk factors; family history; fertility or infertility history, and age at menarche, menopause, and first pregnancy. Preventive measures = frequent self-examination and provider examinations; annual mammography in women older than 40 years. </li></ul></ul><ul><ul><li>For CVD , assess family history and risk factors as BP, cholesterol , DM, smoking, poor diet, and lack of exercise. </li></ul></ul><ul><ul><li>Screen cancer colon, ovary, and uterus. </li></ul></ul><ul><ul><li>It is also important to evaluate bone mass . BMD has proved to be very useful. </li></ul></ul>
  38. 41. 1. Diet & Excercise <ul><li>Diet, exercise, and weight control are important in determining a woman's risks for CVD, osteoporosis, diabetes, breast cancer, and depression. Menopause is a high-risk time for weight gain. </li></ul><ul><li>Together, diet and exercise are crucial components of preventive medicine for women pre-, peri-, and postmenopause . </li></ul>
  39. 42. Diet & Exercise <ul><ul><li>Exercise. </li></ul></ul><ul><ul><li>Aerobic exercise modify lipoprotein levels. </li></ul></ul><ul><ul><li>Brisk walking and vigorous exercise are strongly associated with a reduced risk for coronary events. </li></ul></ul><ul><ul><li>Weight training, Progessive resistance training and weight-bearing exercise have been shown to be effective in increasing BMD, reducing osteoporotic fracture risk, and preventing falls in older women. </li></ul></ul><ul><ul><ul><li>PS. Diet and exercise good for: </li></ul></ul></ul><ul><ul><ul><ul><li>Bone physiology. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Mood. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CVD. </li></ul></ul></ul></ul>
  40. 43. 2. Supplement <ul><li>Calcium and vitamin D are important adjuncts to treatment and preventive health programs. </li></ul><ul><li>Vitamin D together with HRT provide a bone-sparing effect that is superior to that of HRT alone. </li></ul><ul><li>Calcium should begin before menopause. Calcium carbonate (500 mg daily), in premenopausal women prevent bone loss, allowing them to enter menopause with greater bone mass, which may reduce the risk of later bone fracture. </li></ul><ul><ul><li>PS: supplement is good for bone physiology. </li></ul></ul>
  41. 44. 3. Therapeutic Options <ul><li>Questions , </li></ul><ul><ul><li>What is the reason to intervene? Are there symptoms such as hot flushes? The answer is : short-term therapy. </li></ul></ul><ul><ul><li>For postmenopausal woman who has no major complaints but is concerned about osteoporosis, for example. Her family history, risk profile, and bone-mass assessment are valuable adjuncts to help decision making. </li></ul></ul><ul><li>Depending on these variables, the choice of intervention may be: </li></ul><ul><ul><li>Natural supplements, </li></ul></ul><ul><ul><li>Nonhormonal treatments (eg, a bisphosphonate), </li></ul></ul><ul><ul><li>Selective estrogen receptor modulator (SERM), or </li></ul></ul><ul><ul><li>HRT. </li></ul></ul>
  42. 45. a.Estrogen for vasomotor <ul><li>Natural E supplements are popular. </li></ul><ul><li>Black kohosh, genistein, and soy-based products have been shown to be effective for hot flushes. </li></ul><ul><li>Although some data are available for soy-based products, there are no convincing data about efficacy for vaginal health, lowering CVD risk, or improving brain function. </li></ul><ul><li>Because phytoestrogens bind to ERs (ER-beta > ER-alpha), large doses (which are needed to achieve benefit on a statistical basis) may pose some risk for estrogen-responsive cancers, such as breast cancer; although, conventional thinking is that these products are protective for the breast. </li></ul>
  43. 46. b.Bisphophonate for osteoporosis <ul><li>Bisphosphonate may be appropriate for women with or at risk for osteoporosis who cannot or choose not to use HRT. </li></ul>
  44. 47. c. Other treatment for osteoporosis. <ul><li>Osteoprotegerin. This naturally occurring protein is a negative regulator of osteoclast formation. </li></ul><ul><li>Tolerability profile as excellent, with mild pruritis at the injection site. </li></ul>
  45. 48. Other treatment for osteoporosis. <ul><li>Parathyroid Hormone . </li></ul><ul><li>Bisphosphonates. </li></ul><ul><li>SERMs. </li></ul><ul><li>Bisphosphonates, estrogen, and SERMs slow or stop bone loss but they do not replace bone that has already been lost. Currently in clinical development are a group of bone-building peptides -- native parathyroid hormone, its 34- to 38-amino acid N-terminal fragments, and a group of molecules known as second-generation mini-PTHs. [125] </li></ul>
  46. 49. d. SERM <ul><li>Selective agonistic or stimulatory effects (ie, estrogenic) on one organ system and neutral or antagonistic (ie, antiestrogenic) effects on other organ systems. </li></ul>
  47. 50. SERMs <ul><li>Triphenylethylenes </li></ul><ul><li>Clomiphene </li></ul><ul><li>Tamoxifen </li></ul><ul><li>Toremifene </li></ul><ul><li>Droloxifene </li></ul><ul><li>Idoxifene </li></ul><ul><li>Benzothiophenes </li></ul><ul><li>Raloxifene </li></ul><ul><li>LY353381 </li></ul><ul><li>Naphthalenes </li></ul><ul><li>CP336,156 </li></ul><ul><li>Chromans </li></ul><ul><li>Levormeloxifene </li></ul><ul><li>Phytoestrogens </li></ul><ul><li>Genistein </li></ul><ul><li>Daidzein </li></ul><ul><li>Conjugated Estrogens </li></ul><ul><li>Delta8,9-Dehydroestrone sulfate </li></ul>
  48. 51. Ideal SERM <ul><li>Ideally, the use of SERMs should fall into 2 categories . The first would be to relieve symptoms associated with E deficiency. </li></ul><ul><li>The second, more selective use would be to target the antiestrogenic effects of a SERM to 1 organ system (eg, the breast). </li></ul><ul><li>It should have agonistic activity in the brain, bone, CV system (not necessarily the liver), vagina, and urinary system, and antagonistic activity in the breast and uterus. </li></ul>
  49. 52. <ul><li>Theoretically, the ideal SERM's estrogenic activity will improve cognitive function, osteoporosis, Alzheimer's disease, CVD, and stroke. </li></ul><ul><li>The ideal SERM would increase HDL-C levels and reduce LDL-C and total cholesterol. The hepatic effects of a SERM, if excessive, however, increase the risk of venous thromboembolism. </li></ul><ul><li>Age increases the risk of breast cancer, SERM ideally would lower this risk. </li></ul><ul><li>SERM that exerts agonist effects on systems such as bone but does not result in uterine/endometrial stimulation would be ideal. </li></ul>
  50. 53. <ul><li>Then we come to HRT, HT or ET </li></ul>
  51. 54. Women perception of HRT <ul><li>Awareness of HRT is determined by race, educational level, and the perception of going or having gone through menopause. </li></ul><ul><li>Women selected or self-selected for long-term HRT use tended to be healthy: they were thinner, younger, and physically more active; more were involved in professional work; and more had oophorectomies and experienced earlier menopause than the average postmenopausal woman. </li></ul><ul><li>Many women express fear regarding HRT, especially because of the associated risk of breast cancer. </li></ul>
  52. 55. Women perception of HRT <ul><li>Women believe that the leading cause of death in women is breast cancer. Many also believe that only a small percentage of deaths are attributable to CVD. </li></ul><ul><li>The truth, of course, is the reverse. One in 3 women older than 65 years has some evidence of CVD, and the risk of breast cancer after age 65 is 1 in 36. Although it has been widely asserted that the incidence of breast cancer in women is approximately 1 in 8 women, this is the lifetime risk. Age-specific data are quite different, and the risk is 1 in 77 in the fourth decade, 1 in 42 in the fifth decade, and 1 in 45 in the eighth decade. </li></ul>
  53. 56. Benifits <ul><li>Vasomotor. </li></ul><ul><li>Osteoporosis. </li></ul><ul><li>CVD </li></ul><ul><li>Urogenital. </li></ul><ul><li>Cognitive diseases. </li></ul><ul><li>Alzheimer's disease. </li></ul>
  54. 57. Vasomotor <ul><li>It is well established that HRT provides relief from hot flushes. </li></ul><ul><li>But </li></ul><ul><ul><li>Usually it is relived by time. </li></ul></ul>
  55. 58. Osteo, Preven & TT <ul><li>ET clearly decreases bone turnover and prevents postmenopausal bone loss. </li></ul><ul><li>A positive correlation exists between systemic osteoporosis and oral alveolar bone resorption.(Alveolar bone in the maxilla and mandible provides the framework for tooth support.) Estrogen replacement reduces oral alveolar bone loss, increasing the probability of better tooth retention in postmenopausal women. </li></ul>
  56. 60. CHD <ul><li>ET decrease the incidence. </li></ul>
  57. 61. Reversal of urogenital atrophy <ul><li>With estrogen treatment, vaginal cytology can change from a profile of predominantly parabasal cells to one with an increased number of superficial cells. Along with this change, vaginal pH decreases, vaginal blood flow increases, and the electropotential difference across the vaginal mucosa increases to premenopausal levels. </li></ul>
  58. 62. Improv. Mood and Cognitive functions <ul><li>Positive effect of E on neuronal function (eg, growth, survival, synaptic activity). </li></ul><ul><li>E has a positive effect on mood, memory, and quality of life scales, whereas progestins may attenuate some of these effects. </li></ul>
  59. 63. Improv. Mood and Cognitive functions <ul><li>The data on estrogen reducing the risk of Alzheimer's disease, however, are remarkably consistent (RR, 0.4-0.6) among case-control and cohort studies. </li></ul><ul><li>Although estrogen appears to have a protective effect on the development of Alzheimer's disease, it is not central to the pathophysiology of the disease, </li></ul>
  60. 64. What about risks?
  61. 65. RISKS <ul><li>Idiosyncratic reactions (eg, hypertension and venous thrombosis). </li></ul><ul><li>Vag bleeding. </li></ul><ul><li>Endometrial disease. </li></ul><ul><li>Breast cancer. </li></ul>
  62. 66. Idiosyncratic Reactions <ul><li>E usually causes no change in BP; it may actually reduce BP, a finding that has relevance for normotensive as well as hypertensive women. </li></ul><ul><li>In some women, however, HRT may increase both diastolic and systolic BP, but the elevation is rapidly reversible with discontinuation of HRT. </li></ul>
  63. 67. Idiosyncratic Reactions <ul><li>ERT increases venous thromboembolic events (VTEs). The risk of VTEs was higher in the first year of treatment. </li></ul><ul><li>In women with a history of thrombosis, there is an increased risk of VTEs with ERT. Women who have a family history of thrombosis or had VTEs with oral contraceptives or other prior ERT should be discouraged. </li></ul>
  64. 68. Vag Bleeding <ul><li>Vaginal Bleeding, breast tenderness and bloating may also occur but can be alleviated by alterations in dosage and type of preparation. </li></ul><ul><li>Unscheduled bleeding in any postmenopausal woman should be investigated regardless of results of US endometrial thickness, because abnormalities may be present when the endometrial thickness is less than 4 mm. </li></ul><ul><li>Recurrent bleeding during sequential HRT regimens causes many patients to stop treatment. </li></ul>
  65. 69. Endometrial Dis. <ul><li>Endometrial disease occurs with unopposed ERT. </li></ul><ul><li>A woman's risk of developing endometrial cancer with unopposed estrogen use is 2- to 8-fold higher. </li></ul><ul><li>The risk of varying degrees of endometrial hyperplasia is greater than that for endometrial cancer. The risk of endometrial hyperplasia was 20% after 1 year and 40% at the end of 3 years. </li></ul><ul><li>The addition of a progestin eliminated the hyperplasia. </li></ul><ul><li>Endometrial cancer associated with ERT are not aggressive; because it is more likely to be discovered at an earlier stage. </li></ul>
  66. 70. Breast Cancer <ul><li>Most controversial . </li></ul><ul><li>In earlier calculations of HRT-related risk, an RR of 1.1 was ascribed, suggesting a 10% increase in risk relative to no ERT. </li></ul><ul><li>Several meta-analyses have suggested either no significantly increased risk (ie, RR ~ 1.0) or a risk as high as 1.6. </li></ul><ul><li>It is also possible that ERT use causes breast cancer to occur earlier in some women, but it is not clear which women are at greatest risk . </li></ul>
  67. 71. Breast Cancer <ul><li>Decision model for the calculation of breast cancer risk on the basis of 7 risk factors: testosterone levels, BMI, waist-to-hip ratio, alcohol consumption, density to mammography, previous benign disease, and family history. </li></ul><ul><li>Short-term estrogen use (~ 5 years) is not associated with increased breast cancer risk, But controversy surrounds long-term estrogen use (> 10 years). </li></ul><ul><li>The positive association was especially pronounced with continuously combined estrogen-progestin combinations. </li></ul>
  68. 72. Breast Cancer <ul><li>HRT stimulate the growth of ER-positive but not ER-negative breast cancer. The prognostic significance of this is not known. </li></ul><ul><li>For moderate doses of estrogen, the risk of breast cancer is probably in the range of 20% to 30% in those women who are susceptible. </li></ul><ul><li>HRT reduces mammographic sensitivity, because breast parenchymal cell density increases in some women on HRT. </li></ul>
  69. 73. Tibolone; another progestogen <ul><li>Tibolone, a synthetic steroid analogue, is a form of HRT that does not tend to induce bleeding. </li></ul><ul><li>It is effective in maintaining an inactive endometrium while providing estrogenization of the lower genital tract over 6 years. </li></ul><ul><li>Tibolone (2.5 mg/day) can safely relieve menopausal symptoms. </li></ul>
  70. 74. Compliance <ul><li>Bleeding is one of the most common reasons for discontinuance of HRT. Progestins may also cause mood alterations. These side effects have to be dealt with effectively and usually require more flexibility in prescribing habits. It would be prudent to use the lowest dose of progestin necessary to prevent endometrial hyperplasia until more data are available. </li></ul>
  71. 75. HRT status in 2010 <ul><li>Whether or not HRT should be considered is a very individual decision, which must take into account symptoms, risk factors, and individual preferences and needs. Alternatives should always be carefully considered . </li></ul><ul><li>If hormonal therapy is chosen, there should be flexibility in prescribing -- there is no ideal regimen for every woman. </li></ul><ul><li>Estrogen can be used for short-term treatment of symptoms at the lowest dosage that will adequately control hot flushes or vaginal dryness or dyspareunia. </li></ul>
  72. 76. Conclusions <ul><li>There are many effective options for the relief of menopausal symptome, HT is the most effective but it is not always necessary . </li></ul><ul><li>First line is other options , no HT if >50. </li></ul><ul><li>< 50 means < 5ys treatment is not hazardous. </li></ul>
  73. 77. Conclusions <ul><li>Benefits vs breast cancer, unsolved issue </li></ul>
  74. 78. <ul><li>Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable for women who initiate HT close to menopause but decreases in older women and with time since menopause in previously untreated women </li></ul>
  75. 79. <ul><li>The statement suggests that the association between ovarian cancer and HT beyond 5 years , if any, should be considered as rare or very rare, but that women with a positive family history or other increased risk for ovarian cancer should be counseled about this rare association. </li></ul>
  76. 80. <ul><li>Overall data, including those from WHI analysis, suggest that starting EPT in older women with a positive smoking history may promote the growth of existing lung cancers. In contrast, evidence from the WHI and some case-control and cohort studies suggests that use of HT in women younger than 60 years offers some protection against lung cancer. </li></ul>
  77. 81. <ul><li>Although safety of EPT in survivors of breast cancer is controversial, with observational studies suggesting that it is safe and possibly even protective against recurrence, a randomized controlled trial showed a statistically significant 2.4-fold increase in new breast cancer events. ET use in breast cancer survivors has not been proven to be safe and may be associated with an increased risk for recurrence. </li></ul>
  78. 82. <ul><li>HT is currently not recommended as a sole or main indication for coronary protection in women of any age. </li></ul><ul><li>Starting HT by age 50 to 59 years or within 10 years of menopause to treat typical menopausal symptoms does not seem to increase the risk for CHD events, and there is some recent evidence that starting ET in early postmenopause may lower CHD risk. </li></ul><ul><li>So no role for CHD </li></ul>
  79. 83. <ul><li>Current data suggest that when HT is either tapered or abruptly discontinued, rates of vasomotor symptom recurrence are similar. The statement therefore makes no recommendation concerning how to discontinue therapy. </li></ul>
  80. 84. Conclusions <ul><li>Menopause is not a disease, but it have serious clinical sequelae. </li></ul><ul><li>Any intervention is effective for specific symptoms and/or risk profiles. </li></ul><ul><li>We have to guide our female (they are not patients) through the menopausal transition. </li></ul><ul><li>Not every woman will have the same response to a given therapy. Be flexible in prescribing patterns, whether it is for traditional HRT or alternative approaches. </li></ul>
  81. 85. Conclusions <ul><li>Absolute contraindications </li></ul><ul><ul><li>Breast cancer, family </li></ul></ul><ul><ul><li>Endometrial cancer </li></ul></ul><ul><ul><li>Vascular thrombosis </li></ul></ul><ul><ul><li>Unexplained vaginal bleeding. </li></ul></ul><ul><li>Relative contraindications </li></ul><ul><ul><li>Hyperlipidemia. </li></ul></ul><ul><ul><li>> 5 ys treatment. </li></ul></ul>
  82. 86. Conclusions <ul><li>ERT for women with early menopause till they reach the age of menopauase of their peers. </li></ul><ul><li>5 years is OK, 10 yreas need reconsideration. </li></ul><ul><li>We treat the symtoms and not looking for treatment of aging which could be hazardous. </li></ul><ul><li>Exercise, supplement and SERM is part of the solution. </li></ul>
  83. 87. Thank you