1. به نام خداوند بخشنده مهربان
H.R.T
In menopause
دکتر زهرا علامه
دانشیار دانشگاه علوم پزشکی اصفهان

2. Treatment of menopausal symptoms with hormone therapy
Importance of patient age 
Indications 
The most common indication for MHT is vasomotor symptoms (or hot flashes). Vasomotor symptoms occur most often in the late menopausal transition and early postmenopause 

4. Another common indication for estrogen therapy is vulvovaginal atrophy or GSM. The epithelial linings of the vagina and urethra are very sensitive to estrogen, and estrogen deficiency leads to thinning of the vaginal epithelium. This results in GSM (also called vaginal atrophy or atrophic vaginitis), causing symptoms of vaginal dryness, itching, dyspareunia, and sometimes urinary symptoms. Both systemic and vaginal estrogen are effective for genitourinary atrophy symptoms, but we suggest vaginal rather than systemic estrogen for women who have only GSM without other menopausal symptoms such as hot flashes. 

5. Other potential indications for MHT include:
●Mood lability/depression – MHT, alone or in combination with an antidepressant such as a selective serotonin reuptake inhibitor (SSRI), 
●Joint aches and pains – It is unclear if the pain is related to estrogen deficiency or a rheumatologic disorder, but in the WHI, women with joint pain or stiffness at baseline were more likely to get relief with either combined EPT or unopposed ET than with placebo.
CHD – We suggest not using MHT for the prevention of CHD, even in young postmenopausal women. Although the risk profile appears to be more favorable in young women taking unopposed estrogen, use for prevention is still not warranted 

6. Osteoporosis – Although we previously recommended estrogen as a first-line choice for prevention and treatment of osteoporosis, we now recommend bisphosphonates. However, in the occasional patient with persistent menopausal symptoms who cannot tolerate first- and second- line therapies for osteoporosis, estrogen may be a reasonable option. 

7. Cognitive function and dementia – We currently do not suggest the routine use of MHT for peri- and postmenopausal women who are experiencing cognitive symptoms (memory loss and difficulty concentrating). 
In addition, we suggest not using MHT to prevent dementia. 

8. Contraindications history of breast cancer, CHD,
a previous venous thromboembolic event or stroke, 
active liver disease,
 unexplained vaginal bleeding,
 high-risk endometrial cancer, 
 transient ischemic attack

9. Oral estrogens hypertriglyceridemia, active gallbladder disease,
or known thrombophilias such as factor V Leiden (without a personal history of venous thromboembolism [VTE]).
Transdermal estrogen is also preferred for women with migraine headaches with auras.

10. Choosing candidates
 — We consider the initiation of menopausal hormone therapy (MHT) to be a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT (such as a history of breast cancer, coronary heart disease [CHD], a previous venous thromboembolic event or stroke, or active liver disease)

11. Calculating risks
The Endocrine Society guideline suggests calculating cardiovascular and breast cancer risks before initiating MHT [5]. They suggest nonhormonal therapies for symptomatic women who are at high risk (>10 percent 10- year risk) for CVD (table 1) or moderate (1.67 to 5 percent five-year risk) to high risk (>5 percent) for breast cancer. 
 For women at moderate risk of CVD (5 to 10 percent 10- year risk), they suggest transdermal rather than oral estrogen, with micronized progesterone for those with a uterus (table 1). They note that a population-based CVD risk calculator should be used to estimate CVD risk (calculator 1). An online tool such as the National Cancer Institute Breast Cancer Risk Assessment Tool can be used to assess five-year breast cancer risk [12]. Prior to initiating MHT the patient should be up-to-date on breast cancer screening tests.
Prior to initiating MHT the patient should be up-to-date on breast cancer screening tests.

13. Starting estrogen

16. Route
 — We start many women on transdermal 17-beta estradiol because it is associated with a lower risk of VTE, stroke, and hypertriglyceridemia than oral estrogens. 

17. All routes of estrogen administration appear to be equally effective for symptom relief (and bone density), but their metabolic effects differ:
Oral estrogen has more favorable effects on lipid profiles, but there is no evidence that this results in long-term clinical benefit. On the other hand, oral estrogens are associated with increases in serum triglycerides and C-reactive protein. 
Oral estrogens increase sex hormone-binding globulin (SHBG) more than transdermal preparations, which results in lower free testosterone concentrations. In theory, this could result in a negative impact on libido and sexual function, but this has not been proven. Similar effects on thyroxine-binding globulin (TBG) and bioavailable thyroxine (T4) occur with oral estrogen (increased TBG and lower bioavailable T4). Oral estrogens also increase cortisol-binding globulin (CBG), resulting in an increase in total serum cortisol. Interpreting serum cortisol values in a woman taking oral estrogen can therefore be misleading. 
The risks of VTE and stroke appear to be higher with oral when compared with transdermal estrogen.

18. Dose: conjugated estrogen 0.625 mg/day
and 17-beta estradiol (oral 1 mg/day or
transdermal 0.05 mg/day) 
appeared to be equally effective for the treatment of hot flashes 

19.  the current approach is to start with lower doses, such as transdermal estradiol ( mg) or oral estradiol (0.5 mg/day), and titrate up to relieve symptoms. Lower doses are associated with less vaginal bleeding and breast tenderness [19].
Lower doses are also associated with fewer effects on coagulation and inflammatory markers, and a possible lower risk of stroke and VTE than standard-dose therapy 

20. Based upon available data, we suggest starting with lower doses of estrogen (oral 17- beta estradiol [0.5 mg/day] or mg of transdermal estradiol) unless the patient has severe symptoms. If hot flashes are still present after one month, we increase transdermal estradiol to mg and reassess one month later. If symptoms are still not relieved, we increase further to 0.05 mg. An exception to this approach is the patient with severe symptoms; we start with a transdermal dose of 0.05 mg to achieve more rapid relief of symptoms.

21. Standard" doses of estrogen given daily (conjugated estrogen 0
Standard" doses of estrogen given daily (conjugated estrogen mg or its equivalent) are adequate for symptom relief in the majority of women [17,18,22]. An exception is younger women after bilateral oophorectomy. They often require higher doses (eg, up to 0.1 mg transdermal estradiol) for the first two to three years after surgery; the dose can subsequently be tapered down.

22. The lowest available transdermal estradiol dose is 0
The lowest available transdermal estradiol dose is mg; it is approved for prevention of bone loss. However, approximately 50 percent of women derive some benefit for hot flashes [23]. Progestin doses may be lowered with low-dose estrogen, but there is no consensus on optimal regimens.

23. Estrogen should be administered continuously; past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete. Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month.

24. Side effects Factors affecting oral estrogen metabolism
a transdermal estrogen may be better than oral estrogen since it avoids the first-pass hepatic metabolism. 
Oral estrogens increase TBG more than transdermal preparations, which results in lower bioavailable T4. Therefore, in women receiving T4 replacement therapy, the addition of oral ET may increase T4 requirements.
Concurrent acute alcohol ingestion with oral estradiol has been found to cause a threefold rise in serum estradiol concentrations, apparently by slowing the metabolism of estradiol 
Women with end-stage renal disease have higher serum estradiol concentrations after an oral dose of estrogen than do normal women 

25. Adding a progestin — We suggest oral micronized progesterone as our first-line progestin
Our first choice of progestin is natural micronized progesterone (200 mg/day for 12 days/month or 100 mg daily). There are reasons to believe that natural progesterone might be safer for the cardiovascular system (no adverse lipid effects) and possibly the breast.

26. The most extensively-studied formulation for endometrial protection is the synthetic progestin used in the WHI, medroxyprogesterone acetate(MPA) (2.5 mg daily). While MPA is endometrial protective, it was associated with an excess risk of CHD and breast cancer when administered with conjugated estrogen in the WHI. In addition, regimens using continuous versus cyclic MPA may be associated with a higher risk of breast cancer.

27. For women who are perimenopausal or newly menopausal, we start with cyclic administration of oral micronized progesterone (200 mg/day for 12 days of each calendar month). Continuous administration in this population is associated with irregular, unscheduled bleeding due to the exogenous hormones and the continued endogenous ovarian function. For women who are ≥2 to 3 years postmenopause, we use a continuous regimen (micronized progesterone 100 mg/day); irregular and breakthrough bleeding is less of a problem once ovarian function has ceased. While there is often early breakthrough bleeding even after menopause, most women do eventually develop amenorrhea, a desired goal of continuous administration. 

28. Side effects and bleeding
Some women are unable to tolerate cyclic progestin administration (with any type of oral progestin) because of mood side effects and bloating. In addition, cyclic progestins almost always result in monthly withdrawal bleeding, which can be a lifestyle concern for many women. For any of these concerns, we suggest switching to a continuous regimen. This often resolves the issue of mood symptoms and bloating. However, for women who are newly menopausal, breakthrough bleeding can be anticipated.

29. Women who cannot tolerate oral progestins
Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we sometimes suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD) (table 4). Lower doses of levonorgestrel-releasing IUDs for use in menopausal women are available in many countries, but not the United States. 

30. Other progestins that have been used include quarterly regimens (progestin administered only every third month). However, quarterly progestin administration is not considered to be standard therapy and cannot be recommended. Vaginal progesterone inserts are sometimes tried, but endometrial safety data are also limited

31. Conjugated estrogen/bazedoxifene
 Another option is the combination of bazedoxifene, a selective estrogen receptor modulator (SERM treatment of menopausal vasomotor symptoms and osteoporosis prevention. In this combination, the SERM bazedoxifene prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary. Potential candidates include women with moderate-to-severe hot flashes who have breast tenderness with standard estrogen-progestin therapy (EPT) or women who cannot tolerate any type of progestin therapy because of side effects. Like other SERMs, the risk of VTE is increased with bazedoxifene. To date, no additive effect on VTE has been observed with the combination conjugated estrogen/bazedoxifene, but longer studies are needed to fully address this risk.

32. Duration of therapy
For women who choose estrogen or combined EPT, short-term use is suggested (generally not more than five years or not beyond age 60 years However, hot flashes persist for an average of 7.4 years, and many women continue to have symptoms for more than 10 years. Some women with persistent symptoms choose longer-term therapy.

33. For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options before considering resuming estrogen. For those who do not get adequate relief with nonhormonal therapies, we consider extended use of hormone therapy.

34. Data on the attributable risks and benefits of MHT for a period of five years in women ages 50 to 59 years are available and can be used for evidence-based decision making

35. Monitoring with mammography
Routine mammograms and breast exams are recommended in women taking MHT, even when used short-term. In the WHI, the risk of breast cancer with combined EPT did not increase until the fourth year. However, abnormal mammograms were more common with both ET and EPT (although more common with EPT). The majority of abnormal mammograms in the WHI represented requests for additional views. Of note, stopping therapy for one to two months before a mammogram does not reduce recall rates. 

36. Use of oral contraceptives during the menopausal transition
A low-estrogen oral contraceptive (OC) is an option for perimenopausal women who seek relief of menopausal symptoms, who also desire contraception, and who in some instances need control of bleeding when it is heavy [29]. Most of these women are between the ages of 40 and 50 years and are still candidates for OCs. For them, an OC containing 20 mcg of ethinyl estradiol provides symptomatic relief while providing better bleeding control than conventional MHT because the OC contains higher doses of both estrogen and progestin (which suppresses the hypothalamic-pituitary-ovarian axis). OCs should be avoided in obese perimenopausal women because they are at greater risk for thromboembolism.
Contraindications to OC use in this population include smoking, hypertension, and migraine headaches. 

37. Stopping hormone therapy
Tapering
Implications of stopping
Return of estrogen deficiency symptoms is common. In women who have recurrent vasomotor symptoms after stopping therapy, there is currently no way to determine whether the symptoms will resolve quickly or persist for a prolonged time. For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options before considering resuming estrogen.
●Resumption of bone loss .
●Decrease in breast cancer risk .
●The effect of estrogen cessation on CHD, particularly in young postmenopausal women, is unclear .

38. Extended use of MHT (beyond age 60 or even 65 years)
 over 40 percent of women ages 60 to 65 years have persistent hot flashes that can impair sleep and quality of life.
For women who choose extended use of MHT (more than five years or beyond age 60 years), we restart estrogen at the lowest dose possible and make plans for a future attempt to stop the estrogen.

39. SPECIAL ISSUES
Compounded bioidentical hormone therapy
The term "bioidentical hormone" technically refers to a hormone with the same molecular structure as a hormone that is endogenously produced

40. ●There are numerous approved estrogen and progestin formulations in all countries for MHT; therefore, there is no rationale for use of nonapproved products.
●There are no randomized trials demonstrating either efficacy or safety of compounded bioidentical hormone therapy for treating menopausal symptoms.
●The contents, dose, quality, and sterility of these products are not subject to regulatory oversight. When tested, potencies and patterns of absorption of compounded estrogens have been highly variable [50,51].
●These products are not required to include package inserts or the standard warnings that all approved estrogens provide.

41. Role of androgen therapy — The known decrease in ovarian androgen production rates and serum androgen concentrations has caused concern that menopause might be associated with a decline in libido. An age-associated decline in sexual desire has been observed in both men and women. However, it is unclear whether the decline in libido in women is age or menopause related, since studies in women have not shown a significant correlation between libido and the serum estradiol or testosterone concentration [54].
Clinical trials of exogenous testosterone replacement suggest modest benefits of testosterone therapy in some postmenopausal women. However, there are potential risks associated with androgen replacement, and the use of testosterone is limited by the lack of approved and commercially available products for women. Until the beneficial effects of androgen replacement are better established, it cannot be routinely recommended to postmenopausal women. .

42. Migraines — Migraine headaches (with or without aura) are not considered to be a contraindication to MHT. For women with hot flashes and estrogen- associated migraines (which typically worsen during perimenopause), we suggest continuous transdermal hormone regimens (as opposed to cyclic regimens) to avoid triggering estrogen-withdrawal headaches. The effect of MHT on stroke risk in postmenopausal women with migraines is not well studied. However, low doses of transdermal estradiol (≤50 mcg, the dose range we routinely recommend) have not been associated with an excess risk of stroke in normal women
Depression in perimenopausal women — Mood disorders are common during the menopausal transition, often coexisting with vasomotor symptoms. If her main concern is depression and hot flashes are not severe, we start with a selective serotonin reuptake inhibitor (SSRI). On the other hand, if vasomotor symptoms are the major symptom and depression or mood symptoms are mild, we start with MHT . For women in whom depression and vasomotor symptoms are both severe, we start both estrogen and an SSRI and refer to a psychopharmacologist for further consultation and monitoring. In our experience, many women require both MHT and estrogen for optimal symptom relief. The efficacy of estrogen for depression occurring after menopause is unclear.
The risk of depression during perimenopause is higher than during the pre- or postmenopausal years. Perimenopausal depression includes both new-onset (first episode) depression as well as a relapse in women with a history of depresson

43. In one trial of ET for perimenopausal depression, 50 perimenopausal women with major depression, dysthymia, or minor depressive disorders received transdermal estradiol (0.1 mg) or placebo for 12 weeks. Remission of depression occurred in 68 percent of patients compared with only 20 percent receiving placebo [56]. The Kronos Early Estrogen Prevention Study (KEEPS), a trial of MHT in younger menopausal women ages 45 to 54 years who underwent extensive mood evaluations, reported that four years of oral estrogen appeared to improve mood, as women receiving oral conjugated estrogen combined with micronized progesterone had lower depression and anxiety scores than those receiving either transdermal estradiol with micronized progesterone or placebo [57].
SSRIs are effective for perimenopausal depression, and some provide modest benefit for hot flashes as well [58,59] .Data also suggest that adding estrogen to antidepressant therapy may result in additional benefit for perimenopausal women with depression [60].
Primary ovarian insufficiency — Data from the Women's Health Initiative (WHI), a set of MHT trials in older postmenopausal women, should not be extrapolated to women with premature ovarian failure (now termed primary ovarian insufficiency [POI], defined as menopause before age 40 years). Hormone therapy is started at a younger age in these women, and current guidelines suggest that therapy should be continued until the average age of menopause (age 50 to 51 years) to prevent premature bone loss, coronary heart disease (CHD), and stroke. At that point, if hormone therapy is stopped and menopausal symptoms are moderate to severe, the same discussion of potential risks and benefits of MHT should take place.

44. BREAST CANCER
early menopause due to adjuvant chemotherapy and may have vasomotor symptoms due to tamoxifen therapy, ET should not be prescribed. The epidemiologic data and clinical trial data have been inconsistent, but the increased risk of breast cancer recurrence with ET in one trial (Hormonal Replacement After Breast Cancer – Is It Safe? [HABITS]) is of great concern. We therefore do not recommend estrogen for women with a personal history of breast cancer. We suggest that other established means of controlling symptoms or preventing osteoporosis should be utilized before considering ET in these women. .

45. Women with endometrial cancer — Women with low-risk disease and menopausal symptoms are candidates for hormone therapy; for younger women, this is also important to decrease the long-term health consequences of estrogen deficiency. Nonhormonal options are preferred for women with intermediate- or high-risk disease. .
Known thrombophilia — MHT increases the risk of venous thrombosis by approximately twofold. This appears to be true for oral preparations, but perhaps not for transdermal preparations. However, available data come from observational studies, not clinical trials. Data suggest that women who have factor V Leiden and use oral hormone therapy have a 15-fold increased risk of venous thromboembolism (VTE). Therefore, oral MHT should be avoided in postmenopausal women with prothrombotic mutations.

46. Other symptoms associated with perimenopause and menopause that respond to estrogen therapy (ET) include mood lability/depression,genitourinary syndrome of menopause (GSM; vaginal atrophy), and sleep disturbances (when related to hot flashes). .
●Healthy symptomatic women in their 50s should be reassured that the absolute risk of complications for healthy, postmenopausal women taking MHT for five years is very low .
●For healthy, peri/postmenopausal women within 10 years of menopause (or <60 years of age) with moderate to severe vasomotor symptoms, we suggest MHT as the treatment of choice .venous thromboembolic event or stroke, active liver disease, or those at high risk for these complications. .
●We suggest transdermal 17-beta estradiol for many women starting MHT .The transdermal route is particularly important in women with hypertriglyceridemia or risk factors for thromboembolism. However, the baseline risk of both venous thromboembolism (VTE) and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe. All types and routes of estrogen are equally effective for hot flashes. .
●For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options. However, if this approach is unsuccessful and symptoms persist, we resume MHT at the lowest dose possible in carefully selected women. .
●For women with an intact uterus who choose ET, progestin therapy must be added to prevent endometrial hyperplasia and carcinoma. .

47. ●We suggest micronized progesterone as our first-line progestin because it is effective for endometrial hyperplasia, is metabolically neutral, and does not appear to increase the risk of either breast cancer or CHD, although data are limited .
●Recommendations for women who choose not to take systemic estrogen, have contraindications to estrogen, or have stopped their MHT and are having recurrent symptoms are found elsewhere. .
●The use of vaginal estrogen is reviewed in detail elsewhere. .
●We currently suggest not using MHT for the prevention of chronic disease (osteoporosis, CHD, or dementia) .However, women who cannot tolerate other options for osteoporosis may be reasonable candidates. .
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