Summary of the 2023 Thai Menopause Society Clinical Practice Guideline on Menopausal Hormone Therapy.

Menopausal hormone therapy (MHT) has been used for various symptoms of estrogen deficiency and in preventing diseases of aging. The benefits and risks of MHT are the basis of discussions in clinical practice and menopausal women. The Woman’s Health Initiative (WHI), the largest randomized controlled trial (RCT) of MHT in women aged 50–79 years, used only one route (oral), one formula of estrogen (conjugated equine estrogen, CEE), and one progestogen (medroxyprogesterone acetate, MPA). In 2002, the first report emphasized the risks of MHT, particularly breast cancer and cardiovascular risks [ 1 ]. A subsequent reevaluation of existing data with an 18-year follow-up demonstrated that MHT initiation did not increase cardiovascular risks in women < 60 years or those who experienced menopause < 10 years ago. Additionally, a higher incidence of breast cancer was observed in the CEE plus MPA group as compared to the placebo group. In contrast, the CEE alone group showed a reduced incidence of breast cancer. The overall risk of MHT was lower than the first report in this specific age group (50–59 years) [ 2 ]. The Thai Menopause Society (TMS) issued its first position statement in 1994, and the second was developed after the first WHI study report. Evidence of knowledge on MHT has been reported over the past 20 years, including new RCT studies, systematic reviews, meta-analyses, and many guidelines for MHT from the International Menopause Society and many countries. Therefore, the TMS developed the 2023 Position Statement on MHT, which is aimed at gynecologists, general physicians, and other specific physicians who practice in Thailand. The term “Menopausal hormone therapy, MHT” includes estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT). These recommendations are related to the priority of medical care, the prevalence of diseases, Thai-specific attitudes toward menopausal management, and available products in Thailand.

This Clinical Practice Guideline was developed by the TMS Position Statement Writing group, an advisory panel of clinicians and research experts in the field of menopause by reviewing the recommendation of published International Consensus Statements, such as the 2016 International Menopause Society Recommendations on Women’s Midlife Health and Menopause Hormone Therapy [ 3 ], the 2022 Hormone Therapy Position Statement of The North American Menopause Society [ 4 ], the Japan Society of Obstetrics and Gynecology and Japan Society of Menopause and Women’s Health 2017 Guidelines for Hormone Replacement Therapy [ 5 ], and other subsequently published literature using evidence-based analysis. The conclusion of the evidence-based recommendation is in line with the referencing definitions at the level of evidence and strength of recommendation as follows [ 6 7 8 ]: Level of evidence: Level I included meta-analyses of RCTs or at least some RCTs. Level II included non-RCTs or any form of quasiexperimental study. Level III included non-experimental descriptive, correlation, and case-control studies. Level IV included expert committee reports, opinions, clinical experiences of respected authorities, or both. Strength of recommendation: Grade A referred to recommendations that followed Evidence Level I. Grade B referred to recommendations that followed Evidence Level II. Grade C referred to recommendations that followed Evidence Level III. Grade D referred to recommendations that followed Evidence Level IV. Grade GPP referred to the recommendations that followed Good Practice Point. Level I included meta-analyses of RCTs or at least some RCTs. Level II included non-RCTs or any form of quasiexperimental study. Level III included non-experimental descriptive, correlation, and case-control studies. Level IV included expert committee reports, opinions, clinical experiences of respected authorities, or both. Strength of recommendation: Grade A referred to recommendations that followed Evidence Level I. Grade B referred to recommendations that followed Evidence Level II. Grade C referred to recommendations that followed Evidence Level III. Grade D referred to recommendations that followed Evidence Level IV. Grade GPP referred to the recommendations that followed Good Practice Point.

• MHT is the most effective treatment for vasomotor symptoms (Level I). • MHT is the most effective treatment for vasomotor symptoms (Level I). • Both ET and EPT effectively relieve vasomotor symptoms (VMS), and the frequency of hot flashes is reduced by 75%. The effect of treatment starts at 2 weeks and a full response is observed by week 4 of MHT [ 9 ]. • Both oral and transdermal MHT effectively reduce VMS [ 10 ]. • The standard dose of MHT is sufficient to effectively treat VMS. However, another study showed that a daily micro-dose of transdermal ET (0.014 mg) could significantly reduce VMS [ 11 ]. Thus, the lowest effective dose is recommended. • Women who wish to discontinue MHT should be counseled that there is a 50% recurrence of VMS after MHT cessation [ 12 13 ]. • Progestogen-only therapy is an effective treatment option for VMS [ 14 ]. Micronized progesterone (300 mg) nightly significantly reduced VMS and improved sleep as compared to placebo. Although there are many studies regarding progestogen’s safety, most are short-term studies. Therefore, progestogen-only therapy for VMS or sleep is considered off-label, as no long-term study results are available [ 4 14 15 ]. • A meta-analysis reported that tibolone significantly reduced VMS as compared to placebo [ 16 ]. • Both ET and EPT effectively relieve vasomotor symptoms (VMS), and the frequency of hot flashes is reduced by 75%. The effect of treatment starts at 2 weeks and a full response is observed by week 4 of MHT [ 9 ]. • Both oral and transdermal MHT effectively reduce VMS [ 10 ]. • The standard dose of MHT is sufficient to effectively treat VMS. However, another study showed that a daily micro-dose of transdermal ET (0.014 mg) could significantly reduce VMS [ 11 ]. Thus, the lowest effective dose is recommended. • Women who wish to discontinue MHT should be counseled that there is a 50% recurrence of VMS after MHT cessation [ 12 13 ]. • Progestogen-only therapy is an effective treatment option for VMS [ 14 ]. Micronized progesterone (300 mg) nightly significantly reduced VMS and improved sleep as compared to placebo. Although there are many studies regarding progestogen’s safety, most are short-term studies. Therefore, progestogen-only therapy for VMS or sleep is considered off-label, as no long-term study results are available [ 4 14 15 ]. • A meta-analysis reported that tibolone significantly reduced VMS as compared to placebo [ 16 ]. • MHT and local ET improve vulvovaginal atrophy symptoms (Level I). • Local ET may reduce urinary incontinence symptoms and recurrent urinary tract infection (Level I). • Systemic MHT is not useful for preventing or treating urinary incontinence (Level I). • MHT and local ET improve vulvovaginal atrophy symptoms (Level I). • Local ET may reduce urinary incontinence symptoms and recurrent urinary tract infection (Level I). • Systemic MHT is not useful for preventing or treating urinary incontinence (Level I). Systemic MHT, in a dose for VMS treatment, generally improves vaginal symptoms. About 10%–15% of MHT users may remain with vaginal atrophic symptoms, and additional vaginal ET could improve these symptoms and overall satisfaction [ 17 ]. A meta-analysis showed that vaginal ET might reduce urinary incontinence symptoms and recurrent urinary tract infections. In contrast, systemic MHT did not improve either condition [ 18 19 20 ]. • MHT increases bone mineral density and prevents bone loss and osteoporotic fracture in healthy postmenopausal women (Level I). • MHT increases bone mineral density and prevents bone loss and osteoporotic fracture in healthy postmenopausal women (Level I). Both ET and EPT increase bone mineral density. After 3 years of EPT, bone density increased by 3.7% and 4.5% at the hip and vertebrae, respectively. The WHI study demonstrated that MHT reduced hip fracture risk by 33% [ 21 22 ]. Additionally, tibolone can reduce both vertebral and nonvertebral fractures in postmenopausal women [ 23 ]. • MHT may reduce depressive moods (Level I). • MHT improves sleep in women with concomitant vasomotor symptoms (Level I). • There is no evidence that MHT can prevent dementia in menopausal women (Level I). • MHT does not affect cognitive function (Level I). • MHT may reduce depressive moods (Level I). • MHT improves sleep in women with concomitant vasomotor symptoms (Level I). • There is no evidence that MHT can prevent dementia in menopausal women (Level I). • MHT does not affect cognitive function (Level I). Oral and transdermal MHT reduce depressive mood in the perimenopausal period. However, women should be counseled about a relapse of symptoms after MHT cessation [ 24 25 ]. A meta-analysis reported that MHT improved sleep quality, particularly in women with concomitant VMS at baseline; however, the effects of different regimens or routes of hormone administration remain unclear [ 26 27 ]. The outcome of the MHT on sleep quality in women without VMS remains uncertain [ 28 ]. MHT use at any stage of menopause had neither beneficial nor adverse effects on cognitive function. Therefore, the use of MHT alone to prevent cognitive decline is not recommended [ 29 30 31 ]. • Oral administration of MHT increase HDL while reducing LDL and lipoprotein (a) (Level I). • MHT may have a cardiovascular protective effect when initiated in women with < 10 years within menopausal period or in women < 60 years with a low risk of cardiovascular diseases (Level I). • MHT is not recommended for prevention of coronary heart diseases (Level I). • Oral administration of MHT increases the risk of ischemic stroke (Level I). • Transdermal or non-oral routes of MHT does not increase the risk of ischemic stroke (Level II). • Oral administration of MHT increase HDL while reducing LDL and lipoprotein (a) (Level I). • MHT may have a cardiovascular protective effect when initiated in women with < 10 years within menopausal period or in women < 60 years with a low risk of cardiovascular diseases (Level I). • MHT is not recommended for prevention of coronary heart diseases (Level I). • Oral administration of MHT increases the risk of ischemic stroke (Level I). • Transdermal or non-oral routes of MHT does not increase the risk of ischemic stroke (Level II). Oral MHT increases high-density lipoprotein (HDL) cholesterol, lowers low-density lipoprotein (LDL) cholesterol, and decreases fibrinogen levels, while it increases triglyceride levels [ 32 ]. A recent meta-analysis found that MHT, particularly when administered orally, reduces lipoprotein (a) levels which play a significant role in atherosclerosis [ 33 ]. Transdermal MHT had a less beneficial effect on lipid levels [ 34 ]. MHT increases the risk of ischemic stroke but not of hemorrhagic stroke. An increased risk was found when used in postmenopausal women aged >60 years, especially in oral form or at high estrogen doses [ 35 36 ]. • Oral MHT increases the risk of venous thromboembolism (VTEs) (Level I). • Non-oral MHT does not increase the VTEs risk (Level II). • Oral MHT increases the risk of venous thromboembolism (VTEs) (Level I). • Non-oral MHT does not increase the VTEs risk (Level II). The WHI reported an increased risk of venous thromboembolism (VTEs), deep vein thrombosis, and pulmonary embolism in hormone users [ 1 ], which was consistent with a meta-analysis reporting that MHT increased the risk of VTEs in women with older age, obesity, or thrombophilia. However, transdermal and vaginal MHT did not increase the risk of VTE [ 36 37 ]. • Effect of MHT on breast cancer depended on the type of hormone, dosages, duration, and individual risks of the patient (Level I-II). • Effect of MHT on breast cancer depended on the type of hormone, dosages, duration, and individual risks of the patient (Level I-II). The WHI study revealed that EPT (0.625 mg of CEE + MPA) increased breast cancer risk by 9:10,000 individuals per year of treatment. In contrast, women who received ET (0.625 mg of CEE) did not experience a significantly increased risk of breast cancer [ 38 ], and progestogens were considered to stimulate cancer cell growth [ 39 ]. The effects of progestogens on breast cancer depend on their type. Retrospective studies have also shown that MHT with natural or progesterone analogs did not increase the risk of breast cancer [ 40 ]. Breast cancer risk is increased in postmenopausal women using MHT for > 5 years. The longer the duration of MHT use, the greater the breast cancer risk [ 39 41 ]. • ET increases endometrial cancer risk in women with an intact uterus (Level I). • Appropriate dosage and duration of progestogen therapy reduce endometrial cancer risk (Level I). • Intrauterine systems containing levonorgestrel can prevent endometrial stimulation in estrogen users (Level I). • ET increases endometrial cancer risk in women with an intact uterus (Level I). • Appropriate dosage and duration of progestogen therapy reduce endometrial cancer risk (Level I). • Intrauterine systems containing levonorgestrel can prevent endometrial stimulation in estrogen users (Level I). Unopposed ET, even for a duration < 5 years, increases the risk of endometrial cancer [ 42 43 ]. Moreover, the excess risk seemed to persist beyond 5 years of cessation [ 44 ]. EPT has also been shown to prevent endometrial cancer, particularly in women who have not undergone hysterectomy [ 22 ]. The endometrial protection effect of the levonorgestrel intrauterine system does not differ from that of systemic progestogens [ 45 ]. • MHT may increase ovarian cancer risk, principally for serous type (Level II). • Use of MHT is not recommended in women with hormone-dependent ovarian cancers, including granulosa cell tumor and low-grade serous carcinoma (Level II). • MHT may increase ovarian cancer risk, principally for serous type (Level II). • Use of MHT is not recommended in women with hormone-dependent ovarian cancers, including granulosa cell tumor and low-grade serous carcinoma (Level II). Epidemiological findings reported that women who used MHT had a slightly increased risk of developing ovarian cancer, regardless of the type and duration of usage [ 46 47 48 ]. However, this information should be interpreted carefully because of confounding factors. • MHT is not associated with lung cancer (Level II). • MHT is not associated with lung cancer (Level II). Although in vitro studies have shown that estrogen can promote lung cancer cell growth, clinical findings from both an observational study and a case-control study with a ten-year follow-up did not show a significantly increased lung cancer risk [ 49 ]. • MHT reduces the risk of colorectal cancer (Level II). • EPT, but not ET alone, reduces the risk of colorectal cancer (Level I). • MHT may reduce gastric and hepatic cancer risk (Level II). • MHT reduces the risk of colorectal cancer (Level II). • EPT, but not ET alone, reduces the risk of colorectal cancer (Level I). • MHT may reduce gastric and hepatic cancer risk (Level II). The WHI observational study and a recent meta-analysis found a lower risk of colorectal cancer in MHT users as compared to non-users, and this effect diminished after stopping the hormone [ 1 50 ]. However, a long-term study reported a protective effect only in EPT users [ 51 ]. MHT has been shown to decrease the risk of esophageal and gastric cancers by the action on both α- and β- estrogen receptors [ 52 53 ]. It has also been shown to possibly reduce the incidence of primary hepatic cancer, especially in ET users [ 54 ]. A meta-analysis of observational studies demonstrated that the risk reduction did not differ among MHT regimens [ 55 ]. MHT has a beneficial effect on muscle performance in postmenopausal women (Level I) [ 56 ]. MHT reduces muscle weakness and mobility limitations (Level II) [ 57 ]. MHT may reduce tendon stiffness (Level IV) [ 58 ]. The prevalence of knee osteoarthritis was lower in postmenopausal women using MHT than in those who did not use MHT (Level III) [ 59 60 ]. MHT has been shown to improve skin stability and elasticity (Level I) [ 61 ] and the wound healing process (Level III) [ 62 ]. MHT may increase the risk of malignant melanoma (Level II) [ 63 64 ]. • MHT increases the risk of biliary tract disease and the chance of biliary tract surgery (Level I). • MHT increases the risk of biliary tract disease and the chance of biliary tract surgery (Level I). In the WHI study, postmenopausal women who were MHT users had an increased risk of biliary tract disease. Moreover, the ET users were at higher risk of undergoing cholecystectomy [ 65 ]. A meta-analysis confirmed a statistically significant increase in the incidence of gallbladder diseases requiring surgery in both ET and EPT users [ 66 ]. A meta-analysis of 24 RCT studies of both ET and EPT effects on hot flashes/sweating with at least 3 months of follow-up showed that MHT had significant results of 75% lower frequency and an 87% reduction in the severity of hot flashes as compared to the placebo group. None of the groups showed significant differences in adverse effects. However, the placebo group reported a 57.7% lower frequency of hot flashes [ 9 ]. Genitourinary syndrome of menopause that occurs after estrogen deficiency includes vulvar irritation, vaginal dryness and burning sensation, dyspareunia, bleeding during intercourse, and urinary symptoms, such as urinary urgency, dysuria, and recurrence of lower urinary tract infection [ 67 ]. A meta-analysis of vaginal ET efficacy with at least 12 weeks of treatment for postmenopausal vaginal atrophy showed that vaginal ET significantly improved vaginal dryness, vulvar irritation, dyspareunia, dysuria, urinary urgency, frequency, nocturia, and stress urinary incontinence. Vaginal ET had no effect on endometrial thickness in the treatment group [ 68 69 ]. Other menopausal symptoms, including irritable and depressive mood [ 24 70 ], anxiety, muscle or joint pain [ 71 ], and insomnia [ 27 ] may improve after receiving MHT. Primary ovarian insufficiency or women with early menopause who never used MHT had worse cognitive function, memory, mood, sexual health, bone health, and cardiovascular health than women who use MHT [ 72 ]. In addition, a meta-analysis of 18 studies found that women who underwent bilateral salpingo-oophorectomy before the age of 45 years had a significantly increased risk of cardiovascular disease compared with women who were menopausal at the age of 50 years or older. Women with early menopause have a 1.2–1.5 times higher risk of cardiovascular diseases than women> 45 years of age at menopause [ 73 74 ]. A meta-analysis showed that MHT could prevent 33% of vertebral fractures in healthy postmenopausal women as compared to the placebo group [ 75 ], and reduced nonvertebral fractures by 27% in healthy postmenopausal women. The risk reduction was greater when MHT was initiated in women < 60 [ 76 ]. MHT is recommended to prevent osteoporotic fractures in postmenopausal women with a high risk of fracture or postmenopausal women with rapid bone loss. However, the benefits and risks of MHT should be discussed before initiating treatment.

A meta-analysis, which included six retrospective, RCTs, and cohort studies, reported no significant difference in the risk of endometrial cancer recurrence between MHT users and non-users among endometrial cancer survivors [ 79 ]. Therefore, the risks and benefits of MHT in women with a history of endometrial cancer should be individually considered. A meta-analysis of six studies, including RCTs and cohort studies, revealed that MHT in ovarian cancer survivors did not increase the risk of recurrence [ 80 ]. However, data are still limited for other estrogen-sensitive ovarian cancers, such as serous carcinoma and sex cord-stromal cell types [ 81 ]. An observational study showed that MHT was associated with a resistance to lipid-lowering medications in severe hypertriglyceridemia (serum triglyceride level > 400 mg/dL), with or without hypertriglyceridemia-induced pancreatitis in women with familial/non-familial hypertriglyceridemia. The response to lipid-lowering medication improved upon stopping the MHT [ 82 ]. Currently, MHT has some benefits in terms of insulin resistance, abdominal fat distribution, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol ratio, and mean arterial blood pressure. A meta-analysis study of 107 RCT studies revealed that administration of MHT for at least 8 weeks could reduce the risk of newly diagnosed diabetes by 30% (relative risk, 0.7; 95% CI, 0.6–0.9) as compared to the placebo group. Moreover, in postmenopausal women with preexisting diabetes, MHT significantly improved glucose levels and homeostatic model assessment of insulin resistance by 11.5% and 35.8%, respectively [ 83 ]. For cardiovascular risk, a subgroup analysis of the WHI study showed that initiating MHT at < 60 years or within 10 years after menopause may be beneficial for atherosclerotic plaque prevention [ 84 ]. Additionally, transdermal estrogen with or without natural progesterone is the preferable preparation among postmenopausal women with moderate cardiovascular risk as it does not increase metabolic and thrombosis risk [ 85 ]. Currently, there is a report on the benefits of female sex hormones, especially estrogen, on chronic hepatitis, which could delay liver cirrhosis in women compared to men [ 86 ]. In a report of 81 women with chronic active hepatitis B or C, who received transdermal MHT for 5 years revealed no significant change in liver function as compared to the placebo group [ 87 ]. A meta-analysis of 15 observational studies found that oral ET increased the risk of VTE by 1.63 as compared to transdermal ET (risk ratio [RR], 1.63; 95% CI, 1.4–1.9) [ 88 ]. The risk of VTE increased by 3.7 in women whose first-degree relatives had a history of VTE, stroke, or cardiovascular disease in men aged < 55 years or in women aged < 60 years, prothrombotic mutations, or factor V Leiden mutations as compared to women without a family history [ 89 ]. However, the prevalence of factor V Leiden and prothrombin G20210A gene mutations in a group of 500 healthy Thai individuals was only 0.2%, much lower than the prevalence among Caucasians [ 90 ]. Transdermal ET or transdermal ET plus natural progesterone has the lowest risk of VTE and may be used in women with VTE risk [ 88 ].

Menopausal women receiving MHT should be evaluated within 1–3 months for efficacy and adverse effects after the initiation treatment. Menopausal women who use MHT should be followed up every 3–6 months. For women with an average risk of breast cancer who have used hormone therapy for 5 years [ 99 ]. Indications and follow-up examinations performed as mentioned in the 2021 position statement of osteoporosis management from the Thai Osteoporosis Foundation [ 100 ]. Any vaginal bleeding after 6 months of hormone therapy initiation of a continuous combined regimen should be investigated. However, those at high risk for endometrial cancer require immediate examination. Currently, there is no specified duration limit for MHT. The benefits and risks of MHT should be discussed with postmenopausal women and their physicians. Medications can be discontinued abruptly or by tapering the dose. Data directly comparing the effects of abrupt discontinuation with those of slowly tapering are lacking [ 4 ]. • There is no improvement in menopausal symptoms after 3 months of treatment. • The adverse effects occurred after the initiation of MHT. • Severe menopausal symptoms in women with MHT contraindication. • Menopausal women with multiple comorbidities. • There is no improvement in menopausal symptoms after 3 months of treatment. • The adverse effects occurred after the initiation of MHT. • Severe menopausal symptoms in women with MHT contraindication. • Menopausal women with multiple comorbidities.

There have been reports of an association between unopposed ET and an increased risk (2.3–10 times) of endometrial hyperplasia and endometrial cancer as compared to placebo, the risk is dependent on the dose and duration of ET [ 44 ]. In contrast, both combined and sequential EPT regimens significantly decrease endometrial hyperplasia and irregular bleeding risk [ 91 ]. Using progestogens for at least 10–14 days per month can significantly reduce the risk of endometrial hyperplasia and cancer [ 1 31 43 44 91 92 93 ]. A case-control study of MHT with progestogen administered at least 10 days per month reported no significant increase in the risk of endometrial hyperplasia as compared to placebo (RR, 1.3; 95% CI, 0.8–2.2) [ 93 ]. A study of CEE (0.625 mg/day) plus MPA (10 mg/12 days a month) for 3 years showed no significant differences in endometrial hyperplasia risk as compared to a placebo [ 94 ]. The long-term safety of MHT from the WHI study, an RCT of 5.6 years duration using EPT, revealed no significant increase in the risk of endometrial cancer (HR, 0.81; 95% CI, 0.48–1.36) [ 95 ]. The lowest effective dose of estrogen that relieves menopausal symptoms is recommended based on individual consideration (Level I, Grade A). Appropriate dose of progestogen can be determined based on its potency, dosage, and type of estrogen administration (Level I, Grade A) as shown in Table 1 . A meta-analysis of 15 observational studies including 22,489 and 5,671 women receiving oral and transdermal MHT, respectively, for 3–20 years, reveals oral MHT increased the risk of VTE by 1.6 (relative risk, 1.63; 95% CI, 1.4–1.9). However, the risks of stroke and cardiovascular disease did not differ between the groups. Moreover, a systematic review showed that transdermal ET is associated with a lower risk of myocardial infarction and stroke than oral estrogen [ 35 88 ]. The meta-analysis of seven observational studies of transdermal MHT combined with different progestins revealed that norpregnane progestin, such as nomegestral acetate, MPA, and promegestone, increased the risk of VTE (relative risk, 2.42; 95% CI, 1.84–3.18). However, progestins and progesterone did not increase the risk of VTE. A meta-analysis of three observational studies of hormone therapy with natural progesterone use for 5 years, showed that MHT with natural progesterone did not increase breast cancer risk (relative risk, 0.67; 95% CI, 0.55–0.80) [ 96 ]. A 34-month RCT of tibolone revealed a decrease in the risk of breast and colon cancer and no effect on cardiovascular disease and venous thrombosis risk in postmenopausal women [ 16 22 ]. A meta-analysis of 46 studies, reveal that Tibolone did not increase the risk of abnormal uterine bleeding. Moreover, according to the guidelines of the European Society of Human Reproduction and Embryology for the management of women with endometriosis, Tibolone is recommended as an alternative treatment for menopausal symptoms among postmenopausal women with a history of endometriosis because of the lower recurrence rate of endometriosis as compared to other preparations of MHT, including ET and EPT [ 97 ]. A meta-analysis of RCTs and a review of 36 case-control studies revealed that additional testosterone therapy with ET or EPT for < 6 months improved sexual function in postmenopausal women, including sexual desire, pleasure, arousal, orgasm, responsiveness, self-imaging, and sexual concern, as compared to women who did not receive testosterone therapy. Oral testosterone increased LDL levels and decreased total cholesterol, triglyceride, and HDL levels, whereas transdermal testosterone did not affect the serum lipid profiles [ 98 ]. Testosterone therapy is used off-label for < 6 months and should be carefully monitored for side effects.

Symptoms of menopause may include hot flashes, mood swings, sleeplessness, urinary symptoms, vaginal dryness, pain, and dryness of the vagina during sexual intercourse. The duration, severity, and effects of symptoms on daily routine and quality of life should be considered. Other general information should be included as a part of history taking as below. • Gynecology history • Gynecologic and other surgeries • Family history • Personal history • History of sexual intercourse • Gynecology history • Gynecologic and other surgeries • Family history • Personal history • History of sexual intercourse • General physical examination • Height, weight, and body mass index • Breast examination • Waist/hip ratio • Screening for leg edema and varices • Additional examination of women in high-risk groups • Eye and intraocular pressure measurements • Oral and dental health • Vertebral deformities • Muscle mass and strength • General physical examination • Height, weight, and body mass index • Breast examination • Waist/hip ratio • Screening for leg edema and varices • Additional examination of women in high-risk groups • Eye and intraocular pressure measurements • Oral and dental health • Vertebral deformities • Muscle mass and strength • Blood test for complete blood count, fasting plasma glucose, glycated hemoglobin, lipid profiles, thyroid-stimulating hormone, liver, and renal function • Additional tests for women in the high-risk groups • Urine analysis and occult blood in the stool • Other tests, such as cervical cancer screening, a transvaginal ultrasonogram, mammogram or breast ultrasonogram, 25 hydroxy vitamin D, and bone mineral density in high-risk women • Blood test for complete blood count, fasting plasma glucose, glycated hemoglobin, lipid profiles, thyroid-stimulating hormone, liver, and renal function • Additional tests for women in the high-risk groups • Urine analysis and occult blood in the stool • Other tests, such as cervical cancer screening, a transvaginal ultrasonogram, mammogram or breast ultrasonogram, 25 hydroxy vitamin D, and bone mineral density in high-risk women

• Hormone therapy is the most effective treatment for VMS and GSM. • Hormone therapy has been shown to prevent bone loss and fractures. • Risks of hormone therapy depend on type, dose, duration of use, route of administration, whether progestogen use and timing if initiation. • Treatment should be individualized. • Hormone therapy is the most effective treatment for VMS and GSM. • Hormone therapy has been shown to prevent bone loss and fractures. • Risks of hormone therapy depend on type, dose, duration of use, route of administration, whether progestogen use and timing if initiation. • Treatment should be individualized.

An open RCT in postmenopausal women with previous breast cancer showed that the recurrent rate of breast cancer was 3.3 times higher in the hormone therapy group than in the non-hormonal therapy group (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.5–7.4) [ 77 ]. A systematic review of 28 studies showed that estrogen alone, sequential estrogen plus progestin therapy, and tibolone may increase the risk of endometrial cancer as compared to the placebo group. An evaluation of the cause of uterine bleeding is necessary before initiating MHT [ 43 ]. From the WHI study, the risk of VTE, especially in the EPT group, increased by 2.13 (HR, 2.13; 95% CI, 1.39–3.25) as compared to the placebo group [ 1 78 ]. The WHI study reported a 1.39–1.41 increased risk of stroke among the MHT group, including ET (HR, 1.39; 95% CI, 1.10–1.77) and EPT (HR, 1.41; 95% CI, 1.07–1.85), as compared to the placebo group [ 1 78 ].