Menopausal hormone therapy, whether estrogen alone in women with prior hysterectomy, estrogen combined with progestogen for women with a uterus, or the novel hormone therapy of conjugated estrogen combined with bazedoxifene (CEE/BZA), has been shown in randomized clinical trials (RCTs) to provide relief of moderate to severe hot flashes associated with menopause, usually defined at more than seven hot flashes per day or 50 per week to meet FDA criteria. A meta-analysis [12] of VMS studies shows that hormone therapy on average provides relief 75 % of the time compared to 50 % for placebo, although this degree of improvement may depend on dose and route of administration. Very low doses of systemic MHT may not be as effective or may take longer for effectiveness to be realized [13].

Menopausal hormone therapy has been shown to lower the risk of vertebral and hip fractures in postmenopausal women [14] and has been shown to prevent fractures in women without prior fracture [15]. Due to the options of nonhormonal therapies for bone loss, MHT is not commonly used as primary prevention of bone loss due to concerns of risks associated with long-term use of MHT. Women with premature or early surgical or natural menopause will in particular benefit from the bone-protective benefit of MHT [16]. Absolute risks based on results from the WHI trials indicate that 5 years of conventional or standard dose combined MHT reduced the incidence of hip fractures by about one case per 1000 women younger than 70 years and by about eight cases per 1000 women aged 70–79 years [1]. However, anti-fracture efficacy of MHT lasts only for the duration of treatment, and this protection is rapidly lost following discontinuation of MHT [17, 18].

Both topical and systemic MHT have been shown to improve the menopausal symptoms of vaginal dryness, superficial dyspareunia, and urinary frequency and urgency [19]. In the absence of other menopausal symptoms, topical/local estrogen therapy is the preferred approach for VVA if the symptoms are not relieved by nonhormonal, nonprescription remedies, e.g., lubricants and moisturizers, that are widely available over the counter. For those who can’t tolerate vaginal products, there is now an oral selective estrogen receptor modulator (SERM), ospemifene, which is FDA-approved in the USA to treat moderate to severe vaginal atrophy due to menopause and improves other symptoms of VVA including vaginal dryness and urinary urgency [20].

Tibolone is considered a STEAR (selective tissue estrogenic activity regulator). Although widely used outside of the USA, including Europe, Asia, and Australasia, it has not been approved in the USA. It received a non-approvable letter from the US Food and Drug Administration (FDA) in June 2006 for menopausal women, possibly due to the need for additional endometrial safety data. The metabolites of orally ingested tibolone have estrogenic, androgenic, and progestogenic effects [21]. Tibolone has been shown to prevent hot flashes, prevent bone loss, and prevent vaginal atrophy. The progesterone-like effects prevent endometrial thickening and bleeding, and thus there is no need for a progestogen. Tibolone has effects on lipids with lowered total LDL and HDL cholesterol and triglyceride levels but should not be used as primary prevention of heart disease. Tibolone has shown testosterone-like activity that appears to improve mood and libido, with variable sexual response [21, 22]. Tibolone has been shown to prevent bone loss and reduce spinal fractures [23] but has not been shown to prevent hip fractures. The Million Women Study [23] found an increased risk of breast cancer with tibolone, but other RTCs have not shown increases in breast cancer rates, and breast density is not increased [24, 25]. Tibolone is contraindicated in women with breast cancer. An increased risk of stroke [23] has been found in women over 60 years of age (four extra cases/1000 women under 60 and 13 extra cases/1000 women among women in 60s.

The only TSEC which is government approved in the USA consists of conjugated equine estrogen (CEE) combined with the selective estrogen receptor modulator, bazedoxifene (BZA). In the selective estrogen, menopause, and response to therapy (SMART) [26–34] randomized controlled trials, CEE/BZA showed fewer hot flashes (74 % compared to 51 % for placebo); prevention of bone loss, with improvement in night sweats, sleep disruptions, and total cholesterol; signs of VVA, with a neutral effect on the breast and uterus, specifically rates of breast tenderness, breast density changes, and breast cancer; and amenorrhea similar to placebo. The major benefit for women with a uterus is the lack of significant breast tenderness or vaginal bleeding.

RCTs, observational data, and meta-analyses suggest that estrogen-alone MHT may decrease the risk of myocardial infarction and all-cause mortality when initiated in women who are less than age 60 or under 10 years from menopause. This had led to a timing hypothesis, wherein MHT has benefits on the heart when given close to menopause but risks when initiated further from menopause.

In the WHI hormone trials which evaluated MHT for its role in prevention of chronic disease, women who have had a hysterectomy and were under age 60 and/or within 10 years of menopause, reduced incidences of myocardial infarction, composite CHD end points, coronary artery calcification, and all-cause mortality were seen in ET (CEE 0.625) (ref). However, RCTs of EPT (CEE 0.625 mg/MPA 0.25 mg) for women less than 60 years of age or within 10 years of menopause show less consistent results for CHD risk than the ET trials [6].

A recent, randomized, controlled clinical trial – the Kronos Early Estrogen Prevention Study (KEEPS) [41] – evaluated effects of estrogen use (oral CEE 0.45 and transdermal estradiol 0.5) compared to placebo on surrogate markers for cardiovascular disease in younger postmenopausal women within 3 years of onset of menopause and again found no significant association between MHT and cardiovascular benefit.

In keeping with the postulated timing hypothesis, for women in WHI who initiated MHT when aged 60 years and older or more than 10 years from menopause, both ET and EPT increased CHD risk. In the ELITE trial, oral estradiol therapy was associated with less progression of subclinical atherosclerosis (CIMT) than was placebo when therapy was initiated within 6 years after menopause but not with initiation 10 or more years from menopause [42].

In the WHI, the risk of stroke increased significantly with both EPT and ET for increases in ischemic but not hemorrhagic stroke, but the attributable risk for women who initiated HT under age 60 within 10 years of menopause was rare (5 out of 10,000 women per year for EPT and minus one for ET) [Manson 2013]. In Nurses’ health study conventional dose HT was associated with an increased risk of stroke, again with a lower risk in younger women [43].

RCTs and observational studies have shown that postmenopausal hormone therapy use increases the risk of VTE [45], particularly within the first year of use with a doubling of the risk. For healthy menopausal women under 60 and within 10 years of menopause, however, the absolute risk of VTE is low even with oral hormone therapy. Risk is increased (Table 4.2) as women age or if they have other risk factors such as obesity, bedridden, having major surgery or prolonged air travel [45]. Thus discontinuation of HT in advance of major surgery and staying hydrated, moving around, and potentially taking an aspirin during long travel may be suggested to potentially decrease risk.

Oral HT (ET and EPT) increases risk of DVT and PE in women initiating HT regardless of age or time since menopause. The increase in VTE risk in WHI was demonstrated early (highest risks during first 2 years for ET and during 1 year in the EPT trial) [6].

Across studies in the literature, observational and meta-analysis suggest that transdermal preparations, whether estrogen alone or estrogen combined with a progestogen, have substantially lower risk of VTE and possibly stroke than oral, but there are no RCTs of head-to-head comparisons. Evidence from the French E3N study and the Million Women Study [46] suggests that progestogens may play a role in VTE risk [47] although lacking RCT or head-to-head trials.

The memory sub-study of the WHI [48, 49] showed that older women (over age 65) taking combination hormone therapy (CEE 0.625/MPA 2.5 mg) had twice the rate of dementia, including Alzheimer’s disease, compared with women who did not. This risk was increased in women who already had relatively low cognitive function at the start of treatment, a finding also seen in the WEST trial of women with prior stroke. There is no definite evidence that supports the use of HT to prevent or improve cognitive deterioration although observational studies such as CASHE provide suggestive evidence of a protective effect when HT is begun close to menopause when neurons are healthy.

HT has been shown to improve mood in early postmenopausal women with depression or anxiety and possibly may improve mood in perimenopausal depressed women. However, HT is not a treatment for depression, and antidepressant therapy is recommended when treatment for depression is needed [9].

Observational data suggests that women with natural, surgical, or induced menopause before age 40–45 may have increased risk for CHD, osteoporosis, mood changes, dementia, and Parkinson’s disease. HT has been shown to reduce VMS and maintain bone density, and the use of HT until the average age of menopause may reduce these risks [50].

Decreased risk was seen in the WHI for estrogen alone (CEE 0.625) with possible increased rare risk with EPT (CEE 0.625/MPA 2.5 mg) which may be related in part to the use of the progestin (MPA in WHI) and may be related to duration of use. The risk of breast cancer with EPT in WHI was considered rare, with an incidence of <1.0 per 1000 women per year of use which is similar to the risks seen with being sedentary and obese or with alcohol consumption [6].

Progestogen therapy is needed for women with a uterus taking systemic ET to protect against endometrial neoplasm [9]. The exception is that the combination of CEE/BZA provides uterine protection without the need for a progestogen, and tibolone has progestational activity such that it does not require a progestogen.

Sleep, quality of life, sexual function, and joint and muscle pains [9] may improve with systemic hormone therapy although type of hormone, formulation, and dose may affect these.

MHT reduces new onset type 2 diabetes mellitus (T2DM) but is not approved to prevent diabetes [51]. Both aging and menopause have been tied to the increasing incidence of type 2 diabetes mellitus, but the use of hormone therapy has been shown in WHI to have a decreased incidence of type 2 diabetes.

Longer duration of use appears more favorable for ET than EPT, with fewer breast cancers seen at 7 years compared to placebo in the estrogen-only arm of the WHI. Extended duration beyond age 60 or 65 may be considered [52] for persistent recurrent VMS or prevention of bone loss and fracture in selected women after appropriate and ongoing counseling about unclear risk and benefits of extended use.

The ACOG, Endocrine Society, NAMS, EMAS, and IMS do not recommend custom-compounded bioidentical HT (CBHT). Unique concerns of compounding include the lack of approval by any regulatory agency; the lack of safety and efficacy data; no formal testing; the absence of regulatory oversight in manufacturing; concerns about quality, purity, and batch-to-batch consistency; and, oftentimes, a false sense of an improved safety profile [53].

A 40-year-old Caucasian female with surgical menopause with hysterectomy and bilateral salpingo-oophorectomy due to family history of ovarian cancer and large leiomyomatous uterus. She initially did not want to take MHT and began a low-dose selective serotonin reuptake inhibitor (SSRI) but has continued to have bothersome hot flashes at a frequency of 7–10 per day, as well as frequent awakening with night sweats.

Best option for her at this time based on literature of risks of early surgical menopause includes:

A 53-year-old Caucasian female, LMP 12 months ago, with frequent bothersome night sweats and difficulty concentrating who is otherwise healthy and a nonsmoker, BMI 28kg/m2. She exercises regularly. There is no family history of breast cancer but her mother fractured her hip at age 74. She is a candidate for all of the following except:

A 58-year-old Asian female who underwent a hysterectomy for fibroids started estrogen-only therapy for bothersome VMS 5 years ago. She has had improvement but not complete resolution of her hot flashes, night sweats, and sleep disruption. Bone mineral density shows evidence of osteopenia with BMD T-scores of −1.5 at her lumbar spine and −1.2 at her hips. She comes in for discussion about whether to continue MHT.