Menopause is clinically defined as a period of 12 months of amenorrhea in a woman over 45 years of age, in the absence of other biological or physiological cause. The best approach to the diagnosis of perimenopause is a longitudinal evaluation of the history of the menstrual cycle and menopausal symptoms (vasomotor waves, mood swings, sleep disturbances). There is no need for measurement of serum FSH, estradiol, or inhibin levels for diagnostic purposes.

Some medical conditions can mimic conditions of menopause, such as hyperthyroidism, which should always be considered in the differential diagnosis, and occur together with irregular menstruation, sweats (although different from typical hot flushes) and mood changes. Other causes for menstrual cycle changes should be considered, including pregnancy, hyperprolactinemia, and other thyroid diseases. Atypical hot flashes and night sweats may be present in other disorders, such as drug use, pheochromocytoma, carcinoid tumors, or other malignancies [17].

Hormone therapy (HT) in postmenopausal women is currently recommended for use in short-term treatment of moderate to severe vasomotor symptoms. Long-term use for primary or secondary prevention of cardiovascular disease and osteoporosis is no longer recommended [18].

Hormone therapy, estrogen with or without progesterone, remains the gold standard treatment for the relief of menopausal vasomotor symptoms and their consequences. It is therefore a reasonable option for most postmenopausal women, except those with a history of breast cancer, coronary heart disease, previous thromboembolic event or stroke, or those at high risk for these complications. In healthy women, the absolute risk of an adverse event is extremely low [18]. The exclusive use of progesterone also reduces vasomotor symptoms, but less efficiently than estrogen therapy [19].

Both vaginal and urethral epithelia are sensitive to estrogen, and estrogen deficiency leads to their thinning, resulting in vaginal atrophy, which may generate symptoms of vaginal dryness, itching, and often dyspareunia. Both systemic and local estrogen therapy are effective for symptoms of genitourinary atrophy. Vaginal administration (available as creams, tablets, or rings) is an extremely effective therapy, making it an excellent choice for nearly all postmenopausal women (with the exception of patients with breast cancer) and can be administered in the long term, since systemic absorption is minimal [18].

Local estrogen therapy may benefit some women with an overactive bladder. A clinical study demonstrated that using an estradiol ring showed clinical efficacy similar to the use of oxybutynin in women suffering from an overactive bladder [20]. The use of low-dose transdermal estradiol, however, did not affect the development of urinary incontinence [21]. A recent clinical trial reported an increased risk of nephrolithiasis in healthy women on hormone therapy, but the mechanisms involved have not been elucidated [22]. Two studies have shown a reduced risk of recurrent urinary tract infection in women using vaginal estrogen therapy [23, 24].

Hormone therapy is not recommended for the treatment of sexual dysfunction, including decreased libido [18]. There is no evidence that estrogen therapy acts independently in sexual interest, arousal, and orgasmic response. Low doses of local estrogen can improve sexual function merely by increasing local blood flow and vaginal lubrication [25].

Although there is no approval for the use of hormone therapy for the sole purpose of improving the quality of life of women, data shows that symptomatic women show an improvement in some areas of quality of life through relief of vasomotor symptoms. There is no evidence to support this improvement in asymptomatic women [18].

Some randomized controlled trials and those controlled with placebo support the use of estrogen therapy for the prevention of osteoporosis and fractures, including hip fractures and treatment of proven osteoporosis [18]. However, to date, there has been no approval for their use in the treatment of osteoporosis in postmenopausal women without vasomotor symptoms.

The results of the WHI trials indicated some benefits with hormone therapy. Women randomly assigned to estrogen and progesterone had a 34 % reduction in the risk of vertebral and hip fractures (hip, 6 fewer per 10,000 woman-years; vertebral, 6 fewer per 10,000 woman-years; and total, 46 fewer per 10,000 woman years) and fewer cases of diabetes (15 fewer per 10,000 woman-years) than those randomly assigned to placebo [26].

Women randomly assigned to estrogen alone had fewer fractures (hip, 7 fewer per 10,000 woman-years; vertebral, 6 fewer per 10,000 woman-years; and total, 56 fewer per 10,000 woman-years) and fewer cases of invasive breast cancer (8 fewer per 10,000 woman-years) and breast cancer deaths (2 fewer per 10,000 woman-years). Whereas fractures were a major predefined secondary outcome and were determined by clinical and radiographic criteria, diabetes was diagnosed on the basis of a less rigorous approach using post hoc analysis of self-reports [26].

When there are failures or adverse effects of standard therapy for osteoporosis, prolonged use of hormone therapy is an option for women at high risk of osteoporotic fractures. However, its beneficial effects on bone mass and fracture reduction are minimized quickly after its administration has been discontinued [27].

In women who experience premature menopause, unless there are contraindications, hormone therapy should be used for the purpose of bone loss prevention, rather than the standard therapy for osteoporosis, until they reach the age of menopause, when the treatment should be reevaluated [18].

Based on extensive observational data, it was believed that estrogen exerted a cardioprotective effect, and as a result, estrogen therapy was routinely prescribed for primary and secondary prevention of cardiovascular disease (CVD). However, data from the Heart and Estrogen/Progestin Replacement Study (HERS I and II), other small controlled trials and two meta-analyses have not confirmed this protective effect on the heart [28–30].

In 2002, the subgroup of women in the WHI who used the estrogen–progestin combination showed an increased risk of coronary heart disease and breast cancer, and the study was discontinued prematurely. The results of the subgroup that used only estrogen therapy, published in 2004, showed a tendency to a decreased risk of breast cancer, but an increased risk of stroke and thromboembolic disease, and no benefits on coronary heart disease [18, 26].

Some, but not all observational studies suggest that long-term hormonal therapy is associated with a smaller accumulation of calcium in the coronary arteries, data which is strongly correlated with the presence of atheromatous plaques and the risk of future coronary events [31].

The HERS I study demonstrated a twofold to threefold increase in the risk of venous thrombosis and pulmonary embolism with hormone therapy. However, the absolute risk was low, ranging from one case to two or three cases per 100,000 women. The data is related to the oral use of the hormone. The HERS II study found a 2.89 times risk of thromboembolism in users of combined hormone therapy, estrogen/progesterone, compared with the placebo and a trend toward an increased risk of pulmonary embolism. The WHI trial found a risk twice higher of pulmonary embolism in users of combined hormone therapy, representing eight more cases of pulmonary embolism in 10,000 women/year. This risk was attributed to the combination of estrogen and progestin [18, 26]. There is no data for other, non-oral forms of administration of hormonal therapy.

The WHI showed an increase in the risk of stroke, but no effect on hemorrhaging. When all women in that trail were analyzed, there were 8 additional cases of stroke per 10,000 women/year in combined therapy and 11 cases per 10,000 women/year in estrogen-alone therapy, and in both, the risk was eliminated after discontinuation of treatment [26]. In a recent data analysis from the WHI trial involving only women aged 50–59 years, there was no significant effect on the risk of stroke [32]. The risk of stroke did not significantly increase in the HERS I and II studies [33, 34]. The data from observational studies on the association between hormone therapy and stroke have been inconsistent. Various studies have indicated a positive association, but others showed no effect on the risk of stroke [18].

One difference between observational studies and the WHI study is the fact that the women enrolled in the latter presented an average age of 63 years at the start of the use of hormone therapy, about 12 years after menopause had begun [18, 26]. Participants in the observational studies began therapy immediately after the beginning of menopause, with a mean age of 51 years. That is, women from the WHI were older and began using the hormone later, which is unusual in clinical practice. As the atherosclerotic lesions develop early, it is likely that the WHI participants already presented subclinical coronary disease, and therefore would not be candidates for hormonal regime, since hormonal therapy appears to be more effective in primary prevention than in secondary prevention. The idea that differences in age or time since menopause at the start of hormone therapy are responsible for differences in cardiovascular outcomes has become known as the “window of opportunity” [35].

In the observational studies and in animal models that suggested beneficial cardiovascular effects of hormone therapy, the subjects generally initiated therapy at the time of menopause (often for management of vasomotor symptoms), or in animal studies, treatment began immediately after ovariectomy. This contrast with the WHI, I which treatment was initiated more than a decade after menopause in most study participants, led to the development of the “window of opportunity.” This theory proposed that initiation of HT at or shortly after menopause is cardioprotective, whereas starting treatment at a time remote from menopause may be harmful. Indeed, in the WHI, the trend toward lower rates of CVD events was noted in women who were within 10 years of menopause or who were aged 50–59 years at the time of entry into the trial. In the estrogen and progestin arm, women within 10 years of the menopausal transition had a hazard ratio (HR) of coronary heart disease (CHD) events of 0.89, compared with 1.71 in those more than 20 years from menopausal transition. In the conjugated equine estrogen (CEE) alone arm, those aged 50–59 years had an HR of 0.56, compared with older women, whose HR was almost 1.0 [35].

In addition, women enrolled in the CEE arm and aged 50–59 at baseline had coronary calcium measured by computed tomography; women who received CEE had significantly lower scores at trial completion than those who received placebo [31]. In this young population, the incidence of coronary events was low, and the absolute risk of clinical CHD events was small. In a more recent analysis, the results were examined after pooling the data from the WHI estrogen-alone and estrogen and progestin trials [35]. Women enrolled within 10 years of the onset of menopause had a HR for CHD of 0.76 (CI, 0.50–1.16). The HR continued to rise with years since menopause. Initiating therapy from 10 to 19 years after menopause gave a HR of 1.10 (CI, 0.84–1.45), and when initiated after 20 or more years, the HR was 1.28 (CI, 1.03–1.58). The P value for the trend was 0.02, supporting the timing hypothesis, which predicts that protection from atherosclerosis is evident only when hormone therapy is initiated shortly prior to the onset of menopause and before the development of advanced atherosclerotic plaques.

The timing hypothesis is further supported by several recent studies. A Bayesian meta-analysis of hormone therapy mortality in younger postmenopausal women (mean age, 55 years) presented the combined results of 19 randomized clinical trials that enrolled 16,000 women at a mean age of 55 years, totaling 83,000 patient-years. This study showed a relative risk of mortality of 0.73 [18]. The analysis also demonstrated a cardiovascular benefit when HT was initiated early, supporting the timing hypothesis. Current ongoing prospective randomized trials will formally test this hypothesis.

Despite this reassuring data, HT in postmenopausal women is still indicated only for the management of vasomotor symptoms, since there is no data to support its use in primary or secondary prevention of coronary disease. An ongoing primary prevention trial, Kronos Early Estrogen Prevention Study (KEEPS), will evaluate whether early initiation of HT reduces the risk of coronary heart disease through intermediate risk markers such as measures of the intima–media layer and accumulation of calcium in coronary arteries [36]. Another ongoing study, Early versus Late Intervention Trial with Estradiol (ELITE), will assess the appearance or progression of atherosclerosis, through ultrasound measurement of wall thickness in the carotid artery and CT evaluation of the coronary calcification index in early postmenopausal women and in women in late menopause [18, 35].

Another topic of constant debate is the role of the mode of administration of the hormone in relation to the adverse effects observed in large studies. The oral route is associated with an increase in thrombotic effects and decreased synthesis of thrombolytic factors in the liver, induced by the hepatic first-pass of estradiol, which could justify a two- to threefold increase in the risk of thromboembolism observed with the use of oral, but not transdermal estrogen [18, 37]. Low-dose, cyclic, and transdermal formulations have been suggested as potentially favorable alternatives. Unfortunately, no large, prospective, randomized trials exist that carefully compare these alternative regimens. In the KEEPS trial, a transdermal regimen is being directly compared with an oral regimen to determine whether both have an equivalent effect on the progression of atherosclerosis [35].

Large clinical trials have shown that hormone therapy reduces the appearance of type 2 diabetes mellitus (T2DM), despite not having been approved as a prevention measure in this disease. Women in the WHI and HERS studies who received estrogen/progesterone showed an average reduction of 21 % in the incidence of T2DM [38].

Women constantly exposed to endogenous or exogenous estrogens not neutralized by progesterone are at increased risk of developing hyperplasia and endometrial cancer. The risk of endometrial cancer is six to eight times higher in women using estrogen compared with women who do not use it [39].

The relationship between breast cancer and hormone therapy is complex. There are dozens of observational, case–control and cohort studies, with results which are not very consistent. A meta-analysis of observational studies, carried out in 1997, summed up 90 % of the literature (53,705 women with breast cancer, compared with 108,411 controls) and showed that each year of hormone therapy confers a relative risk for breast cancer of 2.3 %, attributable to the use of progesterone [40].

Despite demonstrating an increased incidence, the present study, like others, showed no increase in mortality from the disease. The group of women using estrogen/progestin in the WHI study was discontinued because of the 26 % increase in the risk of breast cancer. That is, for every 10,000 women, 38 developed breast cancer, while among nonusers of hormone therapy, 30 cases of breast cancer in 10,000 women were found [26].

Studies have not clarified whether the risk of breast cancer differs between continuous or intermittent use of progesterone, with observational studies suggesting that the risk may be greater with the continuous use of this drug. It is also unclear whether there is a class effect of progesterone or if a specific agent influences a higher risk of breast cancer. Data from a large observational study suggests that hormone therapy with micronized progesterone carries a low risk of breast cancer with short-term use, but generates an increased risk if used for long periods [41].

It is known that combination therapy and, to a lesser extent, estrogen-alone therapy promote increased proliferation of breast cells, breast tenderness, and increased mammographic density, complicating the interpretation of mammography and delaying the diagnosis of breast cancer [18].

In The Million Women Study (MWS) researchers reported an increased risk of breast cancer in women who start hormone therapy soon after menopause [42]. Women in the WHI study who used estrogen alone had no increased risk of developing breast cancer after an average of 7.1 years of use, and there was even a decrease in the risk in this arm of the study, despite having shown an increase in risk early in treatment. It is claimed that the hypothesis that justifies this reduction in risk is the probable apoptotic effect exerted by estrogen on neoplastic mammary cells in an environment with low levels of estrogen [18]. This finding was not demonstrated in the MWS study [42].

The association between hormone therapy and ovarian cancer is unclear. A cohort study of 44,241 postmenopausal women concluded that women who used estrogen alone as hormone therapy for more than 10 years had a significant risk of developing ovarian cancer, while those who used combined therapy for a short period showed no increased risk [43]. According to data from the MWS, women using hormone therapy are at increased risk for ovarian cancer [44]. Another observational study found a strong association between estrogen and death due to ovarian cancer. Moreover, the risk is increased in women who used estrogen for 10 years or more [18].

In a post hoc analysis of the arm of WHI using combination therapy for an average of 7.1 years, the incidence of non-small cell lung cancer did not increase significantly; there was, however, a significant increase in the number of deaths from this cancer, as well as the presence of metastatic and poorly differentiated tumors. This association was found exclusively in women over 60 years who were smokers or who had a history of smoking. The arm that used only estrogen therapy exhibited no increase in incidence or mortality from lung cancer [45].

Randomized controlled studies of short duration, comparing estrogen with placebo show inconsistent results. The methodology, the type of estrogen, age, the type of menopause (natural or surgical), and, in particular, the tests performed are different. Some studies show benefits in some tests, focused mainly on memory and verbal fluency in patients using estrogen [18]. A meta-analysis concluded that the evidence is still scanty and inconsistent and does not explain the improvement in symptoms and relief from depression, indicating the need to evaluate the various types of hormone therapy used [46].

WHIMS reported hormone therapy (HT), conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA), increased the risk for dementia [HR 1.76 (95 % CI, 1.19–2.60); P = 0.005] and global cognitive decline, with a mean decrement relative to placebo of 0.21 points on the Modified Mini Mental State Examination in women age 65 and older. A subset of WHIMS participants joined the ancillary WHI Study of Cognitive Aging (WHISCA) trials, in which domain-specific cognitive tests and mood were measured annually. Compared with placebo, CEE + MPA had a negative impact on verbal memory over time and CEE-Alone was associated with lower spatial rotational ability at the initial assessment, but the difference diminished over time. The ancillary WHIMS-MRI study measured subclinical cerebrovascular disease to possibly explain the negative cognitive findings reported by WHIMS and the increased clinical stroke in older women reported by the WHI. WHIMS-MRI reported that while CEE + MPA and CEE-Alone were not associated with increased ischemic brain lesion volume relative to placebo; both CEE + MPA and CEE-Alone were associated with lower mean brain volumes in the hippocampus; frontal lobe; and total brain [47].

The evidence linking estrogen use with the prevention of Alzheimer’s disease is still inconsistent. Some observational, case–control and cohort studies have shown reduced incidence of Alzheimer’s disease in women using estrogen compared with nonusers. Not all studies have shown favorable results [18].