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Premature ovarian insufficiency (POI) is probably one of the most devastating diagnoses for women of reproductive age. The major implications for fertility, climacteric symptoms, and quality of life, the great impact of long-term consequences such as bone loss and cardiovascular health, and the lack of a coherent and shared clinical approach make the choice for the right hormonal therapy challenging. In this review we propose an integrated and patient-based hormonal approach for women with POI, from puberty to late reproductive age.

Objectives: To describe the effects of low-dose hormonal replacement therapy (HRT) on quality of life, metabolic parameters and blood pressure in postmenopausal women., Methods: Postmenopausal women untreated with HRT or sex steroids in the previous 12 months were randomized to treatment with 17β-estradiol (1 mg/day) plus drospirenone (2 mg/day) (E2+DRSP) or to calcium (controls). Quality of life was evaluated by the Women's Health Questionnaire (WHQ) at baseline and after 6 and 12 weeks of treatment. Anthropometric, metabolic and blood pressure measurements were performed before and after 3 months of treatment., Results: WHQ domain scores for vasomotor and somatic symptoms, anxiety/fears, depressed mood, sexual behavior and sleep problems decreased significantly in the E2+DRSP group relative to both baseline and control values (p < 0.05). Body mass index was unchanged, while waist circumference decreased significantly (p < 0.001) after E2+DRSP treatment. Significant decreases were also observed after E2+DRSP treatment for blood insulin values, insulin resistance (estimated by homeostasis model assessment) and systolic blood pressure (p < 0.001, all). In subjects with systolic blood pressure < 130 mmHg at baseline, no changes in systolic values were registered, while women with baseline high-normal systolic blood pressure (130-139 mmHg) showed significant decreases (p < 0.0069). E2+DRSP did not modify diastolic blood pressure values. In the calcium-treatment group, there were no significant changes in WHQ scores or in anthropometric, metabolic or blood pressure measurements., Conclusion: In postmenopausal women, E2+DRSP administration improves vasomotor symptoms and general aspects of quality of life and may positively influence cardiovascular risk factors.

Recent controversies with hormone replacement therapy (HRT) have caused much concern in women and their health-care providers. As a result, the number of HRT users in the USA has fallen dramatically. Consequently, the potential HRT-induced reduction in fracture risk is lost so that, in the next few years, we can expect an excess of 43,008 fractures per year in women aged 65 - 69 years. In addition, the recent evidence on the merits of early initiation of HRT on cardiovascular disease risk and neurocognitive function and the effect of type and combination of hormones on breast cancer risk now require an urgent review by the regulatory authorities of their recommendations about HRT.

In the present study we evaluated the effects of climacteric modifications on body weight and fat distribution. From women attending a menopause clinic we selected 2175 untreated, normal healthy women who were divided into three groups: premenopausal (n = 540), perimenopausal (n = 750) and postmenopausal (n = 885), and compared them with 354 postmenopausal women receiving different forms of hormone replacement therapy (HRT). The total body fat tissue mass and distribution were analyzed using dual-energy X-ray absorptiometry. Body weight and body mass index (BMI) were significantly higher in perimenopausal and postmenopausal than in premenopausal women. Mean total body fat and fat as a percentage of soft tissue were significantly (p < 0.05) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. Fat tissue and regional fat tissue as a percentage of total fat tissue were higher in the trunk (p < 0.0001) and arms (p < 0.0001) in perimenopausal and postmenopausal than in premenopausal women. In postmenopausal women, leg fat tissue was significantly (p < 0.05) lower than in premenopausal and perimenopausal groups. Total body and leg lean tissue were significantly lower (p < 0.05) in postmenopausal than in premenopausal and perimenopausal women. In age-matched women with similar BMI, total body fat as a percentage of soft tissue was significantly (p < 0.001) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. As for body fat distribution, fat as a percentage of total fat tissue was significantly higher in the trunk (p < 0.0001) region in perimenopausal and postmenopausal women compared with the premenopausal group. In the legs, fat as a percentage of total fat tissue was significantly higher (p < 0.05) in the premenopausal than in the postmenopausal group. In the arms a slight but not significant (p < 0.18) difference was shown in fat distribution between the three untreated groups. In age-matched HRT-treated postmenopausal women, the fat tissue was similar to that in the premenopausal group. The present results confirm that endocrine changes during the menopausal transition, rather than the aging process, are related to changes in body weight and fat distribution. Perimenopausal and postmenopausal women show a shift to a central, android fat distribution that can be counteracted by HRT.

Despite the clear benefits of long-term hormone replacement therapy (HRT), the majority of patients tend to undergo short-term treatment. The cyclical bleedings induced by the sequential progestogen administration are often unacceptable namely in the elderly postmenopausal women. At the standard doses HRT preparations can also induce annoying hormone-related side effects, both in sequential and continuous combined regimens. Lower HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with high rates of amenorrhea. Continuous administration of low doses of progestins is safe for endometrium protection and minimizes progestin-related side effects. Indeed, it has been demonstrated that low dose HRT can prevent the increase in bone turnover and the consequent bone loss in postmenopausal women. The choice of lower HRT dosages can also be useful for the number of potential disadvantages of standard HRT doses, mainly for long-term treatments. Low dose regimens should be considered as a starting dose to minimize the occurrence of side effects, improving compliance and, therefore, HRT effects on the prevention of long-term consequences of estrogen deprivation.

Aims: In order to assess the effects of menopause and hormonal replacement therapy (HRT) on body weight and body fat distribution (determined by dual energy X-ray), early postmenopausal women were given either oral calcium (500 mg/day, control group, n=13) or HRT, a combination of estradiol valerate (EV, 2 mg/day for 21 days) with cyproterone acetate (CPA, 1 mg/day in the last 10 days of the treatment cycle, n=18; Climen, Schering)., Results: There were no differences in basal body weight and body fat distribution in the two groups before the study. In control group, a significant (P<0.05) increase in body weight (from 63.5+/-2.0 to 68.7+/-2.0 kg after 36 months) paralleled a shift to a prevalent central, android fat distribution with a slight but significant (P<0.05) increase in total body fat mass (from 23.4+/-2.1 to 29.1+/-2.1 kg), an increase in trunk (from 10.1+/-0.4 to 12.7+/-0.4 kg, P<0.05), arms (from 2.4+/-0.2 to 2.9+/-0.2 kg, P<0.05) and legs (from 6.5+/-0.4 to 7.8+/-0.4 kg, P<0.05) fat. In the HRT group total body bone mineral showed a significant increase (from 1086+/-21 to 1128+/-19 mg/cm(2), P<0.05) increase after 36 months, with no significant increase in body weight (from 62.6+/-1.8 to 65.0+/-1.9 kg), and no modifications in trunk (from 10.0+/-0.2 to 10.1+/-0.2 kg) and arms (from 2.4+/-0.1 to 2.6+/-0.1 kg) fat, but a significant increase in legs fat (from 6.9+/-0.3 to 9.9+/-0.4 kg, P<0.05)., Conclusion: Present results demonstrate that menopause is associated with an accelerated increase in body weight and body fat, with a prevalent central, android fat distribution, that can be counteracted at least in part by oral HRT.

The clinical benefits of HRT are clearly established for the relief of menopausal symptoms, improving quality of life and the prevention of osteoporosis. Although research on the impact of HRT (oral, transdermal, tibolone, etc.) and on the effects of raloxifene on CVD is still ongoing, with certain unresolved controversies, studies using a variety of different HRT formulations have shown a clear benefit on surrogate markers of CHD and epidemiological and clinical, although not randomized, studies have demonstrated a CHD reduction in HRT-treated women. Today, HRT may be used for the primary prevention of CVD. Conversely, there is no clear reason to commence HRT solely or primarily to confer an immediate cardiovascular benefit in postmenopausal women with established CHD. Equally, there is no compelling evidence for discontinuing--or indeed not initiating--HRT in women without CVD because of concern about cardiovascular risk. In any case, all medical interventions should be individualized to the specific woman's age, characteristics and needs. The ultimate effects of different dosages, schedules and type of hormones used should be clarified, avoiding inferring the effects of one form of HRT to others. The importance of increased attention to life-style factors such as healthy diet, exercise and cessation of smoking should be underlined since these can confer specific benefits also to menopausal women. For women with known risks for CVD, HRT may contribute to the beneficial effects of life-style improvements and well-established therapies (including blood pressure control, cholesterol-lowering drugs, aspirin, etc.). New strategies, including lower dosages, new estrogens, progestins, and new estrogen-like substances may be designed to target specific needs.

Objective: The aim of this analysis is to find any association between the use of hormone replacement therapy (HRT) and sociodemographic and clinical factors among women attending 54 menopause clinics in Italy., Methods: The analysis includes data relating to 17,851 women who attended one of 54 menopause clinics in Italy for general gynecological evaluations and counselling between 1995 and 1997. The characteristics of women reporting ever HRT use were compared with those of never users. The odds ratios (ORs) of HRT use were computed in relation to selected reference categories, together with their 95% confidence intervals (CIs)., Results: Of the 17,851 women interviewed, 8539 reported ever HRT use. The mean age of the never and ever HRT users was 52.8 years and 53.7 years, respectively. Higher education was associated with an increased frequency of HRT use: in comparison with women reporting no or primary-/middle-school education, the OR of HRT use of women reporting a high-school diploma or university degree was 1.3 (95% CI 1.1-1.6). HRT use tended to be less frequently reported with increasing body mass index (BMI): in comparison with women whose BMI was < 23.4 kg/m2, the OR of HRT use in those with a BMI of 23.4-26.1 kg/m2 and > or = 26.2 kg/m2 was 0.8 (95% CI 0.8-0.9) and 0.6 (95% CI 0.5-0.7), respectively. Among the postmenopausal women, those who had undergone surgical menopause had an OR of HRT use of 1.3 (95% CI 1.2-1.4). A history of breast cancer was associated with a lower frequency of HRT use (OR 0.3, 95% CI 0.2-0.4). Likewise, a history of thromboembolic disease (OR 0.5, 95% CI 0.4-0.7) or myocardial infarction (OR 0.7, 95% CI 0.6-0.9) was associated with a lower frequency of HRT use., Conclusions: In our study population, the variable most closely related to HRT use was education/social class, thus underlining the impact of information campaigns on HRT and women's health. Among the medical determinants, our analysis indicates that a history of myocardial infarction, thromboembolic disease or breast cancer is associated with less frequent use of HRT.

Osteoporosis is perhaps the widest-ranging social, physical, and economic impact of estrogen deficiency. Postmenopausal bone loss is the major determinant of osteoporosis. Osteoporotic risk can be determined by measuring bone mineral density using dual X-ray absorptiometry. The radiation free quantitative bone ultrasound is emerging in the assessment of bone structure giving reliable estimates of fracture risk. Diet and exercise are important in determining a woman's risks for osteoporosis. Hormone replacement therapy clearly decreases bone turnover and prevents postmenopausal bone loss and reduces fractures. Tibolone as well as raloxifene prevent bone loss and solid data demonstrate a reduction of vertebral fractures after raloxifene administration.

Unlabelled: Nowadays different lines of evidence demonstrate the benefits of postmenopausal hormone replacement therapy (HRT). HRT is extremely effective in treating subjective symptoms and can really improve the quality of life of climacteric women. HRT and dementia: Estrogens are potentially relevant to the pathogenesis and treatment of Alzheimer's disease. The effects of different progestogens on cognitive functions and Alzheimer's disease are largely unknown. The prevention of Alzheimer disease might be a major indication to long term HRT. Large prospective, randomized trials will confirm these preliminary data. HRT and osteoporosis: HRT has been strongly correlated with higher bone mineral density and lower fracture incidence. Definite answers in terms of minimum effective dosages, timing and duration of HRT for fracture prevention are needed. HRT and cardiovascular disease: Different lines of evidence suggest that HRT can exert cardioprotective effects with substantial reduction of morbidity and mortality for cardiovascular disease in postmenopausal women. The effects and the role of progestogens in cardiovascular disease prevention are still debated. Prospective, randomized, controlled studies are needed to assess the impact of different HRT regimens on cardiovascular events. HRT and cancer: The major issue in the relationship between HRT and cancer is breast cancer. Long-term and current HRT use are followed by a slight, though significant increase in the risk of breast cancer. Progestogens can modify the cellular response of normal as well as cancer breasts. The possible protective effect of continuous progestogen addition is very interesting and needs further investigation. Alternative to classical HRT: Selective estrogen receptor modulators (SERM). SERMs such as raloxifene (RAL) are a new class of drugs that exert site specific estrogenic or antiestrogenic effects in different target tissues. RAL prevents bone loss and reduces serum cholesterol in postmenopausal women. In contrast to estrogen RAL does not stimulate breast or uterine tissues. In vitro RAL is highly effective at inhibiting the growth of estrogen-dependent breast adenocarcinoma cells. SERMs are expected to represent a major breakthrough for postmenopausal health., Conclusion: HRT can be offered either as a preventive tool or as individualized care on the basis of personal needs. New therapeutic options like the SERMs will offer a substantial medical advancement for the treatment of postmenopausal women.

Objectives: Our aim was to assess the effects of a combined oral contraceptive (OC) preparation on bone quantitative ultrasound and biochemical markers of bone metabolism in perimenopausal women., Design: Bone biochemical markers and bone quantitative ultrasound were evaluated in a longitudinal 2-year follow-up study conducted in healthy, normally menstruating perimenopausal women, perimenopausal oligomenorrheic women, and age-matched oral contraceptive-treated women (20 micrograms of ethinyl estradiol plus 0.15 mg desogestrel). The results were analyzed by factorial or repeated-measures analysis of variance, as appropriate., Results: In normal women, there were no significant modifications in menstrual cycle, plasma FSH and estradiol levels, biochemical markers of bone turnover, and bone quantitative ultrasound. Conversely, in oligomenorrheic women, an increase in the cycle length with a concomitant rise in circulating plasma FSH and parallel decrease of plasma estradiol levels was evident. In this group, an increase in both urinary excretion of hydroxyproline and plasma osteocalcin levels paralleled a decrease in bone quantitative ultrasound. In perimenopausal OC-treated women, the pattern of osteocalcin and urinary excretion of hydroxyproline showed a slight decrease, whereas bone quantitative ultrasound did not show any significant modification., Conclusion: Perimenopausal OC administration can prevent the increase in bone turnover and the decrease in bone quantitative ultrasound that follow the perimenopausal impairment of ovarian function.

Nowadays, postmenopausal women are largely undertreated. Analysis of conflicting results among different studies suggests that hormone replacement therapy (HRT) can prevent osteoporosis and cardiovascular disease in symptomatic, early postmenopausal women. In fact, climacteric symptoms are related to an increased risk of chronic conditions, including hypertension and cardiovascular disease. Different scientific societies have pointed out that patient selection, timing of initiation, and the choice of the type and dose of HRT used are the major determinants of the ultimate effect of HRT on women's health and quality of life in selected women. HRT may prevent chronic conditions when started in symptomatic women before the age of 60 years or within 10 years of the onset of the menopause, taking into consideration the characteristics and risk profiles of each given woman. The bulk of scientific evidence from preclinical, clinical, epidemiological, and also randomized studies indicates that wisely selected HRT is generally useful and rarely dangerous. Following simple and well-established rules, HRT benefits outweigh all of the possible risks. Progestogen choice can make the difference in terms of cardiovascular disease benefits. [ABSTRACT FROM AUTHOR]

A new study by Karim and colleagues has highlighted the intriguing issue of the consequences of cessation of long-term postmenopausal hormone use. While potential reductions in breast cancer risk and in the incidence of newly diagnosed breast cancer in the era after the Women's Health Initiative study have been heavily debated, the implications of withdrawal from hormone therapy for bone health and fracture risk have remained outside the main scope. This new study has now demonstrated that there is a very clear downside in skeletal outcome that should be considered while evaluating the pros and cons of discontinuing hormone therapy. During 532 686 person-years of observation and a follow-up period of 6.5 years, a 55% increased risk for hip fracture was observed in women who stopped hormone therapy. In view of the dramatic decline in the number of hormone users all around the world, this mini-review discusses the 'neglected' skeletal outcomes of such global trends. [ABSTRACT FROM AUTHOR]