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Hormone therapy use has undergone dramatic changes over the past 20 years. Widespread use of hormone therapy in the 1980s and 1990s came to an abrupt halt in the early 2000s after initial findings of the Women's Health Initiative trial were published and the study was terminated. Since then, much has been learned about the characteristics of women most likely to benefit from hormone therapy. There is general agreement that women younger than 60 years or who initiate hormone therapy within 10 years of menopause onset gain short-term benefit in terms of symptomatic relief and long-term benefit in terms of protection from chronic diseases that affect postmenopausal women. Despite accumulating evidence in support of hormone therapy for symptomatic menopausal women, the slow response by the medical community has led to a 'large and unnecessary burden of suffering' by women worldwide. Greater efforts are clearly needed to educate physicians and medical students about the pathophysiology of menopause and the role of hormone therapy in supporting women through the transition. This article provides a brief historical perspective of events that led to the backlash against hormone therapy, explores the current position of guideline groups, and provides practical recommendations to guide first-line management of symptomatic menopausal women.

Type 2 diabetes has reached epidemic proportions in the United States. Large, randomized controlled trials suggest that menopausal hormone therapy (MHT) delays the onset of type 2 diabetes in women. However, the mechanisms and clinical implications of this association are still a matter of controversy. This review provides an up-to-date analysis and integration of epidemiological, clinical, and basic studies, and proposes a mechanistic explanation for the effect of menopause and MHT on type 2 diabetes development and prevention. We discuss the beneficial effects of endogenous estradiol with respect to insulin secretion, insulin sensitivity, and glucose effectiveness; we also discuss energy expenditure and adipose distribution, both of which are affected by menopause and improved by MHT, which thereby decreases the incidence of type 2 diabetes. We reconcile differences among studies that investigated the effect of menopause and MHT formulations on type 2 diabetes. We argue that discrepancies arise from physiological differences in methods used to assess glucose homeostasis, ranging from clinical indices of insulin sensitivity to steady-state methods to assess insulin action. We also discuss the influence of the route of estrogen administration and the addition of progestogens. We conclude that, although MHT is neither approved nor appropriate for the prevention of type 2 diabetes due to its complex balance of risks and benefits, it should not be withheld from women with increased risk of type 2 diabetes who seek treatment for menopausal symptoms., (Copyright © 2017 Endocrine Society.)

Objective: Data on the effect of hormone replacement therapy (HRT) and tibolone on lipoprotein (a) [Lp(a)], an independent risk factor for cardiovascular disease, are heterogeneous and conflicting. Studies of the effect of HRT and tibolone on Lp(a) concentrations in post-menopausal women are reviewed in this meta-analysis., Design and Methods: MEDLINE, Scopus, EMBASE and Cochrane databases were searched (up to February 10, 2017). Two researchers identified randomized controlled studies and extracted data. Potential controversies were resolved by a third reviewer., Results: In 24 eligible studies, HRT caused a significant reduction in Lp(a) concentrations compared with placebo or no treatment [mean relative difference: -20.35%, 95% Confidence Interval (CI): -25.33% to -15.37%, p<0.0001], with significant heterogeneity between studies (I 2 =98.5%), but without evidence of publication bias. No significant effect was found for tibolone (n=7) (mean relative difference: -23.84%, 95% CI: -63.43% to 15.74%, p=0.238) (I 2 =98.7%, but without publication bias). Oral estrogen caused a greater reduction in Lp(a) concentrations than transdermal estrogen (n=10) (mean relative difference: 37.66%, 95% CI: 16.84% to 58.48%, p<0.0001), with significant heterogeneity between studies (I 2 =99%), but no evidence of publication bias. No difference was observed when continuous was compared with cyclical HRT, conventional with low-dose estrogen, and estrogen monotherapy with estrogen combined with progestogen. No difference was observed between HRT and tibolone regarding their effect on Lp(a)., Conclusions: HRT significantly decreases Lp(a) concentrations, with oral being more effective than transdermal estradiol. The type of HRT, dose of estrogen and addition of progestogen do not seem to modify the Lp(a)-lowering effect of HRT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'., Objectives: To evaluate those claims., Methods: Epidemiological criteria of causation were applied to the evidence., Results: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor., Conclusions: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

HRT is known to be effective for the relief of menopausal symptoms and prevention of osteoporosis. HRT should be tailored to the woman, enhancing the beneficial effects of the treatment while minimizing the risks. It is difficult to evaluate data on particular preparations of HRT and the different dosages in isolation. The purpose of this review is to highlight the efficacy and safety specific to oral estradiol and dydrogesterone combinations of four different dose strengths. A systematic literature search using Medline was carried out to identify studies containing efficacy or safety data. The findings of the retrieved publications confirm that estradiol and dydrogesterone combinations give very effective menopausal symptom relief and prevention of osteoporosis whilst maintaining a good safety profile. Data also show that these combinations of HRT give additional benefit to certain metabolic parameters including lipids, insulin, glucose and body fat distribution. By selecting the treatment and dose most suitable for each individual woman at her particular stage of menopause, the benefits can be optimized whilst mitigating the risks. HRT plays an important role in improving and maintaining women's health when used appropriately., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3)., Objective: To evaluate the evidence for causality in the MWS., Methods: Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET., Results: Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported., Conclusion: HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

Sex hormones are fundamental for female development and they are important physiologically to maintain the health and normal functioning of several organs such as the brain, heart and bone. It is now clear that the hormonal changes that occur during a woman's life, particularly her estrogen status, can modulate disease activity. This is especially true for cardiovascular and musculo-skeletal diseases, which are two leading causes of morbidity and mortality in women. With the general aging of the population they represent a serious and growing public health concern. Estrogen synthesis and blood levels fluctuate during a woman's life and in this review three broad periods will be considered: reproductive phase, transition and postmenopausal phase. Generally speaking, women in the reproductive phase of their life are at low risk of cardiovascular and musculo-skeletal disorders. However, the onset of menopause and the loss of ovarian function is associated with a significant increase in the prevalence of diseases such as coronary heart disease, osteoarthritis and osteoporosis. The prevalence of these debilitating diseases continues to increase through the postmenopausal period. Estrogen replacement is an obvious treatment approach to counter the problems associated with the loss of ovarian function and subsequent estrogen deficiency. Overall, oral and transdermal estrogen replacement are similarly effective in relieving menopausal symptoms and disorders that manifest during this period of a woman's life. Transdermal estrogen may be preferable in older women because of its lower thrombogenic potential. In this journey through a woman's life current best evidence relating to cardiovascular and musculo-skeletal risk will be reviewed in line with well documented management strategies., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed., Objective: To evaluate the evidence for unopposed estrogen., Methods: In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study., Results: In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed., Conclusions: The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.

Objectives: Guidelines recommend using the lowest effective dose of oestrogen for the management of vasomotor symptoms in postmenopausal women. The primary aim of this double-blind, multi-centre, randomised study was to assess the efficacy of oral ultra-low dose continuous combined hormone replacement therapy with 17β-oestradiol and dydrogesterone., Study Design: 313 women with ≥50 moderate to severe hot flushes during the previous week were randomised to 0.5 mg 17β-oestradiol/2.5 mg dydrogesterone (E 0.5 mg/D 2.5 mg), 1mg 17β-oestradiol/5mg dydrogesterone (E 1mg/D 5 mg) or placebo for 13 weeks. The placebo group then switched to E 0.5 mg/D 2.5 mg for a further 39 weeks, whilst the other groups continued on the same treatment., Results: After 13 weeks, the reduction in the number of moderate to severe hot flushes/day in the E 0.5 mg/D 2.5 mg group was greater than in the placebo group (-6.4 vs. -4.9, p<0.001) and comparable to that in the 1/5 mg group (-6.3). E 0.5 mg/D 2.5 mg and E 1mg/D 5 mg significantly improved the total Menopause Rating Scale score. The number of bleeding/spotting days was lower with E 0.5 mg/D 2.5 mg than with E 1 mg/D 5 mg. The overall amenorrhoea rate with E 0.5 mg/D 2.5 mg was 81%; this increased to 91% in months 10-12., Conclusions: Continuous combined 0.5 mg 17β-oestradiol and 2.5mg dydrogesterone was effective in alleviating vasomotor symptoms and improving quality of life, and was associated with a high amenorrhoea rate and a good tolerability profile., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Hormone replacement therapy (HRT) can be administered orally and non-orally. Providing equivalent doses are given, all forms of HRT can equally relieve menopausal symptoms and prevent bone loss and osteoporosis. Different routes of administration will have differing metabolic effects, with oral HRT producing a hepatic first-pass effect not seen with non-oral HRT. The first-pass effect can produce benefits including larger reductions in low density lipoprotein cholesterol, lipoprotein(a) and insulin resistance, and larger increases in high density lipoprotein cholesterol. Unwanted effects are seen in increases in triglycerides and in coagulation activation. Cardiovascular effects of oral and transdermal HRT appear to be fairly similar, with improvements in vascular endothelial function, angiotensin-converting-enzyme activity, and in most markers of inflammation. There is a paucity of studies on the effects of transdermal HRT on cardiovascular outcomes, but the few data available suggest similar effects to oral HRT, and dose rather than route of administration is probably more important in this respect. Oral HRT may be preferred in women with evidence of insulin resistance, such as in metabolic syndrome or maturity-onset diabetes mellitus. Transdermal HRT may be preferred in women with coagulation disturbances. But, for the majority of women, personal preference should determine their choice of HRT route.

Hormone replacement therapy (HRT) has profound metabolic effects which impact on the cardiovascular system. These effects include changes in lipids and lipoproteins, glucose and insulin metabolism, haemostatic factors, inflammatory markers and body composition, as well as changes in vascular function and remodelling. Observational studies have demonstrated coronary heart disease benefit with HRT use, in contrast to the outcomes from randomised clinical trials. Lack of benefit in the latter studies appears to arise from early harm caused by HRT which outweighs any later benefit. Such early harm could result from transient increases in thrombogenesis and adverse vascular remodelling, which in turn could arise from starting doses of such therapies that are inappropriately high for the women's age. This problem is avoided in observational studies because the women are much younger and those same starting doses are appropriate for their age. Later benefit could result from oestrogen action on metabolic risk factors and direct arterial effects resulting in reduced atherogenesis. It is therefore possible that more appropriate HRT regimens could be devised to provide coronary benefit without risk of stroke, even in older age groups. Such strategies need to be tested in large clinical trials. The metabolic effects of HRTs are key to providing cardiovascular benefit.

Objective: Levels of angiotensin I-converting enzyme (ACE) in blood are associated with variation in cardiovascular disease risk. Serum ACE activity in women may be reduced by combined oestrogen-progestogen hormone replacement therapy (HRT). However, the relative contribution of each hormonal component to this observation is uncertain. We investigated ACE activity in two groups of healthy postmenopausal women receiving HRT regimens., Design: The first group received placebo or oestrogen-only HRT randomly (oral conjugated equine oestrogens or transdermal 17 beta-oestradiol). The second group was treated with oestrogen-only HRT (oral 17 beta-oestradiol) followed by sequential oestrogen-progestogen HRT (17 beta-oestradiol and dydrogesterone)., Measurements: Assay of blood for soluble ACE activity before and whilst receiving HRT., Results: In the first group, oral conjugated equine oestrogens significantly reduced (P < 0.01) ACE activity by 18% on average relative to pretreatment whereas non-significant changes of -9% and +7% were seen with transdermal 17 beta-oestradiol or placebo treatment, respectively. In the second group oestrogen-only HRT significantly reduced (P < 0.001) ACE activity by 15% on average. The reduction during both the oestrogen-only and combined phases of sequential treatment was 12% and 19%, respectively, compared with pretreatment values (P < 0.01 and P < 0.001). ACE activity also differed significantly (P < 0.05) between the two phases of sequential treatment., Conclusions: Both oestrogen-only and oestrogen-progestogen HRT may reduce ACE activity in blood. Oestrogen and progestogen may exhibit additive effects on blood ACE activity.

Epidemiological studies show a reduction in cardiovascular disease with postmenopausal oestrogen use. Oestrogens have been shown to have both metabolic effects and direct effects on the vasculature, both of which may improve arterial function and reduce or reverse atheroma formation. The metabolic effects include changes in lipids and lipoproteins, glucose and insulin metabolism, coagulation and fibrinolysis. The direct arterial effects include changes in endothelium-dependent processes, ion channels, renin-angiotensin system and remodelling processes. The various actions of oestrogens on the vascular system are reviewed. It is clearly important to understand the biological basis of these effects of oestrogen on the cardiovascular system in order to optimize current and future hormone-replacement therapy in women after natural or surgical menopause.

Hormone replacement therapy comprises natural oestrogen and, when appropriate, progestogen given to postmenopausal women. Population studies have shown that postmenopausal oestrogen administration results in a marked reduction in cardiovascular disease, particularly coronary heart disease, an effect that does not appear to be lost when cyclical progestogen is also included. The way in which the hormones confer this protection has not been fully elucidated, but it includes effects on metabolic processes that contribute to atheroma formation as well as direct effects on the arteries themselves. Oestrogens and progestogens can produce beneficial changes in lipids and lipoproteins, glucose and insulin metabolism, body fat distribution, and coagulation and fibrinolysis. Oestrogen acts directly on blood vessels through both endothelium-dependent and calcium-dependent mechanisms to improve arterial function. More widespread use of HRT could result in a major beneficial impact on cardiovascular disease, the leading cause of death in women.

Objective: We attempted to ascertain whether transdermal postmenopausal estrogen-progestin therapy has the typical effects of oral therapy on serum lipoprotein risk markers for cardiovascular disease., Study Design: Sixty-one postmenopausal women were randomized to receive either transdermal continuous 17 beta-estradiol, 0.05 mg/day, with transdermal cyclic norethindrone acetate, 0.25 mg/day, or oral continuous conjugated equine estrogens, 0.625 mg/day, with oral cyclic dl-norgestrel, 0.15 mg/day. Twenty-nine untreated subjects served as controls. Lipoprotein profiles at 3 and 6 months were compared with baseline values by means of analysis of variance., Results: In the estrogen-alone phase both therapies reduced serum levels of total and low-density lipoprotein cholesterol; high-density lipoproteins were largely unchanged. Oral therapy increased triglycerides whereas this lipid fell with transdermal therapy. In the combined phase of the cycle both therapies reduced triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol., Conclusion: Transdermal and oral therapies had similar effects on lipoprotein cholesterol but different effects on triglycerides.

The evidence now strongly supports a central role for oestrogen in the maintenance of the normal female skeleton. Loss of endogenous oestrogen leads to a period of accelerated bone loss which can be prevented with appropriate oestrogen replacement. The route of administration is not important provided adequate dosages are prescribed. Oestrogens may exert their actions by a direct steroid receptor mechanism or via local and/or systemic factors such as cytokines, prostaglandins or calcitonin. As the requirement for osteoporosis prevention grows, it is essential that the extent of the involvement oestrogen has in skeletal homeostasis is fully recognized.

In man, the major function of calcitonin appears to be prevention of excessive or unwanted bone resorption. There is a striking sex difference in circulating levels, with a relative deficiency in women. Calcitonin secretion in young adults is increased by oestrogens and therefore long periods of oestrogen lack, such as after the menopause, may be associated with a more pronounced calcitonin deficiency. This exaggerated deficiency could be an important factor in the pathogenesis of postmenopausal bone loss, especially since the latter may be due to excessive bone resorption. In a study of the effects of oestrogen treatment on circulating levels of calcitonin, parathyroid hormone, and vitamin-D metabolites in postmenopausal women, the most striking change was a sharp rise in plasma-calcitonin. Oestrogens prevent postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss, and it is suggested that this effect could be mediated, at least in part, through control of calcitonin secretion. Calcitonin may prove effective in the prevention of postmenopausal bone loss. Its place in the treatment of postmenopausal osteoporosis warrants further evaluation.

A major function of calcitonin in humans appears to be maintenance of the skeleton. There is a marked sex difference in circulating calcitonin levels: women have much lower levels. This has led to speculation that calcitonin lack may be one factor involved in the pathogenesis of postmenopausal bone loss. We have measured levels of calcitonin and the other major calcium-regulating hormones in healthy women during the early menopause, and studied the effects of reversing their oestrogen deficiency with natural and synthetic oestrogen. The major findings were that calcitonin levels were increased by oestrogen administration (P less than 0.02-less than 0.001) and that the levels of the bone-resorbing hormones, parathyroid hormone and 1,25 dihydroxyvitamin D, were not higher in postmenopausal than in premenopausal women. We suggest that loss of oestrogen at the menopause accelerates the natural age-related decline of calcitonin secretion, thus further decreasing the calcitonin levels. This leads to increased sensitivity of the skeleton to the actions of the bone-resorbing hormones. It seems likely that the well-known effect of oestrogen in preventing postmenopausal bone loss is achieved, at least in part, by enhancement of calcitonin secretion.

The major function of calcitonin in man appears to be the prevention of excessive or unwanted bone resorption. There is a marked sex difference in circulating levels, with a relative deficiency in women. As calcitonin secretion in young women is known to be increased by estrogens, long periods of estrogen lack - such as the postmenopause - are possibly associated with a more pronounced calcitonin deficiency. This exaggerated deficiency could be an important factor in the pathogenesis of postmenopausal bone loss, especially as the latter is believed to be due to excessive bone resorption. We have studied the effects of three exogenous estrogens on the circulating levels in postmenopausal women of calcitonin, parathyroid hormone, the vitamin D metabolites 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D, and calcium and phosphate. The most striking finding was a sharp rise in the plasma levels of calcitonin. Estrogens are known to prevent postmenopausal bone loss but the mechanism of action remains obscure. We suggest that the beneficial effects of estrogens could be mediated, at least in part, through control of calcitonin secretion. Thus calcitonin may prove effective in the prevention of postmenopausal bone loss and its role in the treatment of established osteoporosis warrants further evaluation.

Calcitonin is a peptide hormone secreted by C-cells which, in humans, are found mainly in the thyroid gland. It now seems that a major physiological function of this hormone in man is the long-term maintenance of the skeleton achieved by control of bone resorption. A marked sex difference in circulating calcitonin levels normally exists, with a relative deficiency in women as compared to men. It has now been found that oestrogens regulate calcitonin secretion and it appears likely that the loss of ovarian function at the menopause accelerates the natural decline in calcitonin secretion which occurs with age. Thus, post-menopausal women are more markedly calcitonin-deficient. Levels of the bone-resorbing hormones, parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D are not elevated post-menopausally and it seems likely that the increased bone resorption which leads to post-menopausal bone loss is due mainly to the loss of oestrogen and calcitonin secretion.