Non-classical effects of vitamin D: Non-bone effects of vitamin D.

Our understanding of vitamin D has improved considerably in recent years. The role of vitamin D in preventing osteoporotic fractures is now well-established. However, an important controversy has emerged in the last decade concerning the effects of the active form of vitamin D (1,25-dihydroxy-vitamin D) on tissues other than bone (non-classical effects). The demonstration that the vitamin D receptor (VDR) is ubiquitously, expressed combined with increasing observational data supporting a relationship between the level of 25-hydroxy-vitamin D in the serum and chronic metabolic disorders, cardiovascular disease and neoplasms, have led to its redefinition as a steroid hormone and the proposal of its use in preventing and/or treating those diseases. This article is an update on the different non-bone or non-classical effects of "vitamin-hormone D", and its potential preventive or therapeutic role in certain diseases, however, this review is not exhaustive. The different modalities of substitution or supplementation proposed in France by the Groupe de Recherche et d'Information sur les Ostéoporoses (GRIO) are also summarised.

It is all in the name: The importance of correct terminology in hormone replacement therapy.

The global increase in life expectancy to 74 years for women, while the median age of the menopause remains at 51 years, means that an increasing number of women will live a significant portion of their adult lives in the menopause. The WHI publications in 2003/4 reported on the dangers of hormone replacement therapy, in particular with respect to breast cancer and dementia risk. This resulted in a dramatic reduction in hormone replacement therapy prescription and use. However, the findings from the WHI studies have been re-appraised, and the new perspective is reflected in the guidance published by NICE in 2015 in which they recommended that more women be offered hormone replacement therapy as the benefits are now perceived to outweigh the risks for most women. However, controversy continues to surround hormone replacement therapy, and there are probably few areas in medicine where the misuse of terminology causes quite as much confusion as in hormone replacement therapy. Commonly used terms such as 'menopausal hormone therapy' and 'hormone replacement therapy' lack specificity and there is an urgent need for correct terminology to accurately describe the hormones replaced.

Natural cycle frozen-thawed embryo transfer in young women with regular menstrual cycles increases the live-birth rates compared with hormone replacement treatment: a retrospective cohort study.

OBJECTIVE: To determine the optimal endometrial preparation protocols of frozen-thawed embryo transfer (FET) in young women with regular menstrual cycles. DESIGN: Retrospective cohort study. SETTING: Public fertility center. PATIENT(S): Infertile women with regular menstrual cycles undergoing FET. INTERVENTION(S): Natural cycle (NC) treatment for patients with proven ovulation in previous cycles or who refused medication (n = 308), or hormone treatment (HT) for patients who could not be frequently monitored (n = 1,538). MAIN OUTCOME MEASURE(S): Live-birth rates. RESULT(S): The live-birth rates were 61.73% in the NC group and 55.11% in the HT group. The effect size of the endometrial preparation on live-birth rates was evaluated in prespecified and exploratory subgroups in each subgroup, and multivariable logistic regression analysis was used to determine which variables could be independently associated with the live-birth rate. The HT patients had a lower chance of live birth in all subgroups: endometrial thickness on the day of progesterone administration, triple-line endometrial pattern, female age at embryo transfer, fertilization type, and protocol in the fresh cycle. Multivariable analysis showed NC to be associated with an increased likelihood of live birth compared with HT. CONCLUSION(S): Natural cycle treatment has a higher chance of live birth than HT for endometrial preparation in young women with regular menstrual cycles.

Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women.

After reports from the Women's Health Initiative randomized trial evaluating estrogen plus progestin, there was a sudden, substantial, and sustained decrease in all categories of menopausal hormone therapy, and the first reduction in age-adjusted breast cancer incidence in more than 20 years was seen in 2003-2004 among US women 50 years of age or older. Subsequent trends in breast cancer incidence have been described, but most reports have not focused on the postmenopausal age group or fully engaged the potential influence of reduced hormone therapy on breast cancer incidence trends by race/ethnicity. To address this gap, this commentary examines trends for annual age-adjusted breast cancer incidence over a 40-year period from 1975 to 2015 for white and black women on the basis of findings from the Surveillance, Epidemiology, and End Results 9 registries. Overall, the sharp decline in breast cancer incidence seen in 2003-2004 was followed in the subsequent decade by a continued low breast cancer incidence plateau in white women that has largely persisted. In contrast, a new discordance between breast cancer incidence trends in black and white women has emerged. In the 2005-2015 decade, a sustained increase in breast cancer incidence in black women has resulted in annual incidence rates comparable, for the first time, to those in white women. This commentary explores the hypothesis that the over-decade-long and discordant changes in breast cancer incidence rates in postmenopausal black and white women are, to a large extent, associated with changes in hormone therapy use in these 2 groups.

Hormonal profile of menopausal women receiving androgen replacement therapy: a meta-analysis.

PURPOSE: Ovarian and adrenal aging leads to a progressive decline in androgen levels and deleterious effects on the quality of life. Despite this, specific replacement is not routinely recommended in the management of women with a physiological or pathological decline in their production, mainly due to the lack of long-term follow-up safety data. The purpose of this paper was to meta-analyze and summarize the existing data about hormonal profile changes in menopausal women receiving androgen replacement treatments. Full-text articles published through May 30, 2018 were found via MEDLINE and Embase and selected according to the strict inclusion criteria. METHODS: Randomized clinical trials and case-control studies were enrolled. Studies not reporting steroid serum levels or not providing a control group were excluded from the analysis. Studies enrolling women with genetic defects or severe chronic systemic diseases were excluded. 113 papers fulfilled the inclusion criteria and 56 papers were included in the analysis. Desired data were compiled and extracted by independent observers. RESULTS: Androgen administration increases E1, E2, testosterone, DHEA and DHEAS serum levels, and reduces SHBG. However, the E1 and E2 increase is evident only when DHEA is administered. CONCLUSIONS: Whatever androgen formulation we choose in postmenopausal women, the end result is a rise in testosterone serum levels. However, DHEA regimen is also associated with an increased estrogenic availability. This might be crucial when choosing the best possible treatment for each patient individually taking into consideration if potential benefits outweigh the risks.

Trends in Prescribing Menopausal Hormone Therapy and Bisphosphonates in Australia and Manitoba, Canada and Adherence to Recommendations.

Background: Recommendations for using menopausal hormone therapy (MHT) and bisphosphonates for postmenopausal osteoporosis management have changed over time. After the release of the Women's Health Initiative (WHI) trial results in 2002, new evidence on risks and benefits of MHT became available, and newer guidelines generally specify that MHT should not be prescribed for prevention of chronic disease, including osteoporosis. This raises the question of whether bisphosphonate prescribing changed over time to compensate for the decrease in MHT use. Materials and Methods: We examined trends in dispensed prescriptions in Australia (national) and Canada (province of Manitoba) in relation to prescribing recommendations. Administrative data were used to describe dispensing patterns and changes for persons of all ages from 1996 to 2008, and for women aged 50 to ≥80 years from 2003 to 2008 in Australia and 1996 to 2008 in Canada. Results: In both geographic settings, MHT dispensing increased 1996-2001, peaked in 2001, and declined substantially thereafter (67% reduction in MHT prescriptions for Australia; 64% reduction for Manitoba, Canada to 2008). From 2003 to 2008, the number of MHT prescriptions declined among all age groups in both settings, with the highest declines among women in their 50s. Concurrently, bisphosphonate dispensing increased until 2005 (2001-2005: 260% increase in the number of prescriptions in Australia; 125% increase in Manitoba) and stabilized thereafter, in both settings. Annual bisphosphonate dispensing rates increased 4.1-10.9% for women in their 70s and 80s in Australia and Manitoba during the period studied. Conclusions: Based on dispensed prescriptions data, more recent guidelines for MHT and bisphosphonates use for postmenopausal osteoporosis, which were updated during the study period (and are still consistent with the current guidelines), appear to have been broadly adhered to in both settings.

Update on methods to enhance growth.

PURPOSE OF REVIEW: To discuss treatments used to enhance growth in pediatric patients with short stature. RECENT FINDINGS: New data confirm the known efficacy of recombinant human growth hormone (rhGH) in growth hormone deficiency (GHD) and idiopathic short stature. The latest data from the Safety and Appropriateness of Growth hormone Treatment in Europe cohort did not indicate a long-term risk of malignancy in those treated for isolated GHD, but possibly increased risk in those with other diagnoses. Recombinant human insulin-like growth factor 1 is effective in treating patients with pregnancy-associated plasma protein A2 deficiency. Gonadotropin-releasing hormone agonists or aromatase inhibitor treatment to delay puberty remains controversial. They are more likely to augment adult height if combined with rhGH treatment in children already receiving rhGH. Preliminary data indicate that recombinant C-type natriuretic peptide (CNP) is safe in children and increases growth velocity upon 42 months of treatment in achondroplasia. SUMMARY: Recent data confirms previous data on rhGH efficacy and safety. Therapies to delay growth plate closure have greatest efficacy to augment height if combined with GH in select diagnoses. Recombinant CNP holds promise as a medical treatment for short stature associated with achondroplasia.

Hormone therapy for first-line management of menopausal symptoms: Practical recommendations.

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.

Women's health 2019: Osteoporosis, breast cancer, contraception, and hormone therapy.

This review summarizes evidence that may enhance and influence clinical practice of women's health. Supporting articles were identified by reviewing high-impact medical and women's health journals published in 2017 and 2018. The chosen articles are pertinent to osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in BRCA1 mutation carriers, breast cancer diagnosis using digital tomosynthesis, and risks of hormonal contraception.

Long-Acting Injectables: Current Perspectives and Future Promise.

The parenteral route of administration is preferred over the oral route for treatment of many chronic and life-threatening diseases due to better patient compliance. Long-acting injectables/depot delivery systems are formulations intended for prolonged/sustained drug release over a long period of time ranging from a few days to months. Depot delivery systems enhance product quality by decreasing dosing frequency, simplifying the drug regimen. Parenteral depots reduce the relapse rate of disease and the maintenance phase of therapy, hence improving efficacy and treatment adherence. However, despite being extensively explored in the last seventy years, only a few depot products have been marketed or have reached commercial viability. The introduction of long-acting injectables of any drug took 9 to 10 years after approval of its oral formulation. Mainly the market has been conquered by long-acting injectables for antipsychotic, substance abuse, and hormonal therapy drugs. This article focuses on the preparation of long-acting injectables with special emphasis on challenges associated with formulation. The evolution and current global market trend of various depot formulations are also discussed. Insight is provided into the promising future of long-acting injectables of protein-based drugs as well as multidrug therapy, along with potential uses in the treatment of chronic diseases like HIV, Parkinson's, and Alzheimer's.

Trends in mammography, hormone replacement therapy, and breast cancer incidence and mortality in Canadian women.

PURPOSE: The purpose of the study is to examine relationships between long-term trends of region- and age-specific rates of mammography, hormone replacement therapy (HRT), and breast cancer incidence and mortality in Canadian women aged 35 years and older. METHODS: Population-based complex surveys were used to estimate mammography use in the past 2 years and ever, and HRT use in the past month. National population-based administrative data were used to estimate breast cancer incidence and mortality. Joinpoint analyses were used to estimate trends in rates and years where trend changed. RESULTS: No consistent relationship between mammography use and breast cancer incidence was observed across age groups. Opportunistic screening occurred prior to the establishment of organized screening programs in Canada and prior to substantial declines in breast cancer mortality observed around 1990. Women aged 35-39 years demonstrated a 62.8% relative decrease in breast cancer mortality between 1950 and 2015 despite lower rates of mammography use in the past 2 years (range 9.4-15.9%) reinforcing important treatment advances. A substantial proportion of women in their 40s report mammography use in the past 2 years (range 35.8-42.2%) and regional variation exists reflecting inconsistencies in guidelines across Canada. CONCLUSION: Rates of mammography use over time do not necessarily reflect national guideline releases or establishment of organized screening programs.

Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles.

Over the last decade the use of frozen-thawed embryo transfer has substantially increased, and currently up to one in two embryos transferred has been cryopreserved. To support implantation, endometrial and embryo maturity are required to be synchronized. This can be achieved in various ways. The most commonly applied endometrial preparation methods are the "natural cycle," in which the sequential estrogen and P necessary for endometrial maturation are derived from the developing follicle, and the "artificial" cycle, in which these are sequentially administered. Review of the published data comparing these approaches does not identify a superior approach in terms of clinical outcomes. However, although the "natural cycle" avoids the need for luteal support, the artificial cycle provides more control over timing of ET, and the "modified" natural cycle, in which ovulation is triggered exogenously, may offer both of these advantages. The optimal monitoring strategy for freeze-thaw cycles remains unclear, because only a few studies have addressed this question. Further studies are also required to determine the ideal dosage, method of administration, and duration of estrogen and P supplementation in artificial cycle frozen embryo transfer.

Menopausal hormone therapy: a better and safer future.

Major advances in menopause hormone therapy (MHT) hold promise in the future of better and safer care for women at and after the menopause. The principal advances are: (1) the critical window or 'window of opportunity' in the 10 years or so after the menopause, during which the benefits of MHT in healthy women exceed any risks; (2) use of transdermal instead of oral administration of estrogen to reduce the risk of venous thromboembolism; (c) investigation of the use of oral micronized progesterone (MP) and vaginal MP to prevent endometrial hyperplasia and carcinoma without any increased risk of breast cancer and venous thromboembolism in postmenopausal women receiving estrogens; vaginal MP prevents endometrial proliferation in the short term but the long-term effects in MHT remain to be established; (4) investigation into the use of intrauterine levonorgestrel-releasing devices (LNG-IUDs), which are an attractive form of MHT in perimenopausal women, providing contraception and reducing uterine bleeding, although the risk of breast cancer with LNG-IUDs requires clarification. Women in the future can look forward to a symptom-free menopause and to safer and more beneficial MHT.

Tissue selective estrogen complex (TSEC): a review.

OBJECTIVE: This review describes historical development of selective estrogen receptor modulators (SERMs) and their combination with estrogens, termed a tissue selective estrogen complex (TSEC), and considers the potential for future TSEC development. METHODS: This narrative review is based on literature identified on PubMed and the TSEC research and development experience of the authors. RESULTS: SERMs have estrogenic and antiestrogenic effects in various tissues; however, no single agent has achieved an optimal balance of agonist and antagonist effects for the treatment of menopausal symptoms. Clinically, a number of SERMs protect against osteoporosis and breast cancer but can exacerbate vasomotor symptoms. Estrogens alleviate menopausal hot flushes and genitourinary symptoms as well as reduce bone loss, but the addition of a progestogen to menopausal hormone therapy to protect against endometrial cancer increases vaginal bleeding risk, breast tenderness, and potentially breast cancer. The search for an effective menopausal therapy with better tolerability led to the investigation of TSECs. Clinical development of a TSEC consisting of conjugated estrogens/bazedoxifene increased understanding of the importance of a careful consideration of the combination's components and their respective doses to balance safety and efficacy. Bazedoxifene is an estrogen receptor agonist in bone but an antagonist/degrader in the endometrium, which has contributed to its success as a TSEC component. Other oral TSEC combinations studied thus far have not demonstrated similar endometrial safety. CONCLUSIONS: Choice of SERM, selection of doses, and clinical trial data evaluating safety and efficacy are key to ensuring safety and adequate therapeutic effect of TSECs for addressing menopausal symptoms.

Um estudo sobre a relação entre a indústria farmacêutica e a classe médica: o caso da promoção e divulgação da terapia de reposição hormonal masculina relacionada ao envelhecimento / A study on the relationship between the pharmaceutical industry and the medical profession: the case of the promotion and disclosure of aging-related male hormone replacement therapy

Este estudo buscou investigar o modo como o processo de promoção e divulgação de categorias diagnósticas e de medicamentos caracteriza-se por uma série de interações em que práticas e discursos de médicos e de profissionais da indústria farmacêutica se influenciam mutuamente, formando uma rede de trocas e apoio mútuo. As trocas dizem respeito a um conjunto de objetos (como brindes e amostras de medicamentos), informações, conhecimento (sob a forma de artigos e/ou conferências), gentilezas, interações sociais que têm na dispensação de determinado(s) medicamento(s) seu propósito final. O objetivo geral desta pesquisa consistiu em analisar a relação entre a indústria farmacêutica e a classe médica no processo de promoção e divulgação de medicamentos e categorias diagnósticas, utilizando a terapia de reposição hormonal masculina relacionada ao envelhecimento como caso de estudo. A fim de atingir o objetivo proposto, escolheu-se três principais meios de coleta de dados: entrevistas semiestruturadas com médicos líderes de opinião, prescritores da terapia de reposição hormonal (TRH) com testosterona (urologistas e endocrinologistas) e propagandistas farmacêuticos da TRH com testosterona; etnografia de congressos científicos, cujos temas se relacionavam ao objeto de pesquisa; análise de material utilizado em curso de formação de propagandista farmacêutico online. Os roteiros de entrevista foram específicos para cada classe profissional e buscaram abordar temas como promoção e divulgação do uso de testosterona relacionado ao envelhecimento masculino e as conexões existentes entre a classe médica e indústria farmacêutica. Utilizou-se a entrevista semiestruturada como instrumento para coleta de dados a fim de buscar informações referentes à dinâmica de interação entre os propagandistas farmacêuticos e a classe médica. A escolha da etnografia de congressos científicos seguiu o pressuposto de que nesses espaços é possível perceber a articulação entre a indústria farmacêutica e a classe médica. Já a opção pela análise de material do curso online ocorreu devido ao objetivo de conhecer e investigar estratégias de marketing farmacêutico dirigidas à classe médica para, posteriormente, fazer um paralelo com o material sobre a TRH com testosterona, coletado durante a pesquisa. A análise do material evidenciou a articulação entre a indústria farmacêutica e a classe médica em diferentes níveis. No entanto, o bjetivo aqui não foi tanto desvendar algo ainda desconhecido ou provar uma hipótese não comprovada. O objetivo foi tão somente acompanhar, em um contexto específico, alguns dos mecanismos através dos quais tais articulações são tecidas de modo a serem ocultadas no mesmo momento em que se realizam

This study sought to investigate how the process of promotion and disclosure of diagnostic categories and medications is characterized through a series of interactions in which the practices and discourses of doctors and professionals of the pharmaceutical industry influence each other, forming a network of exchanges and mutual support. The exchanges pertain to a set of objects (as gifts and drug samples), information, knowledge (in the form of articles and/or conferences), gentleness and social interactions that have in the dispensing of certain medication(s) their final purpose. The main objective of this research was to analyze the relationship between the pharmaceutical industry and the medical profession in the process of promotion and disclosure of medicines and diagnostic categories, using a male hormone replacement therapy related to the aging process as a case of study. In order to achieve the proposed objective, we chose three main means of data collection: semi-structured interviews with doctors who are opinion leaders, prescribers of hormone replacement therapy (HRT) with testosterone (urologists and endocrinologists) and pharmaceutical propagandists of HRT with testosterone; ethnography of scientific congresses that have themes related to the object of research; analysis of materials used in an online pharmaceutical propagandist formation course. The scripts of the interviews were specific for each professional body and sought to approach topics such as the promotion and disclosure of the use of testosterone related to male aging process and the existent connections between the medical professionals and the pharmaceutical industry. A semi-structured interview was used as an instrument to collect data to search for information on the dynamics of interaction between pharmaceutical propagandists and the medical profession. The choice of the ethnography of scientific congress followed the assumption that inside these spaces it is possible to perceive an articulation between the pharmaceutical industry and the medical profession. The option of analyzing online course materials was due to the objective of knowing and investigating pharmaceutical marketing strategies directed to the medical profession to later make a parallel with the material on the testosterone TRH, collected during the research. The analysis of the material shows an articulation between the pharmaceutical industry and the medical profession at different levels. However, our objective was not to unravel something yet unknown or to prove an unproven hypothesis. That being said, we only aim to follow, in a specific context, some of the mechanisms through which such articulations are built so that they are hidden at the same moment in which they are realized

Surgical and pharmacological reassignment: influence on transsexual cardiovascular risk profile.

BACKGROUND/AIM: To evaluate and stratify early cardiovascular risk of transsexuals who underwent pharmacological and/or surgical gender reassignment. METHODS: Fifty-six transsexuals were divided into two groups: group 1 - underwent gonadectomy (orchiectomy for transwomen and hystero-annessiectomy for transmen); group 2 - hormone replacement therapy alone. All participants underwent carotid artery intima-media thickness (C-IMT) and flow-mediated vasodilation (FMD) of brachial artery evaluations. RESULTS: FMD was lower in patients who had undergone gonadectomy compared with non-surgically treated patients (Group 1: 5.711 vs Group 2: 7.339, P < 0.0001). Mean C-IMT was higher in group 1 than group 2 (group 1: 0.733 vs group 2: 0.582). The duration of hormone therapy correlates positively with mean C-IMT (B = 0.001) and negatively with FMD (%) (B = - 0.007). CONCLUSIONS: Cardiovascular risk, which is expressed in terms of endothelial (FMD) and morphological (C-IMT) dysfunction, increases in subjects undergoing gonadectomy compared with those receiving cross-sex reassignment therapy alone.

New Target Sites for Treatment of Osteoporosis.

In the last few years, much progress has been achieved in the discovery of new drug target sites for treatment of osteoporotic disorders, one of the main challenging diseases with a large burden for the public health systems. Among these new agents promoting bone formation, shifting the impaired equilibrium between bone anabolism and bone catabolism in the direction of bone synthesis are inorganic polymers, in particular inorganic polyphosphates that show strong stimulatory effects on the expression of bone anabolic marker proteins and hydroxyapatite formation. The bone-forming activity of these polymers can even be enhanced by combination with certain small molecules like quercetin, or if given as functionally active particles with certain divalent cations like strontium ions even showing by itself biological activity. This chapter summarizes recent developments in the search and development of novel anti-osteoporotic agents, with a particular focus on therapeutic approaches based on the potential application of inorganic polymers and combinations.

Hormone-replacement therapy: current thinking.

For several decades, the role of hormone-replacement therapy (HRT) has been debated. Early observational data on HRT showed many benefits, including a reduction in coronary heart disease (CHD) and mortality. More recently, randomized trials, including the Women's Health Initiative (WHI), studying mostly women many years after the the onset of menopause, showed no such benefit and, indeed, an increased risk of CHD and breast cancer, which led to an abrupt decrease in the use of HRT. Subsequent reanalyzes of data from the WHI with age stratification, newer randomized and observational data and several meta-analyses now consistently show reductions in CHD and mortality when HRT is initiated soon after menopause. HRT also significantly decreases the incidence of various symptoms of menopause and the risk of osteoporotic fractures, and improves quality of life. In younger healthy women (aged 50-60 years), the risk-benefit balance is positive for using HRT, with risks considered rare. As no validated primary prevention strategies are available for younger women (<60 years of age), other than lifestyle management, some consideration might be given to HRT as a prevention strategy as treatment can reduce CHD and all-cause mortality. Although HRT should be primarily oestrogen-based, no particular HRT regimen can be advocated.