Therapeutic options for premature ovarian insufficiency: an updated review.

Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BACKGROUND: Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. METHODS: Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. SUMMARY: Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. CONCLUSIONS: CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Current and future treatment options for adrenal insufficiency.

PURPOSE OF REVIEW: Patients with adrenal insufficiency (AI) irrespective of being on glucocorticoid replacement therapy still suffer from increased morbidity and mortality. A major contributing factor is an inability of conventional glucocorticoid treatment to mirror the physiological cortisol rhythm. Novel strategies to replicate the cortisol rhythm using hydrocortisone infusion pumps and oral modified release hydrocortisone have now been developed and confirmed to offer benefits to patients. RECENT FINDINGS: In the DREAM study, when compared to multiple daily dosing of glucocorticoids Plenadren reduced weight, was less immunosuppressive and resulted in a better quality of life besides reducing infections. Chronocort that provides the early morning rise in cortisol improves androgen concentrations compared to conventional glucocorticoid treatments in congenital adrenal hyperplasia (CAH). Physiological hydrocortisone infusion pumps improve cortisol profiles with better adrenocorticotrophic hormone, glucose control, and quality of life (QOL) with androgen levels better controlled in CAH. SUMMARY: Advances in glucocorticoid replacement for patients with AI are ongoing. Novel approaches to managing AI, enabled by this armamentarium of drug formulations, aims to improve patient health. Currently, their use should be reserved for patients with metabolic complications, very poor QOL and difficult-to-treat CAH. Larger studies based on outcomes are essential to understand to what extent these strategies can replace conventional treatments.

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.

Hormone therapy for trans and gender diverse patients in the general practice setting.

BACKGROUND: In recent years there has been a significant increase in the number of trans, gender diverse and non-binary (TGDNB) people accessing healthcare. For many of these individuals the first port of call will be to their local general practitioner (GP). The TGDNB community is a high-priority population with the highest suicide rates of any population group in Australia. There is evidence that mental health outcomes improve significantly when individuals are able to access gender-affirming hormones. OBJECTIVE: The aim of this article is to provide GPs working in Australia with a practical guide to prescribe gender-affirming hormone therapy to TGDNB patients. DISCUSSION: GPs are ideally placed to provide care for TGDNB patients in the primary care setting. Gender incongruence is no longer viewed as a mental health disorder. In recent years there has been a move away from mandatory psychiatric assessment to more contemporary patient-centred models of care.

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.

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.

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.

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 and Patterns of Testosterone Therapy among U.S. Male Medicare Beneficiaries, 1999 to 2014.

PURPOSE: We explored the Medicare database (1999 to 2014) to provide a comprehensive assessment of testosterone therapy patterns in the older U.S. male population. MATERIALS AND METHODS: We estimated annual age-standardized incidence (new users) and prevalence (existing users) of testosterone therapy according to demographic characteristics, comorbidities and potential indications. RESULTS: There were 392,698 incident testosterone therapy users during 88 million person-years. Testosterone therapy users were predominantly younger, white nonHispanic, and located in South and West U.S. Census regions. On average testosterone therapy use increased dramatically during 2007 to 2014 (average annual percent change 15.5%), despite a decrease in 2014. In 2014 the most common recorded potential indications for any testosterone therapy were hypogonadism (48%), fatigue (18%), erectile dysfunction (15%), depression (4%) and psychosexual dysfunction (1%). Laboratory tests to measure circulating testosterone concentrations for testosterone therapy were infrequent with 35% having had at least 1 testosterone test in the 120 days preceding testosterone therapy, 4% the recommended 2 pre-testosterone therapy tests, and 16% at least 1 pre-testosterone therapy test and at least 1 post-testosterone therapy test. CONCLUSIONS: Testosterone therapy remains common in the older U.S. male population, despite a recent decrease. Although testosterone therapy prescriptions are predominantly for hypogonadism, a substantial proportion appear to be for less specific conditions. Testosterone tests among men prescribed testosterone therapy appear to be infrequent.

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.

Menopausal Hormone Therapy and Risks of First Hospitalized Heart Failure and its Subtypes During the Intervention and Extended Postintervention Follow-up of the Women's Health Initiative Randomized Trials.

BACKGROUND: We assessed whether postmenopausal hormone therapy (HT) was associated with incident heart failure (HF) and its subtypes and examined whether there was a modifying effect of age on the associations. METHODS AND RESULTS: Postmenopausal women aged 50-79 enrolled in the Women's Health Initiative HT trials were analyzed. The 16,486 women with a uterus were randomized to receive conjugated equine estrogens (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo, and 10,739 women with prior hysterectomy were randomized to receive CEE (0.625 mg/day) alone or placebo. Incident HF was defined as the first HF hospitalization. HF with reduced ejection fraction (HFrEF) or preserved EF (HFpEF) was defined as EF < 50% or ≥ 50%. During the intervention phase, median follow-up was 5.6 years in the CEE-plus-MPA trial and 7.2 years in the CEE-alone trial. During the cumulative follow-up of 18.9 years, women randomized to HT vs placebo in the 2 combined trials had incidence rates of 3.90 vs 3.89 per 1000 person-years for total HF; 1.25 vs 1.40 per 1000 person-years for HFrEF, and 1.88 vs 1.79 per 1000 person-years for HFpEF, respectively. There were no significant effects of HT on the risk of total incident HF or its subtypes in either trial, and age at randomization did not significantly modify the results. CONCLUSIONS: Postmenopausal HT did not alter the risk of hospitalization for HF or its subtypes during the intervention or cumulative 18.9 years of follow-up, and results did not vary significantly by age at randomization. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT0000611 https://clinicaltrials.gov/ct2/show/NCT00000611?cond=women%27s±health±initiative&rank=5.

Congestive Heart Failure and Thyroid Dysfunction: The Role of the Low T3 Syndrome and Therapeutic Aspects.

BACKGROUND: Both the morbidity and mortality rates from congestive heart failure (CHF) remain elevated despite the medical and non-medical management of the disease, thus suggesting the existence of residual risk factors such as thyroid dysfunction. Particularly, the 15-30% of patients with CHF, especially those with severe ventricular dysfunction, display the so-called low T3 syndrome (LT3S), which seems to negatively affect the cardiovascular prognosis. OBJECTIVE: Only a few clinical trials have been carried out to verify both the safety and the efficacy of thyroid replacement in the LT3S, aiming to ameliorate the prognosis of CHF, and most of the results were controversial. METHODS: Since the aim of the present review was to briefly overview both the indication and contraindication of triiodothyronine replacement in CHF and LT3S, the authors searched PubMed using the medical subject headings (MeSH) related to the following terms: "congestive heart failure" and "low T3 syndrome" or "euthyroid sick syndrome" or "non-thyroidal sick syndrome". The research study only focused on the narrative and systematic reviews, randomized clinical trials and meta-analysis studies which were conducted before June 2019. RESULTS: Studies conducted in both animal models and humans provided controversial information about the effectiveness and safety of the T3 replacement for improving ventricular dysfunction, particularly in the long-term. CONCLUSION: Further clinical trials are needed to better explore the role of LT3S in patients with CHF and its consequent therapeutic strategy in this clinical setting.

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.

Bone health in adult trans persons: an update of the literature.

PURPOSE OF REVIEW: Hormonal treatment in trans persons can affect bone health. In this review, recent studies published on this topic in adults are discussed. RECENT FINDINGS: Before starting hormonal treatment, trans women were found to have lower bone mineral density than cis men, which seems to be related to lower vitamin D concentrations and lower lean body mass, whereas this was not found in trans men. Short-term and long-term studies show that hormonal treatment does not have detrimental effects on bone mineral density in trans women and trans men. Low estradiol concentrations were associated with a decrease in bone mineral density in trans women. SUMMARY: Based on the reassuring findings in these studies, regularly assessing bone mineral density during hormonal treatment does not seem necessary. This confirms the Endocrine Society Guideline stating that bone mineral density should be measured only when risk factors for osteoporosis exist, especially in people who stop hormonal treatment after gonadectomy. The relationship with estradiol concentrations indicate that hormone supplementation should be adequate and therapy compliance should be stimulated. As vitamin D deficiency frequently occurs, vitamin D supplementation should be considered. Future research should focus on fracture risk and long-term changes in bone geometry.

Migraine in Women.

Migraine is a lifelong condition that disproportionately affects women and, if not effectively managed, can lead to significant disability. It is important for clinicians to have a good understanding of the impact of the hormonal fluctuations that occur throughout a female migraineur's life, so that appropriate, stratified therapies can be implemented. In doing so, whether it is migraine onset at menarche in an adolescent young woman, or migraine worsening in a perimenopausal female migraineur, quality of life can be ensured.

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.

Turner syndrome: mechanisms and management.

Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.

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.