Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long?

Menopausal hormone therapy (HT) was widely used in the past, but with the publication of seminal primary and secondary prevention trials that reported an excess cardiovascular risk with combined estrogen-progestin, HT use declined significantly. However, over the past 20 years, much has been learned about the relationship between the timing of HT use with respect to age and time since menopause, HT route of administration, and cardiovascular disease risk. Four leading medical societies recommend HT for the treatment of menopausal women with bothersome menopausal symptoms. In this context, this review, led by the American College of Cardiology Cardiolovascular Disease in Women Committee, along with leading gynecologists, women's health internists, and endocrinologists, aims to provide guidance on HT use, including the selection of patients and HT formulation with a focus on caring for symptomatic women with cardiovascular disease risk.

2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS: A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

BACKGROUND: The effect of gender-affirming testosterone therapy (TT) on breast cancer risk is unclear. This study investigated the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). METHODS: Of the 444 TMIs who underwent chest-contouring surgeries between 2013 and 2019, breast tissue composition was assessed in 425 TMIs by the pathologists (categories of lobular atrophy and stromal composition) and using our automated deep-learning algorithm (% epithelium, % fibrous stroma, and % fat). Forty-two out of 444 TMIs had mammography prior to surgery and their breast tissue density was read by a radiologist. Mammography digital files, available for 25/42 TMIs, were analyzed using the LIBRA software to obtain percent density, absolute dense area, and absolute non-dense area. Linear regression was used to describe the associations between duration of TT use and breast tissue composition or breast tissue density measures, while adjusting for potential confounders. Analyses stratified by body mass index were also conducted. RESULTS: Longer duration of TT use was associated with increasing degrees of lobular atrophy (p < 0.001) but not fibrous content (p = 0.82). Every 6 months of TT was associated with decreasing amounts of epithelium (exp(ß) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(ß) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(ß) = 1.01, 95%CI 0.98,1.05, adj p = 0.39). The effect of TT on breast epithelium was attenuated in overweight/obese TMIs (exp(ß) = 0.98, 95% CI 0.95,1.01, adj p = 0.14). When comparing TT users versus non-users, TT users had 28% less epithelium (exp(ß) = 0.72, 95% CI 0.58,0.90, adj p = 0.003). There was no association between TT and radiologist's breast density assessment (p = 0.58) or LIBRA measurements (p > 0.05). CONCLUSIONS: TT decreases breast epithelium, but this effect is attenuated in overweight/obese TMIs. TT has the potential to affect the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough.

In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain-derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain-associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage-Dependent Anion Channel, Insulin-Like Growth Factor 1 Receptor, estrogen-metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERß)-Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along-with this, the association between estrogen, estrogen-metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

Investigating the synergistic effects of hormone replacement therapy, apolipoprotein E and age on brain health in the UK Biobank.

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two-thirds of the patients. Yet, the role of sex-specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)-e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two-way interaction and subsequently age of participants via a three-way interaction. Women from the UK Biobank with no self-reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross-sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two-way interactions between HRT and APOE status were modelled, in addition to three-way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition. No clinically meaningful three-way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1-2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%-1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.

Targeting estrogen receptor signaling for treating heart failure.

Heart failure (HF) is a significant public health problem worldwide. It has long been noted that premenopausal women, compared to postmenopausal women and men, have lower rates for developing this disease, as well as subsequent morbidity and mortality. This difference has been attributed to estrogen playing a cardioprotective role in these women, though exactly how it does so remains unclear. In this review, we examine the presence of estrogen receptors within the cardiovascular system, as well as the role they play behind the cardioprotective effect attributed to estrogen. Furthermore, we highlight the underlying mechanisms behind their alleviation of HF, as well as possible treatment approaches, such as hormone replacement therapy and exercise regimens, to manipulate these mechanisms in treating and preventing HF.

Effective growth hormone replacement with once-weekly somapacitan in Japanese children with growth hormone deficiency: Results from REAL4, a phase 3 clinical trial.

OBJECTIVE: Somapacitan is a long-acting growth hormone (GH) derivative developed for the treatment of GH deficiency (GHD). This study evaluates the efficacy and tolerability of somapacitan in Japanese children with GHD after 104 weeks of treatment and after switch from daily GH. DESIGN: Subanalysis on Japanese patients from a randomised, open-labelled, controlled parallel-group phase 3 trial (REAL4, NCT03811535). PATIENTS AND MEASUREMENTS: Thirty treatment-naïve patients were randomised 2:1 to somapacitan (0.16 mg/kg/week) or daily GH (0.034 mg/kg/day) up to Week 52, after which all patients received somapacitan. Height velocity (HV; cm/year) at Weeks 52 and 104 were the primary measurements. Additional assessments included HV SD score (SDS), height SDS, bone age, insulin-like growth factor-I (IGF-I) SDS, and observer-reported outcomes. RESULTS: At Week 52, observed mean HV was similar between treatment groups (10.3 vs. 9.8 cm/year for somapacitan and daily GH, respectively). Similar HVs between groups were also observed at Week 104: 7.4 cm/year after continuous somapacitan treatment (soma/soma) and 7.9 cm/year after 1-year somapacitan treatment following switch from daily GH (switch). Other height-related endpoints supported continuous growth. IGF-I SDS increased in both groups with mean IGF-I SDS within -2 and +2 during the study. Somapacitan was well tolerated, one mild injection site reaction was reported, with no reports of injection site pain. Patient preference questionnaires showed that most patients and their caregivers (90.9%) who switched treatment at Week 52 preferred once-weekly somapacitan over daily GH treatment. CONCLUSIONS: Somapacitan showed sustained efficacy in Japanese children with GHD over 104 weeks and for 52 weeks after switching from daily GH. Somapacitan was well tolerated and preferred over daily GH.

Progesterone levels do not differ between patients with or without endometriosis/adenomyosis both in those who conceive after hormone replacement therapy-frozen embryo transfer cycles and those who do not.

STUDY QUESTION: Do women with endometriosis who achieve a live birth (LB) after HRT-frozen embryo transfer (HRT-FET) have different progesterone levels on the day of transfer compared to unaffected women? SUMMARY ANSWER: In women achieving a LB after HRT-FET, serum progesterone levels on the day of the transfer did not differ between patients with endometriosis and unaffected patients. WHAT IS KNOWN ALREADY: In HRT-FET, several studies have highlighted the correlation between serum progesterone levels at the time of FET and LB rates. In the pathophysiology of endometriosis, progesterone resistance is typically described in the eutopic endometrium. This has led to the hypothesis that women with endometriosis may require higher progesterone levels to achieve a LB, especially in HRT-FET cycles without a corpus luteum. STUDY DESIGN, SIZE, DURATION: We conducted an observational cohort study at the university-based reproductive medicine center of our institution, focusing on women who underwent a single autologous frozen blastocyst transfer after HRT using exogenous estradiol and micronized vaginal progesterone for endometrial preparation between January 2019 and December 2021. Women were included only once during the study period. Serum progesterone levels were measured on the morning of the FET by a single laboratory. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were divided into groups based on whether they had endometriosis or not and whether they achieved a LB. The diagnosis of endometriosis was based on published imaging criteria (transvaginal sonography/magnetic resonance imaging) and/or confirmed histology. The primary outcome was progesterone levels on the day of the HRT-FET leading to a LB in patients with endometriosis compared to unaffected women. Subgroup analyses were performed based on the presence of deep infiltrating endometriosis or adenomyosis. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1784 patients were included. The mean age of the women was 35.1 ± 4.1 (SD) years. Five hundred and sixty women had endometriosis, while 1224 did not. About 179/560 (32.0%) with endometriosis and 381/1224 (31.2%) without endometriosis achieved a LB. Among women who achieved a LB after HRT-FET, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (13.6 ± 4.3 ng/ml vs 13.2 ± 4.4 ng/ml, respectively; P = 0.302). In the subgroup of women with deep infiltrating endometriosis (n = 142) and adenomyosis (n = 100), the mean progesterone level was 13.1 ± 4.1 ng/ml and 12.6 ± 3.7 ng/ml, respectively, with no significant difference compared to endometriosis-free patients. After adjusting for BMI, parity, duration of infertility, tobacco use, and geographic origin, neither the presence of endometriosis (coefficient 0.38; 95% CI: -0.63 to 1.40; P = 0.457) nor the presence of adenomyosis (coefficient 0.97; 95% CI: -0.24 to 2.19; P = 0.114) was associated with the progesterone level on the day of HRT-FET. Among women who did not conceive, there was no significant difference in the mean progesterone level on the day of the HRT-FET between those with endometriosis and those without (P = 0.709). LIMITATIONS, REASONS FOR CAUTION: The primary limitation of our study is associated with its observational design. Extrapolating our results to other laboratories or different routes and/or dosages of administering progesterone also requires validation. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that patients diagnosed with endometriosis do not require higher progesterone levels on the day of a frozen blastocyst transfer to achieve a LB in hormonal replacement therapy cycles. STUDY FUNDING/COMPETING INTEREST(S): None declared. TRIAL REGISTRATION NUMBER: N/A.

Diagnosis and therapeutic approach to bone health in patients with hypopituitarism.

The results of many studies in recent years indicate a significant impact of pituitary function on bone health. The proper function of the pituitary gland has a significant impact on the growth of the skeleton and the appearance of sexual dimorphism. It is also responsible for achieving peak bone mass, which protects against the development of osteoporosis and fractures later in life. It is also liable for the proper remodeling of the skeleton, which is a physiological mechanism managing the proper mechanical resistance of bones and the possibility of its regeneration after injuries. Pituitary diseases causing hypofunction and deficiency of tropic hormones, and thus deficiency of key hormones of effector organs, have a negative impact on the skeleton, resulting in reduced bone mass and susceptibility to pathological fractures. The early appearance of pituitary dysfunction, i.e. in the pre-pubertal period, is responsible for failure to achieve peak bone mass, and thus the risk of developing osteoporosis in later years. This argues for the need for a thorough assessment of patients with hypopituitarism, not only in terms of metabolic disorders, but also in terms of bone disorders. Early and properly performed treatment may prevent patients from developing the bone complications that are so common in this pathology. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary disease.

Morbidities and mortality among hospitalized patients with hypopituitarism: Prevalence, causes and management.

Hypopituitarism is a highly heterogeneous multisystem disorder that can have a major impact on long-term morbidity and mortality, but even more so during acute medical conditions requiring hospitalization. Recent studies suggest a significant in-hospital burden with prolonged length of stay, increased rate of intensive care unit (ICU) admission, and initiation of mechanical ventilation - all of which may lead to an increased risk of in-hospital mortality. On the one hand, patients with hypopituitarism are often burdened by metabolic complications, including obesity, hypertension, dyslipidemia, and hyperglycemia, which alone, or in combination, are known to significantly alter relevant physiological mechanisms, including metabolism, innate and adaptive immune responses, coagulation, and wound healing, thereby contributing to adverse in-hospital outcomes. On the other hand, depending on the extent and the number of pituitary hormone deficiencies, early recognition of hormone deficiencies and appropriate management and replacement strategy within a well-organized multidisciplinary team are even stronger determinants of short-term outcomes during acute hospitalization in this vulnerable patient population. This review aims to provide an up-to-date summary of recent advances in pathophysiologic understanding, clinical implications, and recommendations for optimized multidisciplinary management of hospitalized patients with hypopituitarism.

Impact of elevated serum estradiol levels before progesterone administration on pregnancy outcomes in frozen-thawed embryo transfer for hormone replacement therapy.

OBJECTIVE: The objective of this retrospective cohort study is to investigate the impact of monitoring serum estradiol (E2) levels before progesterone administration within hormone replacement therapy (HRT) on pregnancy outcomes in women undergoing frozen-thawed embryo transfer (FET). METHODS: Analyzed HRT-FET cycles conducted at a reproductive center from 2017 to 2022. Serum E2 levels were measured prior to progesterone administration. Multivariate stratified and logistic regression analyses were performed on 26,194 patients grouped according to terciles of serum E2 levels before progesterone administration. RESULTS: The clinical pregnancy rate (CPR) and live birth rate (LBR) exhibited a gradual decline with increasing serum E2 levels across the three E2 groups. Even after controlling for potential confounders, including female age, body mass index, infertility diagnosis, cycle category, number of embryos transferred, fertilization method, indication for infertility, and endometrial thickness, both CPR and LBR persistently showed a gradual decrease as serum E2 levels increased within the three E2 groups. The same results were obtained by multivariate logistic regression analysis. CONCLUSIONS: This large retrospective study indicates that elevated serum E2 levels before progesterone administration during HRT-FET cycles are associated with reduced CPR and LBR post-embryo transfer. Therefore, it is advisable to monitor serum E2 levels and adjust treatment strategies accordingly to maximize patient outcomes.

Development and testing of patient-centered education about hormone replacement therapy for women at high genetic risk of breast and ovarian cancer.

OBJECTIVE: In this study, we aimed to develop education to assist BRCA mutation carriers in making informed decisions about HRT in the context of risk-reducing surgery, while simultaneously clarifying their treatment-specific values and reducing decisional conflict. METHODS: We enrolled premenopausal BRCA mutation carriers ages 19-49 without prior cancer or risk-reducing salpingo-oophorectomy to structured interviews in which they reviewed education about the risks and benefits of HRT. Materials included literature-derived data demonstrating associations between HRT and commonly considered health outcomes (breast cancer, vasomotor symptoms, sexual functioning, cardiovascular disease, osteoporosis, and blood clots). Participants completed the 16-item Decisional Conflict Scale (DCS) before and after education, communicated their preferences by rating and ranking the six outcomes, and provided feedback to inform iterative revisions of the educational content. RESULTS: 25 participants completed interviews. DCS scores decreased significantly from 54.6 to 22.8 following education (p < 0.001); sub-scores for uncertainty (71.7 to 37.3), informed (71.7 to 15.3), values clarity (53.7 to 17.0), effective decision (44.2 to 25.5), and support (35.0 to 17.7) also decreased significantly. Participants ranked cardiovascular disease as the most important outcome to consider, followed by breast cancer, osteoporosis, blood clots, decline in sexual function, and hot flashes. Participants with prior mastectomy (N = 10) ranked breast cancer as the most important outcome 25% of the time, compared to 80% in participants without mastectomy (N = 15). CONCLUSION: Following education, BRCA mutation carriers had significantly less decisional conflict regarding the choice to use HRT. This pilot study was successful in generating a prototype educational aid for further testing.

The role of estrogen in Alzheimer's disease pathogenesis and therapeutic potential in women.

Estrogens are pivotal regulators of brain function throughout the lifespan, exerting profound effects from early embryonic development to aging. Extensive experimental evidence underscores the multifaceted protective roles of estrogens on neurons and neurotransmitter systems, particularly in the context of Alzheimer's disease (AD) pathogenesis. Studies have consistently revealed a greater risk of AD development in women compared to men, with postmenopausal women exhibiting heightened susceptibility. This connection between sex factors and long-term estrogen deprivation highlights the significance of estrogen signaling in AD progression. Estrogen's influence extends to key processes implicated in AD, including amyloid precursor protein (APP) processing and neuronal health maintenance mediated by brain-derived neurotrophic factor (BDNF). Reduced BDNF expression, often observed in AD, underscores estrogen's role in preserving neuronal integrity. Notably, hormone replacement therapy (HRT) has emerged as a sex-specific and time-dependent strategy for primary cardiovascular disease (CVD) prevention, offering an excellent risk profile against aging-related disorders like AD. Evidence suggests that HRT may mitigate AD onset and progression in postmenopausal women, further emphasizing the importance of estrogen signaling in AD pathophysiology. This review comprehensively examines the physiological and pathological changes associated with estrogen in AD, elucidating the therapeutic potential of estrogen-based interventions such as HRT. By synthesizing current knowledge, it aims to provide insights into the intricate interplay between estrogen signaling and AD pathogenesis, thereby informing future research directions and therapeutic strategies for this debilitating neurodegenerative disorder.

Estrogen replacement therapy and non-hormonal medication use among patients with uterine cancer.

OBJECTIVE: As the prognosis for endometrial cancer is excellent, management of the effects of estrogen deprivation has an important influence on quality of life. We examined the trends in the use of estrogen replacement therapy (ERT) and non-hormonal medications among patients with uterine cancer following surgery. METHODS: The MarketScan Database was used to identify patients 18-49 years who underwent hysterectomy plus oophorectomy and those aged 50-75 years who underwent hysterectomy between 2008 and 2020. ERT and non-hormonal treatments of menopause were identified preoperatively and postoperatively. After propensity score balancing, difference-in-differences (DID) analyses were performed to compare the pre-and-postoperative changes in ERT and non-hormonal medication use between groups. The trends in postoperative use of ERT were assessed and tested using Cochran-Armitage trend tests. RESULTS: A total of 19,700 patients with uterine cancer and 185,150 controls were identified. Overall, postoperative ERT use decreased for both age groups and for patients with and without uterine cancer. The DID in ERT use between those with uterine cancer and those with benign pathology after hysterectomy was -37.1% (95% CI, -40.5 to -33.6%) for patients 18-49 years of age and - 10.4% (95% CI, -10.9 to -9.9%) for those 50-75 years. The DID for non-hormonal medication use between those with uterine cancer and those with benign pathology after hysterectomy was 11.2% (95% CI, 7.8 to 14.7%) for younger patients and 3.4% (95% CI, 2.9 to 4.0%) for those 50-75 years. The postoperative new ERT use has been declining over time in patients with uterine cancer in those 18-49 years of age (P = .02) and those 50-75 years of age (P < .001). CONCLUSIONS: The use of ERT is uncommon and has declined over time in patients with uterine cancer. Conversely, non-hormonal medications are more commonly used among patients with uterine cancer.

Luteal phase support using micronized vaginal progesterone as pessaries or capsules in artificial cycles: is there any difference?

RESEARCH QUESTION: Is there a difference between the proportion of patients with serum progesterone <8.8 ng/ml on the day of embryo transfer when micronized vaginal progesterone (MVP) for luteal phase support (LPS) is given as pessaries versus capsules? DESIGN: This retrospective, matched-cohort, single-centre study compared pessaries (Cyclogest) versus capsules (Utrogestan, Progeffik) for LPS in hormone replacement treatment-embryo transfer (HRT-ET) cycles. Patients under 50 years old with a triple-layer endometrial thickness of ≥6.5 mm underwent transfer of one or two blastocysts. Serum progesterone concentrations were measured on the day of transfer; patients with concentrations <8.8 ng/ml received a single 'rescue' dose of additional progesterone by subcutaneous injection. RESULTS: In total 2665 HRT-ET cycles were analysed; 663 (24.9%) used pessaries for LPS and 2002 (75.1%) used capsules. Mean serum progesterone concentrations with standard deviations on the day of embryo transfer were significantly higher in the group using MVP pessaries compared with those using capsules (14.5 ± 5.1 versus 13.0 ± 4.8 ng/ml; P = 0.000). The percentage of participants with suboptimal serum progesterone concentrations on the day of embryo transfer (<8.8 ng/ml) was significantly lower in the pessary group than the capsule group (10.3%, 95% confidence interval [CI] 7.9-12.6% versus 17.9%, 95% CI 16.2-19.6%; adjusted odds ratio 0.426, 95% CI 0.290-0.625; P = 0.000). No differences in pregnancy outcome were observed between the groups. CONCLUSIONS: Using MVP pessaries rather than capsules for LPS resulted in significantly fewer patients having suboptimal serum progesterone concentrations on the day of embryo transfer. Consequently, almost 50% fewer patients in the pessary group needed rescue treatment.

Association between endometrial thickness and birthweight of singletons from vitrified-warmed cycles: a retrospective cohort study.

RESEARCH QUESTION: What is the association between endometrial thickness (EMT) and the birthweight of singleton infants born from frozen-thawed embryo transfer cycles? DESIGN: This retrospective cohort study was conducted from January 2016 to December 2019. Participants were categorized into a natural cycle (NC, n = 8132) group and hormone replacement therapy (HRT, n = 4975) group. Only singleton deliveries were included. The primary outcomes were measures of birthweight and relevant indexes. Multivariable logistic regression and multivariable-adjusted linear regression models that incorporated restricted cubic splines were used. RESULTS: In the HRT group, the risk of delivering a small for gestational age (SGA) infant was increased in women with an EMT <8.0 mm (adjusted odds ratio [aOR] 1.85, 95% confidence interval [CI] 1.17-2.91) compared with women with an EMT of 8.0 to <12.0 mm, and increased with an EMT ≥12.0 mm (aOR 1.85, 95% CI 1.03-3.33). An inverted U-shaped relationship was found between EMT and birthweight in women with HRT. No significant differences were shown in birthweight z-score, or being SGA or large for gestational age, in singletons among the three EMT groups in the natural cycles. CONCLUSIONS: A thinner endometrium seen in women undergoing HRT cycles was associated with a lower birthweight z-score, as well as a higher risk of SGA. However, no significant association was observed between EMT and birthweight z-score or SGA in the NC group. It is noteworthy that a thicker endometrium was not associated with a higher birthweight in frozen-thawed embryo transfer (FET) cycles. Women with a thin endometrium who achieve pregnancy require specialized attention, particularly if they are undergoing FET with HRT cycles.

Hormone replacement therapy and periodontitis progression in postmenopausal women: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the responses of periodontal environment to hormone replacement therapy (HRT) in postmenopausal women with or without periodontitis. BACKGROUND: HRT is a common and effective strategy for controlling menopausal symptoms, while the changes of periodontal environment under it, particularly in postmenopausal women with periodontitis, remain unclear. METHODS: As a prospective cohort study, a total of 97 postmenopausal women receiving HRT were screened, including 47 with and 50 without periodontitis. Correspondingly, 97 women did not receiving HRT were screened as controls during the same period. The full-mouth sulcus bleeding index (SBI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) were measured using periodontal probes. The levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) in the gingival crevicular fluid were measured using enzyme-linked immunosorbent assay. In addition, cone beam computed tomography was performed to measure the alveolar bone height (ABH) and bone mineral density (BMD). RESULTS: In postmenopausal women without periodontitis, no significantly changes on periodontal parameters were observed after HRT. In women with stage II periodontitis, SBI, BOP, IL-6, and TNF-α were significant decreased after one year and two years of HRT. Compared to the controls, women with stage II periodontitis who underwent HRT had significantly lower CAL and ABH and higher BMD in the second year. The incidence of at least one site with CAL increase ≥1 mm between baseline and 2 years was significantly lower in the HRT group than in the control group in women with stage II periodontitis. In addition, HRT was significantly associated with a decrease in SBI, BOP, IL-6, and TNF-α in the first year and with a decrease in CAL, SBI, BOP, IL-6, and ABH and an increase in BMD in the second year. CONCLUSIONS: In postmenopausal women with stage II periodontitis, HRT is associated with the alleviation of inflammation within two years and the remission of alveolar bone loss in the second year. HRT appears to decrease the incidence of CAL increase ≥1 mm within 2 years in women with periodontitis by inhibiting inflammation and alveolar bone loss.

Should hormone replacement therapy (any route of administration) be considered in all postmenopausal women with lower urinary tract symptoms? Report from the ICI-RS 2023.

AIMS: This International Consultation on Incontinence-Research Society report aims to summarize the evidence and uncertainties regarding the use of hormone replacement therapy by any route in the management of lower urinary tract symptoms (LUTS) including recurrent urinary tract infections (rUTI), with a review of special considerations for the elderly. Research question proposals to further this field have been highlighted. METHODS: An overview of the existing evidence, guidelines, and consensus regarding the use of topical or systemic estrogens in the management of LUTS. RESULTS: There are currently evidence and recommendations to offer topical estrogens to postmenopausal women with overactive bladder symptoms as well as postmenopausal women with rUTIs. Systemic estrogens however have been shown in a meta-analysis to have a negative effect on LUTS and, therefore are not currently recommended. CONCLUSIONS: Although available evidence and recommendations exist for the use of topical estrogens, few women are commenced on these in primary care. There remain large gaps still within our knowledge of the use of estrogens within the management of LUTS, particularly on when it should be commenced, the length of time treatment should be continued for, and barriers to prescribing.

Systematic Review on Gender-Affirming Testosterone Therapy and the Risk of Breast Cancer: A Challenge for Physicians Treating Patients from Transgender and Gender-Diverse Populations.

Conflicting evidence exists about the risk of breast cancer in transgender and gender-diverse (TGD) patients treated with testosterone. This review aimed to summarize current knowledge regarding the risk of breast cancer associated with gender-affirming testosterone treatment (GATT). A systematic literature search using the Preferred Reporting Items for Systematic Review and Meta-Analysis checklist was conducted in January 2023 through Ovid, Scopus, and Web of Science databases. English-language, peer-reviewed articles evaluating breast cancer in TGD patients after GATT that met the inclusion criteria were included. This review included 22 articles, with 14 case reports, 4 case series, and 4 retrospective cohort studies. The review identified 26 TGD patients who developed breast cancer post-GATT therapy, with inconclusive evidence on the relationship between testosterone and the risk of breast cancer in TGD patients. This uncertainty in part arises from the mechanisms governing testosterone's effects within breast tissue, with contrasting theories proposing both proliferative and antiproliferative impacts. Considering this ambiguity, it is imperative for healthcare providers to engage in informed discussions with patients prior to initiating hormone therapy to discuss potential adverse effects, including the possibility of breast cancer development in TGD individuals. Patient education and shared decision-making are essential components of responsible care in this context.

Reduced protein carbonylation on hormone therapy is associated with improved fibrinolysis in postmenopausal women: the impact of PAI-1 and TAFI activity.

Hormone therapy (HT) has been reported to reduce protein carbonylation (PC) in postmenopausal women, in whom fibrinolysis is impaired. We investigated whether PC affects fibrinolysis and if HT modulates this effect. We enrolled 150 women aged 55.5 ± 4.7 years in a randomized interventional open-label study, including 50 on standard oral HT, 50 on ultra-low-dose HT, and 50 controls. PC, along with global fibrinolysis (clot lysis time, CLT), fibrinolysis proteins, and prothrombotic markers were determined at baseline and at 24 weeks. Patients with the baseline top quartile PC (> 2.07 nM/mg protein) had 10.3% longer CLT, higher activity (but not antigen) of TAFI (+ 19.9%) and PAI-1 (+ 68.1%) compared to the remainder. No differences were observed in thrombin generation, factor VIII, plasminogen or α2-antiplasmin. On-treatment PC decreased by 16.4% (p < 0.0001), without differences related to the type of HT, compared to baseline and by 30% compared to controls, in whom PC and fibrinolysis markers remained unchanged. Patients with PC > 2.07 nM/mg had shortened CLT during HT compared to baseline, along with lower PAI-1 (-69%) and TAFI (-26%) activity. In this subgroup CLT was 5.8% shorter compared to controls with the highest PC. In postmenopausal women with increased PC, HT was accompanied by PC reduction and faster clot lysis together with decreased PAI-1 and TAFI activity.