Challenges in Diagnosis and Treatment of Male Hypogonadism.

Hypogonadism is a condition characterized by diminished or absent production of sex hormones by the testicles in men and the ovaries in women. Hypogonadism is classified into primary and secondary hypogonadism. Each type of hypogonadism can be caused by congenital and acquired factors. There are many factors that contribute to the occurrence of hypogonadism, including genetic and developmental disorders, infection, kidney disease, liver disease, autoimmune disorders, chemotherapy, radiation, surgery, and trauma. This represents the considerable challenge in diagnosing hypogonadism.The goals of treatment include restore sexual functionality and well-being, initiating and sustaining virilization, osteoporosis prevention, normalize growth hormone levels in elderly men if possible, and restoring fertility in instances of hypogonadotropic hypogonadism. The main approach to treating hypogonadism is hormone replacement therapy. Male with prostate cancer, breast cancer, and untreated prolactinoma are contraindicated for hormone replacement therapy. When selecting a type of testosterone therapy for male with hypogonadism, several factors need to be considered, such as the diversity of treatment response and the  type of testosterone formulation. The duration of therapy depends on individual response, therapeutic goals, signs and symptoms, and hormonal levels. The response to testosterone therapy is evaluated based on symptoms and signs as well as improvements in hormone profiles in the blood. Endocrine Society Clinical Practice Guideline recommend therapeutic goals based on the alleviation of symptoms and signs, as well as reaching testosterone levels between 400 - 700 ng/dL (one week after administering testosterone enanthate or cypionate) and maintaining baseline hematocrit.Hormone therapy is the primary modality in the management of hypogonadism. The variety of signs and symptoms makes early diagnosis of this condition challenging. Moreover, administering hypogonadism therapy involves numerous considerations influenced by various patient factors and the potential for adverse effects. This poses a challenge for physicians to provide targeted hypogonadism therapy with minimal complications.

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk. METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated. RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10-8). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10-14); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10-3), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk. CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

Gender-affirming hormone therapy and cardiovascular health in transgender adults.

A growing number of people identify as transgender and gender non-binary in the USA and worldwide. Concomitantly, an increasing number of patients are receiving gender-affirming hormone therapy (GAHT) to achieve gender congruence. GAHT has far-ranging effects on clinical and subclinical markers of cardiovascular risk. Transgender patients also appear to be at higher risk for cardiovascular diseases compared to their cisgender peers and the impact of gender-affirming therapy on cardiovascular health is unclear. Studies on the effect of GAHT on cardiovascular outcomes are confounded by differences in GAHT regimens and methodological challenges in a diverse and historically hard-to-reach population. Current cardiovascular guidelines do not incorporate gender identity and hormone status into risk stratification and clinical decision-making. In this review, we provide an overview on the cardiometabolic impact and clinical considerations of GAHT for cardiovascular risk in transgender patients.

Increased rate of pancreatitis in gender diverse and transgender patients on hormone therapy: a case series study.

BACKGROUND: There is limited data on the incidence of gastrointestinal-specific pathology in gender non-conforming (GNC) populations. METHODS: Retrospective analysis of pancreatitis incidence rates in transgender and GNC persons exposed and not exposed to gender-affirming hormone therapy (GAHT). RESULTS: 7 of the 1333 patients on hormone therapy had an incidence of pancreatitis. 0 of the 615 patients with no history of GAHT use developed pancreatitis. Representing a 6.96 (95% CI 2.76 to 848.78) for the development of pancreatitis in patients with exposure to GAHT therapy. CONCLUSION: Clinicians working with GNC individuals should be aware of this possible association.

Association between menopausal hormone therapy and the risk of gastric cancer: A Korean nationwide population-based cohort study.

OBJECTIVE: Gastric cancer (GC) is more common in men than women, but also more common among postmenopausal than premenopausal women. The protective effect of reproductive hormones against GC remains unclear. Therefore, we evaluated the association between menopausal hormone therapy (MHT) and the risk of GC in women. METHODS: We investigated the national cohort data of women aged over 40 years who underwent health checkups by the Korean National Health Insurance Service in 2009. After excluding individuals with missing data and those previously diagnosed with cancer, 1,354,621 postmenopausal women were included and divided into groups according to their MHT history. We followed the study population until 2018 and analyzed the hazard ratios (HR) with 95 % confidence intervals (CIs) for the incidence rate of GC in a multivariate adjusted model. RESULTS: The number of women with and without a history of MHT was 214,723 (15.9 %) and 1,139,898 (84.1 %), respectively. During the mean 8.32 ± 0.8 years of follow-up, a total of 12,496 GC cases developed in the study population (10,962 MHT non-users; 1534 MHT users). In the adjusted model, MHT was associated with a 12 % decrease in the development of GC relative to non-use of MHT (HR 0.88; 95 % CI 0.83-0.93). Exposure to MHT for >2 years was linked to a reduction in GC risk, particularly when initiated before the age of 50, giving a 45 % risk reduction. CONCLUSIONS: According to our large-scale prospective national cohort study, exogenous MHT is associated with a decreased risk of GC in postmenopausal women.

Cardiovascular safety of testosterone replacement therapy in men: an updated systematic review and meta-analysis.

INTRODUCTION: The cardiovascular (CV) safety of testosterone (T) replacement therapy (TRT) is still conflicting. Recent data suggested a TRT-related increased risk of atrial fibrillation (AF). The aim of this study was to systematic review and meta-analyze CV risk related to TRT as derived from placebo controlled randomized trials (RCTs). AREAS COVERED: An extensive Medline, Embase, and Cochrane search was performed. All placebo-controlled RCTs reporting data on TRT-related CV safety were considered. To better analyze the role of T on AF, population-based studies investigating the relationship between endogenous circulating T levels and AF incidence were also included and analyzed. EXPERT OPINION: Out of 3.615, 106 studies were considered, including 8.126 subjects treated with TRT and 7.310 patients allocated to placebo. No difference between TRT and placebo was observed when major adverse CV events were considered. Whereas the incidence of non-fatal arrhythmias and AF was increased in the only trial considering CV safety as the primary endpoint, this was not confirmed when all other studies were considered (MH-OR 1.61[0.84;3.08] and 1.44[0.46;4.46]). Similarly, no relationship between endogenous T levels and AF incidence was observed after the adjustment for confounders Available data confirm that TRT is safe and it is not related to an increased CV risk.

Testosterone Replacement Therapy in Orthopaedic Surgery.

Testosterone replacement therapy (TRT) is an indicated treatment of several medical conditions including late-onset hypogonadism, congenital syndromes, and gender affirmation hormonal therapy. Increasing population age, medical benefits, and public awareness of TRT have resulted in increased prevalence of its utilization. However, TRT is not without concern for adverse risks including venous thromboembolic complications, cardiovascular events, and prostate issues. In the field of orthopaedic surgery, research is beginning to delineate the complex relationship between TRT and the development of orthopaedic conditions and potential effects on surgical interventions and outcomes. In this review, we discuss current literature surrounding TRT and subsequent development of osteoarthritis, incidence of total joint arthroplasty, musculotendinous pathology, postoperative infection risk, improvements in postoperative rehabilitation metrics, enhancement of osseous healing, and increased bone-implant integration. The authors suggest future areas of investigation that may provide guidance on how surgeons can mitigate adverse risks while optimizing benefits of TRT in the orthopaedic patient.

Hormone replacement therapy and breast cancer incidence in Korean women.

OBJECTIVES: After the 2002 Women's Health Initiative (WHI) study, the global use of menopausal hormone therapy (MHT) declined, and despite subsequent studies indicating a low risk of breast cancer, concerns about MHT usage persist. We examined the relationship between changes in MHT use and changes in the incidence of breast cancer from 2002 to 2020 in South Korea. STUDY DESIGN: This study used tumor registry information from 2002 to 2020 from the Korean Statistical Information Service and analyzed the incidence rate of invasive breast cancer in women, who were divided into two age groups: <50 and >50 years. The numbers of MHT prescriptions in Korea between 2002 and 2020 was determined from pharmacy data. RESULTS: The incidence of breast cancer per 100,000 women in South Korea increased from 34.3 in 2002 to 96.4 in 2020. Breast cancer incidence rates increased annually in both groups of women (those aged under and over 50 years), with no significant difference between the two (p = 0.614). Prescriptions for estrogen therapy (ET) in 2020 were 52.7 % lower than those in 2002. Prescriptions for estrogen-progesterone therapy (EPT) decreased by 27.9 % over the same period. Conversely, tibolone prescriptions, which had initially decreased by 25.4 % in 2004, subsequently showed a steady increase and were 93.6 % higher in 2020 than in 2002. CONCLUSION: The incidence of breast cancer increased annually in Korean women of all ages; however, the use of ET and EPT for MHT has declined since 2002, particularly the use of EPT after 2010. MHT, especially EPT, did not significantly increase the incidence of breast cancer in Korean women.

Transformation or replacement - Effects of hormone therapy on cardiovascular risk.

Hormone therapy (HT) is important and frequently used both regarding replacement therapy (HRT) and gender affirming therapy (GAHT). While HRT has been effective in addressing symptoms related to hormone shortage, several side effects have been described. In this context, there are some studies that show increased cardiovascular risk. However, there are also studies reporting protective aspects of HT. Nevertheless, the exact impact of HT on cardiovascular risk and the underlying mechanisms remain poorly understood. This article explores the relationship between diverse types of HT and cardiovascular risk, focusing on mechanistic insights of the underlying hormones on platelet and leukocyte function as well as on effects on endothelial and adipose tissue cells.

Does hormone therapy exacerbate other venous thromboembolism risk factors?

OBJECTIVE: Postmenopausal symptoms in women at higher risk for venous thromboembolism (VTE) due to comorbidities are often undertreated because of concerns that hormone therapy (HT) may increase VTE risk; however, it is unclear how much HT impacts risk of VTE when compared with other risk factors. METHODS: This is a case-control study in a commercial claims database from 2007 to 2019. Women aged 50 to 64 years (n = 223,949) were classified as cases if they had an International Classification of Diseases code indicating an acute VTE plus a filled prescription for an anticoagulant, placement of intravascular vena cava filter, or death within 30 days of diagnosis. Controls were matched 10:1 to each case by index date and age. Risk factors and comorbidities present within the year before index were examined. Exposure was defined as a HT prescription within 60 days before index. RESULTS: There were 20,359 VTE cases and 203,590 matched controls. A conditional logistic regression indicated that the greatest risks for VTE were from metastatic cancer (odds ratio [OR], 13.66; 95% CI, 12.64-14.75), hospitalization/surgery (OR, 8.51; 95% CI, 8.09-8.96), trauma (OR, 3.52; 95% CI, 3.32-3.73), comorbidity burden (OR, 3.51; 95% CI, 3.34-3.69), history of hypercoagulable condition (OR, 3.10; 95% CI, 2.87-3.36), and varicose veins (OR, 2.87; 95% CI, 2.56-3.22). Regarding hormone exposure, we observed ORs of 1.51 (95% CI, 1.43-1.60) for any recent hormone exposure; 1.13 (95% CI, 1.04-1.23; number needed to harm, 4,274) for unopposed estrogen menopausal HT; 1.23 (95% CI, 1.10-1.38; number needed to harm, 2,440) for combined menopausal HT; and 5.22 (95% CI, 4.67-5.84) for combined hormonal contraceptives compared with no recent HT exposure. CONCLUSIONS: Hormone therapy exposure did not appear to adversely influence other risk factors, and exposure generally played a minor role in VTE risk. Contraceptives, however, were a strong risk factor.

Cardiovascular risk assessment in women: which women are suited for menopausal hormone therapy?

Individual risk assessment for atherosclerotic cardiovascular disease is important for safe menopausal hormone prescription. Besides the traditional risk factors, female-specific risk variables related to pregnancy and gynecologic conditions importantly contribute to a more tailored risk assessment in women at middle age. Of these, prior pre-eclampsia/HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome and early spontaneous menopause (<40 years) seem to be the strongest adverse risk variables. Concomitant inflammatory disorders should also be taken into account. Adding a coronary artery calcium score with a computed tomography scan to risk assessment has a high predictive value for future cardiovascular events. This should be considered to discriminate between low-risk and high-risk women when uncertainty exists. In women at intermediate risk, menopausal hormone therapy can be easily combined with preventive medication if cardiovascular risk factors are present. In women at higher risk who have severe disabling vasomotor symptoms, a lower dosage of hormone therapy can be considered in good collaboration between the gynecologist and the cardiologist/vascular specialist.

Menopausal hormone therapy and risk for dementia in women with CKD: A nationwide observational cohort study.

AIM: The risk for dementia is increased in postmenopausal women. The incidences of premature menopause and dementia have increased in patients with chronic kidney disease (CKD). The potential benefits of hormone replacement therapy (HRT) on cognitive function may be a more critical issue for patients with CKD. METHODS: Women aged >40 years with or without HRT were identified using the 2009 National Health Screening Questionnaire. Women who were newly diagnosed with CKD between 2009 and 2013 were enrolled. HRT was used as an exposure variable, and participants were followed from the day CKD was diagnosed to December 2019. The hazard ratio (HR) for dementia was evaluated using Cox proportional hazards regression analysis. RESULTS: We included 755 426 postmenopausal women with CKD. The median follow-up period was 7.3 (IQR, 5.8-8.7) years. All-cause dementia, Alzheimer's disease, and vascular dementia occurred in 107 848 (14.3%), 87 833 (11.6%), and 10 245 (1.4%) women, respectively. HRT was significantly associated with a lower risk for dementia in the adjusted Cox regression model (all-cause dementia: HR 0.80; 95% confidence interval [CI] 0.78-0.82; p < 0.001; Alzheimer's disease: HR 0.80; 95% CI 0.77-0.82; p < 0.001; vascular dementia: HR 0.80; 95% CI 0.74-0.87; p < 0.001). CONCLUSIONS: HRT was significantly associated with a lower risk for CKD-related cognitive dysfunction in postmenopausal women. Prospective studies are needed to determine whether HRT lowers the risk for dementia in menopausal women with CKD.

Short-term Impact of Hormone Replacement Therapy on Risk of Breast Cancer in BRCA Mutation Carriers: A Nationwide Study in South Korea.

PURPOSE: BRCA1/2 mutations are well-known risk factors for breast and ovarian cancers in women. Risk-reducing salpingo-oophorectomy (RRSO) is the standard treatment for preventing ovarian cancer with BRCA mutations. Postmenopausal syndrome (symptoms after RRSO can be alleviated by hormone replacement therapy (HRT); however, the use of HRT in carriers of BRCA mutations has been controversial because of the concern that HRT increases the risk of breast cancer. This study aimed to evaluate the effects of HRT in BRCA mutation carriers who underwent RRSO. MATERIALS AND METHODS: A total of 151 carriers, who underwent RRSO between 2013 and 2020 after the diagnosis of BRCA1 or BRCA2 mutations were selected and followed up for a median of 3.03 years. Patients were divided into two groups: those who received HRT after RRSO (n=33) and those who did not (n=118). We compared the incidence of breast cancer over time between these two groups. RESULTS: There was no significant difference in the incidence of breast cancer between women who received HRT and those who did not (p=0.229). Multivariate logistic regression analysis, adjusted for age and parity revealed no significant difference in the risk of breast cancer between these two groups (hazard ratio, 0.312; 95% confidence interval, 0.039 to 2.480; p=0.278). CONCLUSION: In this study, we found no relationship between post-RRSO HRT and breast cancer in the population with BRCA mutations. Therefore, healthcare providers may consider the alleviation of symptoms of postmenopausal syndrome through HRT in patients who underwent RRSO.

Withholding of Hormone Replacement Therapy Prior to Total Joint Arthroplasty Surgery to Reduce the Risk of Postoperative Thromboembolic Events: Is It Justified?-A Systematic Review of Clinical Practice Guidelines.

BACKGROUND: Hormone replacement therapy (HRT), menopausal hormone therapy (MHT), and estrogen-containing medications are frequently withheld before elective lower limb arthroplasty, based on a perceived risk of venous thromboembolism (VTE). However, evidence linking HRT, MHT, and an increased VTE risk is equivocal. This systematic review evaluated the concordance of international clinical practice guidelines (CPGs) on the withholding of HRT or MHT. METHODS: The PubMed, Google Scholar, Cochrane, and Ovid databases were searched for CPGs for the preoperative, perioperative, and postoperative management of patients on HRT and MHT undergoing elective lower limb arthroplasty. This was supplemented by an internet search. There were 7 international CPGs in English, from Europe and North America, published between January 2000 and February 2023 reviewed against the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE-II) criteria, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. RESULTS: The guidelines reviewed revealed a mixed picture on HRT or MHT withdrawal and use in arthroplasty, with some featuring detailed advice on the preoperative and postoperative management of HRT or MHT (Scottish Intercollegiate Guidelines Network), while others featured no guidance (American College of Chest Physicians). The evidence referenced in these guidelines highlighted studies showing HRT or MHT to play a limited role in increasing VTE risk, with most studies from the 1990s and 2000s. CONCLUSIONS: Based on current evidence, non-estrogen-containing transdermal HRT or MHT should not be withheld in patients undergoing elective joint arthroplasty, though further evidence is required to justify withholding estrogen-containing forms.