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.

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.

Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer.

Importance: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer. Objective: To determine whether the risk of breast cancer-specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT). Design, Setting, and Participants: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer-specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023. Exposure: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort. Main Outcomes and Measures: The primary outcome was time to breast cancer-specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer-specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade. Results: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer-specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer-specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94). Conclusions and Relevance: Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

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.

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.

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.

Exploring the potential for a set of UK hormone replacement therapy eligibility guidelines: A suggested proposal on the topic of venous thromboembolism.

OBJECTIVE: To explore the feasibility for a set of hormone replacement therapy (HRT) eligibility guidelines that follow a similar structure and appearance to the UKMEC guidance for contraception. To enable non-specialists to feel confident in safely prescribing HRT and to aid selection of the most appropriate first line treatment. METHODS: A literature review was undertaken with evidence summarised on the topic of venous thromboembolism (VTE) which is an area frequently considered a barrier to prescribing. Medical eligibility tables which separated HRT by type were then produced for a set of VTE-related topics. RESULTS: The literature search confirmed the importance of distinguishing between different types and routes of administration when considering the suitability of HRT. Much of the evidence has been based on older synthetic types of HRT and whilst they still have a role in management, these medications carry different risks to the now more accepted use of body identical types. The search also highlighted the nuances involved, increasing the complexity of forming guidelines, with the need for consideration to be given to an individual's own perception of risks and benefits. CONCLUSION: The demand for HRT has risen in recent years and there is a need for this to be managed effectively, particularly for patients in primary care. The production of this type of guidance will enable the non-specialist to feel confident in safe and evidence-based prescribing. The guidelines are also designed to demonstrate to prescribers which complex patients should be referred onto menopause specialists.

Hormone Replacement Therapy and Psoriasis Risk: A Nationwide Population-Based Cohort Study.

BACKGROUND: Hormone replacement therapy (HRT) is used to relieve menopause symptoms, but has been reported to be associated with coronary heart disease and cancers in women. However, a link between HRT and psoriasis has yet to be established. The aim of this study was to determine the association between HRT and the risk of psoriasis. METHODS: We executed a nationwide population-based study. A total of 1,130,741 post-menopause women were enrolled in the national health care insurance database based on the enrollment criteria. The study population was classified into four groups based on the duration of the HRT, and the risk of psoriasis was analyzed. RESULTS: The incidence rates of psoriasis per 1,000 person-years were 3.36 and 4.09 in the no history of HRT and ≥ 5 years of HRT, respectively. After adjustment for age, smoking, alcohol intake, regular exercise, body mass index, diabetes mellitus, hypertension, and dyslipidemia, the most prolonged duration of the HRT group (≥ 5 years) exhibited significantly increased risk of developing psoriasis (hazard ratio, 1.22; 95% confidence interval, 1.16-1.29). CONCLUSION: We propose that HRT in post-menopausal women is associated with an increased likelihood of psoriasis development.

Prostate Safety Events During Testosterone Replacement Therapy in Men With Hypogonadism: A Randomized Clinical Trial.

Importance: The effect of testosterone replacement therapy (TRT) on the risk of prostate cancer and other adverse prostate events is unknown. Objective: To compare the effect of TRT vs placebo on the incidences of high-grade prostate cancers (Gleason score ≥4 + 3), any prostate cancer, acute urinary retention, invasive prostate procedures, and pharmacologic treatment for lower urinary tract symptoms in men with hypogonadism. Design, Setting, and Participants: This placebo-controlled, double-blind randomized clinical trial enrolled 5246 men (aged 45-80 years) from 316 US trial sites who had 2 testosterone concentrations less than 300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk. Men with prostate-specific antigen (PSA) concentrations greater than 3.0 ng/mL and International Prostate Symptom Score (IPSS) greater than 19 were excluded. Enrollment took place between May 23, 2018, and February 1, 2022, and end-of-study visits were conducted between May 31, 2022, and January 19, 2023. Intervention: Participants were randomized, with stratification for prior CVD, to topical 1.62% testosterone gel or placebo. Main Outcomes and Measures: The primary prostate safety end point was the incidence of adjudicated high-grade prostate cancer. Secondary end points included incidence of any adjudicated prostate cancer, acute urinary retention, invasive prostate surgical procedure, prostate biopsy, and new pharmacologic treatment. Intervention effect was analyzed using a discrete-time proportional hazards model. Results: A total of 5204 men (mean [SD] age, 63.3 [7.9] years) were analyzed. At baseline, the mean (SD) PSA concentration was 0.92 (0.67) ng/mL, and the mean (SD) IPSS was 7.1 (5.6). The mean (SD) treatment duration as 21.8 (14.2) months in the TRT group and 21.6 (14.0) months in the placebo group. During 14 304 person-years of follow-up, the incidence of high-grade prostate cancer (5 of 2596 [0.19%] in the TRT group vs 3 of 2602 [0.12%] in the placebo group; hazard ratio, 1.62; 95% CI, 0.39-6.77; P = .51) did not differ significantly between groups; the incidences of any prostate cancer, acute urinary retention, invasive surgical procedures, prostate biopsy, and new pharmacologic treatment also did not differ significantly. Change in IPSS did not differ between groups. The PSA concentrations increased more in testosterone-treated than placebo-treated men. Conclusions and Relevance: In a population of middle-aged and older men with hypogonadism, carefully evaluated to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer and other prostate events were low and did not differ significantly between testosterone- and placebo-treated men. The study's findings may facilitate a more informed appraisal of the potential risks of TRT. Trial Registration: ClinicalTrials.gov Identifier: NCT03518034.

Cholesterol Levels, Hormone Replacement Therapy, and Incident Dementia among Older Adult Women.

Previous studies revealed that hormone replacement therapy (HRT) probably has a protective effect for preventing dementia in post-menopausal women. However, the results were still controversial. The association between cholesterol levels and incident dementia in older women is not fully understood either. We conducted a retrospective analysis on a cohort of non-demented women aged older than 50 years, which was registered in the History-based Artificial Intelligence Clinical Dementia Diagnostic System database from September 2015 to August 2021. We followed this cohort longitudinally to examine the rates of conversion to dementia. Using a Cox regression model, we investigated the impact of the quartile of total cholesterol (TC) levels on incident dementia, adjusting for age, sex, education, neuropsychiatric symptoms, neuropsychological assessments, HRT, as well as various vascular risk factors and medications. We examined a cohort of 787 participants, comprising 539 (68.5%) individuals who did not develop dementia (non-converters). Among these non-converters, 68 individuals (12.6%) were treated with HRT. By contrast, there were 248 (31.5%) who did develop dementia (converters). Among the converters, 28 individuals (11.3%) were treated with HRT. The average follow-up durations were 2.9 ± 1.5 and 3.3 ± 1.6 years for non-converters and converters, respectively. Compared to the lowest quartile of TC levels (<153), the hazard ratios (HR) for converting to dementia were 0.61, 0.58, and 0.58 for the second (153-176), third (177-201), and highest (>201) quartiles, respectively (all p < 0.05). However, the low-density lipoprotein cholesterol (LDL-C) level and HRT did not alter the rate of conversion to dementia. In conclusion, the lowest quartile of TC increased incident dementia in post-menopausal women without dementia; however, HRT did not contribute to conversion to dementia. Some studies suggest that post-menopausal women who have reduced estrogen levels might have an increased risk of Alzheimer's disease if they also have high cholesterol. Nonetheless, the evidence is inconclusive, as not all studies support this finding. The "Lower LDL-C is better" strategy for preventing cardiac vascular disease should be re-examined for the possible serial adverse effects of new onset dementia due to very low cholesterol levels.