Low Total Testosterone Levels Research Articles

Impact of COVID-19 on testicular function: a systematic review and meta-analysis.

Studies investigating the effects of SARS-CoV-2 on male reproductive function are few and heterogeneous, and results are often conflicting. This systematic review and meta-analysis was carried out on studies conducted in men with active or anamnestic SARS-CoV-2 infection to evaluate its consequences on the male sex hormone profile and semen parameters. This meta-analysis follows the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols. PubMed, Scopus, Cochrane, and Embase databases were searched to identify relevant studies. We originally selected 3553 articles. After the eligibility phase, 16 articles met our inclusion criteria encompassing 11 case-control studies and 5 cohort studies (2 prospective and 3 retrospective studies). We performed the quantitative analysis with Comprehensive Meta-Analysis Software. Cochran-Q and heterogeneity (I2) indexes were used to assess statistical heterogeneity. Sensitivity analysis and publication bias tests were also performed. Overall, 1250 patients with active or recent (up to 80 days before) COVID-19 infection and 1232 matched healthy controls were included. Sperm concentration, total sperm count, and total motility were significantly lower in patients compared with controls. Patients also showed lower levels of total testosterone and follicle-stimulating hormone, and higher levels of luteinizing hormone, 17β-estradiol, and prolactin compared with healthy controls. None of the included studies found the presence of SARS-CoV-2 mRNA in the semen of infected patients. The present systematic review and meta-analysis suggests the presence of an association between SARS-CoV-2 infection and primary testicular damage manifested with a picture of altered steroidogenesis and worsening spermatogenesis. The absence of the virus in the seminal fluid indicates a low possibility of sexual transmission of the infection to partners and offspring. However, our findings mostly show short-term follow-up, while few studies have considered the long-term consequences of the viral infection, thus further studies are needed to evaluate the long-term consequences on male reproductive health.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

We describe studies determining the association between testosterone therapy (TTh) and mortality. We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. During a median follow-up interquartile range (IQR) of 114 (84-132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio=0.23, 95% confidence intervals=0.14-0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.

Endogenous sex hormones and nonalcoholic fatty liver disease in US adults.

Sex steroid hormones and sex hormone-binding globulin (SHBG) have a role in predisposing individuals to nonalcoholic fatty liver disease (NAFLD), but their effects are known to differ between men and women. The testosterone-to-estradiol ratio (T/E2 ratio) and free androgen index (FAI) were known biomarkers for the hormonal milieu. We investigated whether sex steroid hormones, T/E2 ratio, FAI, and SHBG were associated with NAFLD in US adults. A cross-sectional analysis using the 2013-2016 National Health and Nutrition Examination Survey (NHANES) was performed. NAFLD was defined by utilizing the Hepatic Steatosis Index (HSI) and the US fatty liver index (USFLI) without other causes of chronic liver disease. Out of 8687 subjects (49.5% male), low total testosterone levels were associated with progressively higher odds of NAFLD in men. Increasing T/E2 ratio was inversely associated with higher odds of NAFLD in men. Low serum SHBG levels were independently associated with an increased risk of NAFLD regardless of sex and menopausal status. Increasing FAI was independently associated with NAFLD. When we additionally adjusted for SHBG, T/E2 ratio, not total testosterone, was inversely associated with NAFLD in a dose-dependent manner. Increasing FAI was associated with higher odds of NAFLD in premenopausal women and marginally associated with NAFLD in postmenopausal women. The T/E2 ratio and SHBG were inversely associated with an increased risk of NAFLD in men. In women, increasing FAI was associated with NAFLD, whereas SHBG was inversely associated with NAFLD.

Causal relationship between female reproductive factors, sex hormones and uterine leiomyoma: a Mendelian randomization study

Research questionAre the observed associations between female reproductive factors and sex hormones with the risk of uterine leiomyoma truly causal associations? DesignThe putative causal relationships between female reproductive factors and sex hormones with uterine leiomyoma were investigated using two-sample Mendelian randomization. Statistics on exposure-associated genetic variants were obtained from genome-wide association studies (GWAS). The uterine leiomyoma GWAS from the FinnGen and FibroGENE consortia were used as outcome data for discovery and replication analyses, respectively. Results were pooled by meta-analysis. Sensitivity analyses ensured robustness of the Mendelian randomization analysis. ResultsWhen FinnGen GWAS were used as outcome data, a causal relationship was found between age at menarche (OR 0.84, P < 0.0001), age at menopause (OR 1.08, P < 0.0001), number of live births (OR 0.25, P < 0.001) and total testosterone levels (OR 0.90, P < 0.001) with the risk of uterine leiomyoma. When FibroGENE GWAS were used as outcome data, Mendelian randomization results for age at menopause, the number of live births and total testosterone levels were replicated. In the meta-analysis, a later age at menopause (OR 1.08, P < 0.0001) was associated with an increased risk of uterine leiomyoma. A higher number of live births (OR 0.25, P < 0.0001) and higher total testosterone levels (OR 0.90, P < 0.0001) were associated with a decreased risk of uterine leiomyoma. ConclusionsA causal relationship between later age at menopause, lower number of live births and lower total testosterone levels with increased risk of uterine leiomyoma was found.

Association between sex steroid hormones and subsequent hyperglycemia during pregnancy.

Sex steroid hormones may play a role in insulin resistance and glucose dysregulation. However, evidence regarding associations between early-pregnancy sex steroid hormones and hyperglycemia during pregnancy is limited. The primary objective of this study was to assess the relationships between first trimester sex steroid hormones and the subsequent development of hyperglycemia during pregnancy; with secondary evaluation of sex steroid hormones levels in mid-late pregnancy, concurrent with and subsequent to diagnosis of gestational diabetes. Retrospective analysis of a prospective pregnancy cohort study was conducted. Medically low-risk participants with no known major endocrine disorders were recruited in the first trimester of pregnancy (n=319). Sex steroid hormones in each trimester, including total testosterone, free testosterone, estrone, estradiol, and estriol, were assessed using high-performance liquid chromatography and tandem mass spectrometry. Glucose levels of the 1-hour oral glucose tolerance test and gestational diabetes diagnosis were abstracted from medical records. Multivariable linear regression models were fitted to assess the associations of individual first trimester sex steroids and glucose levels. In adjusted models, first trimester total testosterone (β=5.24, 95% CI: 0.01, 10.46, p=0.05) and free testosterone (β=5.98, 95% CI: 0.97, 10.98, p=0.02) were positively associated with subsequent glucose concentrations and gestational diabetes diagnosis (total testosterone: OR=3.63, 95% CI: 1.50, 8.78; free testosterone: OR=3.69; 95% CI: 1.56, 8.73). First trimester estrone was also positively associated with gestational diabetes (OR=3.66, 95% CI: 1.56, 8.55). In mid-late pregnancy, pregnant people with gestational diabetes had lower total testosterone levels (β=-0.19, 95% CI: -0.36, -0.02) after adjustment for first trimester total testosterone. Early-pregnancy sex steroid hormones, including total testosterone, free testosterone, and estrone, were positively associated with glucose levels and gestational diabetes in mid-late pregnancy. These hormones may serve as early predictors of gestational diabetes in combination with other risk factors.

(305) Impact of Melatonin Supplementation on Testosterone Levels in U.S. Adult Men

Abstract Introduction Among US adults, the prevalence of melatonin supplement consumption significantly increased in the last two decades across all demographic groups. Despite scant evidence, melatonin is widely used as an over-the-counter sleep aid. Because sleep disorders are associated with testosterone deficiency, we examined the associati.n between melatonin supplementation and serum testosterone levels. Objective Evaluate the association between melatonin supplementation and serum testosterone levels in adult males living in the United States. Methods The National Health and Nutrition Examination Survey (NHANES) was used to analyze interviews, physical examinations, and laboratory tests. Data from three cycles (2011-2012, 2013-2014, and 2015-2016) was combined (appended) to study the association between melatonin usage and early morning serum total testosterone (TT) levels. Selection criteria included men aged 18 and older; exclusion criteria included the reported use of testosterone, clomiphene, or anastrozole medications or supplements in the past 30 days. Additionally, participants with missing values for age, body mass index (BMI), sleep habits, or EMSTT were excluded from the analysis. Statistical analysis was performed using SPSS v.28. Continuous variables were presented as medians and interquartile ranges [25 - 75]. To determine the association between of low EMSTT (T &amp;lt; 300 ng/dL = low) and clinical variables, demographics characteristics, a multivariable-adjusted logistic regression analysis was performed. Results After selection, 7,656 participants were analyzed, of those, the median age was 47 [31 - 63] years old, the median TT level was 389.9 [289 - 513.9] ng/dL, and 27.4% of participants were found to have low TT, and 51 (0.7%) reported melatonin supplementation. Among individuals who reported melatonin intake in the past 30 days, the average intake was approximately 1 mg/day. On multivariable adjusted analysis increase age (OR = 1.019, p &amp;lt; 0.001), and BMI (OR = 1.133, p &amp;lt; 0.001) were associated with increased risk of low TT. However, we did not find an association with low testosterone among men who reported melatonin supplementation (p=0.898) even after analyzing for confounding variables. Conclusions These findings suggest that melatonin supplementation within the past 30 days was not associated with low TT levels in a nationally representative sample of men aged 18 and older. Further analyses are needed to highlight the dose-response relationship and examine the potential effects of exposure to supratherapeutic doses and chronic intake. Disclosure No

Sleep duration and testosterone levels in community older men: results from the West China Health and Aging Trend study.

To the Editor: Testosterone is a fundamental male sex hormone produced by the testicular Leydig cells. Testosterone levels are affected by age, peaking in the 20s and 30s and gradually declining thereafter.[1] Low testosterone level may predispose men, especially older men, to a poor prognosis or death in coronavirus disease 2019 (COVID-19).[2] Therefore, testosterone levels have a significant impact on the health status of older men. The identification of modifiable non-drug factors affecting testosterone levels in older men is important for improving their health. Chronic sleep changes are common in older adults. Testosterone production is dependent on sleep, and plasma testosterone levels vary with a circadian rhythm. However, there is a lack of large-scale population-based studies to explore the effect of sleep duration on testosterone levels in older men. The present study is a cross-sectional analysis based on the West China Health and Aging Trend (WeCHAT) study. WeCHAT is an ongoing prospective multicenter cohort study of community-dwelling Chinese older people and initiated in 2018, and it aims to understand the health status and influencing factors of the older adults in Western China. A total of 7538 people from 18 ethnic groups in four western provinces of China (Sichuan, Yunnan, Guizhou, and Xinjiang) participated in the study. The study was registered with a clinical trials registry (No. ChiCTR1800018895), the research protocol was approved by our institutional Ethics Committee (West China Hospital, China, No. 2017-445), and written informed consent was obtained from all participants. Detailed inclusion and exclusion criteria are shown in Supplementary Figure 1, https://links.lww.com/CM9/B325. We collected the required data through an electronic questionnaire and in-person interviews. Sleep duration was self-reported by participants in response to the following question: “During the past month, how many sleep time did you get at night (average hours for one night)?” Participants were also required to provide a blood sample for morning testing of the total testosterone (TT) level. Detailed processing and quality control steps are shown in Supplementary File, https://links.lww.com/CM9/B325. Baseline demographic information comprised body mass index (BMI), age, education level, and marital status. Smoking was evaluated by enquiring about smoking frequency, number of cigarettes, and whether the participant had attempted to quit. The frequency of drinking alcohol was used to assess drinking habit. This study used the modified Fried frailty phenotype to assess physical frailty. Nutritional status was measured using the Mini Nutritional Assessment Short Form, with scores of <8 points indicating normal nutritional status. The cognitive performances of the participants were assessed using the Chinese version of the 10-point Short Portable Mental Status Questionnaire. Scores of ≥5, suggesting moderate to severe cognitive function impairment, were categorized as cognitive impairment in the present study. Chronic diseases status, including diabetes, hypertension, chronic obstructive pulmonary disease, coronary heart disease, and stroke, was collected through face-to-face interview by medical staff. To address the non-linear association between sleep duration and TT and identify appropriate cut-off values of sleep duration, a generalized additive model and smooth curve fitting (penalized spline method) were used. The inflection point was calculated using a recursive algorithm, and then we constructed a two-phase piecewise linear regression model on either side of the inflection point to identify possible significant threshold effects. We determined the best fit model based on the P value of the log-likelihood ratio test. We identified the short- and long-sleep groups based on the inflection point. Differences in the patients’ baseline characteristics between the short-sleep and long-sleep groups were compared. Categorical variables were described as frequencies (percentage), and continuous variables were described as mean ± standard deviation or median (the 25th–75th percentile). Variables were compared using the chi-squared test, Fisher's exact test, Wilcoxon rank sum test, or Student's t-test as appropriate. All statistical tests were two-sided, and a P value of < 0.05 was considered as statistically significant. We used multivariable linear regression to analyze the possible association between sleep duration and TT level and constructed two models to test the stability of this relationship. Model I was adjusted for BMI, age, ethnic group, education level, marital status, smoking history, and alcohol use. Model II was adjusted for BMI, age, ethnic group, education level, marital status, smoking history, alcohol use, cognitive performance, nutritional status, physical frailty, and chronic diseases. Besides, subgroup analyses were performed by BMI. Using the likelihood ratio test, the P value for the interaction of sleep duration and BMI on TT level was also assessed. To verify the stability of our findings, we conducted a series of additional sensitivity analyses. The detailed methods and results are shown in Supplementary File, https://links.lww.com/CM9/B325. R statistical software (http://www.R-project.org, The R Foundation, Vienna, Austria) was used to perform the analyses above. We enrolled 1628 men aged ≥60 years in the current study. The mean age was 68.5 ± 5.9 years, mean BMI was 24.59 ± 3.72 kg/m2, and the median TT was 428.00 (314.00–554.25) ng/dL [Supplementary Table 1, https://links.lww.com/CM9/B325]. Results from smooth curve fitting and generalized additive models suggested that the association between sleep duration and testosterone levels in older men was non-linear when adjusting for the covariates (including age, ethnic group, education level, marital status, smoking history, alcohol use, nutrition status, and physical frailty) [Supplementary Figure 2, https://links.lww.com/CM9/B325]. Moreover, we found that the inflection point was 9.5 h by two-phage piecewise linear regression and recursive algorithm (P for log-likelihood ratio test: <0.001). There was a significant threshold effect, with insignificant effects on the left of the inflection point and a significant association of longer sleep duration with higher TT levels on the right of the inflection point (β = 640.92, 95% confidence interval [CI] = 380.42–901.42; P < 0.001). Based on the cut-off of 9.5 h, the enrolled patients were divided into a short-sleep group (<9.5 h, n = 1477) and a long-sleep group (≥9.5 h, n = 151). Supplementary Table 1, https://links.lww.com/CM9/B325 showed the detailed characteristics of the participants based on the different sleep durations. The results of the linear regression analyses revealed that long sleep duration was significantly associated with higher TT level (β = 436.48, 95% CI = 181.81–691.15; P < 0.001), after adjusting for BMI, age, ethnic group, education level, marital status, smoking history, and alcohol use status. After adding additional adjustment variables of cognitive performance, nutritional status, physical frailty, and the number of chronic diseases, the association between sleep duration and TT level remained stable, and the long sleep was significantly associated with obviously higher TT levels compared with short sleep group (β = 617.84, 95% CI = 227.45–1008.23; P = 0.002). Then, sleep duration was included in the analysis as a continuous variable, and the results of the linear regression analysis remained unchanged after adjusting for the covariates, showing that sleep duration was significantly associated with increased testosterone levels (β = 75.04, 95% CI = 8.21–141.86; P = 0.028). We then performed subgroup analyses by BMI, which also revealed an association between sleep duration and TT level [Supplementary Table 2, https://links.lww.com/CM9/B325]. There was no statistically significant association between sleep duration and TT level in the BMI ≥ 25 kg/m2 group. By contrast, longer sleep duration in the BMI < 25 kg/m2 group was significantly associated with increased TT level (β = 134.98, 95% CI = 7.90–262.06; P = 0.038). A significant interaction regarding BMI with the sleep duration and TT level was identified (P for the interaction = 0.010). To verify the stability of our findings, we conducted a series of additional sensitivity analyses. The detailed methods and results are shown in Supplementary Files and Supplementary Tables 3–8, https://links.lww.com/CM9/B325. The present study demonstrated that longer sleep duration was associated with a higher testosterone level among older men with BMI < 25 kg/m2. The physiological mechanisms behind the association between sleep and testosterone levels have not been determined. The hypothalamic-pituitary-gonadal axis is the primary mechanism regulating testosterone production and secretion. Basic research based on animal models has revealed that short sleep duration may not negatively affect gonadotropin-releasing hormone secretion in the hypothalamus, but negatively affect the pituitary gland, especially luteinizing hormone secretion, resulting in a decrease of testosterone production and secretion. On the other hand, sleep promotes inflammatory homeostasis by affecting multiple inflammatory mediators such as cytokines, which also affects the testosterone level. Chronic sleep deprivation (short sleep duration, sleep disturbance) contributes to chronic systemic low-grade inflammation and is associated with various diseases. Inflammatory factors, including IL-1, IL-6, IL-17, and tumor necrosis factor, have been reported to affect testosterone levels by activating inflammation. Besides, the interstitial macrophages located near the Leydig cells also affect testosterone levels by producing reactive oxygen species. This study has several strengths and limitations. Previously reported studies, which evaluated sleep duration and testosterone levels, were mainly limited to laboratory-controlled conditions with small cohorts. Given the background of aging society, and the changes of sleep and testosterone levels in the elderly, our study is one of the few studies focusing on sleep duration and testosterone levels in older men and using multicenter data from a large prospective cohort. The establishment of this cohort allowed comprehensive data collection and standardized laboratory measurements on a representative sample of older men in Western China. Of course, there are also some limitations. First, owing to the cross-sectional design, we could not draw a causal relationship between increased sleep duration and increased serum testosterone levels. Second, as in other population-based studies of sleep duration,[3,4] the sleep duration information was self-reported by participants, which may lead to recall bias. Third, owing to the limitations of the WeCHAT study database, the participants’ values of sex hormone-binding globulin and free testosterone were unavailable. Although low TT levels have been shown to be a predictor for a variety of men's health problems,[5] more precise indicators, such as free testosterone, can better reflect hormone activity. Therefore, we will conduct more comprehensive data collection in future research. Overall, our study revealed the association between sleep duration and testosterone levels, providing evidence for improving androgen levels through lifestyle modifications. We also provided population-based research evidence for future interventional clinical trials. In conclusion, for older men with normal BMI, achieving >9.5 h of sleep was associated with higher testosterone levels. Our findings can help aging management in older men. In men with low androgen concentrations, good sleep habits and ensuring >9.5 h of sleep may be an effective non-pharmacological intervention to improve androgen concentrations. Funding This work was supported by the National Key Research and Development Program of China (No. 2017YFC0908003), National Natural Science Foundation of China (Nos 81902578 and 81974098), China Post-doctoral Science Foundation (No. 2017M612971), Post-doctoral Science Research Foundation of Sichuan University (No. 2020SCU12041), Post-doctoral Research Project, West China Hospital, Sichuan University (No. 2018HXBH085), and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (No. Z2018C01). Conflicts of interest None.

Low Total Testosterone Levels in Men with Newly Diagnosed Early-Onset Type 2 Diabetes: A Cross-Sectional Study in China.

There is a bidirectional interaction between circulating testosterone and blood glucose levels. We aim to investigate the testosterone levels in men with early-onset type 2 diabetes (T2DM). A total of 153 drug naive men with T2DM were enrolled in the study. Early- (n = 63) and late-onset (n = 90) T2DM was classified according to age 40 years old. Clinical characteristics and plasma for biochemical criterions were collected. Gonadal hormones were measured using chemiluminescent immunometric assay. The concentrations of 3β- and 17β-HSD were determined using ELISA. Compared with men with late-onset T2DM, those with early-onset T2DM had lower serum total testosterone (TT), sex hormone-binding globulin (SHBG), and FSH, but higher dehydroepiandrosterone sulfate (DHEA-S) level (p < 0.05). The mediating effect analysis showed that the decreased TT levels in patients with early-onset T2DM were associated with the higher HbA1c, BMI, and triglyceride in these patients (both p < 0.05). The early-onset of T2DM directly correlated with increased DHEA-S (both p < 0.01). The 3β-HSD concentration in the early-onset T2DM group was lower than that in the late-onset T2DM group (11.07 ± 3.05 vs. 12.40 ± 2.72 pg/mL, p = 0.048) and was positively correlated with fasting C-peptide, while negatively correlated with HbA1c and fasting glucagon (p all < 0.05). Patients with early-onset T2DM showed inhibition of conversion from DHEA to testosterone, which may attribute to the low level of 3β-HSD and high blood glucose in these patients.

The Effects of Long-Term Self-Dosing of Cannabidiol on Drowsiness, Testosterone Levels, and Liver Function

Introduction: Previous research indicated that cannabidiol (CBD) may result in low levels of male total testosterone (TT), elevations in liver tests (LTs), and daytime drowsiness (DD). We investigated the prevalences of TT and LT in a large adult sample self-administering CBD and determined the effect self-dosing of CBD has on the severity of DD. Methods: Adult participants (18–75 years of age) who self-dose CBD orally for a minimum of 30 days were recruited for this decentralized observational study from companies that offer CBD products. Participants were sent their usual CBD regimen. A clinical study platform was used on a phone app to obtain consent and collect study data. Data included demographic information, reasons for self-dosing, dosage, current medications and dosage, medical history, adverse effects, effects on DD, and efficacy. After 30 days, LT and TT were obtained and follow-up LT was offered to participants who demonstrated elevated values of alanine transaminase (ALT). Results: A total of 28,121 individuals were contacted, 1,475 met the criteria and were enrolled, and 1,061 (female: 65.2%, male: 34.8%) completed the study. Most of the participants used full-spectrum CBD oil or CBD isolate with the mean ± SD daily dose of CBD for all users of 55.4 ± 37.8 mg. CBD use was associated with a significant decrease in DD and a decrease in the prevalence of low TT in males >40 years of age. The prevalences of elevations in ALT and aspartate aminotransferase were not significantly different from those of the general adult population, and the prevalences of elevated levels of alkaline phosphatase and bilirubin were less than those of a healthy adult population. There was no relationship between LT and CBD dose. Conclusions: In this large-sample study, self-dosing CBD was not associated with an increased prevalence of elevation of LT or low levels of TT in men. Furthermore, CBD administration decreased DD and was associated with a lower prevalence of low testosterone levels in older men as compared to age-adjusted population norms.

Testosterone, sex hormone-binding globulin and dehydroepiandrosterone levels and cervical length of Egyptian women with a history of recurrent miscarriages, polycystic ovary syndrome and without the conditions at three stages of pregnancy

Total testosterone (TT), sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA) levels, and cervical length (CL) were investigated in pregnant Egyptian women with polycystic ovary syndrome (PCOS, n = 38), history of miscarriages (RM, n = 40) and without the conditions (HC, n = 40). At week 8, the RM had lower levels of TT (p = 0.000) and free androgen index (FAI) (p = 0.000) and higher SHBG (p = 0.000) and DHEA (p < 0.05) than the PCOS. Compared with the HC, they had elevated SHBG (p < 0.05) and DHEA (p = 0.001) and reduced CL (p = 0.000). TT (p = 0.001) and FAI (p = 0.000) were higher and SHBG (p = 0.000) and CL (p = 0.001) lower in the PCOS than in the HC group. At week 16, TT (p = 0.000) and FAI (p = 0.000) were higher, and SHBG (p = 0.000) and CL (p < 0.05) lower in PCOS than in RM and HC. The PCOS had elevated FAI than the RM (p = 0.000) and HC (p = 0.001) at week 20. The DHEA, SHBG and CL abnormalities in PCOS and RM may compromise pregnancy outcomes. IMPACT STATEMENT What is already known on this subject? Hyperandrogenaemia, low sex hormone-binding globulin (SHBG), shortened cervical length (CL) and polycystic ovary syndrome (PCOS) are the most cited risk factors for recurrent miscarriages (RM). However, the published data are inconsistent, perhaps because of the confounding effects of ethnicity and nutritional milieu. What do the results of this study add? The study’s findings comprising ethnically and socially homogenous women demonstrate that PCOS and RM are characterised by elevated dehydroepiandrosterone (DHEA) and shortened CL, and PCOS by reduced SHBG. These abnormalities would be expected to have an adverse impact on pregnancy outcomes. What are the implications of these findings for clinical practice and/or further research? Twenty-weeks DHEA and CL values have the potential to predict outcome risk in women with a history of RM and PCOS. Further research on other population groups is required to validate the current study’s findings.

Frailty of Prostate Cancer Patients Receiving Androgen Deprivation Therapy: A Scoping Review.

This study aimed to explore the existing literature on frailty experienced by patients with prostate cancer (PC) receiving androgen deprivation therapy (ADT). Database and manual searches were conducted to identify relevant studies published in English, with no limitation on the year of publication, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. Four databases-PubMed, Cochrane Library, EMBASE, and CINAHL-were used for database searches and reference lists, related journals, and Google Scholar were used for manual searches. A total of 12 studies were analyzed for this scoping review. Of these, only 2 were intervention studies, and 1 was a randomized controlled trial. Among the two intervention studies, the multidisciplinary intervention program, including psychological counseling, nutritional coaching, and supervised group physical exercise did not show significant improvement in frailty. In contrast, high-dose vitamin D supplementation significantly decreased frailty. The conceptual and operational definitions of frailty used in each study varied, and the most used one was mainly focused on physical functions. As a result of analyzing the other health-related variables associated with frailty in patients with PC receiving ADT, age, metastases, comorbidities, and incident falls were related to a high frailty level. As for the physiological index, high levels of C-reactive protein, and interleukin-6, and fibrinogen, low levels of total testosterone, lymphocyte count, and creatinine were associated with a high level of frailty. A few studies explored the relationship between psychological and cognitive variables and frailty. Further research related to frailty in patients with PC receiving ADT should be conducted, and effective interventions to manage frailty should be developed. Additionally, research that considers not only the physical domain of frailty but also the psychological, cognitive, and social domains needs to be conducted.

Clinical and laboratory differences between chromosomal and undefined causes of non-obstructive azoospermia: A retrospective study.

Knowledge of clinical and laboratory differences between chromosomal and undefined causes aids etiological research on non-obstructive azoospermia. Compare clinical and laboratory differences between men with non-obstructive azoospermia due to chromosomal anomalies versus undefined causes. A cross-sectional retrospective study conducted at a public university hospital in Campinas (Brazil). All men aged 20-40 years with non-obstructive azoospermia were included in the analysis. The 107 cases included 14 with Klinefelter syndrome (KS) (13%), 1 with mosaic KS, 4 with sex development disorders (2 testicular XX, 1 NR5A1 gene mutation, and 1 mild androgen insensitivity syndrome) (4%), 9 with other non-obstructive azoospermia etiologies (8%), and 79 with undefined causes. The 22 chromosomal anomaly cases (14 KS, 1 mosaic KS, 2 testicular XX, 4 sex chromosome anomalies, and 1 autosomal anomaly) were compared with the 79 undefined cause cases. The KS group had lower average testicular volume, shorter penile length, and lower total testosterone levels but greater height, arm span, serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and gynecomastia frequency (absent in the undefined group and affecting more than half of the KS group). Patients with testicular XX DSD had LH, FSH, and penile length data intermediate between the KS and undefined cause groups, testicular volume similar to the KS group, and other data similar to the undefined group. Clinical and laboratory data differentiate men with non-obstructive azoospermia and chromosomal anomalies, particularly KS and testicular XX, from those with undefined causes or other chromosomal anomalies.

Effect of High-Fructose Diet-Induced Metabolic Syndrome on the Pituitary-Gonadal Axis in Male Rats.

Plasma testosterone levels have been found to decrease in older insulin-resistant male patients. Both lower total testosterone levels and a higher incidence of metabolic syndrome have also been reported. The aim of this study was to investigate the effects of high-fructose diet-induced diabetes on both the testosterone release by Leydig cells and the activity of the hypothalamus-pituitary-gonadal (HPG) axis in male rats. Male rats were fed with either standard chow (control group) or a high-fructose diet (fructose-fed group) for 21 weeks. Hyperglycemia, hyperinsulinemia, and hypertension were observed in the fructose-fed group. Moreover, plasma testosterone and LH levels decreased in the fructose-fed group compared to the control group. Sperm motility was also reduced by 15% in the fructose-fed rats. In contrast, the basal release of testosterone from rat Leydig cells was not altered by fructose feeding. Moreover, in vitro studies showed that the testosterone release, in response to different stimulants, including forskolin (an adenylyl cyclase activator, 10-5 M), 8-Br-cAMP (a permeable analog of cAMP, 10-5 M), A23187 (a calcium ionophore, 10-5 M), or 25-hydroxy-cholesterol (water-soluble cholesterol, 10-5 M), did not significantly differ between the fructose-fed and control groups. Interestingly, the release of testosterone in response to human chorionic gonadotropin (hCG, 0.05 IU/mL) was enhanced by eightfold in the control group, but elevenfold in the fructose-fed group. LH receptor expression in rat Leydig cells was also increased. Moreover, LH secretion from the anterior pituitary was altered in the fructose diet-fed group. These results suggest that fructose diet-fed rats have lower plasma testosterone levels, which can lead to a higher sensitivity of hCG in Leydig cells.

ODP292 A Xanthomatous Hypophysitis: Always Think Twice Before Pituitary Resection.

Abstract Background A xanthomatous hypophysitis is a rare form of primary hypophysitis common in females. Clinical case: A 47-year-old male was referred for pituitary adenoma resection. The patient presented with low libido and facial and body hair loss for 3 years. He reported increased thirst and nocturia for 2 years. 24-hr fluid intake showed 4,800 ml intake and 6,700 ml output. Physical examination revealed tanner 5 pubic hair with testicle size 12 ml bilaterally. He had a normal visual field. Laboratory testing revealed low morning total testosterone level of 108 ng/dL (241-872), low LH 0.39 mIU/mL (1.14-8.75) and low FSH 1.28 mIU/mL (1.37-13.58). Other pituitary hormones showed normal TSH 0.634 uIU/ml (0.35-4.9) with low free T4 0.64 (0.7-1.48), IGF-1 107 ng/mL (74-196), prolactin 10.92 mcg/mL (3.46-19.4), morning cortisol 8.9 mcg/dL (3.7-19.4). A 1 mcg ACTH stimulation test showed an inappropriate increase in cortisol level of 16.1 mcg/dL with baseline ACTH 28 pg/mL (0-46). Regarding polyuria, biochemical testing showed serum Na 148 mmol/L (136-145), Uosm 307 mOsm/Kg (50-1300), and Sosm 307 mOsm/kg (275-290). After the therapeutic trial with oral DDAVP, urine output significantly decreased. Subsequent tests showed serum Na 144 mmol/L, Uosm of 295 mOsm/kg, and Sosm of 278 mOsm/kg. The final diagnosis was hypopituitarism and central diabetes insipidus. MRI showed an enlarged pituitary gland with 2 decreased enhancing nodules in the post-contrast study of the anterior lobe measuring 4.2 and 6.7 mm in diameter. No stalk thickening was detected. There was no compression on adjacent organs. Since the pituitary lesions could not explain the hypopituitarism and DI. The surgery was postponed, and he underwent an endoscopic transsphenoidal biopsy. The procedure yielded a milky fluid content, and a circumferential dissection of a soft-yellow capsule was done. Pathology examination revealed a chronic hypophysitis with clusters of foamy macrophages. Immunohistochemistry showed positive for CD3, CD20, and CD138. A CD68 was positive in multiple clusters of foamy macrophages, while an IgG4 was negative. The final diagnosis is xanthomatous hypophysitis. The patient was treated with hormonal replacement therapy of levothyroxine, prednisolone, testosterone, and DDAVP. Until now, there are 36 cases in the literature reporting xanthomatous hypophysitis. The prevalences of hormonal deficits are 36.1% adrenal insufficiency, 42.4% central hypothyroidism, 54.6% central DI, 36.4% hypogonadism, 63.6% GH deficiency, and 54.6% hyperprolactinemia. The common MRI characteristic is a cystic mass with a ring or peripheral enhancement. Pituitary stalk thickening is shown in 50% of cases. Conclusion This clinical case demonstrated the rare entity of xanthomatous hypophysitis presenting with secondary AI, hypogonadotropic hypogonadism, central hypothyroidism, and DI. The discrepancy between clinical history and the MRI findings was a clue for pituitary biopsy leading to the final diagnosis and avoidance of unnecessary surgery. Presentation: No date and time listed

PMON96 A Curious Case of Isolated Oculomotor Nerve Palsy From a Non-Functional Gonadotroph Adenoma

Abstract Introduction Pituitary adenoma typically presents with signs and symptoms of hormone hypersecretion and only 30% of cases present clinically as nonfunctioning adenomas. Furthermore, amongst these less than 5% are associated with ocular nerve palsies. We report a rare case of isolated, unilateral oculomotor nerve palsy due to a non-functional gonadotroph adenoma expanding into the left cavernous sinus. Case 48 years old male with a pertinent medical history of Type 2 Diabetes Mellitus presented to the ER with 3 days of intractable generalized headache associated with double vision, nausea, and increased lethargy. On initial examination, he had findings of oculomotor nerve palsy on the left eye (ptosis, the eye being down and out, and non-reactive pupil to direct or consensual light stimulation) while the rest of his examination was normal. His initial blood work was non-revealing and normal. He underwent extensive imaging including an initial CT scan showing a pituitary macroadenoma, followed by a pituitary-focused MRI brain revealing a hyperplastic pituitary lesion measuring 17.8 mm×22.5 mm in axial axis and 16.4 mm×14.4 mm in sagittal axis with extension into the left cavernous sinus. Biochemical workup was done to evaluate the pituitary function and it revealed a low total testosterone level (95 ng/ml) with a suppressed LH (2.1IU/l) and FSH (1.76 mIU/ml), a low fT4 (0.58 ng/dl) with a suppressed TSH (0.68 mIU/l), low cortisol (1.2 mcg/dl) with a suppressed ACTH of &amp;lt; 5 pg/ml and normal IGF-1 and prolactin levels. He was given stress dose steroids and underwent transsphenoidal resection of the pituitary mass. Pathology of the specimen showed immunoreactivity for SF1 and ASU which was suggestive of a gonadotroph adenoma. The patient showed no signs or symptoms of diabetes insipidus post-operatively, however, was managed for secondary adrenal insufficiency, hypothyroidism, and hypogonadism. He was discharged home on hydrocortisone, levothyroxine, and metformin. He followed up at the Neuroendocrine clinic within a week of discharge and maintained a regular outpatient follow-up where he showed gradual improvement in his symptoms. Conclusion Visual impairment from a non-secreting pituitary adenoma is usually from chiasmal compression. Very rarely, pituitary macroadenoma expands laterally into the cavernous sinus and compresses the oculomotor nerve causing signs and symptoms of third nerve palsy. This case highlights the importance of recognizing different presentations of nonfunctional pituitary adenoma early as this could improve both the morbidity and mortality associated with them. Reference Choong, K., Lee, S L. Pituitary Macroadenoma with invasion into the cavernous sinus, cranial nerve palsies (Endocrine Today) Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON17 Impaired cortisol regulation in Myotonic dystrophy

Abstract Introduction - Myotonic dystrophy (MD) is the most common cause of adult-onset muscular dystrophy. It has impaired HPA axis regulation with exaggerated ACTH response to CRH mediated stimuli and abnormal cortisol metabolism. We present a case of myotonic dystrophy in a male with elevated cortisol levels. Case report - 54-year-old male with a past medical history of type 1 myotonic dystrophy (MD1) presented for evaluation of hypogonadism with complaints of feeling fatigued, progressive weakness of muscles. During the workup, he was noted to have elevated cortisol levels 30.2 mcg/dL (6-18.4) with elevated ACTH 220 pg/mL (10-48). Other notable lab results included low total testosterone levels of 231, 185 with elevated LH of 17.3 m IU/ml (2-9) and FSH 37.7 m IU/ml (1-12). Prolactin levels were minimally elevated to 21.4 ng/mL (4-15.2). On further inquiry, the patient did not have headaches or vision changes. The patient did not report weight gain, easy bruising, change in facial appearance. Physical exam was significant for bilateral gynecomastia and small testes. No cushingoid facies, abdominal stria, proximal myopathy was noted. Given elevated ACTH and cortisol levels, further laboratory data showed a lack of suppression of cortisol levels with 1 mg dexamethasone - cortisol 2.9 micro g/dL (&amp;lt;1.8), elevated midnight salivary cortisol - 0.130, 0.102 ug/dl (0.010-0.090), and normal 24-hour urine cortisol levels -15 mcg/24 hours. Discussion – Even though Cushing's disease is one of the differential diagnoses for the above case, high cortisol levels have been reported in MD. Few mechanisms suggested causing this abnormality are increased ACTH responsiveness to CRH-mediated stimuli and abnormal cortisol metabolism. Patients with MD have high pro-inflammatory (IL-1 and TNF-a) markers, which mediate the increased ACTH responsiveness to CRH-mediated stimuli centrally by stimulating the HPA axis.1 In addition, IL-6 chronically stimulates steroidogenesis from the adrenal gland, whereas TNF-α inhibits ACTH-induced adrenal steroid synthesis and increases 11BHSD1 activity. Along with the impaired HP axis, abnormal metabolism of cortisol also contributes to elevated cortisol levels. Increased activity of 11 BHSD1 has been hypothesized to cause impaired clearance of cortisol.2 Impaired diurnal variation for cortisol is also seen in MD with elevated 24-hour cortisol levels. Elevated cortisol levels as in our case can be a diagnostic dilemma given impaired cortisol regulation as seen in MD. References Åsa Johansson et.al. Abnormal Cytokine and Adrenocortical Hormone Regulation in Myotonic Dystrophy, The Journal of Clinical Endocrinology &amp; Metabolism, Volume 85, Issue 9, 1 September 2000, Pages 3169–76.Åsa Johansson et.al. Glucocorticoid Metabolism and Adrenocortical Reactivity to ACTH in Myotonic Dystrophy, The Journal of Clinical Endocrinology &amp; Metabolism, Volume 86, Issue 9, 1 September 2001, Pages 4276–83 Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Environmental exposure to organophosphate esters and suspected non-alcoholic fatty liver disease among US adults: A mixture analysis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. We evaluated NAFLD using the US FLI to determine whether there is an association between urinary organophosphorus (OPE) levels and the "prevalence" of NAFLD in US individuals. The current study included 1,102 people aged 20 years and older with information from the 2011-2014 U.S. National Health and Nutrition Examination Survey. NAFLD was assessed using the U.S. FLI. Individual OPE metabolites and OPE combinations were linked to NAFLD using logistic regression and weighted quantile sum (WQS) regression. All analyzes were carried out separately on males and females. The possible impacts of age, serum total testosterone (TT), and menopausal state, as well as the importance of the interaction term with exposure, were investigated using stratified analysis. Bis (2-chloroethyl) phosphate and bis (1,3-dichloro-2-propyl) phosphate were associated with NAFLD in all males after adjusting for covariates (P < 0.05). A combination of OPEs (OPE index) was positively linked with NAFLD in the WQS analysis of all males (odds ratio for OPE index: 1.52; 95% CI: 1.06, 2.19). Stratified analyzes for males revealed that considerable connections were largely confined to individuals over 60 years old or with low total testosterone. In women, the connection was limited and inconsistent, except for the OPE index, which was positively linked with NAFLD in post-menopausal women. In this study, environmental exposure to OPE was linked to an elevated risk of NAFLD in males, particularly those over 60 years old or with low TT levels. Aside from the continuous positive connection of a combination of OPEs with NAFLD risk in post-menopausal women, these correlations were weaker in women. However, these findings should be taken with caution and verified in future investigations by collecting numerous urine samples in advance to strengthen OPE exposure estimates.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Smoking promotes vascular damage in apparently healthy men with low testosterone and increased subclinical inflammation

Abstract Background Testosterone deficiency and increased inflammation are both associated with an unfavourable vascular profile. Aim of the study was to examine whether smoking significantly deteriorates the effect of these pathophysiological mechanisms on arterial wall properties. Methods Carotid intima media thickness (cIMT) and aortic pulse wave velocity (aPWV) were measured in 87 smokers and 112 aged-matched never smokers (mean age: 49±5 yrs) with no other cardiovascular (CV) risk factors/or manifest CV/atherosclerotic disease. Plasma total testosterone (TT) and high sensitivity reactive protein (hsCRP) levels were measured in the whole study population. Results Both smokers and never smokers were divided into four subgroups according to measured low or normal TT levels (low TT&amp;lt;3.5 ng/ml) and high or low hsCRP levels. BMI and LDL-C levels were not different between the subgroups. In smokers the four TT/CRP subgroups had comparable cumulative tobacco smoke exposure. In smokers the low TT/high CRP subgroup had significantly higher aPWV and cIMT compared to the three other subgroups (P&amp;lt;0.01 and P&amp;lt;0.05, respectively by ANOVA, figures A-B) while in never smokers the four TT/CRP subgroups had comparable aPWV and cIMT (all P&amp;gt;0.05, figures C-D). The differences in aPWV and cIMT measurements between TT/CRP subgroups in smokers remained statistically significant after adjustment for age. Conclusions The study shows that low TT combined with high CRP are associated with increased carotid IMT and aortic PWV in smokers with no other CV risk factors, while in never smokers the effect of combined low TT and high CRP concentration was not significant. Considering the predictive value of aortic stiffness and carotid thickness, the finding of this study imply interrelationships between tobacco cigarette smoke, subclinical inflammation and low testosterone level regarding changes in arterial wall properties. Funding Acknowledgement Type of funding sources: None.

Additive predictive value of low testosterone level in hypertensive men with hypercholesterolemia

Abstract Purpose Hypercholesterolemia is common in hypertensive patients and its presence increases the risk of cardiovascular (CV) complications. Decreased concentration of testosterone appears commonly in men with hypertension, and is an independent predictor of CV events. We investigated the utility of testosterone concentration measurement as an aid in the risk prediction of CV events in men with arterial hypertension and high LDL levels. Methods A cohort of 321 men with arterial hypertension and without known diabetes or atherosclerotic CVD (mean age: 54±9 years) were followed for the occurrence of major adverse cardiovascular events (MACE), (CV death, coronary artery disease, stroke). Total testosterone (TT) and LDL levels were measured in all patients. We used Cox proportional hazards regression to analyze the associations between LDL, serum testosterone and CV outcomes. Results During a mean follow-up of 6 years (range: 1–11 years), 31 (9.5%) patients demonstrated a MACE. Patients in the CV-event group were older and they had higher LDL and lower baseline TT levels compared to subjects in the event-free survival group (all P&amp;lt;0.01) while BMI, systolic blood pressure and smoking exposure (pack-years) were similar. Based on the observed distribution of baseline LDL levels the study cohort was divided in two groups: low LDL (&amp;lt;130 mg/dl) and high LDL (≥130 mg/dl). According to baseline TT level distribution the study cohort was divided in two groups: normal TT (&amp;gt;4.0 ng/mL) and low TT (≤4.0 ng/mL). Subjects in the high LDL group, had no increased risk of MACE compared to subjects in the low LDL group (HR 1.35; 95% CI 0.75–2.04) in the multivariable model. Moreover, there was no statistically significant association between low TT and risk of MACE. HR for low TT vs high TT was 1.48 (95% CI 0.85–2.16). We then subdivided the two LDL (high vs low) groups into subgroups according to presence of low or normal TT. Cox regression analysis revealed that the subgroup of men with both low TT and high LDL had an almost 2-fold higher risk of MACEs compared to the other three LDL/TT subgroups (adjusted hazard ratio: 2.07; 95% CI 0.94–3.56, P=0.035). Figure 1 shows the cardiac event-free survival curve of males with both baseline low TT and high LDL level with that of males in the other three LDL/TT subgroups (log rank: 11.3, P=0.008). Conclusion Low testosterone concentration is associated with a shorter event-free period in hypertensive patients with higher LDL levels. The measurement of testosterone concentration may be useful to further stratify the risk of middle-aged men with arterial hypertension and hypercholesterolemia. Funding Acknowledgement Type of funding sources: None.