Testosterone therapy for functional hypogonadism in middle-aged and elderly males: current evidence and future perspectives.

Population aging is a global phenomenon driving research focus toward preventing and managing age-related disorders. Functional hypogonadism (FH) has been defined as the combination of low testosterone levels, typically serum total testosterone below 300-350 ng/dL, together with manifestations of hypogonadism, in the absence of an intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis. It is usually seen in middle-aged or elderly males as a product of aging and multimorbidity. This age-related decline in testosterone levels has been associated with numerous adverse outcomes. Testosterone therapy (TTh) is the mainstay of treatment for organic hypogonadism with an identifiable intrinsic pathology of the HPT axis. Current guidelines generally make weak recommendations for TTh in patients with FH, mostly in the presence of sexual dysfunction. Concerns about long-term safety have historically limited TTh use in middle-aged and elderly males with FH. However, recent randomized controlled trials and meta-analyses have demonstrated safe long-term outcomes regarding prostatic and cardiovascular health, together with decreases in all-cause mortality and improvements in various domains, including sexual function, body composition, physical strength, bone density, and hematopoiesis. Furthermore, there are numerous insightful studies suggesting additional benefits of TTh, for instance in cardio-renal-metabolic conditions. Specifically, future trials should investigate the role of TTh in improving symptoms and prognosis in various clinical contexts, including sarcopenia, frailty, dyslipidemia, arterial hypertension, diabetes mellitus, fracture risk, heart failure, stable angina, chronic kidney disease, mood disorders, and cognitive dysfunction.

Off-label use of clomiphene citrate to treat anabolic androgenic steroid induced hypogonadism upon cessation among men (CloTASH) - A pilot study protocol.

Background: Non-prescribed anabolic androgenic steroid (AAS) use is associated with AAS-induced hypogonadism (ASIH), and metabolic, cardiovascular, and mental health risks. Symptoms of ASIH (fatigue, depression, anxiety, sexual dysfunction) are hard to endure following cessation, but there is no consensus on whether endocrine treatment should be used to treat ASIH. This proof-of-concept study aims to explore safety of off-label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency, and to study changes in health risks after cessation. Methods: In this open-labeled non-randomized off-label hormone intervention pilot study, we shall include males with AAS dependence intending to cease use. The 16-week intervention included clomiphene citrate, transdermal testosterone gel for the first four weeks and optional human chorionic gonadotropin (hCG) from week 4 if low treatment response. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention, and at 6- and 12 months post cessation. Change in self-reported symptoms of hypogonadism and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without the medical intervention. The study may provide valuable clinical insights and may be used to inform the design of future intervention studies.

Effect of Combined Low Dose hCG, FSH and Testosterone therapy (LFT Regimen) versus Conventional High Dose hCG and FSH on Spermatogenesis and Biomarkers in Men with Hypogonadotropic Hypogonadism.

OBJECTIVE: In male Congenital hypogonadotropic hypogonadism(CHH), it was observed that lower dose human gonadotropic hormone(hCG) can maintain normal intratesticular testosterone(ITT) levels. We propose this study to compare the Low-Dose hCG, follicle stimulating hormone(FSH), and Testosterone(T) [LFT Regimen] to conventional treatment to induce virilization and fertility. DESIGN: This open-label randomized pilot study was conducted from June 2020 to December 2021. SUBJECTS AND OUTCOME MEASURES: CHH were randomly assigned to either the LFT regimen (Group A)-low-dose hCG (500U thrice per week), FSH(150U thrice per week) and T(100mg biweekly) or conventional therapy(GroupB) with high hCG dose(2000U thrice per week) and the same FSH dose. The hCG dosage was titrated to reduce Anti-mullerian hormone(AMH) by 50% and normalization of plasma T in groups A and B, respectively. The primary objective was to compare the percentage of individuals who achieved spermatogenesis between the two groups. RESULTS: Out of 30 patients, 23(76·7%) subjects achieved spermatogenesis, and the median time was 12(9-14·9)months. There was no difference in achieving spermatogenesis between the two groups (64·3%vs87·5%,p=0·204), and even the median time for spermatogenesis was similar (15monthsvs12months,p=0·248). Both groups had non-significant median plasma AMH at spermatogenesis,[6·6ng/ml(3·3-9·76) vs 4·41ng/ml(2·3-6·47),p=0·298]. Similarly, the median plasma Inhibin B at spermatogenesis between groups were comparable[152·4pg/ml(101·7-198·0)vs149·1pg/ml(128·7-237·3),p=0·488]. CONCLUSIONS: A reasonable approach to induce fertility in male CHH is to initiate combination therapy using FSH, low-dose hCG targeting AMH <6·9 ng/ml, along with T to achieve normal range. Monitoring AMH could serve as a proxy indicator of spermatogenesis.

Variety of genetic defects in GnRH and hypothalamic-pituitary signaling and development in normosmic patients with IHH.

Introduction: Normosmic isolated hypogonadotropic hypogonadism (nIHH) is a clinically and genetically heterogeneous disorder. Deleterious variants in over 50 genes have been implicated in the etiology of IHH, which also indicates a possible role of digenicity and oligogenicity. Both classes of genes controlling GnRH neuron migration/development and hypothalamic/pituitary signaling and development are strongly implicated in nIHH pathogenesis. The study aimed to investigate the genetic background of nIHH and further expand the genotype-phenotype correlation. Methods: A total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied. Results: Causative defects regarded as at least one pathogenic/likely pathogenic (P/LP) variant were found in 23 patients (34%). For another 30 individuals, variants of unknown significance (VUS) or benign (B) were evidenced (45%). The most frequently mutated genes presenting P/LP alterations were GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 2 each). Monogenic variants with solid clinical significance (P/LP) were observed in 15% of subjects, whereas oligogenic defects were detected in 19% of patients. Regarding recurrence, 17 novel pathogenic variants affecting 10 genes were identified for 17 patients. The most recurrent pathogenic change was GNRHR:p.Arg139His, detected in four unrelated subjects. Another interesting observation is that P/LP defects were found more often in genes related to hypothalamic-pituitary pathways than those related to GnRH. Conclusions: The growing importance of the neuroendocrine pathway and related genes is drawing increasing attention to nIHH. However, the underestimated potential of VUS variants in IHH etiology, particularly those presenting recurrence, should be further elucidated.

Society for endocrinology guideline for understanding, diagnosing and treating female hypogonadism.

Female hypogonadism (FH) is a relatively common endocrine disorder in women of premenopausal age, but there are significant uncertainties and wide variation in its management. Most current guidelines are monospecialty and only address premature ovarian insufficiency (POI); some allude to management in very brief and general terms, and most rely upon the extrapolation of evidence from the studies relating to physiological estrogen deficiency in postmenopausal women. The Society for Endocrinology commissioned new guidance to provide all care providers with a multidisciplinary perspective on managing patients with all forms of FH. It has been compiled using expertise from Endocrinology, Primary Care, Gynaecology and Reproductive Health practices, with contributions from expert patients and a patient support group, to help clinicians best manage FH resulting from both POI and hypothalamo-pituitary disorders, whether organic or functional.

Sexual health and testosterone concentration in male lymphoma survivors: A systematic review.

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%-50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%-80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%-61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health.

Association between varicocele and hypogonadism, or erectile dysfunction: A systematic review and meta-analysis.

OBJECTIVE: To assess the association between varicocele and hypogonadism, or erectile dysfunction. METHODS: We searched MEDLINE, EMBASE, LILACS, CENTRAL, and other sources. We included cohort, case-control, and cross-sectional studies. The primary outcome was the association between varicocele and hypogonadism, or erectile dysfunction, and the secondary outcome included semen analysis. We assessed the risk of bias with the Newcastle-Ottawa Scale. We performed statistical analysis in Review Manager 5.3 and reported information about the Odds Ratio (OR) with a 95% confidence interval. We produced a forest plot for the primary outcome. RESULTS: We included ten studies in qualitative analysis and six studies in quantitative analysis. Most of the cross-sectional studies showed a low risk of bias, not so for the two case-control studies, which represented a high risk of bias. Most of the reports described a correlation between having varicocele and presenting low testosterone levels: the meta-analysis showed that there is a significant association between varicocele and hypogonadism (OR 3.27 95% CI 1.23 to 8.68). Regarding varicocele and erectile, only one study showed a significant difference in erectile function in comparison to varicocele patients and men without varicocele. CONCLUSION: There is an association between varicocele presence and hypogonadism, although more studies are needed. Besides, not much is reported about an association between varicocele and erectile dysfunction, but impairment can occur through hormone disturbances.

Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center.

Introduction: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS. Methodology: A longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound. Results: A total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases. Conclusion: Our study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12-13 years, taking into consideration the uterus size. Further prospective studies are needed.

Prevalence and risk factors predisposing low bone mineral density in patients with thalassemia.

Background: A common complication of thalassemia is secondary osteoporosis. This study aimed to assess the prevalence and factors associated with low BMD in thalassemic patients. Method: This is a cross-sectional study. Eligible patients were males aged within 18-49 years or premenopausal women diagnosed with thalassemia in Chiang Mai University Hospital between July 2021 and July 2022. The diagnosis of low BMD by dual-energy x-ray absorptiometry (DXA) was defined as a Z-score of -2.0 SD or lower in either the lumbar spine or femoral neck. Clinical factors associated with low BMD were analyzed using a logistic regression model. Results: Prevalence of low BMD was 62.4% from 210 patients with a mean age of 29.7 ± 7.6 years. The predominant clinical characteristics of low BMD thalassemia patients were being female, transfusion-dependent (TDT) and a history of splenectomy. From multivariable analysis, the independent variables associated with low BMD were transfusion dependency (odds ratio, OR 2.36; 95%CI 1.28 to 4.38; p=0.006) and body mass index (BMI) (OR 0.71; 95%CI 0.61 to 0.82; p<0.001). Among patients with low BMD, we observed a correlation between a Z-score with low IGF-1 levels (ß=-0.42; 95% CI -0.83 to -0.01; p=0.040), serum phosphate levels (ß=0.40; 95% CI 0.07 to 0.73; p=0.016) and hypogonadism (ß=-0.48, 95% CI -0.91 to -0.04, p=0.031). Conclusion: This study found a prevalence of low BMD in 62.4% of subjects. Factors associated with low BMD were TDT and BMI. Within the low BMD subgroup, hypogonadism, serum phosphate and low serum IGF-1 levels were associated with a lower Z-score.

Weight Loss Improved Hypothalamic GH Deficiency but not Hypogonadotropic Hypogonadism in a Man With Down Syndrome.

Down syndrome (DS) is associated with several endocrine disorders, including diabetes, obesity, and primary hypogonadism. Here, we present a man with DS who manifested with atypical hypogonadotropic hypogonadism and in whom weight loss resulted in the improvement of hypothalamic GH deficiency. A 27-year-old man with DS and severe obesity was admitted for hypoxia resulting from obesity hypoventilation syndrome. Laboratory tests showed normal levels of LH and FSH despite low testosterone and free testosterone levels. Moreover, thyroid stimulating hormone and prolactin levels were slightly elevated, although a euthyroid function was observed, and GH and IGF-1 levels were low. Endocrinological stimulation tests revealed hypogonadotropic hypogonadism and hypothalamic GH deficiency. Reduction in body weight by 35.3% resulted in the improvement of the IGF-1, thyroid stimulating hormone, and prolactin levels to the reference range, whereas the LH and FSH levels remained low, despite slight elevation. Levels of leptin, which suppresses the hypothalamus-gonadotroph-gonadal axis and upregulates thyrotropin-releasing hormone expression, decreased with weight loss. Furthermore, ghrelin, whose levels increase with weight loss, stimulates GH secretion. Thus, leptin and ghrelin could have contributed to the observed changes in the pituitary hormone profile after weight loss.

Testosterone concentrations and associated predictors in men with cystic fibrosis: a retrospective, single-center study.

BACKGROUND: Men with cystic fibrosis (CF) have sexual health concerns such as delayed puberty, infertility, and hypogonadism. The causes and prevalence of hypogonadism have not been well studied. The purpose of this study was to determine the prevalence of a low testosterone concentration in men with CF. METHODS: This retrospective study was approved by the Emory University Institutional Review Board (IRB). Data were extracted from the electronic medical records of adult men with CF receiving care at the Emory Cystic Fibrosis Center. A total of 129 men with CF were followed at our center from 2016 to 2023. Of these individuals, 76 men with CF (58.9%) had at least one serum total testosterone measurement. Seven individuals were excluded from this study since they were currently receiving testosterone therapy, leaving a final sample size of 69 individuals for the analysis. Demographic data, serum testosterone concentrations, and other factors associated with low testosterone concentrations were collected. Low testosterone was defined as a value below 300 ng/dL. Regression analyses were used to determine factors associated with low testosterone levels. RESULTS: The mean (± SD) age of the 69 eligible participants was 33.34 ± 10.98 years. The mean testosterone concentration was 421 ± 158.5 ng/dL with 27.54 percent of men with a testosterone value below 300 ng/dL. The mean hemoglobin level was 14.23 ± 2.18 g/dL. Testosterone levels were positively related to hemoglobin levels. Time of day of measurement and age were not associated with testosterone levels. CONCLUSION: Roughly a quarter of men with CF demonstrated low testosterone in our sample. Low hemoglobin was associated with low testosterone levels in men with CF. Neither time of day nor age influenced testosterone concentrations in this sample.

Effect of testosterone replacement therapy on lower urinary tract symptoms: A systematic review and network meta-analysis.

OBJECTIVE: In this study, we aimed to perform a network meta-analysis (NMA) to investigate the effects of different testosterone replacement therapy (TRT) administration routes on lower urinary tract symptoms (LUTS) in aging men with late-onset hypogonadism (LOH). METHODS: A systematic search of PubMed, Embase, The Cochrane Library, CNKI, WanFang Data, and VIP was conducted to identify randomized controlled trials (RCTs) reporting data on International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) level, or prostate volume. NMA was performed, and subgroup analysis was conducted to assess the impact of TRT duration on outcomes. RESULTS: A total of 21 RCTs involving 2453 participants were included. For pairwise meta-analysis, p values for TRT delivered by transdermal, intramuscular, and oral routes were as follows: IPSS: 0.93, 0.20, and 0.76; PSA level: 0.20, 0.27, and 0.98; prostate volume: 0.18, 0.04, and 0.16. There were no significant differences in IPSS, PSA level, or prostate volume between TRT routes. In subgroup analysis, long-term intramuscular TRT significantly decreased IPSS (p = 0.03), short-term transdermal TRT increased PSA levels (p < 0.001), and short-term intramuscular TRT increased the prostate volume (p = 0.04). Other forms of TRT showed no significant change in IPSS, PSA level, and prostate volume compared with the placebo. Indirect comparison of the three administration routes demonstrated no significant differences in IPSS, PSA level, and prostate volume. Nevertheless, surface under the cumulative ranking curve analysis indicated that intramuscular TRT had an 83% probability of being the best method for decreasing IPSS. CONCLUSIONS: The results demonstrate that TRT does not worsen LUTS regardless of the administration route. Intramuscular TRT may be the preferred treatment for aging men with LOH and LUTS. Intramuscular TRT may be the preferred treatment for men with LOH and LUTS. Further research is warranted to validate these findings and optimize TRT management strategies.

Pulsatile gonadotropin-releasing hormone therapy induces spermatogenesis in pituitary stalk interruption syndrome: A case report and review of the literature.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a rare anatomical defect of the pituitary gland falling under the spectrum of holoprosencephaly phenotypes. It is characterized by a deficiency in anterior pituitary hormones, such as growth hormone, gonadotropins, and thyroid hormones. Due to the syndrome's rarity and nonspecific manifestations, there is a lack of standardized treatment strategies. Consequently, early diagnosis through imaging and on-time intervention are crucial for improving patients' outcomes. CASE SUMMARY: A 30-year-old man presented with absent secondary sexual characteristics and azoospermia. Laboratory evaluation revealed a deficiency in gonadotropins, while thyroid function was mostly within normal ranges. Magnetic resonance imaging of the pituitary gland showed pituitary stalk agenesis, hypoplasia of the anterior pituitary, and ectopic posterior pituitary, leading to the diagnosis of PSIS. Initially, the patient underwent 6 mo of gonadotropin therapy without significant changes in hormone levels and secondary sexual characteristics. Pulsatile gonadotropin-releasing hormone therapy was then administered, resulting in the detection of sperm in the semen analysis within 3 mo. After 6 mo, routine semen tests showed normal semen quality. The couple faced challenges in conceiving due to abstinence and underwent three cycles of artificial insemination, which was unsuccessful. They also attempted in vitro fertilization, but unfortunately, the woman experienced a miscarriage 10 wk after the embryo transfer. CONCLUSION: Early detection, accurate diagnosis, and timely treatment are crucial in improving the quality of life and fertility of PSIS patients.

Sex hormone binding globulin (SHBG) serum levels and insulin resistance in men on chronic hemodialysis.

BACKGROUND: In males with end stage renal disease biochemical hypogonadism is a frequent finding. Testosterone and sex hormone binding globulin (SHBG) have been associated with insulin resistance, a well-known condition in uremia. The aim of the present study was to investigate in males on chronic hemodialysis the relationship of testosterone and SHBG serum levels with insulin resistance. METHODS: In a cross-sectional study we enrolled men treated with chronic hemodialysis who did not suffer from an acute illness or other endocrinopathy, as well as primary hypogonadism, and were not hospitalised. Diabetes mellitus, diabetic nephropathy or previous transplantation were not exclusion criteria. As controls we used a community-based group of healthy males matched for age and Body Mass Index (BMI). We assessed the BMI (kg/m2) from body weight and height, the body fat content (%) by bioelectrical impedance and serum testosterone (ng/ml), SHBG (nmol/L) and estradiol (pg/ml) by standard methods. Testosterone < 3.25 ng/ml defined biochemical hypogonadism. In non-diabetic males, we calculated the homeostasis model assessment index (HOMA-R), an estimate of insulin resistance, from serum fasting insulin and glucose. RESULTS: 27 men (age 54.4 ± 19 years) on chronic hemodialysis (treatment duration 29.1 ± 14.4 months) and 51 healthy men (age 47.1 ± 9.6 years) were included. In men on hemodialysis vs. healthy men there were increased serum levels of SHBG (40.9 ± 26.9 vs. 27.6 ± 11.9 nmol/L; p = 0.031) and a significantly enhanced frequency of biochemical hypogonadism (22.2 vs. 3.9%; p = 0.011). In cases without diabetes (n = 22) a significant correlation was observed between the HOMA-R (r = -0.586, p = 0.004) and the fasting insulin levels (r = -0.650, p = 0.001) on the one hand and the serum SHBG levels on the other. CONCLUSIONS: Our findings confirm enhanced prevalence of biochemical hypogonadism in males on chronic hemodialysis. In non-diabetic cases the serum levels of SHBG correlated with serum insulin and insulin resistance.

Case report: An adolescent female with anosmic hypogonadotropic hypogonadism, intellectual disability, and papillary thyroid carcinoma: heterozygous deletion of TCF12.

Background: Isolated hypogonadotropic hypogonadism is a heterogeneous clinical entity. There is a growing list of molecular defects that are associated with hypogonadotropic hypogonadism (HH). TCF12, a recently identified molecular defect, causes craniosynostosis and is suggested to be used as a biomarker for prognosis in various cancer types. Recently, TCF12 variants were shown in a cohort with HH. Case presentation: A 15.3 years old female patient was referred to the endocrinology clinic for obesity. She had been gaining weight from mid-childhood. She had her first epileptic seizure at the age of 15.1 years and mildly elevated thyroid autoantibodies were detected during evaluation for etiology of seizures. She had not experienced menarche yet. She was operated for left strabismus at the age of 7 years. School performance was poor and she was receiving special education. Tanner stage of breast was 1 and pubic hair was 3. The endocrine workup revealed hypogonadotropic hypogonadism. Also, the Sniffin' Sticks test detected anosmia. Thyroid ultrasonography was performed due to the mildly elevated thyroid autoantibodies, and thyroid nodules with punctate calcifications were detected. Total thyroidectomy and central lymph node dissection were performed regarding the cytological findings of the nodules and multicentric papillary thyroid carcinoma with no lymph node metastasis was detected on pathology specimens. Regarding the phenotypic features of the patients, whole exome sequencing was performed and heterozygous deletion of exon 1 and exon 6-8 in TCF12 was detected. Conclusion: Haploinsufficiency of TCF12 causes anosmic HH. Probably due to the incomplete penetrance and variable expressivity of the disease, patients could display variable phenotypic features such as intellectual disability, developmental delay, and craniosynostosis. Further description of new cases with TCF12 variations could enhance our understanding of craniosynostosis and its potential link to Kallmann syndrome associated with this gene.

Efficacy of GnRH Pulses in Hypogonadism Secondary to Primary Empty Sella: Case Report.

This study aims to assess the effectiveness of pulsed gonadotropin-releasing hormone (GnRH) micropump replacement therapy in the treatment of hypogonadotropic hypogonadism (HH) caused by primary empty sella (PES).The efficacy of pulsed GnRH replacement therapy using the micropump was evaluated in a middle-aged male patient with HH who had experienced the loss of his only child. Relevant literature was also consulted to compare the differences between pulse GnRH treatment and conventional treatment in terms of the development of secondary sexual characteristics, sex hormone levels, sperm production rate, and sperm activity rate in male patient with HH.In this report, a 45-year-old male diagnosed with HH and PES presented with fatigue and decreased libido. The main characteristics included decreased follicle stimulating hormone (FSH) levels of 0.03 mIU/mL, luteinizing hormone (LH) levels of 0.02 mIU/mL, and testosterone (T) levels of 0.72 nmol/L. Magnetic resonance imaging (MRI) revealed an empty sella. Semen analysis showed a small number of normal sperm with reduced motility. During treatment with the micropump pulse GnRH, the patient experienced no side effects and showed improvements in fatigue, reduced libido, sexual urge, anxiety, and feelings of inferiority. LH, FSH, and T levels returned to normal, while sperm activity rate increased to 79.9%. Ultimately, the patient's spouse achieved a natural pregnancy.Pulsed gonadotropin delivery using the micropump demonstrates good efficacy and tolerability, and aligns more closely with the physiological rhythm of GnRH secretion in the human body.

Testosterone and neurobehavioral outcomes in special operations forces military with multiple mild traumatic brain injury.

BACKGROUND: U.S. Special Operations Forces (SOF) are at increased risk of multiple mild traumatic brain injury (mmTBI). Testosterone was prescribed for several participants in a VA program designed to address sequelae of mmTBI for SOF. OBJECTIVE: To determine testosterone prevalence in the Palo Alto VA Intensive Evaluation and Treatment Program (IETP) and observe for association between testosterone and neurobehavioral outcomes. METHODS: A retrospective cohort study included patients in the Palo Alto VA IETP. Sociodemographic data, testosterone blood levels, and neurobehavioral outcomes were collected from medical records. RESULTS: 55 IETP participants were included: six were testosterone users; the rest were classified as non-users. Testosterone use in this population is 11%, higher than reported national averages in the U.S. Of the 6 testosterone users, 2 (33%) had a formal diagnosis of hypogonadism prior to initiation of testosterone. Neurobehavioral outcome scores between testosterone users and non-users failed to show statistically significant differences, except for the PROMIS pain score, which was higher in the testosterone user population. CONCLUSION: The current study did not find an association between mmTBI, testosterone use, or testosterone level and neurobehavioral outcomes. This study highlights a need to further examine the relationship between hypogonadism, mmTBI, SOF culture around testosterone, and the effects of testosterone use in this population.

Circulating adrenal and gonadal steroid hormones heterogeneity in active young males and the contribution of 11-oxy androgens.

The classical androgens, testosterone and dihydrotestosterone, together with dehydroepiandrosterone, the precusrsor to all androgens, are generally included in diagnostic steroid evaluations of androgen excess and deficiency disorders and monitored in androgen replacement and androgen suppressive therapies. The C11-oxy androgens also contribute to androgen excess disorders and are still often excluded from clinical and research-based steroids analysis. The contribution of the C11-oxy androgens to the androgen pool has not been considered in androgen deficiency. An exploratory investigation into circulating adrenal and gonadal steroid hormones in men was undertaken as neither the classical androgens nor the C11-oxy androgens have been evaluated in the context of concurrent measurement of all adrenal steroid hormones. Serum androgens, mineralocorticoids, glucocorticoids, progesterones and androgens were assessed in 70 healthy young men using ultra high performance supercritical fluid chromatography and tandem mass spectrometry. Testosterone, 24.5 nmol/L was the most prominent androgen detected in all participants while dihydrotestosterone, 1.23 nmol/L, was only detected in 25% of the participants. The 11-oxy androgens were present in most of the participants with 11-hydroxyandrostenedione, 3.37 nmol, in 98.5%, 11-ketoandrostenedione 0.764 in 77%, 11-hydroxytestosterone, 0.567 in 96% and 11-ketotestosterone: 0.440 in 63%. A third of the participants with normal testosterone and comparable 11-ketotestosterone, had significantly lower dehydroepiandrosterone (p < 0.001). In these males 11-hydroxyandrostenedione (p < 0.001), 11-ketoandrostenedione (p < 0.01) and 11-hydroxytestosterone (p < 0.006) were decreased. Glucocorticoids were also lower: cortisol (p < 0.001), corticosterone (p < 0.001), cortisone (p < 0.006) 11-dehydrocorticosterone (p < 0.001) as well as cortisol:cortisone (p < 0.001). The presence of dehydroepiandrosterone was associated with 16-hydroxyprogesterone (p < 0.001), which was also significantly lower. Adrenal and gonadal steroid analysis showed unexpected steroid heterogeneity in normal young men. Testosterone constitutes 78% of the circulating free androgens with the 11-oxy androgens abundantly present in all participants significantly contributing 22%. In addition, a subset of men were identified with low circulating dehydroepiandrosterone who showed altered adrenal steroids with decreased glucocorticoids and decreased C11-oxy androgens. Analysis of the classical and 11-oxy androgens with the additional measurement of dehydroepiandrosterone and 16-hydroxyprogesterone may allow better diagnostic accuracy in androgen excess or deficiency.

Longitudinal Evaluation of Reproductive Endocrine Function in Men with ACTH-Dependent Cushing Syndrome.

CONTEXT: Hypogonadism may be caused by Cushing syndrome (CS) and may intensify its adverse consequences. OBJECTIVE: To determine the frequency of male hypogonadism before and after curative surgery for CS, and its cause. DESIGN: Post-hoc analyses of prospective cohort studies. SETTING: Clinical research center. PATIENTS: Men with ACTH-dependent CS. Cohort 1 (C1) (n=8, age 32.5±12 y; studied 1985-1989); Cohort 2 (C2) (n=44, 42.7 ± 15.1 y; studied 1989-2021). INTERVENTIONS: C1: Every 20-minute blood sampling for 24h before and 1-40 months after surgical cure. Three subjects underwent GnRH stimulation tests pre- and post-surgery. C2: Hormone measurements at baseline and 6 and 12 months (M) post-cure. MAIN OUTCOME MEASURES: C1: LH, FSH, LH pulse frequency and LH response to GnRH. C2: LH, FSH, testosterone (T), free T, fT4, T3, TSH and UFC levels and frequency of hypogonadism pre- and post-surgery. RESULTS: C1: mean LH and LH pulse frequency increased after surgery (p < 0.05) without changes in LH pulse amplitude, mean FSH, or peak gonadotropin response to GnRH. C2: 82% had baseline hypogonadism (total T 205 ± 28 ng/dL). Thyroid hormone levels varied inversely with UFC and cortisol. LH, total and free T, and SHBG increased at 6M and 12M post surgery, but hypogonadism persisted in 51% at 6M and in 26% at 12M. CONCLUSION: Hypogonadism in men with CS is widely prevalent but reversible in ∼75% of patients one year after surgical cure and appears to be mediated through suppression of hypothalamic GnRH secretion, and modulated by thyroid hormones.