Hypogonadism Research Articles

Male Menopause: Concept Challenges and Coping Strategies

Men’s health is globally in crisis and worsening due to limited healthcare policies, and under-developed societal awareness and education. Men frequently realize reproductive health services as being meant for females because of this they do not see a place for themselves in those services. Male menopause, or more accurately, testosterone deficiency syndrome (TDS) is one of the new issues which can affect the quality of life in older men. It is a natural phenomenon that occurs with age in men and is diagnosed by clinical manifestation and a decrease in serum testosterone levels; it affects the performance of many systems of the body from the head to toe. Moreover, age-related comorbid diseases such as diabetes, heart disease, renal disease, obesity, metabolic syndrome, and some medications such as glucocorticoids, cigarettes and alcohol also contribute to the decline in testosterone levels. There are numerous challenges faced by men in Africa during the climacteric period and they are accentuated by several intermediating factors which range from ignorance, to cultural taboos and even lack of adequate facilities to cater for their health needs. If these middle-aged men continue to experience the challenges of male menopause without effective coping strategies, their quality of life is at stake. This paper therefore stresses challenges of male menopause and recommends lifestyle changes, healthy emotion focused coping strategies and other relaxation techniques to improve the quality of life of elderly men experiencing male menopause.

Testicular volume is a noninvasive predictor of sperm retrieval failure in idiopathic nonobstructive azoospermia.

We investigated the prognostic importance of noninvasive factors in predicting sperm retrieval failure in idiopathic nonobstructive azoospermia (iNOA). We studied 193 patients with nonobstructive azoospermia who underwent microsurgical testicular sperm extraction. The Chi-square test and Mann-Whitney U tests for clinical parameters and seminiferous tubule distribution were used for between-group comparisons. A logistic regression analysis was conducted to identify predictors of retrieval failure. Area under the receiver operating characteristic curve for each variable was evaluated, and the net clinical benefit was calculated using a clinical decision curve. Patients with iNOA had a lower sperm retrieval rate than those with known causes. Moreover, testicular volume was an independent factor affecting sperm extraction outcomes (odds ratio = 0.79, P < 0.05). The testicular volume cut-off value was 6.5 ml (area under the curve: 0.694). The patients with iNOA were categorized into two groups on the basis of the distribution of seminiferous tubules observed. The sperm retrieval rate and testicular volume were significantly different between the groups with a uniform or heterogeneous tubule distribution. There was also a significant association between a uniform tubule distribution and testicular volume. In conclusion, a testicular volume of more than 6.5 ml effectively predicts microsurgical testicular sperm extraction failure due to a uniform tubule distribution in patients with iNOA.

Risk for testicular germ cell tumors and spermatogenesis failure in post-pubertal undescended testes.

Cryptorchidism is a well-defined risk factor for testicular germ cell tumors, whereas the underlying mechanisms have not been fully elucidated. Surgical procedures to reposition undescended testicles into the scrotum (orchidopexy) in early childhood are recommended both to increase fertility potential and to reduce the risk of developing testicular tumors. However, treatment in the post-pubertal period is controversial. The aim of this study is to review the histopathology of orchiectomy specimens and determination of spermatogenesis in post-pubertal patients with non-treated cryptorchidism. Retrospective chart review was performed to assess the occurrence of TGCTs and determine spermatogenesis in post-pubertal individuals who underwent inguinal orchiectomy for undescended testis between January 2010 and December 2019. Age at the time of surgery, laterality, location of theundescended testis and pathology results were evaluated. All pathology specimens were reviewed by a blinded pathologist. There were 23 patients in the cohort with a mean age of 21years (range 13-46years). All testes were in the inguinal canal. Our results indicated that 1 patient had seminoma. In the histological evaluation of the remaining 22 patients in whom no tumor was detected, normal spermatogenesis was not observed in any patient. Further, seminiferous tubules were not found in 19 patients. Maturation arrest was detected in the remaining 3 patients. Testicular germ cell carcinoma was found in 4% of the patients who underwent post-pubertal orchiectomy. In addition, none of the undescended testes had normal spermatogenetic activity. Thus, orchiectomy should be considered in post-pubertal males with unilateral undescended testis that do not need the endocrinological activity of the testis.

(070) Androgen Status in Men and Risk Of COVID-19 Complications: An Analysis of United States Claims Data

Abstract Introduction Biological males have had worse COVID-19 outcomes compared to females. Yet, the impact of hypogonadism (HG) on COVID complications remains unclear. Objective We sought to compare COVID complications in males with various androgen status (eugonadal, treated HG, untreated HG) to females to evaluate the effect of testosterone levels on COVID outcomes. Methods We used the IBM MarketScan database of commercial claims encounters to identify patients ages 18+ with a COVID diagnosis (n=756,855). We compared eugonadal males (no HG diagnosis), untreated HG males (HG diagnosis without therapy), treated HG males (HG diagnosis and testosterone prescription within 180 days before COVID diagnosis) to females. Rates of intensive care unit (ICU) admission co-occurring with initial COVID diagnosis were modeled using logistic regression. Acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF), and use of critical care services (CCS) were modeled using Cox proportional hazards models. Outcomes were regressed against group, age, rurality, and Charlson Comorbidity Index. Results Eugonadal males (n=315,050) were at higher odds of ICU admission (OR: 1.611, 95% CI: 1.549-1.676), having ARDS (HR 1.766, CI: 1.670-1.868), having ARF (HR 1.609, CI: 1.575-1.644), and needing CCS (HR 1.696, CI: 1.652-1.742) compared to females. Treated HG males (n=2,343) and untreated HG males (n=22,614) were also more likely to experience all adverse outcomes compared to females. For untreated HG males the effect was less pronounced compared to eugonadal males and treated HG males for all outcomes (Figure 1). There were no differences in odds of all outcomes for castrate males (n=89) compared to females due to small sample size. Conclusions Eugonadal males, treated HG males, and untreated HG males were more likely to have adverse COVID outcomes compared to females. This effect was most pronounced for eugonadal and treated HG males compared to untreated HG males, suggesting normal androgen status is detrimental to COVID-19 outcomes. This is one of the largest studies to show a complex relationship between testosterone and COVID outcomes. Disclosure No.

(330) Testosterone Replacement Therapy in Hypogonadism: A Single Center Longitudinal Analysis of Treatment Patterns and Clinical Outcomes

Abstract Introduction Male hypogonadism impacts the production of hormone production, which plays a key role in masculine growth. It has also been shown to impair certain male reproductive functions or delay development. Objective The goal of this study is to describe the characteristics and treatment outcomes for patients with a diagnosis of Hypogonadism (HG) presenting to an academic urology center. Methods An IRB was approved to conduct a longitudinal study on the outcomes of male hypogonadism at a high-volume tertiary referral center. Men diagnosed with hypogonadism were identified by ICD 10 code (E 29.1). Clinical, demographic, laboratory, and testosterone replacement therapy and outcomes were extracted from the EMR. Results This retrospective study included 537 patients with a median age of presentation of 52 years (IQR: 42-68). At the initial visit, 66% presented with low libido, 65% with erectile dysfunction (ED), and 6% with depression. On initial hormonal evaluation, median (IQR) measurements for testosterone, free testosterone, and estradiol were 294 (217.5-417), 6.1 (4.45-8.0), and 4 (2-17) respectively. 227 (56.5%) patients elected to begin Testosterone Replacement Therapy (TRT). Of these, five treatment types of TRT were observed: 114 (53%) patients elected for intramuscular TRT, 25 (12%) utilized a pellet implant, 74 (34%) utilized topical treatment TRT, 3 (1.4%) used pellet and topical, and 1 (0.5%) used topical and intramuscular. Following TRT, 143 (79%) patients endorsed an improvement in ED, 175 (84%) reported improved libido, 176 (84%) reported increased energy levels, and 88 (59%) showed improvement in muscle mass. Follow-up labs measuring testosterone, free testosterone, and estradiol demonstrated medians of 486 (IQR: 296.5-802.8), 15.3 (IQR: 6.9-88.7), and 16.45 (IQR: 3-28.85) respectively. Adverse events while on TRT were 32 (15%) polycythemia, 3 (1.4%) VTE’s, and 3 (1.4%) MI. Conclusions Sexual dysfunction is a prominent symptom encountered by men with hypogonadism. However, only 56.5% of hypogonadal men pursue TRT, with intramuscular injections being the most commonly prescribed formulation. In our longitudinal cohort, we report that polycythemia and cardiovascular events are uncommon sequela after TRT. Further randomized control trials are warranted to better understand cardiovascular events' association with TRT. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast Investor: Sprout.

(249) Multiple sclerosis (MS) and Hypogonadism (HG): Is There a Relationship? - A Systematic Review

Abstract Introduction Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is widely recognized as a disease primarily affecting women. However, recent studies have shown that patients with MS, both male and female, may also suffer from hypogonadism, a condition characterized by decreased testosterone production and decreased gonadal function. The relationship between MS and hypogonadism is complex and not fully understood, with recent evidence showing that hypogonadism may have a significant impact on the quality of life and disease progression of MS patients. Objective This review aims to provide an overview of the current knowledge regarding the relationship between MS and hypogonadism, including the mechanisms underlying this relationship, the effects of hypogonadism on MS patients, and the potential benefits and drawbacks of testosterone replacement therapy for MS patients with hypogonadism. Methods This scientific review analyzed 19 articles that investigated the potential relationship between MS, testosterone levels, and hypogonadism. The articles were published between November 2008 and March 2022 and were identified through a comprehensive search of the PubMed database. The search terms used included “multiple sclerosis,” “testosterone,” “hypogonadism,” and “MS and testosterone levels.” The inclusion criteria for articles were as follows: (1) articles that investigated the relationship between MS, testosterone levels, and hypogonadism, (2) articles that were published in English, and (3) articles that provided original data. Exclusion criteria included (1) articles that were not related to the topic, (2) reviews and editorials, and (3) articles that did not provide original data. Results Of the 19 articles reviewed, 11 described a positive correlation between low testosterone levels and dysfunction within the hypothalamic-pituitary-gonadal axis in individuals with MS. These findings suggest that low testosterone levels may contribute to dysfunction within the hypothalamus-pituitary-gonadal axis, which plays a crucial role in regulating testosterone production. The results also showed a relationship between sexual dysfunction and low testosterone levels, as well as a positive correlative relationship between these two factors. Conclusions The reviewed articles indicate a complex relationship between MS, testosterone levels, and the hypothalamic-pituitary-gonadal axis, with low testosterone levels potentially contributing to dysfunction in this axis and to sexual dysfunction. Further research is needed to better understand the effects of testosterone therapy on MS and sexual dysfunction in MS patients. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Advisory board and speaker for Coloplast; consultant for Cynosure; advisory board and speaker for Halozyme; intellectual property with Masimo; advisory board for Promescent; consultant for Sprout; advisory board for Xialla.

(082) Integrated Urology and Primary Care Model Improves Outcomes for Men with Testosterone Deficiency

Abstract Introduction Testosterone deficiency affects approximately 4-5 million men in the United States. The bidirectional association between testosterone deficiency and metabolic syndrome has been well-established. The diagnosis of testosterone deficiency should serve as a trigger for medical evaluation of other comorbidities. Furthermore, male sex is an independent predictor of decreased routine health maintenance; men are 40% less likely to have a primary care provider (PCP) compared to women in the United States. Thus, many patients who present to the urologist for symptomatic testosterone deficiency might have undiagnosed or poorly managed comorbidities coupled with a lack of a PCP. Objective We sought to investigate the impact of offering primary care access within an integrated Men’s Health Center to men presenting for initial evaluation of symptomatic testosterone deficiency. Methods This is a retrospective single institution study. All new patients presenting with testosterone deficiency between October 2019 and October 2022 were offered evaluation by a PCP within a university-based Men’s Health Center. Patients who were seen by the PCP underwent standard health screening and blood work including a lipid profile, liver function testing, and diabetes screening with hemoglobin (Hgb) A1c. All data were collected from the electronic medical record and deidentified. Institutional review board (IRB) exemption was obtained. Variables collected for analysis included age, race, body mass index (BMI), testosterone level on presentation, prior access to a pre-existing PCP, and number of visits attended with our PCP. Outcomes measured include new diagnoses made by the PCP and referral patterns to other specialties. All statistical analysis was conducted utilizing SPSS version 28. Results 81 men were evaluated over the 3-year study period. Median age was 49.0 (range: 21.2-93.7 years). 48 men (59%) established continuity of care and were seen by our PCP for more than 1 visit. 33 men (41%) did not have a pre-existing PCP. Older men were significantly more likely to have a pre-existing PCP (OR 1.06 [95% CI: 1.02-1.10], p&amp;lt;0.001). Hispanic men were significantly less likely to have an existing PCP (OR 0.16 [95% CI: 0.03-0.84], p=0.01). Newly diagnosed comorbidities included hypertension (41%), obesity (37%), hyperlipidemia (27%), obstructive sleep apnea (OSA; 25%), depression (23%), and diabetes (14%). 41 patients (51%) were prescribed a new medication. 21 patients (26%) were referred to nutrition, with mean BMI decrease of 1.75. 26 patients (32%) underwent sleep medicine evaluation for OSA. 27 (33%) and 37 patients (46%) received a flu vaccination and immunization updates. 11 patients (14%) were referred for screening colonoscopy. Patients who established continuity of care were significantly more likely to be treated for a new diagnosis (p&amp;lt;0.001) and receive a flu vaccination (p=0.007; Table 1). Conclusions This is the first report of integrated primary care and urology evaluation for testosterone deficiency. This comprehensive model results in improved outcomes including increased access to subspecialty referrals, objective weight loss, treatment of new diagnoses, updated immunizations, and cancer screening. Further studies are needed to assess reproducibility across other institutions, cost-effectiveness of this model, and patient satisfaction. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific, Endo Pharmaceuticals.

Plasma steroid concentrations reflect acute disease severity and normalise during recovery in people hospitalised with COVID-19.

Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID-19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID-19 and with post-COVID symptoms have glucocorticoid and sex hormone deficiencies. Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID-19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow-up 5 months after hospitalisation (Post-hospitalisation COVID-19 study). Plasma steroids were quantified by liquid chromatography-mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and validated symptom scores. Data are presented as geometric mean (SD). In the acute cohort (n = 239, 66.5% male), plasma cortisol concentration increased with disease severity (cortisol 753.3 [1.6] vs. 429.2 [1.7] nmol/L in fatal vs. least severe, p < .001). In males, testosterone concentrations decreased with severity (testosterone 1.2 [2.2] vs. 6.9 [1.9] nmol/L in fatal vs. least severe, p < .001). In the follow-up cohort (n = 198, 62.1% male, 68.9% ongoing symptoms, 165 [121-192] days postdischarge), plasma cortisol concentrations (275.6 [1.5] nmol/L) did not differ with in-hospital severity, perception of recovery, or patient-reported symptoms. Male testosterone concentrations (12.6 [1.5] nmol/L) were not related to in-hospital severity, perception of recovery or symptom scores. Circulating glucocorticoids in patients hospitalised with COVID-19 reflect acute illness, with a marked rise in cortisol and fall in male testosterone. These findings are not observed 5 months from discharge. The lack of association between hormone concentrations and common post-COVID symptoms suggests steroid insufficiency does not play a causal role in this condition.

Erectile function in men with COVID-19 six months after recovery

Background. Based on the results of epidemiological studies, it was found that coronavirus disease 2019 (COVID-19) affects men more often than women. Among COVID-19 complications, erectile dysfunction is considered a marker of endothelial dysfunction and one of the main factors for the development of cardiovascular diseases. Lower total and free testosterone levels are predictors of adverse prognosis in males with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Testosterone deficiency syndrome is considered an independent risk factor of cardiometabolic disorders. The purpose of the study is to investigate the state of erectile function in men who suffered from COVID-19 six months after recovery. Materials and methods. Seventy-two men suffering from COVID-19 and being treated in an infectious disease hospital were examined 6.90 ± 0.29 months after recovery. Their average age was 45.23 ± 3.01 years. The control group included 18 conditionally healthy men aged 43.18 ± 2.90 years. The state of erectile function was assessed using the International Index of Erectile Function (IIEF). The concentration of testosterone was determined by the enzyme-linked immunosorbent assay with DRG (Germany) and DiaMetra (Italy) kits. All measurements were performed on the Stat Fax 3200 analyzer. Statistical comparison of the obtained results between groups was performed according to the Student’s test. A value of p &lt; 0.05 was considered to be signifi­cant. Results. In addition to erectile dysfunction, as evidenced by a reduced corresponding integrative indicator “erectile function” of IIEF-15 in men with COVID-19, a decrease in sexual desire was found, as well as a deterioration of sensations in the form of a decrease in ejaculation frequency and orgasmic sensations during sex contacts. The average serum level of total testosterone was 10.9 nmol/l and was significantly reduced compared to that in the control group. Analysis of individual indicators showed that testosterone level was decreased in 10 patients and was within the normal range in 13 men with COVID-19. The average serum concentration of total testosterone in the examined men after the disease was 10.73 ± 1.07 nmol/l and was significantly reduced compared to that of the control group. Conclusions. There was an erectile dysfunction in men who suffered COVID-19, it was confirmed by a probable decrease in IIEF-15 score and integrative indicators of erectile function. A significant decrease in the blood concentration of total testosterone was detected in the examined men, which may be one of the causes of erectile dysfunction. Large-scale prospective, randomized, controlled trials in patients infected with SARS-CoV-2 are needed to provide an understanding of the molecular mechanisms that cause erectile dysfunction.

A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia.

Both non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) are pathological conditions characterized by premature and frequently complete gametogenesis failure. Considering that the conserved meiosis I steps are the same between oogenesis and spermatogenesis, inherited defects in meiosis I may result in common causes for both POI and NOA. The present research is a retrospective investigation on an Iranian family with four siblings of both genders who were affected by primary gonadal failure. Proband, an individual with NOA, was subjected to clinical examination, hormonal assessment, and genetic consultation. After reviewing the medical history of other infertile members of the family, patients with NOA went through genetic investigations including karyotyping and assessment of Y chromosome microdeletions, followed by Whole exome sequencing (WES) on the proband. After analyzing WES data, the candidate variant was validated using Sanger sequencing and traced in the family. WES analysis of the proband uncovered a novel homozygote nonsense variant, namely c.118C>T in MSH4. This variant resulted in the occurrence of a premature stop codon in residue 40 of MSH4. Notably, the variant was absent in all public exome databases and in the exome data of 400 fertile Iranian individuals. Additionally, the variant was found to co-segregate with infertility in the family. It was also observed that all affected members had homozygous mutations, while their parents were heterozygous and the fertile sister had no mutant allele, corresponding to autosomal recessive inheritance. In addition, we conducted a review of variants reported so far in MSH4, as well as available clinical features related to these variants. The results show that the testicular sperm retrieval and ovarian stimulation cycles have not been successful yet. Overall, the results of this study indicate that the identification of pathogenic variants in this gene will be beneficial in selecting proper therapeutic strategies. Also, the findings of this study demonstrate that clinicians should obtain the history of other family members of the opposite sex when diagnosing for POI and/or NOA.

Prevalence of osteopenia and osteoporosis in middle-aged and older Korean men with testosterone deficiency syndrome: a cross-sectional study

Testosterone plays an important role in regulating fertility, muscle mass and bone density. Low bone mineral density has been reported in men with testosterone deficiency syndrome (TDS); however, there is limited research available on the prevalence of TDS. In this study, we aimed to determine the prevalence of osteoporosis and osteopenia in middle-aged and older men (n = 4707, age: 40–79 years) with TDS. Their total serum testosterone levels were measured, and TDS was defined as a testosterone level of ≤3.5 ng/mL. To assess bone mineral density, we used dual-energy X-ray absorptiometry to measure the density at the lumbar spine (L1–L4) and femoral neck (T-score: osteopenia ≤−1.0; osteoporosis ≤−2.5). We performed logistic regression analysis to calculate adjusted odds ratios (AORs) after adjusting for age, body mass index, physical activity and VO2peak (Volume oxygen peak). The results showed a significant difference in physical activity between men with TDS and those without TDS (NTDS) in both middle-aged and older age groups (p &lt; 0.05). Among middle-aged men, the AOR for osteopenia in the lumbar spine was 1.2-fold higher (Confience interval, CI (Confidence interval), 1.017–2.698), and in the femoral neck, it was 1.3-fold higher (CI, 1.012–3.013) for individuals with TDS compared to those without TDS. In older men, the AOR for osteopenia in the femoral neck increased by 1.4-fold (CI, 1.029–2.530). In conclusion, our findings suggest that middle-aged men with TDS have a higher likelihood of experiencing osteopenia in both the lumbar spine and femoral neck, while older men are more likely to have osteopenia, specifically in the femoral neck, but not osteoporosis.

Rate of testicular histology failure in predicting successful testicular sperm extraction.

The management of Non-Obstructive (NOA) Azoospermia or Obstructive Azoospermia (OA) patients relies on testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection (ICSI). In NOA patients the sperm recovery is successful in only 50% of cases and therefore the ability to predict those patients with a high probability of achieving a successful sperm retrieval would be a great value in counselling the patient and his partner. Several studies tried to suggest predictors of a positive TESE (e.g. FSH concentration), but most concluded that diagnostic testicular biopsy (histology) is best. This is a retrospective analysis of 526 TESE patients. After the extraction of the testis, the resulting sample was immediately given to the embryologist, who examined the tubules for sperm cryopreservation. During the same procedure, a different specimen was destined to the histological analysis. The comparison between the two methodological approaches was carried out through a score. Concordance between TESE and testicular histology outcomes was found in 70,7% of patients; discordance was found in 29,3% of patients. Among the discordance outcomes, in approximately 95% we found at least 1 sperm in the TESE retrieval, while the histology report did not find any spermatozoa or found not enough compared to our evaluation; in only 5% of cases we did not find any spermatozoa or found not enough compared to what was detected in the testicular histology. Based on our experience, to increase diagnostic accuracy, a larger biopsy should be sent to the histopathology laboratory; another option may be to use TESE cell suspension (the same embryologists employ for cryopreservation) for cytological evaluation of spermatogenesis.

Combining ternary phase diagrams and multiphase coupled matrix-based Monte Carlo to model phase dependent compositional and molar mass variations in high impact polystyrene synthesis

High impact polystyrene (HIPS) production starts from a homogeneous grafting of styrene (St) on polybutadiene (PB). However, already at low St conversion, the reaction mixture becomes heterogeneous due to the incompatibility between polystyrene (PS) and PB. First a PS-rich phase appears, dispersed in a PB-rich phase, and then the situation reverses. At even higher St conversions, the PB-rich phase also includes PS occlusions (defined as a third phase). In the present work, a multiphase coupled matrix-based Monte Carlo (CMMC) model is presented, tracking the molecular variations of individual molecules for the first time per phase. This is done accounting for (i) phase equilibria as inputted based on a literature-based ternary phase diagram for St-PB-PS mixtures, and (ii) diffusional limitations by means of apparent rate coefficients, demonstrating a preference for the composite kt model for the representation of the gel-effect. The simplified single phase model output is acceptable up to St conversions of 30 %, justifying the previous efforts on tuning modeling parameters also including model validation for high yield general purpose PS synthesis. However, at higher St conversions (up to 60 %), a single phase model predicts too high St amounts in the graft copolymer, and too low PS average chain lengths and dispersities. Furthermore, post-processing at a given St conversion reveals the contributions to the total PS log-molar mass distribution (log-MMD) from the PS-rich phase, the PB-rich phase, and PS occlusions. Moreover, the multimodality of the observed (total) log-MMD is uniquely explained based on these contributions, with specifically a more pronounced second peak due to blocked mass transfer of PS to the PS-rich phase at higher St conversions.

Pubertal attainment and Leydig cell function following pediatric hematopoietic stem cell transplantation: a three-decade longitudinal assessment.

Impaired testosterone secretion is a frequent sequela following hematopoietic stem cell transplantation (HSCT) in pediatrics, but long-term longitudinal trendlines of clinical and biochemical findings are still scanty. Monocentric, retrospective analysis. Male patients transplanted <18 years between 1992 and 2021, surviving ≥2 years after HSCT and showing, upon enrollment, clinical and biochemical signs consistent with pubertal onset and progression were included. Clinical and biochemical data collected every 6-12 months were recorded. Of 130 patients enrolled, 56% were prepubertal, while 44% were peri-/postpubertal upon HSCT. Overall, 44% showed spontaneous progression into puberty and normal gonadal profile, while the remaining experienced pubertal arrest (1%), isolated increase of FSH (19%), compensated (23%) or overt (13%) hypergonadotropic hypogonadism. Post-pubertal testicular volume (TV) was statistically smaller among patients still pre-pubertal upon HSCT (p 0.049), whereas no differences were recorded in adult testosterone levels. LH and testosterone levels showed a specular trend between 20 and 30 years, as a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. A variable degree of gonadal dysfunction was reported in 85%, 51%, 32% and 0% of patients following total body irradiation- (TBI), busulfan-, cyclophosphamide- and treosulfan-based regimens, respectively. TBI and busulfan cohorts were associated with the lowest probability of gonadal event-free course (p<0.0001), while it achieved 100% following treosulfan. A statistically greater gonadotoxicity was detected after busulfan than treosulfan (p 0.024). Chemo-only regimens were associated with statistically larger TV (p <0.001), higher testosterone (p 0.008) and lower gonadotropin levels (p <0.001) than TBI. Accordingly, the latter was associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 2.34, CI 1.08-8.40), whereas being pre-pubertal upon HSCT was associated with a reduced risk (OR 0.15, CI 0.08-0.30). a) patients pre-pubertal upon HSCT showed a reduced risk of testicular endocrine dysfunction, despite smaller adult TV; b) patients showed downwards trend in testosterone levels after full pubertal attainment, despite a compensatory increase in LH; c) treosulfan was associated to a statistically lower occurrence of hypogonadism than busulfan, with a trend towards larger TV, higher testosterone levels and lower gonadotropins.

#110 : Diagnostic Approach and Clinical Recommendations for Non-obstructive Azoospermia: Global Andrology Forum Survey Results

Background and Aims: Non-obstructive azoospermia (NOA) is the most common form of male infertility, characterized by an absence of sperm in ejaculate and is caused by testicular failure. While NOA afflicts 10-38.3% of infertile males, there is no specific recommendations in EAA/EAU guidelines on its clinical diagnosis or WHO guidelines on semen analysis. Therefore, we conducted a global survey to assess the standard approach of practitioners in the diagnosis and management of NOA. Method: The Global Andrology Forum (GAF) conducted a survey on 436 independent practicing entities from 55 countries. We compiled data from 336 respondents (andrologists, urologists, fertility specialists). Information collected included frequency of NOA, varicocele, frequency of obtaining semen, interval between obtaining semen samples, hormone evaluation (FSH, LH, prolactin, total/free testosterone, SHBG, estradiol, inhibin), genetic testing (karyotype, Y-chromosome deletion, CFTR, Kal1) and referral to genetic counsellors. Results: The majority of participants (80%) either reported &lt;10% or 10-25% NOA frequency in their population (Fig. 1A). 40.6% of participants stated that 10-25% of men with NOA cases have a clinically significant varicocele (Fig. 1B). For NOA diagnosis, majority of participants cited the requirement of at least two semen samples, with a period of 14-29 days as the interval between two semen analyses. To achieve high-quality semen, consideration must be given to an abstinence period (2-7days) and the complete collection of ejaculates. The survey reported FSH (97%), LH (86.9%) and total testosterone (92.9%) tests as most frequently used for NOA patients (Fig. 2A). The initial hormonal evaluation of a patient with suspected NOA should include total testosterone levels and LH, as these hormones are the primary regulators of spermatogenesis. Karyotype analysis (86.2%), Y-microdeletion (88.3%), CFTR (21.9%) and Kal1 (2.7%) were most routinely performed genetic tests (Fig. 2B). Referrals to genetic counsellors is recommended as these defects have the potential to be passed to future generations. Conclusion: This global study evaluates NOA frequency, clinical diagnosis and management by specialists, in an effort to fill the gap in NOA research. Concomitantly, we provide GAF expert recommendations to enhance our collective understanding of NOA, optimize patient care and improve the management of NOA.

Favorable Fertility Outcome in a Large Cohort of Sickle Cell Disease Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Fertility preservation is an important consideration for individuals with sickle cell disease (SCD) who may face reproductive challenges. While SCD itself does not directly affect fertility, certain complications and its treatment such as hematopoietic cell transplantation (HCT) can impact the reproductive health in SCD patients. HCT is a potential curative therapy for SCD, however, one of the negative outcomes is the premature gonadal failure and infertility. Both male and female patients have different risk factors that may impact the fertility post-transplant. Therefore, these patients should undergo fertility preservation counselling pre transplant. In this study, we report the fertility outcome of large transplant cohort undergoing Non-myeloablative (NMA) conditioning regimen. Methods: We retrospectively collected the data for all SCD patients who were ≥ 14 years old and who underwent allogeneic HCT in our center from 2015 until 2022 with a minimum of 1 year follow up post-transplant. All patients received hydroxyurea for 2 to 3 months pre- transplant at maximum tolerated dose. The conditioning regimen was alemtuzumab 1 mg /kg divided over 5 days from day - 7 to day -3 and Total Body Irradation 200 cGy on day -2 (with testicular shielding for male patients). Graft versus host disease prophylaxis with sirolimus started from day -1 and continued for at least 1 year post-transplant. We started the fertility program in October 2019 where all patients get counselled for fertility preservation methods. Male patients undergo sperm cryopreservation after holding hydroxyurea for 3 months and female patients were referred to a specialized oncology fertility clinic for either oocyte cryopreservation or treatment with Gonadotropin-releasing hormone (GnRH) agonists pre transplant. Primary objective of the study was to assess post-transplant fertility (defined by either ability to conceive for married patients, or development of azoospermia for male patient or secondary amenorrhea for female patients). Secondary objectives were to assess pre transplant fertility, assess the success of different fertility preservations methods and finally to assess for risk factors (pre- transplant and transplant) that affect the fertility potential. Results: We identified a total of 200 SCD patients who underwent HCT. Out of these 200 patients, 107 (54%) were included in our fertility program. The median post-transplant follow up was 3.5 years (1 - 7.5). One hundred and twelve patients (56%) were male, and eighty eight (44%) were female patients. All patients were on hydroxyurea pre transplant with average dose 1000 mg and a duration of less than 2 years in 47 (23.5%) patients, 2 to 5 years in 94 (47%) patients and more than 5 years in 59 (39.5%) patients. Other baseline characteristics are shown in table 1. In the pre-transplant fertility assessment; 58 patients were married and 48 (82%) of them had children pre transplant. 36 male patients attempted sperm cryopreservation and were successful in 33 (91%). 39 female patients received Leuprolide (GNRH agonists) pre-transplant with no complications and 6 female patients attempted oocyte cryopreservation and all were successful. One patient developed cerebral venous thrombosis during the oocyte cryopreservation course. For the post-transplant fertility assessment; out of 57 married patients 26 (45%) were able to conceive. From these 26 pregnancies; 20 ended with successful live-births, 1 ended with abortion and 5 are still pregnant. 6 patients were able to conceive twice and one patient had one twin babies. For male patients 74 did semen analysis at minimum 1 year post-transplant; 35 (47%) had azoospermia and 39 (53%) had viable sperms. Majority recovered spermatogenesis after 1 year (24 patients), at 2 years (9 patients) and after 3 years (3 patients). Three male patients had Azoospermia at one year but was able to conceive successfully without repeating the test. For female patients 71 (80.7%) were able to regain menses and 17 (19.3%) developed secondary amenorrhea. Table 2 shows the pre and post-transplant fertility measures outcome. In conclusion In this study, we have shown the fertility outcomes of male and female patients with SCD undergoing NMA conditioning HCT can be preserved in a significant proportion of patients. All adult patients should be counselled for fertility preservation methods before undergoing curative allogeneic HCT.

Endocrinopathies in Hemoglobinopathies: What Is the Role of Iron?

Hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD), are common genetic blood disorders. Endocrine disorders are frequent manifestations of organ damage observed mainly in patients with β-thalassemia and rarely in SCD. Iron overload, oxidative stress-induced cellular damage, chronic anemia, and HCV infection contribute to the development of endocrinopathies in β-thalassemia. The above factors, combined with vaso-occlusive events and microcirculation defects, are crucial for endocrine dysfunction in SCD patients. These endocrinopathies include diabetes mellitus, hypothyroidism, parathyroid dysfunction, gonadal and growth failure, osteoporosis, and adrenal insufficiency, affecting the quality of life of these patients. Thus, we aim to provide current knowledge and data about the epidemiology, pathogenesis, diagnosis, and management of endocrine disorders in β-thalassemia and SCD. We conducted a comprehensive review of the literature and examined the available data, mostly using the PubMed and Medline search engines for original articles. In the era of precision medicine, more studies investigating the potential role of genetic modifiers in the development of endocrinopathies in hemoglobinopathies are essential.

Longitudinal Assessment of Pubertal Attainment and Testicular Function Following Pediatric Hematopoietic Stem Cell Transplantation: The Role of the Conditioning Regimen

Introduction. Endocrine disorders and impaired gonadal function are the most frequent sequelae after transplantation. Methods. Male patients &amp;lt;18 years transplanted in the period 1992-2021 in the Pediatric Transplant Unit in Monza, surviving more than 2 years after HSCT, who either experienced spontaneous puberty (Tanner stage ≥2, testicular volume (TV) ≥4 mL or serum testosterone ≥0.2 ng/mL) or received pharmacological pubertal induction were included in this study. Longitudinal endocrine evaluations were performed every 6-12-months, including Tanner stage and TV assessment and LH, FSH, total testosterone, among laboratory data. Results. Of 130 patients (median age 9 years at HSCT, 21 years at last follow-up) fulfilling inclusion criteria, 65% were transplanted for acute leukemia, 9% for other malignancies and 26% for non malignant diseases after a TBI (45%), busulfan (27%), 14% treosulfan-based or 15% a different chemo-only conditioning. Upon HSCT 56% were prepubertal (PreP) and 44% where either peri- or postpubertal (PostP). The pubertal status upon the last endocrine evaluation was consistent with Tanner stage 3, 4 and 5 in 15%, 23% and 62% of the patients, respectively. Overall, 44% had spontaneously progressed into puberty and had a normal gonadal profile (NOR) and 56% had experienced either pubertal arrest (1%), isolated increase of FSH (IIF 19%), compensated hypergonadotropic hypogonadism (cHH, 23%) or overt hypergonadotropic hypogonadism (oHH, 13%). Gonadal outcome was not affected by pubertal status upon HSCT (p 0.298), even though, out of 81 patients who had achieved Tanner stage 5, TV was statistically greater in the PostP (12.2±5.1 ml) than in the PreP cohort (10.3±4.1 ml, p 0.049), whereas there were no significant differences in the last testosterone level recorded in the two cohorts, as well as in the hypogonadal versus the event-free patients (p 0.53), with events defined as any gonadal issue (IIF, cHH, oHH). TV was significantly lower in patients who developed any endocrine disfunction versus those who didn't. LH and testosterone levels showed a specular trend between 20 and 30 years, when a progressive decrease in sexual steroids was associated with a compensatory increase of the luteinizing hormone. Overall, adult LH (p 0.728) as well as FSH levels (p 0.318) were superimposable in the PreP and PostP cohorts. In terms of the impact of the conditioning regimen on gonadal outcomes, a certain degree of gonadal dysfunction (ranging from isolated increase of FSH to hypogonadism or pubertal arrest) was recorded in 37% of the patients overall, and in 85% of the patients after TBI, 51% after busulfan and 32% after cyclophoshamide/fludarabine, whereas no abnormal findings were found among the 18 patients exposed to treosulfan. The likelihood of a gonadal event-free course was lowest for the TBI and busulfan cohorts, both overall (p&amp;lt;0.0001) and for PreP patients (p&amp;lt;0.0001), whereas it was 100% among the 18 patients conditioned with treosulfan-based schedules. A remarkably greater gonadotoxicity was detected in the busulfan compared with the treosulfan cohort (p 0.024), with a similar trend in the PreP and PostP subcohorts. Busulfan/cyclophosphamide-based conditioning regimens were associated with statistically larger median TV (p &amp;lt;0.001), higher testosterone levels (p 0.008) and lower LH/FSH levels (p &amp;lt;0.001) than those exposed to TBI. Conditioning regimen (p 0.047) and pubertal status upon HSCT (p &amp;lt;0.0001) were the only variables significantly associated with testicular outcomes in the Cox model, with exposure to TBI being associated with a 2-fold increase in the risk of gonadal failure compared to busulfan (OR 1.93, CI 1.08-3.70), whereas being pre-pubertal upon HSCT was protective, as it was associated with a halved risk of developing any degree of testicular damage (OR 0.50, CI 0.26-0.70). Conclusions. We demonstrated a i. halved risk of developing post-HSCT hypogonadism in prepubertal patients at HSCT, despite overall smaller final testicular volume; ii. downwards trend in testosterone levels after the achievement of full spontaneous puberty compensated by an inverse upwards trend in LH levels; iii gonadal-sparing profile of treosulfan compared to busulfan-based regimens, with a statistically lower occurrence of hypogonadism and a trend towards larger testicular volume, higher testosterone levels and lower gonadotropins.

SAT436 Endocrine Disruptor Of Organochlorine Pesticides Levels In Saudi Arabian Produce

Abstract Disclosure: M.S. Alokail: None. N.M. Al-Daghri: None. A.M. Alnaami: None. S. Sabico: None. S.D. Hussain: None. O.E. Amer: None. S.H. Abd-Alrahman: None. Food monitoring (FM) is a system used to evaluate and monitor hazardous contaminants, including pollutants such as organochlorine pesticides (OCPs). Long term exposure to organochlorine pesticides (OCPs) can lead to a variety of endocrine and reproductive disruptors including gonadal changes, changes in reproductive behavior, reduced sperm quality, an increase in organ malformations, testicular failure, fetal defects, thyroid dysfunction, and lactation. The present study aimed to determine and quantify OCPs in different local produce collected from different regions in Saudi Arabia. A total of 179 local produce samples were obtained in four regions in Saudi Arabia: Riyadh (N=55), Qassim (N=61), Eastern province (N=38) and Western region (N=25). Solid phase extraction method (QuEChERS) was used to detect OCP residues in samples and levels were quantified using gas chromatograph-electron capture detector (GC-ECD). The results have shown that a total of 11 OCPs were detected overall (9 OCPs in Qassim, Eastern province and Riyadh; 8 in Western region). Levels of alpha BHC was highest in Riyadh; 6 OCPs were highest in Qassim (Beta-BHC, Delta BCH, Dieldrin, Gamma-BHC, heptachlorepoxide and heptachlor); 4 OCPs were highest in the Eastern province (DDD, DDE, endosulfan and endrin), with endrin and endosulfan having the highest levels among all OCPs assessed. A total of 6 OCPs were found in all regions at varying concentrations (Beta-BHC, DDE, Delta-BCH, Dieldrin, endosulfan and heptachlor. Worthy to note is that heptachlorepoxide was found only in Qassim. In conclusion, the endocrine disruptor pesticides such as OCP residues require further investigation for a possible etiologic role in some hormone related cancers such as breast cancer. Presentation: Saturday, June 17, 2023

THU098 Gonadotropin Secreting Pituitary Tumor Presenting As Primary Hypogonadism

Abstract Disclosure: J.N. Shapiro: None. T.X. Lu: None. J. Eapen: None. J.G. Karam: None. Gonadotroph adenomas are the most common subtype of nonfunctional pituitary adenomas, with 35 percent secreting enough LH or FSH to raise serum gonadotropin levels, but clinical syndromes due to hypersecretion of gonadotropins are rare. A low testosterone level with high FSH or LH can mislead to a diagnosis of concomitant primary hypogonadism rather than a secreting pituitary adenoma. We present a case of a patient with an FSH-secreting pituitary macroadenoma presenting with low testosterone levels. The patient is a 67-year-old man incidentally found to have a pituitary macroadenoma measuring 12 x 13 x 12 millimeters, impinging upon the optic chiasm on MRI of the brain obtained for headaches. Visual field tests revealed abnormalities compatible with glaucoma, but not chiasm compression. He has no symptoms of hormonal excess or deficit, although his wife reported decreased erectile function. Physical examination was unremarkable except for an atrophic left testicle. Pituitary hormone function tests (ACTH, AM cortisol, IGF-1, prolactin, thyroid function tests, and 24-hour urine free cortisol) were within normal range, except for an elevated FSH 14.8-18.1 mIU/mL and decreased testosterone in range of 185-256 ng/dL, with normal LH at 7.0 mIU/mL, for which he was referred for urology for evaluation of primary hypogonadism. The patient underwent transsphenoidal resection of the pituitary adenoma. Postoperative pathology revealed a pituitary adenoma, gonadotroph cell type, with immunohistochemical staining scattered positive FSH, and rare positive LH. Postoperative MRI showed post-surgical changes with no residual nodular enhancement. Following surgery, the patient suffered from severe clinical hypogonadism with episodes of profuse diaphoresis and extreme fatigue. Postoperative laboratory values revealed panhypopituitarism with undetectable testosterone level, and low LH and FSH levels. The patient was successfully treated with hydrocortisone, levothyroxine, and testosterone, with resolution of his symptoms. Our patient presented with a pituitary macroadenoma, low testosterone, and high FSH suggestive initially of primary hypogonadism, but found ultimately to have an FSH-secreting adenoma. He likely had underlying hypogonadism, primary or secondary, and although his adenoma secreted FSH, it was not enough to maintain testosterone level in normal range, possibly in part due to biologically inactive FSH molecules or to primary testicular failure. The extremely low testosterone levels postoperatively suggest that his testicular function was mostly stimulated by the adenoma secreted FSH and was therefore drastically lost after surgery. This case increases awareness to consider a gonadotropin-secreting tumor in the differential diagnosis of a pituitary adenoma with high FSH or LH, even when testosterone level is unexpectedly low. Presentation: Thursday, June 15, 2023