App-based Therapy of Erectile Dysfunction Using a Digital Health Application (EDDIG Study): A Randomized, Single-blind, Controlled Trial.

BACKGROUND AND OBJECTIVE: While international guidelines advocate for a multifaceted approach to treating erectile dysfunction (ED) involving physical activities, psychological support, and education, structured programs are infrequent. To address this gap, an app-based therapy was developed, offering a systematic approach. This randomized, single-blind controlled trial aimed to assess the effectiveness of an app-based therapeutic in improving ED. METHODS: A total of 241 patients (49.74, standard deviation 12.73 yr) with ED (International Index of Erectile Function [IIEF]-5 <22) were randomized to the 12-wk app-based therapy (treatment group [TG], n = 122) or a waiting list for the app with continuation of their current management protocol (control group [CG], n = 119). Patients on long-term medication for ED were included, but subsequent exclusion occurred for those starting new medication. Coprimary endpoints were improvements from baseline to 12 wk in erectile function (IIEF-5), disease-related quality of life (QOL-Med-15), and patient activation (Patient Activation Measure [PAM-13]). KEY FINDINGS AND LIMITATIONS: Erectile function (IIEF-5) improved by 4.5 points in the TG versus 0.2 points in the CG (p < 0.0001, 95% confidence interval [CI] 3.4-5.0) group. Quality of life (QOL-Med) improved by 20.5 points in the TG versus -0.0 points in the CG (p < 0.0001, 95% CI 19.2-26.0) group. Patient activation (PAM-13) improved by 11.2 points in the TG versus 0.6 points in the CG (p < 0.0001, 95% CI 9.1-13.6) group. Phosphodiesterase type 5 inhibitor intake had no influence on all observed treatment effects. CONCLUSIONS AND CLINICAL IMPLICATIONS: App-based therapy of patients with ED provided a significant, clinically meaningful improvement. Quality of life and patient activation were also enhanced significantly. This program has the potential to change clinical practice in the treatment of ED. PATIENT SUMMARY: A therapy app improved sexual function and overall well-being for men experiencing erectile dysfunction, leading to better quality of life.

Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

OBJECTIVE: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD. METHODS: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established via linear/multiple regression. RESULTS: TU was significantly associated with lower AMSS values compared with that at baseline/prior assessment during the initial 42 months treatment; 259 of the 260 men showed improvement. In the 361 men not on TU, AMSS values increased during 60 months of follow-up compared with that at baseline/prior assessment; improvement after 60 months was evident in 1 man, whilst AMSS remained the same or worsened in 213 and 147 men, respectively. In men on TU, baseline AMSS was inversely associated with ΔAMSS (R2 = 0.97), with no other factors reaching significance. Baseline AMSS, age, serum total testosterone (TT), waist circumference (WC), and diastolic blood pressure (BP) were associated with ΔAMSS in men not on TU. DISCUSSION: We show that TU was associated with lower AMSS in men with adult-onset TD whilst non-treatment led to increased values. Baseline AMSS values inversely predicted ΔAMSS in both groups.

TRACK_9: Testosterone replacement assessment: Classical vs. functional hypogonadism­knowledge from a 9­year study

BACKGROUND AND OBJECTIVE: The longitudinal efficacy and clinical utility of Testosterone Therapy (TTh) in ameliorating functional hypogonadism (FH) remain contentious, with long-term data being scarce. To address this lacuna, a comprehensive long-term registry study, stratifying patients across a spectrum of hypogonadal etiologies, offers a robust investigative paradigm. MATERIALS AND METHODS: This 9-year registry, encompassing 650 patients (equivalent to 4,362 cumulative years of treatment), included 188 patients diagnosed with FH (mean age 42.3 ± 11.3 years) and 462 individuals with classical hypogonadism (CH). The cohort segregated into 266 men with primary hypogonadism (PH, mean age 34.0 ± 11.7 years) and 196 with secondary hypogonadism (SH, mean age 31.9 ± 12.0 years). Uniform treatment across the cohort involved intramuscular administration of testosterone undecanoate (1,000 mg). A comparative analysis was conducted focusing on anthropometric, metabolic, and safety parameters. RESULTS: Serum testosterone levels increased from 6.6 ± 2.4 to 19.3 ± 2.9 nmol/L (p < 0.001). TTh was linked with weight reduction and decreased waist circumference (WC) in both CH and FH cohorts (both p < 0.001). Cox regression and Kaplan-Meier analyses delineated disparities: men with FH demonstrated a higher propensity for losing > 10% body weight and > 5% WC compared to CH (hazard ratio [HR] 1.3 [1.1-1.4], p = 0.008 and HR 1.4 [1.3-1.5], p = 0.001). Increases in hematocrit > 50% were uniform across groups, albeit amelioration of anemia was more pronounced in FH versus CH (p = 0.002). Increments of prostate-specific antigen (PSA) levels were more likely to occur in FH (HR 1.3 [1.1-1.6], p = 0.003). FH patients exhibited pronounced improvements in metabolic parameters and in aging male symptom score (AMS) and IIEF-EF questionnaire scores. These effects were markedly modulated by age and initial weight. Subgroup analysis of age-matched obese patients revealed an accentuated impact of TTh in CH compared to FH. DISCUSSION AND CONCLUSION: The therapeutic outcomes of TTh across distinct hypogonadal populations demonstrate heterogeneous responses, significantly influenced by diagnostic categorization, age, and baseline risk factor profiles.

Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

AIMS: To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). MATERIALS AND METHODS: A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). RESULTS: The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). CONCLUSIONS: Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.

Novel perspectives of testosterone therapy in men with functional hypogonadism: traversing the gaps of knowledge.

INTRODUCTION: In the past decade, there has been a significant augmentation in the corpus of evidence pertaining to functional hypogonadism. Despite this, prevailing clinical guidelines continue to advise against the universal screening for hypogonadism in middle-aged and elderly males. FINDINGS: Numerous randomized controlled trials have scrutinized the effects of testosterone therapy in males afflicted with type 2 diabetes and/or obesity. However, these guidelines uniformly assert that lifestyle modifications and weight reduction should be the primary intervention strategies in overweight and obese males, relegating testosterone therapy to a secondary, selective option. It is extensively documented that testosterone therapy can yield substantial improvements in various metabolic parameters as well as ameliorate symptoms of erectile dysfunction. Moreover, recent studies have demonstrated the potential of testosterone therapy in reversing type 2 diabetes in males with low-normal testosterone levels who are at elevated risk for this condition, in comparison to the outcomes achievable through lifestyle modifications alone. CONCLUSION: This focused review article aims to present a comprehensive update on the latest data concerning the innovative aspects of testosterone therapy in males with functional hypogonadism, particularly in the context of type 2 diabetes and/or obesity. Additionally, it will delve into the cardiovascular safety of such interventions within this high-risk demographic, with a special emphasis on insights gleaned from the TRAVERSE trial.

Spontaneous alterations in semen parameters are associated with age, accessory gland function and the FSHB c.-211G>T variant.

BACKGROUND: There is a strong within-subject alteration of semen parameters in men with infertility. However, it remains unknown in which subgroup variations are likely to occur and which semen parameters are affected. OBJECTIVE: To evaluate parameters associated with spontaneous alterations in semen analysis. PATIENTS AND METHODS: We retrospectively selected 3456 men with infertility without known causes affecting spermatogenesis or sperm output for analysis of repeated ejaculate samples. Exclusion criteria comprised sperm concentration <1 million/mL, abnormal follicle-stimulating hormone or low testosterone, and low bitesticular volume (<10 mL). Grouped linear two-level nested mixed-effect models were applied. The analyzed parameters included abstinence time, bitesticular volume, age, accessory gland markers, follicle-stimulating hormone, and FSHB c.-211 variants. RESULTS: Groups include A (n = 397): ≥1.0 to <5.0 million/mL, B (n = 708): ≥5.0 to <15.0 million/mL, and C (n = 2351): ≥15.0 million/mL. Groups A, B, and C: changes in ejaculate volume were associated with alterations in total sperm count and motility (p < 0.003). Changes were, controlled for abstinence time (p < 0.001), related to α-glucosidase, fructose, or zinc (p = 0.005-0.02). Group A + B: fluctuations in follicle-stimulating hormone level influenced sperm concentration/count (p = 0.004-0.02), albeit only in men with FSHB c.-211 GG (p = 0.007-0.02). T-allele carriers did not show changes in follicle-stimulating hormone levels (p > 0.1). Group B: age <50 years (p = 0.007-0.01) and normal bitesticular volume (p = 0.008-0.02) were associated with spontaneous increases in sperm concentration, count, and motility. CONCLUSION: Semen parameters exhibit intra-individual alterations associated with organic, hormonal, and genetic variables. Changes are pronounced in younger men with normal bitesticular volume and oligozoospermia to almost normozoospermia. The effect is modulated by abstinence time, accessory gland function, and fluctuations in follicle-stimulating hormone level, which is bound to FSHB c.-211G>T variant. Judgment of semen analysis should be based on two semen samples, with abstinence times between 4 and 5 days. As a future perspective, it might be investigated whether younger men with normal bitesticular volume who are unable to elicit increases in serum follicle-stimulating hormone (FSHB c.-211 genotype of GT/TT) benefit from improving accessory gland function and increasing follicle-stimulating hormone.

[Interdisciplinary and Psychiatric Treatment of Anabolic Androgenic Steroids Users]. / Interdisziplinäre und psychiatrisch-psychotherapeutische Behandlung bei Gebrauch von anabolen androgenen Steroiden.

Interdisciplinary and Psychiatric Treatment of Anabolic Androgenic Steroids Users Abstract. The prevalence of anabolic androgenic steroid (AAS; anabolic steroids) use in recreational sports is underestimated. Due to the influence of social media, an increase in AAS use in recreational sports and in the general population is to be expected. AAS use is associated with significant physical and mental health consequences, and the psychiatric consequences include the risk of developing addictive behaviour. The widespread stigmatization of AAS use also by professionals often undermines users' trust in physicians and drives them into the arms of so-called "gurus." The tightening of anti-doping practices in sports and an exclusively prohibitive stance have so far failed to convincingly curb the problem in recreational sports. Harm reduction strategies could help patients to get the help they need from primary care providers.

Interdisciplinary and Psychiatric Treatment of Anabolic Androgenic Steroids Users.

The prevalence of anabolic androgenic steroid (AAS; anabolic steroids) use in recreational sports is underestimated. Due to the influence of social media, an increase in AAS use in recreational sports and in the general population is to be expected. AAS use is associated with significant physical and mental health consequences, and the psychiatric consequences include the risk of developing addictive behaviour. The widespread stigmatization of AAS use also by professionals often undermines users' trust in physicians and drives them into the arms of so-called "gurus." The tightening of anti-doping practices in sports and an exclusively prohibitive stance have so far failed to convincingly curb the problem in recreational sports. Harm reduction strategies could help patients to get the help they need from primary care providers.

[IPED Use in Recreational Sports]. / IPED-Gebrauch im Freizeitsport.

IPED Use in Recreational Sports Abstract. Abtract: IPED consumers seek medical advice when uncertain as to their use. Due to shame or fear of stigmatization IPED consumers are often reluctant to talk about their drug use; they fear prejudice and a lack of experience when caring for this specific patient group. In order to strengthen trust, a non-judgmental, non-stigmatizing and supportive attitude is essential. The interaction should primarily lead to an understanding of why AAS are being used, what the patient's concerns are, and why medical help is being sought, without judgment or condemnation of the behavior. If no motivation to abstain from drug use is found during the consultation, harm reduction should be sought and the consequences of use addressed. Regular talks and active harm reduction can increase the confidence in evidence-based treatment to achieve personal motivation to abstain under medical supervision.

IPED in Recreational Sports.

IPED consumers seek medical advice when uncertain as to their use. Due to shame or fear of stigmatization IPED consumers are often reluctant to talk about their drug use; they fear prejudice and a lack of experience when caring for this specific patient group. In order to strengthen trust, a non-judgmental, non-stigmatizing and supportive attitude is essential. The interaction should primarily lead to an understanding of why AAS are being used, what the patient's concerns are, and why medical help is being sought, without judgment or condemnation of the behavior. If no motivation to abstain from drug use is found during the consultation, harm reduction should be sought and the consequences of use addressed. Regular talks and active harm reduction can increase the confidence in evidence-based treatment to achieve personal motivation to abstain under medical supervision.

The HEAT-Registry (HEmatopoietic Affection by Testosterone): comparison of a transdermal gel vs long-acting intramuscular testosterone undecanoate in hypogonadal men.

CONTEXT: Testosterone (T) therapy of hypogonadal men requires stable kinetics, tolerance and attenuation of symptoms. Both intramuscular injections of the long-acting ester T undecanoate (TU) and transdermal application of T gel offer a proven efficacy. As T has marked effects on hematopoiesis, an elevation of hematocrit has to be considered during T therapy. OBJECTIVE: To compare the effects of a transdermal T gel with long-acting intramuscular TU on hematopoiesis, controlling for age, diagnosis, androgen receptor susceptibility and obesity. DESIGN: Prospective two-arm open registry, minimum duration of 26 weeks per patient. Putative modulators of erythropoiesis entering regression models were type of medication, type of hypogonadism, delta of total testosterone concentrations, waist circumference, age as well as (in a sub-group) androgen receptor gene CAG repeat length. SETTING: Tertiary university based andrological outpatient department. PATIENTS: 802 hypogonadal men, 498 receiving T gel and 304 receiving intramuscular TU, median age 40 years (interquartile range = 25). RESULTS: Follow-up visits after initiation of treatment occurred between treatment weeks 26-30. Serum T concentrations increased markedly in both patient groups. Men receiving intramuscular TU exhibited an increased hematocrit (>50%) to a significantly higher amount than men receiving T gel (69/304 vs. 25/498, p < 0.001). Corresponding results were seen for higher values of hematocrit (>52% and >54%). Advanced age (p = 0.009), higher waist circumference (p = 0.01), higher delta testosterone (p = 0.007) and functional vs classical hypogonadism (p = 0.04) contributed to the effect in stepwise multiple regression models. Attenuated androgen action (longer androgen receptor CAG repeats) mitigated the effect (p = 0.01) in a subgroup of 574 patients. Men with anemia (hemoglobin ≤12.7 g/dl) were more likely to move out of the pathological range when receiving TU vs T gel (41/53 vs. 49/89 p = 0.01). CONCLUSIONS: T substitution with intramuscular TU or T gel increase T concentrations effectively. Long-acting TU leads to a higher rate of hematocrit levels >50%, whilst at the same time it seems to be more efficient to ameliorate anemia in the subgroup of respectively affected hypogonadal patients . This applies especially to obese older men with functional hypogonadism.

German version of the Hypogonadism Impact of Symptoms Questionnaire: Psychometric properties and association with testosterone levels.

In German, the 'Aging Males' Symptom Scale (AMS)' is available for the assessment of symptoms of hypogonadism in men of advanced age. An English questionnaire named 'Hypogonadism Impact of Symptoms' (HIS-Q), applicable also in young males has recently been developed in the United States. We intended to: (1) evaluate the psychometric properties of the German translation of the short form of the HIS-Q (HIS-Q-SF-D); (2) explore the association of individual patient scores with their respective serum testosterone levels. The HIS-Q-SF-D was completed by 174 men attending an Andrology outpatient clinic. Test-retest reliability was excellent, with high test-retest correlations (r = 0.883) and Cronbach`s Alpha of 0.948 for the total score. Convergent validity was supported by high Spearman`s correlation between the HIS-Q-SF-D total score and the AMS total score (r = 0.817); also by the significant differences in the HIS-Q-SF-domain scores between males with total testosterone levels above and below 12 nmol/l. Therefore, the HIS-Q-SF-D shows good psychometric properties. As shown by the ROC-analyses for testosterone above and below levels of 12 nmol/l, the HIS-Q-SF-D cannot replace testosterone measurement for the establishment of the diagnosis of male hypogonadism.

Machine learning based prediction models in male reproductive health: Development of a proof-of-concept model for Klinefelter Syndrome in azoospermic patients.

BACKGROUND: Due to the highly variable clinical phenotype, Klinefelter Syndrome is underdiagnosed. OBJECTIVE: Assessment of supervised machine learning based prediction models for identification of Klinefelter Syndrome among azoospermic patients, and comparison to expert clinical evaluation. MATERIALS AND METHODS: Retrospective patient data (karyotype, age, height, weight, testis volume, follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, prolactin, semen pH and semen volume) collected between January 2005 and June 2019 were retrieved from a patient data bank of a University Centre. Models were trained, validated and benchmarked based on different supervised machine learning algorithms. Models were then tested on an independent, prospectively acquired set of patient data (between July 2019 and July 2020). Benchmarking against physicians was performed in addition. RESULTS: Based on average performance, support vector machines and CatBoost were particularly well-suited models, with 100% sensitivity and >93% specificity on the test dataset. Compared to a group of 18 expert clinicians, the machine learning models had significantly better median sensitivity (100% vs. 87.5%, p = 0.0455) and fared comparably with regards to specificity (90% vs. 89.9%, p = 0.4795), thereby possibly improving diagnosis rate. A Klinefelter Syndrome Score Calculator based on the prediction models is available on http://klinefelter-score-calculator.uni-muenster.de. DISCUSSION: Differentiating Klinefelter Syndrome patients from azoospermic patients with normal karyotype (46,XY) is a problem that can be solved with supervised machine learning techniques, improving patient care. CONCLUSIONS: Machine learning could improve the diagnostic rate of Klinefelter Syndrome among azoospermic patients, even more for less-experienced physicians.

The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers.

INTRODUCTION: Long term complications of COVID-19, the disease caused by the SARS-CoV-2, involve many organ systems, dramatically worsening the quality of life, and finally contributing to impaired physical functioning. Despite the presence of well-identified pathogenetic mechanisms, the effect of "Long COVID" on sexual health has been only marginally addressed. OBJECTIVES: To provide coverage of the current literature on long COVID, its epidemiology, pathophysiology, and relevance for erectile function. METHODS: Comprehensive review of literature pertaining to the epidemiology and pathophysiology of long COVID, and its relevance for erectile function. RESULTS: Symptoms of long COVID are highly prevalent and involve almost all systems of the human body, with a plethora of clinical manifestations which range from minor nuisances to life-threatening conditions. "Brain fog" and fatigue are the most common complaints, although other neuropsychiatric complications, including sensory dysfunctions, anxiety, depression, and cerebrovascular events have also been reported. The respiratory and cardiovascular systems are also affected, with dyspnea, pulmonary fibrosis, endothelial dysfunction, and myocarditis occurring in some COVID long haulers. A subset of patients might develop endocrine manifestations, including onset of diabetes, thyroid dysfunction, and hypogonadism. Overall, long COVID features many complications which can impair erectile function by multiple pathogenetic mechanisms, and which could require tailored treatment: (i) careful investigation and management from the sexual medicine expert are therefore much needed, (ii) and future research on this topic is warranted. CONCLUSION: in COVID-19 long haulers, several complications can adversely affect erectile function which, upon future tailored studies, could be used as biomarker for the severity of the long COVID disease and for its follow-up. Sansone A, Mollaioli D, Limoncin E et al. The Sexual Long COVID (SLC): Erectile Dysfunction as a Biomarker of Systemic Complications for COVID-19 Long Haulers. Sex Med Rev 2022;10:271-285.

New Insights Into Extended Steroid Hormone Profiles in Transwomen in a Multi-Center Setting in Germany.

BACKGROUND: Little information is available on steroid hormone profiles in transwomen on the day of gender affirming surgery (GAS) after gender affirming hormone therapy (GAHT). AIM: We compared extended serum steroid hormone profiles of 77 transwomen with 3 different treatment regimens in order to get more insight on how GAHT changes the hormone system. METHODS: Samples were obtained from 3 independent clinics. Individuals in clinic A (n = 13) and B (n = 51) discontinued GAHT 4-6 weeks and 2 weeks before GAS, individuals in clinic C (n = 13) continued treatment. Testicular tissue, blood samples and questionnaires on age, weight, height, and medication use were received from each patient. Steroid hormones were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), 6 sex hormones were determined by immunofluorometric assays, and ELISA. Spermatogenesis was scored using the Bergman/Kliesch score. OUTCOMES: Participants were not different with regard to age, BMI, treatment duration, and dosage. Feminized blood serum levels with low LH, low FSH and low testosterone, however, were achieved in persons taking GAHT until GAS. Significantly reduced cortisone levels were seen after stopping GAHT before GAS. RESULTS: GAHT had marked effects on the sex-steroid profile in each person. Factor analysis provided a model explaining 78% of the variance and interdependency of sex steroid levels. Stopping treatment was inversely associated with intactness of the corticosteroid-axis with adrenal steroidogenesis as well as it was inversely associated with pituitary-gonadal hormone production. CLINICAL IMPLICATIONS: Transwomen generally did not have elevated cortisone levels but differed significantly depending on and when GAHT was stopped. STRENGTHS & LIMITATIONS: This is the first study examining the steroid hormone profiles of transgender persons on the day of GAS in a multi-center setting. Additional studies (including follow ups before and after GAS and stress questionnaires) will be necessary to assess these conflicting results about the possible psychological impact on persons undergoing GAS to improve care. CONCLUSION: Concerning feminized blood serum levels, continued GAHT seems the better alternative, however stopping treatment 4-6 weeks prior to surgery was associated with reduced cortisone levels. Schneider F, Wistuba J, Holterhus P-M, et al. New Insights Into Extended Steroid Hormone Profiles in Transwomen in a Multi-Center Setting in Germany. J Sex Med 2021;18:1807-1817.

Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men.

The relative proportional increase of the elderly population within many countries will become one of the most significant social transformations of the twenty-first century and, for the first time in history, persons aged 65 or above outnumbered children under five years of age globally. One in four persons living in Europe and Northern America will be aged 65 or over. One of the goals of ISSAM is to raise awareness of the special health needs of older men. Since a significant number of aging men will eventually become testosterone deficient, the Hypogonadism panel of ISSAM updates its guidelines.

Pituitary response to GnRH stimulation tests in different FSHB-211 G/T genotypes.

STUDY QUESTION: Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes? SUMMARY ANSWER: The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs. WHAT IS KNOWN ALREADY: The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.6 ± 10.3 years) undergoing a GnRH stimulation test for diagnostic purposes in cases of secondary hypogonadism. PARTICIPANTS/MATERIALS, SETTING, METHODS: A GnRH stimulation test was performed by administering an i.v. bolus of 100 µg of the GnRH-analogue gonadorelin acetate to all patients, with blood samples drawn from the cubital vein immediately prior to injection (T0) and 30 (T1) and 45 minutes (T2) after. Clinical and genetic data were retrieved from a computerized database. Linear longitudinal mixed-effect models were used to assess the effects of SNP genotype on FSH and LH levels over time via additive and recessive models. MAIN RESULTS AND THE ROLE OF CHANCE: An overall marked increase in serum FSH and LH following administration i.v. of 100 µg of an LHRH-analogue was found (P < 0.0001 for linear trend, both models). Peak levels of LH were significantly higher in TT carriers than in GT and GG carriers (P = 0.012); no significant between-groups difference was found concerning stimulated FSH levels. In both the additive and recessive model, the main effect of T allele(s) did not reach statistical significance concerning FSH levels (P = 0.9502 and P = 0.8576, respectively), yet interaction effects over time demonstrated an attenuated response in T-allele carriers compared to the GG-allele carriers (P = 0.0219 and P = 0.0276). Main and interaction effects for LH were significant in both the additive (P = 0.0022 and P = 0.0013, respectively) and recessive model (P = 0.0025 and P = 0.0016, respectively). LIMITATIONS, REASONS FOR CAUTION: Given the retrospective nature of the study and the small number of TT carriers, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The FSHB c.-211G>T polymorphism might result in an impaired response to endogenous, as well as exogenous, GnRH stimulation. This finding might contribute to the clinical phenotype of reduced testicular volume and sperm count for patients carrying one or two T alleles. STUDY FUNDING/COMPETING INTEREST(S): Parts of the study were supported by the German Research Foundation (CRU326 Male Germ Cells). On behalf of all authors, the corresponding author states that there is no conflict of interest. TRIAL REGISTRATION NUMBER: NA.