Risks of Serious Injury with Testosterone Treatment.

BACKGROUND: Injury causes significant morbidity and mortality that is sometimes attributed to testosterone and violence. We hypothesized that prescribed testosterone might be associated with the subsequent risk of serious injury. METHODS: We conducted a self-matched individual-patient exposure-crossover analysis comparing injury risks before and after initiation of testosterone. We selected adults treated with testosterone in Ontario, Canada, from October 1, 2012, to October 1, 2017 (enrollment) and continued until October 1, 2018 (follow-up). The primary outcome was defined as an acute traumatic event that required emergency medical care. RESULTS: A total of 64,386 patients were treated with testosterone of whom 89% were men with a median age of 52 years. We identified 34,439 serious injuries during the baseline interval before starting testosterone (584 per month) and 7349 serious injuries during the subsequent interval after starting testosterone (565 per month). Rates of injuries were substantially above the population norm in both intervals with no significant increased risk after starting testosterone (relative risk = 1.00; 95% confidence interval: 0.96-1.04, P = 0.850). The unchanged risk extended to diverse patients, was observed for different formulations and applied to all injury mechanisms. In contrast, testosterone treatment was associated with a 48% increased risk of a thromboembolic event (relative risk = 1.48; 95% confidence interval: 1.25-1.74, P < 0.001). CONCLUSIONS: Testosterone treatment was associated with a substantial baseline risk of serious injury that did not increase further after starting therapy. Physicians prescribing testosterone could consider basic safety reminders to mitigate injury risks.

Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.

BACKGROUND: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). OBJECTIVE: To review the mechanism by which TRT could damage the cardiovascular system. MATERIALS AND METHODS: Comprehensive literature search of recent clinical and experimental studies. RESULTS: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via ß1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. DISCUSSION: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. CONCLUSIONS: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Critical evaluation of different available guidelines for late-onset hypogonadism.

BACKGROUND: Late-onset hypogonadism (LOH) is a syndrome characterized by clinical and biochemical evidence of low testosterone levels with advancing age. In recent years, several guidelines, position statements and other recommendations have become available. It is unclear whether similar indications are reported in these documents. OBJECTIVE: To review similarities and differences among available documents on the management of hypogonadism, with a special focus on LOH. MATERIALS AND METHODS: PubMed, Google and international societies websites were searched on March 2020 for documents published in the last 10 years on the management of hypogonadism and LOH. RESULTS: Nine documents were found, each developed by: (a) the American Urological Association; (b) the British Society for Sexual Medicine; (c) the Canadian Medical Association; (d) the Endocrine Society; (e) the Endocrine Society of Australia; (f) the European Academy of Andrology; (g) the European Association of Urology; (h) the International Consultation for Sexual Medicine; and (i) the International Society for the Study of Aging Male. DISCUSSION: Despite similar principles, differences were found both for the diagnostic workup and follow-up. Particularly, discrepancies were reported both for total and free testosterone levels for diagnosis and for total testosterone for monitoring. CONCLUSION: Available documents differ in terms of specific recommendations for the management of hypogonadism and LOH. Given the relevant clinical implications of adequate management of these disorders, future guidelines should report more consistent measures to be adopted in clinical practice.

Late-onset hypogonadism: Prostate safety.

BACKGROUND: There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. OBJECTIVES: The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. RESULTS: Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. CONCLUSION: Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?

INTRODUCTION: Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. METHODS: We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. RESULTS: Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11-256) and follow-up time was relatively short (6 weeks to 12 months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. CONCLUSION: AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long-term safety profile.

Obesity and male hypogonadism: Tales of a vicious cycle.

Obesity prevalence, particularly in children and young adults, is perilously increasing worldwide foreseeing serious negative health impacts in the future to come. Obesity is linked to impaired male gonadal function and is currently a major cause of hypogonadism. Besides signs and symptoms directly derived from decreased circulating testosterone levels, males with obesity also present poor fertility outcomes, further evidencing the parallelism between obesity and male reproductive function. In addition, males with androgen deficiency also exhibit increased fat accumulation and reduced muscle and mineral bone mass. Thus, compelling evidence highlights a vicious cycle where male hypogonadism can lead to increased adiposity, while obesity can be a cause for male hypogonadism. On the opposite direction, sustained weight loss can attain amelioration of male gonadal function. In this scenario, a thorough evaluation of gonadal function in men with obesity is crucial to dissect the causes from the consequences in order to target clinical interventions towards maximized improvement of reproductive health. This review will address the causes and consequences of the bidirectional relationship between obesity and hypogonadism, highlighting the implicit male reproductive repercussions.

MOSH Syndrome (Male Obesity Secondary Hypogonadism): Clinical Assessment and Possible Therapeutic Approaches.

Male obesity secondary hypogonadism (MOSH) impairs fertility, sexual function, bone mineralization, fat metabolism, cognitive function, deteriorates muscle mass and alters body composition. The aim of this pilot study was to evaluate the effect of dietary intervention and physical activity on the MOSH patient's hormonal profile after a 10% weight loss compared to baseline. Fourteen male patients were enrolled. Hormonal, lipid, glycemic profiles and body composition were determined at baseline and after a 10% weight loss. Aging Male Symptoms Scale (AMS) and Yale Food Addiction Scale (YFAS) were administered to patients in order to investigate hypogonadal symptoms and food addiction. Compared to baseline, a significant increase of Total Testosterone (TT) (300.2 ± 79.5 ng/dL vs. 408.3 ± 125.9 ng/dL, p = 0.002, 95% CI 26.8; 167.7) and a reduction of 17-Beta Estradiol level (48.3 ± 14.9 pg/mL vs. 39.2 ± 15.2 pg/mL, p = 0.049, 95% CI 3.1; 0.0) were observed. Total Fat Mass (FM) percentage, android and gynoid fat mass percentage (39.2 ± 6.4% vs. 36.2 ± 5.8%, p = 0.0001, 95% CI 22.5; 62.3; 51.5 ± 6.8% vs. 47.6 ± 6.8%, p = 0.001, 95% CI 0.6; 1.8, vs. 39.2 ± 6.2% vs. 36.5 ± 6.3% p = 0.0001, 95% CI 0.9; 2.0 respectively) were significantly decreased after nutritional intervention. In addition, total Fat Free Mass (FFM) in kg was significantly reduced after 10% weight loss (62.3 ± 2.8 kg vs. 60.3 ± 7.7 kg, p = 0.002, 95% CI 45.0; 93.0). Lifestyle changes, specifically dietotherapy and physical activity, induce positive effects on hypogonadism due to obesity.

The correlation between highly sensitive C-reactive protein levels and erectile function among men with late-onset hypogonadism.

We investigated the correlation between highly sensitive C-reactive protein (hs-CRP) levels and erectile function, and assessed the clinical role of hs-CRP levels in men with late-onset hypogonadism (LOH) syndrome. For 77 participants, we assessed Sexual Health Inventory for men (SHIM) score, Aging Male Symptoms (AMS) score and International Prostate Symptom Score (IPSS). We also evaluated free testosterone (FT), hs-CRP, total cholesterol, triglyceride levels, high density lipoprotein cholesterol, hemoglobin A1c, body mass index, waist size and blood pressure. We attempted to identify parameters correlated with SHIM score and to determine the factors affecting cardiovascular risk based on hs-CRP levels. A Spearman rank correlation test revealed that age, AMS score, IPSS and hs-CRP levels were significantly correlated with SHIM score. Age-adjusted analysis revealed that hs-CRP and IPSS were the independent factors affecting SHIM score (r= -0.304 and -0.322, respectively). Seventeen patients belonged to the moderate to high risk group for cardiovascular disease, whereas the remaining 60 belonged to the low risk group. Age, FT value and SHIM score showed significant differences between the two groups. A multivariate regression analysis demonstrated that SHIM score was an independent factor affecting cardiovascular risk (OR: 0.796; 95%CI: 0.637-0.995).

RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries, penile length and girth, erectile function, and nocturnal penile tumescence and duration.

BACKGROUND: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man's self-esteem and as a result partner relationship and quality of life. OBJECTIVES: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n = 88) with symptomatic LOH complaints and symptoms. MAIN OUTCOME MEASURES: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT. MATERIALS AND METHODS: Eighty-eight LOH men (Mage 51.1 years) with erectile dysfunction, all with serum TT <10.4 nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months. RESULTS: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12 min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16 cm/s) and end diastolic velocity of the penile arteries. CONCLUSION: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.

[Testosterone deficiency, metabolic syndrome and diabetes mellitus]. / Déficit de testosterona, síndrome metabólico y diabetes mellitus.

Testosterone deficiency in adult age is associated with a decrease in libido, energy, hematocrit, muscle mass and bone mineral density, as well as with depression. More recently, testosterone deficiency has also been associated with various components of the metabolic syndrome, which in turn is associated with a five-fold increase in the risk of cardiovascular disease. Low testosterone levels are associated with increased insulin resistance, increase in fat mass, low HDL cholesterol, higher triglyceride levels and hypertension. Testosterone replacement therapy in patients with testosterone deficiency and type 2 diabetes mellitus and/or metabolic syndrome has shown reductions in insulin resistance, total cholesterol, LDL cholesterol and triglycerides and improvement in glycemic control and anthropometric parameters.

Male obesity and subfertility, is it really about increased adiposity?

The prevalence of overweight and obesity in reproductive-aged men is increasing worldwide, with >70% of men >18 years classified as overweight or obese in some western nations. Male obesity is associated with male subfertility, impairing sex hormones, reducing sperm counts, increasing oxidative sperm DNA damage and changing the epigenetic status of sperm. These changes to sperm function as a result of obesity, are further associated with impaired embryo development, reduced live birth rates and increased miscarriage rates in humans. Animal models have suggested that these adverse reproductive effects can be transmitted to the offspring; suggesting that men's health at conception may affect the health of their children. In addition to higher adiposity, male obesity is associated with comorbidities, including metabolic syndrome, hypercholesterolemia, hyperleptinemia and a pro-inflammatory state, all which have independently been linked with male subfertility. Taken together, these findings suggest that the effects of male obesity on fertility are likely multifactorial, with associated comorbidities also influencing sperm, pregnancy and subsequent child health.

[Plasma testosterone, obesity, metabolic syndrome and diabetes]. / Testostérone plasmatique, obésité, syndrome métabolique et diabète.

The frequency of diabetes and/or metabolic syndrome rises concurrently with that of body mass index (BMI). In adult men, plasma testosterone level changes evolve inversely to that of BMI. Plasma total testosterone, sex hormone-binding globulin (SHBG) and free testosterone are significantly lower in adult men with a clinical and biological pattern of metabolic syndrome (MetS) than in those without such a pattern. After adjustment for confounding factors, diabetes type 2 (DT2) remains associated with a significant decrease of plasma testosterone level. The androgenic blockade, used as a treatment for disseminated prostate cancer, induces a metabolic pattern similar to MetS. In men older than 65 years, a decrease of plasma testosterone level is associated with an increased risk of stroke or of death linked to a cardiovascular event. After exclusion of contraindications, the substitution with androgens of a demonstrated hypogonadism in a obese patient, notably when obesity is associated with a pattern of MetS and/or a DT2, could have some metabolic and cardiovascular advantages.

The effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis.

CONTEXT: Androgen-replacement therapy (ART) is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism syndrome. Urologists have been concerned about the possibility of ART causing prostate growth. OBJECTIVE: To assess the relationship between ART and prostate growth. EVIDENCE ACQUISITION: A literature review was performed to identify all published randomized controlled trials (RCTs) of androgen treatment for hypogonadism. The search included the Medline, Embase, and Cochrane Controlled Trials Register databases. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis were conducted. EVIDENCE SYNTHESIS: Results of 16 RCTs involving a total of 1030 patients were analyzed. Seven RCTs were short-term (<12 mo) and nine were long-term (12-36 mo) comparisons of ART with a placebo; ART was administered transdermally, orally, or by injection. Respective p values for injection, transdermal administration, and oral administration of short-term ART were as follows: PSA level: 0.07, 0.01, and 0.95; prostate volume: 0.70, 0.79, and 0.32; IPSS: 0.78, 0.98, and no oral; Qmax: 0.92, no transdermal, and 0.10. Respective p values for injection, transdermal administration, and oral administration of long-term ART were as follows: PSA level: 0.42, 0.51, and 0.57; prostate volume: 0.35, 0.59, and 0.47; IPSS: 0.34, 0.32, and 0.97; Qmax: 0.11, 0.63, and no oral. Neither short-term nor long-term ART showed significant changes in the four determinants of prostate growth investigated compared with placebo. CONCLUSIONS: This meta-analysis shows that regardless of the administration method, neither short-term nor long-term ART increases the risk of prostate growth. Further high-quality, prospective studies are required to confirm this observation.

Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach.

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

Fertile eunuch syndrome with the mutations (Trp8Arg and Ile15Thr) in the beta subunit of luteinizing hormone.

Fertile eunuch syndrome is caused by isolated LH deficiency, but its pathophysiology still remains controversial. We report a case of fertile eunuch syndrome with homozygous Trp8Arg and Ile15Thr mutations in the LH beta subunit gene. An 18-year-old man was admitted to our hospital for hypogonadism. Examination of genitalia revealed Tanner G1PH1, whereas both testes were elastically palpated and developed up to 18 ml. Endocrinological evaluations revealed normogonadotropic hypogonadism and there were normal responses after GnRH and hCG stimulation. Intratesticular testosterone concentration was almost normal (1.34 x 10(3) ng/g). By PCR direct sequencing, homozygous Trp (8) Arg and Ile (15) Thr mutations in exon 2 of LH beta were detected. Normal virilization and improved semen parameters were achieved after hCG supplementation. To our knowledge, this is the first case of fertile eunuch syndrome with homozygous Trp (8) Arg and Ile (15) Thr mutations in beta subunit of LH gene.

The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor.

Mutations in the GnRH receptor (GnRH-R) gene have been reported to cause idiopathic hypogonadotropic hypogonadism (IHH). Herein, we describe a 26-yr-old male with a mild phenotypic form of IHH, the fertile eunuch syndrome (IHH in the presence of normal testicular size and some degree of spermatogenesis), associated with a homozygous mutation (Gln106Arg) in the GnRH-R. This mutation, located in the first extracellular loop of the GnRH-R, has been previously shown to decrease but not eliminate GnRH binding. The proband had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and a normal adult male testicular size of 17 mL at baseline. After only 4 months of treatment with hCG alone, he developed sperm in his ejaculate and his wife conceived. Following cessation of hCG therapy, the patient demonstrated reversal of his hypogonadotropism as evidenced by normal adult male testosterone levels and the appearance of pulsatile luteinizing hormone secretion. This case thus expands the emerging clinical spectrum of GnRH-R mutations, provides the first genetic basis for the fertile eunuch variant of IHH and documents the occurrence of reversible IHH in a patient with a GnRH-R mutation.