Male Hypogonadotropic Hypogonadism Research Articles

Randomized Trial: Combined Vs Monotherapy in Male Hypogonadotropic Hypogonadism

Randomized Trial: Combined Vs Monotherapy in Male Hypogonadotropic Hypogonadism

Kissing Carotid Arteries Causing Male Hypogonadotropic Hypogonadism

Kissing Carotid Arteries Causing Male Hypogonadotropic Hypogonadism

Pulsatile gonadotropin-releasing hormone: clinical applications of a physiologic paradigm

Gonadotropin-releasing hormone (GnRH) is a fundamental driver of human reproduction. A pulsatile pattern of GnRH secretion is essential to achieve pituitary stimulation, gonadotropin secretion, and normal gonadal function. Pulsatile GnRH administration is used to treat anovulation and male hypogonadotropic hypogonadism. Pulsatile GnRH ovulation induction is effective and safe because it allows to avoid ovarian hyperstimulation syndrome and reduce the occurrence of multiple pregnancies. This physiology-inspired therapeutic tool has also permitted to elucidate several pathophysiologic features of human reproductive disorders.

RF25 | PMON76 Kissing carotid arteries: An unusual cause of male hypogonadotropic hypogonadism.

Abstract Background Aneurysms of the internal carotid arteries are a rare cause of pituitary dysfunction1. While there are reports of primary amenorrhea in females due to ectatic internal carotid arteries2, hypogonadism in a male due to "kissing internal carotid arteries" causing compression of the pituitary gland has not previously been reported. Clinical Case A 27-year-old male with history of Crohn's disease, obesity, depression and sleep apnea on CPAP presented to endocrinology clinic for evaluation of low testosterone levels diagnosed 9 months prior to his initial visit. At the time of initial evaluation patient was using intramuscular testosterone cypionate 120mg weekly with total testosterone of 2.43 ng/mL (2.50-9.50 ng/mL). Testosterone replacement therapy was discontinued at that time to assess the hypothalamic-pituitary-gonadal (HPG) axis. After 9 months without testosterone treatment, repeat labs demonstrated total testosterone 0.91 ng/mL, bioavailable testosterone 0.69 ng/mL (1.10-4.0 ng/mL), SHBG 8 nmol/L (10-89 nmol/L), LH 3.1 mIU/mL (2-12 mIU/mL), FSH 2.7 mIU/mL (1.5-10 mIU/mL), estradiol 23 pg/mL (6-44 pg/mL), IGF-1 193 ng/mL (85-310 ng/mL), prolactin 10 ng/mL (3-23 ng/mL), TSH 1.03 mIU/L (0.3-5.5 mIU/L), FT4 1.15 ng/dL (0.76-1.70 ng/dL), 8 AM cortisol 13.5 ug/dL (5.3-22.5 ug/dL) and ACTH 37 pg/mL (5-52 pg/mL). Semen analysis was also performed which was unremarkable. Pituitary MRI revealed symmetric ectatic cavernous portions of the internal carotid arteries compressing and distorting the normal anatomy of the anterior pituitary gland consistent with "kissing carotid arteries." MRA was performed which did not demonstrate aneurysm or malformation of the cavernous internal carotid arteries. Patient was started on subcutaneous semaglutide 0.25mg weekly which was titrated to 1mg weekly for treatment of obesity. Testosterone replacement therapy was not re-initiated given future fertility goals and normal semen analysis. Conclusion To our knowledge, this is the first reported case of kissing internal carotid arteries causing isolated hypogonadotropic hypogonadism in a male patient. References 1) Heshmati HM, Fatourechi V, Dagam SA, Piepgras DG. Hypopituitarism caused by intrasellar aneurysms. Mayo Clin Proc. 2001 Aug;76(8): 789-93. doi: 10.1016/S0025-6196(11)63222-9. PMID: 11499817 2) Sahin M, Dilli A, Karbek B, Unsal IO, Gungunes A, Colak N, Uçan B, Cakal E, Ozbek M, Delibasi T. Unusual cause of primary amenorrhea due to kissing internal carotid arteries. Pituitary. 2012 Jun;15(2): 258-9. doi: 10.1007/s11102-012-0393-9. PMID: 22492265. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:44 p.m. - 12:49 p.m.

Characteristics of male idiopathic hypogonadotropic hypogonadism (IHH) patients

Characteristics of male idiopathic hypogonadotropic hypogonadism (IHH) patients

Energy deficit as a cause of transient male hypogonadotropic hypogonadism: a successful resolution of a primary infertility

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Clinical application of aromatase inhibitors to treat male infertility.

Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia or various degrees of asthenospermia and oligozoospermia. Spermatogenesis is a complex and coordinated process, which is under precise modulation by the hypothalamic-pituitary-gonadal (HPG) axis. An aberrant hormone profile, especially an imbalance between testosterone (T) and estradiol (E2), plays an essential role in male infertility. In the male, E2 is produced mainly from the conversion of T by the aromatase enzyme. Theoretically, reducing an abnormally elevated T:E2 ratio using aromatase inhibitors (AIs) could restore the balance between T and E2 and optimize the HPG axis to support spermatogenesis. For decades, AIs have been used to treat male infertility empirically. However, owing to the lack of large-scale randomized controlled studies and basic research, the treatment efficacy and safety of AIs in male infertility remain controversial. Therefore, there is a need to summarize the clinical trials and relevant basic research on the application of AIs in the treatment of male infertility. In this narrative review, we summarized the application of AIs in the treatment of male infertility, including the pharmacological mechanisms involved, clinical trials focused on patients with different types of infertility, factors affecting treatment efficacy and the side-effects. A literature search was performed using MEDLINE/PubMed and EMBASE, focusing on publications in the past four decades concerning the use of AIs for treating male infertility. The search terms included AI, male infertility, letrozole, anastrozole, testolactone, azoospermia, oligozoospermia, aromatase polymorphisms, obesity and antiestrogens, in various combinations. Clinical studies demonstrate that AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men. Large-scale surveys suggest that obesity may result in symptoms of hypogonadism in both fertile and infertile males, such as decreased semen quality and attenuated sexual function, which can be improved by AIs treatment. Polymorphisms of the aromatase gene CYP19A1, including single nucleotide polymorphisms and tetranucleotide TTTA repeats polymorphism (TTTAn), also influence hormone profiles, semen quality and treatment efficacy of AIs in male hypogonadotropic hypogonadism and infertility. The side-effects of AIs in treating male infertility are various, but most are mild and well tolerated. The application of AIs in treating male infertility has been off-label and empirical for decades. This narrative review has summarized the target patients, dose, treatment duration and side-effects of AIs. Polymorphisms of CYP19A1 that may affect AIs treatment efficacy were also summarized, but a full understanding of the mechanisms involved in AIs action requires further study.

Evaluating the Combination of Human Chorionic Gonadotropin and Clomiphene Citrate in Treatment of Male Hypogonadotropic Hypogonadism: A Prospective Study.

BackgroundIn this study, we evaluated MHH patients who wished to preserve fertility, assessing the efficacy of a short course (12 months) of a combined hCG +clomiphene citrate.Materials and MethodsThe cross-sectional study included 19 patients with hypogonadotropic hypogonadism who were admitted to the Andrology and Fertility Hospital of Hanoi between March 2016 and March 2018. Using hCG every three days in combination with clomiphene citrate 25mg per day until normal testosterone levels are reached, maintain the dose until spermatozoa are present.ResultsThe mean age was 30.2 ± 5.6. Differences in penis length between the time before and after treatment were significant (p=0.005). The average dose of hCG using in our study was 5579 ± 1773.7 IU. After treatment 6 months and 12 months, the changes in clinical features in all patients and the total hypogonadotropic hypogonadism group were statistically significant (p<0.001). In particular, the differences in testosterone hormone levels in the partial hypogonadotropic hypogonadism group were also statistically significant (p=0.03). No adverse event was observed in our study. The number of patients appearing sperm in the semen is 9 patients (47.4%) after 12 months, but most of the sperm were completely deformed (<1%), and the average motility in the progressive motility group was below 8%.ConclusionIn conclusion, a combination of hCG and clomiphene citrate may be an option for MHH patients who desired fertility. After 12 months, 47.4% of patients have sperm in semen but almost all of them were deformity. Hormone profile and secondary sexual characteristics improved significantly. There was no adverse event in our study that considered it as safe therapy.

Patient-reported outcomes and biochemical alterations during hormonal therapy in men with hypogonadotropic hypogonadism who have finished infertility treatment.

Male hypogonadotropic hypogonadism (MHH) is effectively treated by gonadotropins with a high rate of ejaculate sperm and paternity; however, there is no information regarding the appropriate management, including patient-reported outcomes (PROs), of men with MHH who have finished infertility treatment. To compare health-related quality of life, erectile function and biochemical alterations in men with MHH who were treated with testosterone replacement therapy (TRT) or human chorionic gonadotropin (hCG). Twenty-six MHH patients (mean age: 34 years) who needed to improve their androgen deficiency symptoms underwent either hCG therapy (n = 16, started with self-injection of 2,000-7,500 IU per week) or TRT (n = 10, testosterone enanthate 250 mg every 3 weeks). The 36-item Short Form Health Survey (SF-36) questionnaire, five-item International Index of Erectile Function (IIEF-5) and hormonal and biochemical analyses were assessed every 3 months. Changes and comparison of each treatment regarding these parameters were analyzed. Both hCG and TRT significantly improved all domains of the SF-36, except for bodily pain and social functioning. hCG significantly improved the general and mental health domains compared with TRT. Significant improvements in IIEF-5 were observed with both treatments, showing significant improvement with hCG compared to TRT. TRT caused progressive testicular atrophy. There were significant decreases in waist circumference and triglycerides in both treatment groups and significant elevations in prostate-specific antigen and hematocrit. Both hCG and TRT are effective and safe, with preferable PROs by hCG, for treating androgen deficiency in men with MHH who do not need infertility treatment.

Male hypogonadotropic hypogonadism in various genetic disorders

Introduction and purpose: Male hypogonadism is diagnosed in patients with total testosterone under 9-12nmol/L (250-350ng/dl) in serum which is associated with numerous symptoms which can severely lower the quality of patients life. Due to the cause and associated levels of gonadotropins it can be divided to hypergonadotropic and hypogonadotropic hypogonadism. Hypogonadotropic hypogonadism occurs far less often, but it’s considered to remain underdiagnosed. The purpose of this study is to review most of the inborn diseases that involve hypogonadotropic hypogonadism as one of their components.Current state of knowledge: Patients with Kallmann syndrome constitute the majority of confirmed hypogonadotropic hypogonadism cases, however due to variable epidemiological data and differing diagnosing processes the exact incidence cannot be estimated – it ranges from 1 in 85 000, to 1 in 5000 males and about 3-4 times less often in women. Other conditions that can occur with hypogonadotropic hypogonadism are Isolated Gonadotropin-Releasing Hormone deficiency, Gonadotropin disorders, Prader-Willi Syndrome, some pleiotropic syndromes like CHARGE syndrome, Patau syndrome, Pfeiffer syndrome, Hartsfield syndrome, Waardenburg syndrome, Bardet-Biedl syndrome, or other syndromes. The evaluation and treatment of some of these conditions does not involve hypogonadism or other gonadal disorders due to short lifespan, which cause the underestimations in hypogonadism morbidity.Conclusions: Regardless of lower incidence of hypogonadotropic hypogonadism compared to hypergonadotropic type, endocrinologists should stay aware of its under-diagnosis and actively search for signs of low gonadotropic hormones and gonadotropin-releasing hormone levels in hypogonadal patients.

Gonadotropin Treatment for the Male Hypogonadotropic Hypogonadism.

Hypogonadotropic hypogonadism (HH) is caused by a dysfunction in the hypothalamus and/or the pituitary gland and it can be congenital or acquired. This condition is biochemically characterized by low or inappropriately normal gonadotropin levels along with low total testosterone levels. If fertility is not an issue, testosterone therapy is the treatment of choice to induce and maintain secondary sexual characteristics and sexual function. Spermatogenesis is frequently impaired in patients with HH, but usually responsive to hormonal therapy such as gonadotropin therapy or GnRH supplementary/replacement therapy. When gonadotropins are the choice of treatment, conventional therapy includes human chorionic gonadotropin (hCG) along with different FSH formulations: human menopausal gonadotropins (hMG), highly purified urinary FSH preparations (hpFSH) (e.g., urofollitropin) or recombinant FSH (rFSH). The combination of FSH and hCG demonstrated to be associated with better outcomes than single compounds, whereas similar results were obtained with different FSH preparations in male individuals; both regarding the ability to stimulate spermatogenesis and eventually inducing physiology pregnancy. Gonadotropins can be administered either subcutaneously or intramuscularly. The combination therapy with hCG and FSH for a period of 12-24 months was found to promote testicular growth in almost all patients, spermatogenesis in approximately 80% and pregnancy rates in the range of 50%. Gynecomastia is the most common side effect of gonadotropin therapy and is due to hCG stimulation of aromatase causing increased secretion of estradiol. The therapeutic success is higher in patients with post-pubertal HH, in those without previously undescended testes, in patients with higher baseline testicular volume, who underwent repeated cycles of therapy and in patients with higher baseline inhibin B serum concentrations. Reversal of hypogonadism can occur in up to 10% of patients but its physiopathologic mechanism has yet to be elucidated. In conclusion, gonadotropin therapy is effective in promoting puberty and in supporting spermatogenesis onset and preservation in HH patients with either hypothalamic or pituitary conditions.

SUN-092 Effect of Pubertal Induction with Gonadotropins and GnRH Therapy in Male Hypogonadotropic Hypogonadism: Meta-Analysis

Background: The use of gonadotropins is a recent strategy for inducing puberty in adolescent males with hypogonadotropic hypogonadism (HH). Testosterone use has been discouraged in patients who desire to preserve fertility. Human chorionic gonadotropin (hCG) has been recommended for inducing puberty in HH; however, several clinicians administer hCG in combination with other gonadotropins. The benefits of using combination gonadotropin therapies (hCG+) over hCG monotherapy in pre-pubertal adolescent males with HH has not been clearly established. We performed a meta-analysis to assess the outcomes of hCG compared to hCG+ in terms of virilizing effects and testicular growth in peripubertal boys with HH. Methods: We evaluated for heterogeneity among studies. We calculated pooled means for the post-treatment mean testicular volume (MTV), testosterone (T) level, and penile length for the hCG monotherapy and hCG+ treatment groups. We performed a meta-regression analysis to examine the contribution of various factors to post-treatment outcomes including baseline T level, age, treatment duration, and study quality. Results: The meta-analysis included seven studies. All participants were prepubertal (age range: 13.3–25.9 years), with weighted mean treatment durations of 10.95 months for hCG monotherapy and 28.2 months for hCG. There was significant heterogeneity in baseline age (Q = 121.71; df = 1; P < 0.001) and T levels (Q = 436.74; df = 1; P < 0.001) between the two treatment groups. The hCG+ group had a larger post-treatment MTV, but it was not significantly different between the two groups (6.60 mL [95% CI, 3.18–10.02] for hCG monotherapy vs. 10.02 mL [95% CI, 8.30–11.75] for hCG+; P = 0.079). Post-treatment T levels differed significantly between the two groups (101.89 ng/dL [95% CI, 50.7–153.08] for hCG monotherapy vs. 424.10 ng/dL [95% CI, 304.59–543.62] for hCG+; P < 0.0001). A meta-regression analysis of post-treatment T levels showed that baseline age, baseline T level, and study grade did not contribute significantly to the difference between treatment groups. Treatment duration explained 3.04% of the difference between the two groups (P < 0.0001). After adjusting for treatment duration, the post-treatment T level remained significantly higher in the hCG+ group compared to the hCG monotherapy group. The hCG+ was also associated with better outcomes for post-treatment penile length, although these findings relied on data from only three studies. Conclusion: Our study indicates that hCG+ therapies provide potential benefits over hCG monotherapy for pubertal induction in males with HH, regarding T levels and penile growth, with no difference in testicular growth between treatments. Prospective pediatric studies are needed to assess the benefits of these therapies in patients with HH and, ultimately, to establish guidelines for gonadotropin therapy in the adolescent population.

Is There Room for SERMs or SARMs as Alternative Therapies for Adult Male Hypogonadism?

Hypogonadotropic hypogonadism (HH) can be sustained by organic or functional alterations of the hypothalamic-pituitary-testicular axis. Functional HH is related to systemic alterations, such as obesity or chronic inflammatory diseases, but could contribute to a negative course of the illness. For such situation, according to results obtained in infertile women, the administration of selective estrogen receptor modulators (SERMs) has been proposed in males too, with positive results on both metabolic and sexual function. This class of medications increases gonadotropin levels via antagonism to the estrogenic receptor; similar biological effects are also exerted by aromatase inhibitors (AIs), despite different mechanism of action. After a brief review of trials regarding SERMs and AIs use in male HH, we describe the structure and function of the androgen receptor (AR) as a basis for clinical research about compounds able to bind to AR, in order to obtain specific effects (SARMs). The tissue selectivity and different metabolic fate in comparison to testosterone can potentiate anabolic versus androgenic effects; therefore, they might be a valid alternative to testosterone replacement therapy avoiding the negative effects of testosterone (i.e., on prostate, liver, and hematopoiesis). Trials are still at an early phase of investigation and, at the moment, the application seems to be more useful for chronic disease with catabolic status while the validation as replacement for hypogonadism requires further studies.

Optimal treatment for spermatogenesis in male patients with hypogonadotropic hypogonadism.

Background:To compare the efficacies of gonadotropin-releasing hormone (GnRH) pulse subcutaneous infusion with combined human chorionic gonadotropin and human menopausal gonadotropin (HCG/HMG) intramuscular injection have been performed to treat male hypogonadotropic hypogonadism (HH) spermatogenesis.Methods:In total, 220 idiopathic/isolated HH patients were divided into the GnRH pulse therapy and HCG/HMG combined treatment groups (n = 103 and n = 117, respectively). The luteinizing hormone and follicle-stimulating hormone levels were monitored in the groups for the 1st week and monthly, as were the serum total testosterone level, testicular volume and spermatogenesis rate in monthly follow-up sessions.Results:In the GnRH group and HCG/HMG group, the testosterone level and testicular volume at the 6-month follow-up session were significantly higher than were those before treatment. There were 62 patients (62/117, 52.99%) in the GnRH group and 26 patients in the HCG/HMG (26/103, 25.24%) group who produced sperm following treatment. The GnRH group (6.2 ± 3.8 months) had a shorter sperm initial time than did the HCG/HMG group (10.9 ± 3.5 months). The testosterone levels in the GnRH and HCG/HMG groups were 9.8 ± 3.3 nmol/L and 14.8 ± 8.8 nmol/L, respectively.Conclusion:The GnRH pulse subcutaneous infusion successfully treated male patients with HH, leading to earlier sperm production than that in the HCG/HMG-treated patients. GnRH pulse subcutaneous infusion is a preferred method.

Metabolic Disorders and Male Hypogonadotropic Hypogonadism.

Several studies highlight that testosterone deficiency is associated with, and predicts, an increased risk of developing metabolic disorders, and, on the other hand, is highly prevalent in obesity, metabolic syndrome and type-2 diabetes mellitus. Models of gonadotropin releasing hormone deficiency, and androgen deprivation therapy in patients with prostate cancer, suggest that hypogonadotropic hypogonadism might contribute to the onset or worsening of metabolic conditions, by increasing visceral adiposity and insulin resistance. Nevertheless, in functional hypogonadism, as well as in late onset hypogonadism, the relationship between hypogonadotropic hypogonadism and metabolic disorders is bidirectional, and a vicious circle between the two components has been documented. The mechanisms underlying the crosstalk between testosterone deficiency and metabolic disorders include increased visceral adipose tissue and insulin resistance, leading to development of metabolic disorders, which in turn contribute to a further reduction of testosterone levels. The decrease in testosterone levels might be determined by insulin resistance-mediated and, possibly, pro-inflammatory cytokine-mediated decrease of sex hormone binding globulin, resulting in a temporary increased free testosterone available for aromatization to estradiol in visceral adipose tissue, followed by a subsequent decrease in free testosterone levels, due to the excess of visceral adipose tissue and aromatization; by a direct inhibitory effect of increased leptin levels on Leydig cells; and by a reduced gonadotropin secretion induced by estradiol, inflammatory mediators, leptin resistance, and insulin resistance, with the ultimate determination of a substantial hypogonadotropic hypogonadism. The majority of studies focusing on the effects of testosterone replacement therapy on metabolic profile reported a beneficial effect of testosterone on body weight, waist circumference, body mass index, body composition, cholesterol levels, and glycemic control. Consistently, several interventional studies demonstrated that correction of metabolic disorders, in particular with compounds displaying a greater impact on body weight and insulin resistance, improved testosterone levels. The aim of the current review is to provide a comprehensive overview on the relationship between hypogonadotropic hypogonadism and metabolism, by clarifying the independent role of testosterone deficiency in the pathogenesis of metabolic disorders, and by describing the relative role of testosterone deficiency and metabolic impairment, in the context of the bidirectional relationship between hypogonadism and metabolic diseases documented in functional hypogonadotropic hypogonadism. These aspects will be assessed by describing metabolic profile in men with hypogonadotropic hypogonadism, and androgenic status in men with metabolic disorders; afterwards, the reciprocal effects of testosterone replacement therapy and corrective interventions on metabolic derangements will be reported.

Recurrent reversal of male congenital hypogonadotropic hypogonadism and atypical fertility: A case report.

Recurrent reversal of male congenital hypogonadotropic hypogonadism and atypical fertility: A case report.

SAT-295 Low Dose rFSH Prior to HCG-rFSH Therapy in Kallmann Syndrome

[Background] Kallmann syndrome (KS) is known as a disorder characterized by hypogonadotropic hypogonadism and anosmia. Sato et al. reported that approximately 60% of Congenital male hypogonadotropic hypogonadism (CMHH) could not achieve sufficient spermatogenesis with the current hCG-rFSH combination therapy. [Objective] With the aim of improving gonadal function of KS, we treat KS patient with new methods proposed by Sato et al. and the effectiveness of low dose of rFSH mono-therapy followed by hCG-rFSH in an adolescent patient is discussed.[Case report] At the age of 14 years, he was diagnosed as KS because of cryptorchidism and micropenis in infancy and delayed puberty and hyposmia in adolescence, and identified with KAL1 mutation. The responses of LHRH stimulation were low levels (peak LH 0.85 mIU/mL, peak FSH 2.05 mIU/mL). The levels of testosterone responded for HCG stimulation test were 0.29 ng/mL before stimulation and 0.81 ng/mL after stimulation.From the age of 15 years, low dose rFSH (75 IU) was administered daily for 10 weeks, then switched to hCG-rFSH. Every six months, replacement doses of hCG and rFSH were increased. His height gain was 10.8 cm after treatment. Testicular volume was 2 mL when treatment began and increased to 6 mL in two years.Then, testosterone reached adult level. [Conclusion] Low dose rFSH therapy prior to hCG-rFSH to treat adolescent patients with KS seems to gain pubertal development slowly but improve testosterone secretion sufficiently.

Reversible male hypogonadotropic hypogonadism due to energy deficit.

Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis. We reviewed the literature, including two unpublished cases. We identified 23 cases, aged median (range) 20years (16-33), with a body mass index of 15.9kg/m2 (12.5-20.5). Total testosterone was 3.0nmol/L (0.6-21.3), and luteinizing hormone (LH) 1.2mIU/L (<0.2-7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism. Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin-like growth factor-1 in 71%), hypercortisolaemia (50%) and a nonthyroidal illness picture (67%). In cases with longitudinal measurements following weight regain, serum testosterone (n=14) increased from median [interquartile range] 3.2nmol/L [1.9-5.1] to 14.3nmol/L [9.3-21.2] (P<0.001), and LH (n=8) from 1.2IU/L [0.8-1.8] to 3.5IU/L [3.3-4.3] (P=0.008). Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit. The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and pro-inflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required.

Pituitary-testicular Axis Dysfunction in Methimazole-induced Hypothyroidism in Rats.

IntroductionThyroid hormones play a major role in the regulation of testicular maturation and growth and in the control of Sertoli and Leydig cell functions in adulthood. When naturally occurring, hypothyroidism causes male hypogonadotropic hypogonadism and Sertoli cell function disorders, but when iatrogenic and methimazole-induced its influence on the pituitary-testicular axis function with respect to Sertoli cells is poorly known.Material and MethodsMale adult Wistar rats (n = 14) were divided into two groups: E – taking methimazole orally for 60 days, and C – control animals. After 60 d, the concentrations in serum of testosterone, follicle-stimulating and luteinising hormones, and inhibins A and B were measured. Testicles were examined morphologically: the apoptotic Sertoli cell percentage (ASC%) and number of these cells functional per tubular mm2 (FSCN/Tmm2) were calculated.ResultsIn group E, inhibin A was higher while inhibin B was lower than in group C. ASC% was higher and FSCN/Tmm2 lower in group E than in group C.ConclusionA specific modulation of Sertoli cell function in the course of methimazole-induced hypothyroidism leads to a simultaneous concentration increase in inhibin A and decrease in B. Inhibin A might share responsibility for pituitary-testicular axis dysfunction and hypogonadotropic hypogonadism in this model of hypothyroidism.

AMH and INSL3 in testicular and extragonadal pathophysiology: what do we know?

It is commonly accepted that testicular function is prevalently regulated by the hypothalamic-pituitary-gonadal axis: The pulsatile secretion of GnRH by the hypothalamus induces pituitary expression of the two gonadotropins FSH and LH, which then stimulate Sertoli and Leydig cells, respectively, therefore regulating steroidogenesis and spermatogenesis. However, a growing body of evidence has recently suggested that other hormones act on the reproductive tract since the early phases of fetal development. Anti-Müllerian hormone and INSL3 are still largely used only for research purposes despite being increasingly recognized as markers of Sertoli and Leydig cells function, respectively. Provide an up-to-date review of the role of anti-Müllerian hormone and INSL3 in human pathophysiology according to current evidence. A thorough literature review was performed on PubMed, OVID MEDLINE/EMBASE and Google Scholar for papers concerning anti-Müllerian hormone and INSL3 in human males. INSL3 is not acutely regulated by the hypothalamic-pituitary axis but is constitutively secreted by Leydig cells, therefore representing a valid marker for their number and status. Anti-Müllerian hormone expression, on the other hand, is downregulated by androgens, therefore occurring mostly at the early stages of testicular differentiation and before the onset of puberty. Several conditions affecting testicular development, such as male hypogonadotropic hypogonadism, and their treatment have been associated to specific pattern of INSL3 and anti-Müllerian hormone expression, proving a role for both hormones in the diagnostic and therapeutic management. Recent reports suggest a role for both anti-Müllerian hormone and INSL3 in extra gonadal physiology, such as cardiovascular and bone health. Anti-Müllerian hormone and INSL3 are markers of Sertoli and Leydig cells maturation, respectively, usually involved in the pathogenesis of disorders of sexual differentiation. However, their role in testicular pathology has only been hinted at in the last decades. Recent evidence supports an involvement of both anti-Müllerian hormone and INSL3 in extragonadal pathophysiology as well.