Clinical and genetic analysis of an isolated follicle-stimulating hormone deficiency female patient.

OBJECTIVE: To characterize the clinical features of a female patient with isolated follicle-stimulating hormone (FSH) deficiency and to investigate the underlying mechanisms of FSH inactivation. METHODS: The proband was a 29-year-old woman with primary amenorrhea, impaired pubertal development, and infertility. Subsequently, reproductive endocrine was screened. DNA sequencing was conducted for the identification of FSHß mutation. RT-PCR, western blots, in vitro immunometric assay, and bioassay were performed to confirm the impact of the mutation on FSH expression and biological activity. Molecular model consisting of FSHα and mutant FSHß subunit was built for the structural analysis of FSH protein. RESULTS: The evaluation of reproductive endocrine revealed undetectable basal and GnRH-stimulated serum FSH. Sequencing of the FSHß gene identified a homozygous nonsense mutation at codon 97 (Arg97X). RT-PCR and western blot analysis revealed the mutation Arg97X did not affect FSHß mRNA and protein expression. But in vitro immunometric assay and bioassay demonstrated the production of normal bioactive FSH protein was disturbed by the mutation Arg97X. Structural analysis showed the surface structure of the resulting mutant FSH presented with lock-and-key, mosaic binding pattern, while the native structure was an encircling binding mode. CONCLUSION: The mutation Arg97X could disturb structural stability of the resulting FSH protein consisting of FSHα and mutant FSHß subunit, which may lead to FSH deficiency.

Isolated follicle-stimulating hormone (FSH) deficiency in two infertile men without FSH ß gene mutation: Case report and literature review.

OBJECTIVE: Congenital FSH deficiency is an exceptional cause of male infertility most often attributed to FSH ß gene mutations. The few published cases report azoospermia, severe testicular hypotrophy and normal testosterone levels associated with normal virilization. We report the exploration of two young men aged 26 and 27 years with severe sperm abnormalities, moderate testicular hypotrophy and isolated FSH deficiency. METHODS: Several FSH, LH, total testosterone and inhibin B assays and FSH ß gene sequencing were performed. RESULTS: FSH was almost undetectable at baseline and poorly responsive to GnRH test, whereas LH was normal at baseline and increased after GnRH test. Testosterone levels were within the adult range, while inhibin B levels were upper-normal to high. No FSH ß gene mutations were found. Exogenous FSH treatment was followed by spontaneous pregnancy in one case and required intra-cytoplasmic sperm injection (ICSI) in the other. CONCLUSIONS: The paradoxical high levels of inhibin B reflect the presence of functional Sertoli cells and may explain the isolated FSH deficiency. An intra-gonadal factor stimulating inhibin B secretion is discussed.

Hypothalamic-Pituitary Disorders in Childhood Cancer Survivors: Prevalence, Risk Factors and Long-Term Health Outcomes.

CONTEXT: Data on hypothalamic-pituitary (HP) disorders in systematically evaluated childhood cancer survivors are limited. OBJECTIVE: To describe prevalence, risk factors, and associated adverse health outcomes of deficiencies in GH deficiency (GHD), TSH deficiency (TSHD), LH/FSH deficiency (LH/FSHD), and ACTH deficiency (ACTHD), and central precocious puberty (CPP). DESIGN: Retrospective with cross-sectional health outcomes analysis. SETTING: Established cohort; tertiary care center. PATIENTS: Participants (N = 3141; median age, 31.7 years) were followed for a median 24.1 years. MAIN OUTCOME MEASURE: Multivariable logistic regression was used to calculate ORs and 95% CIs for associations among HP disorders, tumor- and treatment-related risk factors, and health outcomes. RESULTS: The estimated prevalence was 40.2% for GHD, 11.1% for TSHD, 10.6% for LH/FSHD, 3.2% for ACTHD, and 0.9% for CPP among participants treated with HP radiotherapy (n = 1089), and 6.2% for GHD, and <1% for other HP disorders without HP radiotherapy. Clinical factors independently associated with HP disorders included HP radiotherapy (at any dose for GHD, TSHD, LH/FSHD, >30 Gy for ACTHD), alkylating agents (GHD, LH/FSHD), intrathecal chemotherapy (GHD), hydrocephalus with shunt placement (GHD, LH/FSHD), seizures (TSHD, ACTHD), and stroke (GHD, TSHD, LH/FSHD, ACTHD). Adverse health outcomes independently associated with HP disorders included short stature (GHD, TSHD), severe bone mineral density deficit (GHD, LH/FSHD), obesity (LH/FSHD), frailty (GHD), impaired physical health-related quality of life (TSHD), sexual dysfunction (LH/FSHD), impaired memory, and processing speed (GHD, TSHD). CONCLUSION: HP radiotherapy, central nervous system injury, and, to a lesser extent, chemotherapy are associated with HP disorders, which are associated with adverse health outcomes.

Conditional Deletion of FOXL2 and SMAD4 in Gonadotropes of Adult Mice Causes Isolated FSH Deficiency.

The glycoprotein FSH, a product of pituitary gonadotrope cells, regulates ovarian follicle development in females and spermatogenesis in males. FSH is a heterodimer of the common α gonadotropin subunit and the hormone-specific FSHß subunit (a product of the Fshb gene). Using a conditional knockout approach (Cre-lox), we previously demonstrated that Fshb expression in mice depends on the transcription factors forkhead box L2 (FOXL2) and SMAD4. Deletion of Foxl2 or Smad4 alone led to FSH deficiency, female subfertility, and oligozoospermia in males. Simultaneous deletion of the two genes yielded a greater suppression of FSH and female sterility. The Cre-driver used previously was first active during embryonic development. Therefore, it is unclear whether FOXL2 and SMAD4 play important roles in the development or adult function of gonadotropes, or both. To address this question, we developed a tamoxifen-inducible Cre-driver line, which enabled Foxl2 and Smad4 gene deletions in gonadotropes of adult mice. After tamoxifen treatment, females with previously demonstrated fertility exhibited profound reductions in FSH levels, arrested ovarian follicle development, and sterility. FSH levels were comparably reduced in males 1 or 2 months after treatment; however, spermatogenesis was unaffected. These data indicate that (1) FOXL2 and SMAD4 are necessary to maintain FSH synthesis in gonadotrope cells of adult mice, (2) FSH is essential for female reproduction but appears to be unnecessary for the maintenance of spermatogenesis in adult male mice, and (3) the inducible Cre-driver line developed here provides a powerful tool to interrogate gene function in gonadotrope cells of adult mice.

Isolated follicle stimulated hormone deficiency in male: case report.

BACKGROUND: Recent rapid advances in assisted reproductive health technologies enables couples with subfertility to conceive through various intervention. Majority of treatment modalities target the female partner. However it is important to identify and treat male factor subfertility right at the outset. We report a case of isolated follicle stimulating hormone deficiency resulting in azoospermia and primary subfertility. CASE PRESENTATION: A 28 year otherwise healthy male presented with primary subfertility with a healthy female counterpart. He was found to have non obstructive azoospermia with low seminal fluid volume. He had normal external genitalia and potency with increased libido. Further evaluation revealed an isolated deficiency of follicle stimulating hormone with elevated testosterone levels. His luteinizing hormone and prolactin levels were normal. Contrast enhanced CT scan of chest, abdomen and pelvis and MRI scan of the pituitary fossa were normal too. CONCLUSION: In the era of modern reproductive technology it is important to further evaluate males with non-obstructive azoospermia to detect underlying gonadotropin deficiency.

Gender Differences in the Relationship between Sex Hormone Deficiency and Soft Drusen.

PURPOSE: To investigate the association between sex hormone deficiency and soft drusen in women and men. MATERIALS AND METHODS: We retrospectively reviewed the medical records and fundus photographs of subjects who underwent a health screening for additional examination of climacterium and age-related changes including sex hormone status. In women, sex hormone deficiency was defined as cessation of menstruation that had lasted for at least 12 months and follicular stimulating hormone (FSH) levels ≥ 25 mIU/mL; in men, it was defined as testosterone levels ≤ 3.5 ng/mL. The subjects were divided into two groups-the soft drusen and control groups-based on the presence of soft drusen in the fundus photographs. The total drusen area was measured using ImageJ™ software. RESULTS: Of total 2036 subjects, 638 (271 women; 367 men) were included. Two hundred thirteen subjects (33.4%) had soft drusen (97/271 women, 116/367 men). In women, sex hormone deficiency was more common in the soft drusen group than in the control group (P < 0.001); this was not the case in men. Multivariate logistic regression analysis revealed that sex hormone deficiency was an independent risk factor for soft drusen in women (P < 0.001; odds ratio [OR] = 3.494), as was age (P < 0.001; OR = 1.092). A long post-menopausal period was a risk factor for large soft drusen (≥ 125 µm). (P < 0.001; OR = 1.220). Age was significantly associated with total drusen area in both women (P = 0.022; ß = 0.406) and men (P = 0.015; ß = 0.246). CONCLUSIONS: Sex hormone deficiency and its duration were significantly associated with the development and progression of soft drusen in women but not in men. It may be necessary to assess and manage the sex hormone deficiency in women with age-related macular degeneration.

Novel FSHß mutation in a male patient with isolated FSH deficiency and infertility.

Isolated follicle stimulating hormone (FSH) deficiency due to mutations in FSHß is an extremely rare autosomal recessive disease that has only been reported in ten patients to date. Symptoms of the disease include amenorrhoea and hypogonadism in women and azoospermia and normal testosterone levels in men. This study describes a Chinese male patient who presented with cryptorchidism and infertility. His serum hormonal profile revealed low FSH, elevated LH and normal testosterone levels. Sequence analysis identified a novel homozygous mutation in the FSHß gene (c.343C > T) predicted to result in a premature termination codon and a truncated FSH protein (p.R115X). Both parents were heterozygous carriers of the mutation with normal pubertal development and fertility. The patient's testicular volume increased after one year of exogenous FSH replacement therapy at which point spermatocytes were detected in seminal samples, indicating potential future spermatogenesis. The expanded spectrum of FSHß mutations and associated clinical manifestations described in this study may improve the diagnosis and treatment of this disease.

IGF-I levels reflect hypopituitarism severity in adults with pituitary dysfunction.

PURPOSE: To evaluate the utility of Insulin-like growth factor I (IGF-I) standard deviation score (SDS) as a surrogate marker of severity of hypopituitarism in adults with pituitary pathology. METHODS: We performed a retrospective data analysis, including 269 consecutive patients with pituitary disease attending a tertiary endocrine clinic in 1990-2015. The medical files were reviewed for the complete pituitary hormone profile, including IGF-I, and clinical data. Age-adjusted assay reference ranges of IGF-I were used to calculate IGF-I SDS for each patient. The main outcome measures were positive and negative predictive values of low and high IGF-I SDS, respectively, for the various pituitary hormone deficiencies. RESULTS: IGF-I SDS correlated negatively with the number of altered pituitary axes (p < 0.001). Gonadotropin was affected in 76.6 % of cases, followed by thyrotropin (58.4 %), corticotropin (49.1 %), and prolactin (22.7 %). Positive and negative predictive values yielded a clear trend for the probability of low/high IGF-I SDS for all affected pituitary axes. Rates of diabetes insipidus correlated with IGF-I SDS values both for the full study population, and specifically for patients with non-functioning pituitary adenomas. CONCLUSIONS: IGF-I SDS can be used to evaluate the somatotroph function, as a valid substitute to absolute IGF-I levels. Moreover, IGF-I SDS predicted the extent of hypopituitarism in adults with pituitary disease, and thus can serve as a marker of hypopituitarism severity.

Hypogonadotropic Hypogonadism in a Boy with Myopathy.

Hypogonadism is seldom seen together with myopathy, although testosterone contributes to muscle strength. We present here a rare case of hypogonadotropic hypogonadism with myopathy in a 20 year old male. He had flaccid quadriparesis with raised creatinine phosphokinase. Hormone assays revealed low testosterone as well as low luteinising hormone and follicle stimulating hormone levels. Tests to exclude androgen deficiency should be carried out in male patients with myopathy.

Clinical and Hormonal Features of a Male Adolescent with Congenital Isolated Follicle-Stimulating Hormone Deficiency.

AIM: Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. METHODS: A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSHß gene was amplified and sequenced. RESULTS: Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSHß gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. CONCLUSION: We herein described an adolescent male with isolated FSH deficiency due to a novel FSHß gene mutation associated with a prepubertal testes size and normal virilisation.

Central precocious puberty following the diagnosis and treatment of paediatric cancer and central nervous system tumours: presentation and long-term outcomes.

OBJECTIVES: To estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes. DESIGN: Retrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA). PATIENTS AND MEASUREMENTS: Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow-up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively. RESULTS: Eighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non-HPA tumours. Height <-2SDS was more common at the last follow-up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow-up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR = 2·1, 95% CI 1·0-4·3) and longer follow-up with obesity (OR = 1·3, 95% CI 1·1-1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <-2SDS, and LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas. CONCLUSIONS: Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.

[Endocrine sequelae after treatment of pediatric cancer: From childhood to adulthood]. / Séquelles endocriniennes après traitement d'un cancer pédiatrique : de l'enfance à l'âge adulte.

Endocrine sequelae are among the most frequently reported complications in childhood cancer survivors, affecting 40 to 60% of these patients during adult life. Most of these complications are the result of cranial radiation therapy for brain or facial tumor, lymphoma or leukemia. The present review describes the main endocrine disturbances observed in this population, including disorders of hypothalamic-pituitary axis, especially the frequently observed growth hormone deficiency and disorders of puberty, thyroid and parathyroid dysfunction, obesity and metabolic syndrome, alterations in glucose metabolism and decreased bone mineral density. Gonadal dysfunction is not described, since it is detailed in another chapter. During childhood, prompt diagnosis and management of endocrine complications allow improvement of final height outcome and body composition (lean body mass and bone mass), reducing morbidity and impaired quality of life later in adulthood. Risk of developing a second neoplasm after growth hormone therapy in cancer survivors is also addressed. Life-long follow-up and management of endocrine deficiencies are essential to reduce late morbidity especially cardiovascular risk, and to diagnose late-onset deficiencies as well as radiation-induced thyroid nodules and cancer.

Relationship between pituitary stalk (PS) visibility and the severity of hormone deficiencies: PS interruption syndrome revisited.

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings. OBJECTIVE: The major objective of the study was to systematically describe the disease including clinical presentations, imaging findings and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS. METHODS: This was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared. RESULTS: Of the 74 patients with PSIS, age at diagnosis was 25 (22-28) years. Absent pubertal development (97·3%) was the most common presenting symptom, followed by short stature. Insulin tolerance test (ITT) and gonadotrophin-releasing hormone (GnRH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone (GH), gonadotrophins, corticotrophin and thyrotrophin were 100%, 97·2%, 88·2% and 70·3%, respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone (LH), follicle stimulation hormone (FSH) and hormones from targeted glands including morning cortisol, 24-h urine free cortisol, free triiodothyronine (FT3), free thyroxine (FT4) and testosterone (T) in male than patients with visible PS. Moreover, patients with invisible PS had lower peak LH and FSH in GnRH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups. CONCLUSIONS: The prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS.

Anterior hypopituitarism in adult survivors of childhood cancers treated with cranial radiotherapy: a report from the St Jude Lifetime Cohort study.

PURPOSE: To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies. PATIENTS AND METHODS: Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness. RESULTS: The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness. CONCLUSION: Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes.

Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center.

BACKGROUND: Children initially diagnosed with isolated GH deficiency (IGHD) have a variable rate to progress to combined pituitary hormone deficiency (CPHD) during follow-up. OBJECTIVE: To evaluate the development of CPHD in a group of childhood-onset IGHD followed at a single tertiary center over a long period of time. PATIENTS AND METHODS: We retrospectively analyzed data from 83 patients initially diagnosed as IGHD with a mean follow-up of 15.2 years. The Kaplan-Meier method and Cox regression analysis was used to estimate the temporal progression and to identify risk factors to development of CPHD over time. RESULTS: From 83 patients initially with IGHD, 37 (45%) developed CPHD after a median time of follow up of 5.4 years (range from 1.2 to 21 years). LH and FSH deficiencies were the most common pituitary hormone (38%) deficiencies developed followed by TSH (31%), ACTH (12%) and ADH deficiency (5%). ADH deficiency (3.1 ± 1 years from GHD diagnosis) presented earlier and ACTH deficiency (9.3 ± 3.5 years) presented later during follow up compared to LH/FSH (8.3 ± 4 years) and TSH (7.5 ± 5.6 years) deficiencies. In a Cox regression model, pituitary stalk abnormalities was the strongest risk factor for the development of CPHD (hazard ratio of 3.28; p = 0.002). CONCLUSION: Our study indicated a high frequency of development of CPHD in patients initially diagnosed as IGHD at childhood. Half of our patients with IGHD developed the second hormone deficiency after 5 years of diagnosis, reinforcing the need for lifelong monitoring of pituitary function in these patients.

Biochemical and MRI findings of Kallmann's syndrome.

Kallmann's syndrome is a neuronal migration disorder characterised by anosmia/hyposmia and hypogonadotropic hypogonadism. We present a case of a 21-year-old man who was unable to sense smell since birth and who displayed non-development of secondary sexual characteristics for the past 10 years. Blood investigations showed low basal levels of serum follicle stimulating hormone (FSH), serum luteinising hormone (LH) and serum testosterone. After a gonadotropin releasing hormone challenge test there was a slight increase in serum FSH and serum LH, and after a human chorionic gonadotropin (HCG) challenge test the patient's serum testosterone level increased to 34 times that of his basal level. MRI of the brain showed absence of bilateral olfactory bulbs and sulcus with an apparently normal appearing pituitary gland, and bilateral loss of distinction between the gyrus rectus and medial orbital gyrus, thus confirming the diagnosis. The patient is on treatment with injection of HCG 2000 IU deep intramuscular twice a week and is on follow-up.

Congenital hypogonadotropic hypogonadism and Kallmann syndrome as models for studying hormonal regulation of human testicular endocrine functions.

Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination.

Follicle-stimulating hormone synthesis and fertility depend on SMAD4 and FOXL2.

Follicle-stimulating hormone (FSH) is an essential regulator of gonadal function and fertility. Loss-of-function mutations in the FSHB/Fshb gene cause hypogonadotropic hypogonadism in humans and mice. Both gonadotropin-releasing hormone (GnRH) and activins, members of the transforming growth factor ß (TGFß) superfamily, stimulate FSH synthesis; yet, their relative roles and mechanisms of action in vivo are unknown. Here, using conditional gene-targeting, we show that the canonical mediator of TGFß superfamily signaling, SMAD4, is absolutely required for normal FSH synthesis in both male and female mice. Moreover, when the Smad4 gene is ablated in combination with its DNA binding cofactor Foxl2 in gonadotrope cells, mice make essentially no FSH and females are sterile. Indeed, the phenotype of these animals is remarkably similar to that of Fshb-knockout mice. Not only do these results establish SMAD4 and FOXL2 as essential master regulators of Fshb transcription in vivo, they also suggest that activins, or related ligands, could play more important roles in FSH synthesis than GnRH.

Aromatase excess syndrome: a rare autosomal dominant disorder leading to pre- or peri-pubertal onset gynecomastia.

Overexpression of CYP19A1 encoding aromatase results in a rare genetic disorder referred to as aromatase excess syndrome (AEXS). Male patients with AEXS manifest pre- or peri-pubertal onset gynecomastia, gonadotropin deficiency, and advanced bone age, while female patients are mostly asymptomatic. To date, 30 male patients with molecularly confirmed AEXS have been reported. A total of 12 types of submicroscopic rearrangements, i.e., two simple duplications, four simple deletions, two simple inversions, and four complex rearrangements, have been implicated in AEXS. Clinical severity of AEXS primarily depends on the types of the rearrangements. AEXS appears to account for a small number of cases of pre- or peri-pubertal onset gynecomastia, and should be suspected particularly when gynecomastia is associated with an autosomal dominant inheritance pattern, characteristic hormone abnormalities and/or advanced bone age. Treatment with an aromatase inhibitor appears to benefit patients with AEXS, although long-term safety of this class of drugs remains unknown.

Male reproductive endocrinology: when to replace gonadotropins.

Infertility is generally defined as a couple's inability to conceive after 1 year of unprotected intercourse. When infertile couples seek assistance, a male factor will be identified half of the time. Once the male has been evaluated, there are four main categories to describe his infertility: (1) idiopathic, (2) post-testicular/obstructive, (3) primary-where the Sertoli and/or Leydig cells of the testis fail, and (4) secondary-where there is a problem with the hypothalamus and/or pituitary. The last, hypogonadotropic hypogonadism (HH), accounts for up to 2% of infertile men. HH is either congenital or acquired and usually can be successfully treated by medical intervention. This review will focus on the hypothalamus-pituitary-gonadal axis, specific defects of this coordination center, and potential interventions for improving male-factor fertility.