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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., (Copyright © 2019 Endocrine Society.)

Pituitary hormones folitropin (follicle-stimulating hormone, FSH) and lutropin (luteinising hormone, LH) are known as the key regulators of human reproduction. However, their receptors have been identified also in several organs and tissues beyond the reproductive system, and there is cumulating evidence of their direct extra-gonadal actions. The expression of LH receptors (LHR) was found in the brain and adrenal cortex. FSH receptors (FSHR) were found to be expressed in osteoclasts, monocytes, adipocytes, and peri- and intra-tumoural blood vessel endothelia of malignant tumours. Other localisations of FSHR and LHR are also suggested by immunohistochemistry, but these findings need confirmation using molecular biology techniques. Because the high levels of gonadotropins are a constant phenomenon during human aging, especially in postmenopausal women, it is hypothesised that the direct actions of FSH and LH are involved in the pathogenesis of age-related disorders. The proposal of therapy based on the inhibition of gonadotropin hypersecretion is also discussed.

Background/purpose: The role of LH during controlled ovarian stimulation (COS) in the general population remains contentious. There is no consensus on the indications for LH supplementation during COS. The purpose of this study is to determine whether menotropin supplement is associated with decreases in early pregnancy loss rates in patients exhibiting low endogenous LH during COS., Method: This is a single-center, retrospective cohort from a university-affiliated hospital. Patients were enrolled from the in-vitro fertilization center from January, 2011 to December, 2014. Patients who experienced a LH level ≦ 0.8 mIU/mL during stimulation were identified, and patients that received menotropin supplementation were compared to those without menotropin supplementation. Outcome variables, including the number of oocytes retrieved, embryos obtained, implantation rates, pregnancy rates and early pregnancy loss rates, were compared., Results: Patients that experienced low LH during GnRH antagonist protocol and were supplemented with menotropin were associated with lower early pregnancy loss when compared with patients without menotropin supplementation (26.7% vs. 11.5%, p = 0.045). More specifically, in patients who exhibited early-onset low LH, before the use of GnRH antagonists, menotropin supplementation was associated with significantly lower early pregnancy loss compared with non-supplemented patients (3.3% vs. 29.0%, OR: 0.08, p = 0.012). Beneficial effects persisted after adjusting for confounders (aOR: 0.103, 95% CI: 0.011-0.933)., Conclusion: Menotropin supplementation is associated with decreased early pregnancy loss in patient who exhibited low LH during GnRH antagonist cycles. This effect is especially prominent in patients who experience low LH before the start of GnRH antagonists., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: The purpose of this study was to investigate a novel mutation in the luteinizing hormone beta-subunit (LHB) gene in one male patient with hypogonadism due to selective luteinizing hormone (LH) deficiency., Methods: Sanger sequencing of one 28-year-old man born to consanguineous parents was performed. Treatment with human chorionic gonadotropin (hCG) (2000 IU, twice a week) was initiated for 3 months, followed by 5000 IU weekly to date., Results: We identified a novel c.84G>A[p.W28X] nonsense LHB mutation. The W28X mutation produces a truncated LHB peptide of seven amino acids, which prevents the synthesis of intact LH. After 40 days of treatment with hCG, the patient exhibited a few spermatozoa in the semen. Treated for 6 months, the patient exhibited normal seminal parameters., Conclusions: We identified a novel mutation in the LHB gene in a male patient with hypogonadism and provided evidence that LHB nonsense mutation can cause selective LH deficiency. We reconfirmed hCG treatment may restore male fertility due to LHB mutation.

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.

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., (© 2015 John Wiley & Sons Ltd.)

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.

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., (© 2015 John Wiley & Sons Ltd.)

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.

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., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Progesterone production from the corpus luteum is critical for natural reproduction. Progesterone supplementation seems to be an important aspect of any assisted reproductive technology treatment. Luteal phase deficiency in natural cycles is a plausible cause of infertility and pregnancy loss, though there is no adequate diagnostic test. This article describes the normal luteal phase of the menstrual cycle, investigates the controversy surrounding luteal phase deficiency, and presents the current literature for progesterone supplementation during assisted reproductive technologies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (© 2015 by American Society of Clinical Oncology.)

Cryptorchidism is the most common cause of non-obstructive azoospermia in man. In contrast to the general belief that temperature-dependent effects on the undescended gonad damage cryptorchid testes before sexual maturation is complete, molecular pathology strongly supports the theory that impaired mini-puberty is responsible for azoospermia and infertility in cryptorchidism. Molecular biological observations favor LH deficiency, with EGR4 as a master regulatory gene in Leydig cell dysgenesis, as the reason for impaired mini-puberty, and recent evidence supports the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway., (© 2015 The Author(s) Published by S. Karger AG, Basel.)

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., (2014 BMJ Publishing Group Ltd.)

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., (Copyright © 2014. Published by Elsevier Masson SAS.)

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., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: A 2:1 (150 IU:75 IU) follitropin alfa:lutropin alfa formulation has been developed. A 3-year post-marketing surveillance study is ongoing in Germany to explore the use of this formulation in routine clinical practice., Materials and Methods: An 11-month interim analysis of data from assisted reproductive technology (ART) cycles only is described., Results: Data were available from 857 patients undergoing 919 cycles of ART at 19 centres. Most patients (58.7%) were aged ≥ 35 years, and many (41.3%) were undergoing their first ART cycle. Main reasons cited by physicians for prescribing this formulation were poor response in a previous treatment cycle (n = 303) and low basal luteinizing hormone (LH) level (n = 107). Mean (standard deviation) duration of ovarian stimulation was 10.8 (2.6) days. In 90.7% of cycles, the 2:1 formulation was administered throughout the stimulation period. Most frequent LH daily dose was 75 IU. Embryo transfer was conducted in 741 cycles; clinical pregnancy rate per transfer was 27.5%. Three cases of ovarian hyperstimulation syndrome developed in three patients (3/741 [0.4%] cycles); one required hospitalization. No other major safety events were reported., Conclusion: This interim analysis shows that use of the 2:1 formulation for ovarian stimulation during routine ART procedures is effective in achieving clinical pregnancies and is associated with a positive safety profile.

Objective: To clarify the outcome of all cases of Rathke's cleft cysts (RCC) treated surgically and followed up in Oxford during a long-term period., Subjects and Methods: The records of all patients with RCC seen in the Department of Endocrinology between January 1978 and June 2009 were reviewed., Results: A total of 33 patients (20 females, median age 43 years) were identified. At presentation, major visual field defects were detected in 58% of patients and gonadotrophin, ACTH and TSH deficiency in 60, 36 and 36% of patients respectively. Desmopressin treatment was required in 18% of patients. Treatment consisted of cyst evacuation combined with or without biopsy/removal of the wall. Post-operatively, visual fields improved in 83% of patients with impairment, whereas there was no reversal of ACTH or TSH deficiency or of diabetes insipidus. All but one subject had imaging follow-up during a mean period of 48 months (range 2-267). Cyst relapse was detected in 22% of patients at a mean interval of 29 months (range 3-48 months); in 57% of them, the recurrence was symptomatic. Relapse-free rates were 88% at 24-months and 52% at 48-months follow-up. At last assessment, at least quadrantanopia was reported in 19% of patients, gonadotrophin, ACTH and TSH deficiency in 50, 42 and 47% of patients respectively. Desmopressin treatment was required in 39% of patients., Conclusions: In this study of patients with RCC and long-term follow-up, we showed a considerable relapse rate necessitating long-term monitoring. Surgical intervention is of major importance for the restoration of visual field defects, but it does not improve endocrine morbidity, which in the long-term affects a substantial number of patients.

We report a 21-year-old man with severe fatigue due to hypopituitarism. At the age of 6 years, he was diagnosed with short stature due to a GH deficiency accompanied by a sphenoid cystic lesion. Laboratory findings and provocative tests for pituitary hormone function revealed ACTH, LH, FSH, TSH, and GH deficiency. Computed tomography and magnetic resonance imaging revealed transsphenoidal cephalocele due to a defect in the floor of the sella turcica. At 6 years, he only had severe GH deficiency and poor response of LH to LHRH. Hypothalamic-pituitary dysfunction and pituitary herniation have progressed subsequently; we observed a longitudinal progression of hypothalamic-pituitary dysfunction caused by transsphenoidal cephalocele. This dysfunction requires the selection of a treatment that will not aggravate the condition further.

Context and Objective: In men with infertility secondary to gonadotropin deficiency, treatment with relatively high dosages of human chorionic gonadotropin (hCG) stimulates intratesticular testosterone (IT-T) biosynthesis and spermatogenesis. Previously we found that lower dosages of hCG stimulated IT-T to normal. However, the minimal dose of hCG needed to stimulate IT-T and the dose-response relationship between very low doses of hCG and IT-T and serum testosterone in normal men is unknown., Design, Setting, Patients, and Intervention: We induced experimental gonadotropin deficiency in 37 normal men with the GnRH antagonist acyline and randomized them to receive one of four low doses of hCG: 0, 15, 60, or 125 IU sc every other day or 7.5 g daily testosterone gel for 10 d. Testicular fluid was obtained by percutaneous aspiration for steroid measurements at baseline and after 10 d of treatment and correlated with contemporaneous serum hormone measurements., Results: Median (25th, 75th percentile) baseline IT-T was 2508 nmol/liter (1753, 3502 nmol/liter). IT-T concentrations increased in a dose-dependent manner with very low-dosage hCG administration from 77 nmol/liter (40, 122 nmol/liter) to 923 nmol/liter (894, 1017 nmol/liter) in the 0- and 125-IU groups, respectively (P<0.001). Moreover, serum hCG was significantly correlated with both IT-T and serum testosterone (P<0.01)., Conclusion: Doses of hCG far lower than those used clinically increase IT-T concentrations in a dose-dependent manner in normal men with experimental gonadotropin deficiency. Assessment of IT-T provides a valuable tool to investigate the hormonal regulation of spermatogenesis in man.

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ss sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome., (Copyright 2010. Published by Elsevier Masson SAS.)

In the last decades a growing interest has been dedicated to prevention, diagnosis and therapy of male genital pathologies, such as varicocele, infertility and erectile dysfunction in the population involved in sport activities. High incidence (up to 30%) of varicocele has been reported in a population of athletes and up to 60-80% in the subgroup of body-builders. The incidence of varicocele specifically increases with hours of training, in a linear model. Controversial data come from literature about the effects of physical activity on fertility, with prevalence of trials demonstrating worsening of seminal parameters. Furthermore, it has been demonstrated that physical stress in healthy male athletes can interfere with LH levels. Bicycling is one of the major risk factors for erectile dysfunction, with incidence of 13-24%. This is due to the prolonged compression of perineal arteries leading to reduced chronic penile perfusion. Bioengineering studies have been the basis for industry to produce specifically shaped saddles that significantly reduce and minimize compressive effects. Finally, high frequency of lower urinary tract symptoms (LUTS) in cyclists has been related to increased incidence of erectile dysfunction in comparison with normal population.

Men with mutations in LHB, the gene encoding the beta subunit of luteinizing hormone (LHB), have azoospermia with absent or few fetal Leydig cells. We report a mutation in LHB in a man and his sister. The man presented with absence of virilization, undetectable luteinizing hormone, and a low serum testosterone level. He had complete spermatogenesis with a normal sperm count. The mutant luteinizing hormone had a low level of partial activity in vitro. We concluded that the residual luteinizing hormone activity, resulting in the expression of steroidogenic enzymes in few mature Leydig cells producing small amounts of intratesticular testosterone (20.2 ng per gram), was sufficient for complete and quantitatively normal spermatogenesis., (Copyright 2009 Massachusetts Medical Society.)

Context: Acromegaly is associated with increased morbidity and mortality. Treatment options include surgery, radiotherapy, and medical therapy., Aims: The objective of the study was to examine the role of prolactin status, prior surgery, and radiotherapy on the response to medical therapy in patients with acromegaly and assess the relative efficacy of dopamine agonist therapy compared with somatostatin analog therapy., Materials and Methods: A total of 276 patients with acromegaly received either dopamine agonists (DA) and/or somatostatin analogs (SSA). One hundred seventy-two patients had received surgery and 73 radiotherapy prior to receiving medical therapy. One hundred ninety-eight of 276 received DA, and 143 of 276 received SSA. GH and IGF-I values at baseline and after 12 months on therapy were analyzed., Results: In the DA group, basal prolactin concentration did not predict response to therapy, GH percent reduction: hyperprolactinemia, 26.7% (-10.4 to 48) vs. normoprolactinemia, 34.8% (0.2-53.2), P = 0.58; IGF-I percent reduction: hyperprolactinemia 30.0% (9.2-43.1) vs. normoprolactinemia 16.8% (4-37), P = 0.45. Prior surgery was not associated with any difference in response to DA: GH percent reduction (P = 0.1) and IGF-I percent reduction (P = 0.08). By contrast, prior radiotherapy was associated with an enhanced efficacy of GH response to DA, P = 0.02. In the SSA group, there was no effect of prior surgery or radiotherapy on response of GH, but radiotherapy was associated with less marked IGF-I percent reduction (P = 0.05). SSA were more potent than DA at decreasing both GH [62.8% (20.7-85%) vs. 42.4% (-6.5 to 68.6), P < 0.008] and IGF-I [SSA 40.4% (0-64.3) vs. 8% (0-40.8), P = 0.05]., Conclusions: The effects of DA are irrespective of baseline prolactin concentrations. Prior radiotherapy is associated with differences in GH and IGF-I response to DA and SSA therapy.

The inhibins are secreted alpha:beta heterodimers of the TGF-beta superfamily that are mainly synthesized in Sertoli cells and granulosa cells, and are critical regulators of testicular and ovarian development and function. Mice homozygous for a targeted deletion of the inhibin alpha subunit gene (Inha(-/-)) develop sex cord-stromal tumors in a gonadotropin-dependent manner. Here, we determine the contribution of LH to gonadal tumorigenesis by generating mice deficient in both inhibins and LH. Inha(-/-)Lhb(-/-) mice have increased survival and delayed tumor progression, and these observations correlate with lower serum FSH and estradiol levels compared to Inha(-/-) controls. Double mutant testicular tumors demonstrate decreased expression of cyclin D2, while double mutant ovarian tumors have elevated expression of p15(INK4b) and trend toward higher levels of p27(Kip1). We conclude that LH is not required for tumor formation in the absence of inhibins but promotes tumor progression, likely through alterations in serum hormone levels and cell cycle regulators.

A case diagnosed as Bardet-Biedl syndrome with polydactyly and hypertension has been presented here. Bardet-Biedl syndrome is an autosomal recessive disorder, which includes renal dystrophy, dystrophic extremities (often polydactyly), obesity, hypogenitalism, renal disease, and mental retardation. It was first described by John Z. Laurence and Robert Moon. The basic components of the syndrome were established by George Bardet in 1920 and Arthur Biedl in 1922. Although it is still referred to as Laurence-Moon-Bardet-Biedl in some reports, it has recently acquired the name Bardet-Biedl syndrome. Patients were generally lost due to renal insufficiency at young ages.

Objective: To assess the requirement for luteinizing hormone (LH) in women deficient in LH and follicle-stimulating hormone (FSH)., Research Design and Methods: A prospective, randomized, parallel-group, multicentre study was carried out in tertiary care and academic medical centres. Women with anovulatory amenorrhoea > or = 1 year, serum oestradiol (E(2)) < 60 pg/mL (< 220 pmol/L) and low normal serum gonadotrophins were randomized in cycle A to a fixed daily dose of recombinant human (r-h) FSH (150 IU) and r-hLH 0, 25, 75 or 225 IU. Cycles B and C were not randomized., Main Outcome Measures: Follicular development, ovulation and luteinization., Results: In cycle A, follicular development was achieved by 63.6% (7/11), 100% (9/9), 72.7% (8/11) and 66.7% (6/9) of patients who received r-hFSH and r-hLH 0, 25, 75 or 225 IU/day, respectively (p = not significant). Among patients with basal serum LH of < 1.2 IU/L, a dose-response relationship of r-hLH to follicular development was observed (p = 0.039). Fourteen of 34 patients (41.2%) wishing to conceive became pregnant. Among patients with hypogonadotrophic hypogonadism (HH) treated with r-hFSH alone, a transition from LH dependence to independence was observed between basal LH values of > or = 1.2 IU/L and < or = 1.6 IU/L. The r-hLH was well tolerated and no serious adverse events occurred during treatment. The most common treatment-related events were related to the reproductive system and the gastrointestinal tract., Conclusions: Recombinant human LH provides a safe treatment option for women with HH. This small study also provided evidence suggestive of an LH threshold: follicular development was suboptimal when less than 75 IU/day r-hLH was administered.

Objective: To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency., Design: Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries., Patients: Thirty-nine patients with LH < 1.2 IU/l and FSH < 5.0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa., Measurements: Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle >or= 17 mm; (ii) serum E(2) level >or= 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level >or= 25 nmol/l., Results: In the analysis of evaluable patients, 66.7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20.0% (2 of 10) of patients receiving placebo (P = 0.023). In the intent-to-treat analysis, follicular development was achieved in 65.4% (17 of 26) of patients receiving lutropin alfa and 15.4% (2 of 13) of patients receiving placebo (P = 0.006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response (P = 0.034). Lutropin alfa was well tolerated., Conclusion: Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.

Lutropin alfa is the first and only recombinant human form of luteinizing hormone (LH) developed for use in the stimulation of follicular development. Dose-finding studies revealed a significant dose-dependent increase in the rate of optimal follicular development among women with hypogonadotropic hypogonadism and profound LH deficiency (<1.2 IU/L) who received subcutaneous lutropin alfa 0-225 IU/day plus follitropin alfa. Similarly, in a double-blind, randomized study, the rate of optimal follicular development was significantly higher in women with hypogonadotropic hypogonadism and profound LH deficiency receiving subcutaneous lutropin alfa 75 IU/day plus follitropin alfa than in those receiving placebo plus follitropin alfa. Lutropin alfa with follitropin alfa may also be of benefit in certain subgroups of normogonadotropic women (e.g. those with an inadequate response to prior follitropin alfa monotherapy, those aged >or=35 years, and those with profound LH downregulation or who required excessive exogenous follitropin alfa). However, one study in older women (>or=35 years) did not show any advantage of lutropin alfa supplementation. Once-daily subcutaneous lutropin alfa was generally well tolerated in hypogonadotropic hypogonadal women, with the majority of adverse events being of mild to moderate severity.

Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. We describe the clinical features of a consanguineous family in which three siblings, two men and one woman, had hypogonadism related to isolated luteinizing hormone deficiency. These subjects have a newly discovered homozygous mutation of a 5' splice site in LHB: IVS2+1G-->C. This mutation disrupts the splicing of messenger RNA (mRNA), generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone. We also determined that the female phenotype of this LHB mutation is characterized by normal pubertal development, secondary amenorrhea, and infertility., (Copyright 2007 Massachusetts Medical Society.)

Objective: To estimate the prevalence and predictive factors of hypopituitarism following traumatic brain injury (TBI)., Design: A cross-sectional cohort study., Patients: One hundred and four hospitalized TBI patients (26F/78M), median age 41 (range 18-64) years, body mass index (BMI) 25 (17-39) kg/m(2); severity: mild [Glasgow Coma Scale (GCS) score 13-15) n = 44, moderate (GCS 9-12) n = 20, severe (GCS < 9) n = 40]., Measurements: Patients were evaluated 13 (10-27) months post-injury, with measurement of baseline (0800-1000 h) and post-stimulatory hormonal levels during an insulin tolerance test (ITT) (86%) or, if contraindicated, an arginine(arg)-GHRH test + Synacthen test (14%). Insufficiencies were confirmed by retesting., Results: Hypopituitarism was found in 16 (15%) patients, affecting one axis in 10, two axes in four and more than two axes in two patients. The GH axis was most frequently affected (15%), followed by secondary hypoadrenalism (5%), hypogonadism (2%), hypothyroidism (2%) and diabetes insipidus (2%). The risk of pituitary insufficiency was increased in patients with severe TBI as opposed to mild TBI [odds ratio (OR) 10.1, 95% confidence interval (CI) 2.1-48.4, P = 0.004], and in those patients with increased intracerebral pressure [OR 6.5, 95% CI 1.0-42.2, P = 0.03]. Patients with only one affected axis were all GH deficient; 60% (n = 6) of these were overweight or obese., Conclusion: The prevalence of hypopituitarism was estimated at 16%. Although high, this value was lower than previously reported, and may still be overestimated because of well-known confounding factors, such as obesity. Indicators of increased TBI severity were predictive of hypopituitarism, with a high negative predictive value. Neuroendocrine evaluation should therefore be considered in patients with severe TBI, and in particular in those with increased intracerebral pressure (ICP).

Incidence and prevalence of hypopituitarism are estimated to be 4.2 per 100,000 per year and 45.5 per 100,000, respectively. Although the clinical symptoms of this disorder are usually unspecific, it can cause life-threatening events and lead to increased mortality. Current research has refined the diagnosis of hypopituitarism. Identification of growth hormone and corticotropin deficiency generally requires a stimulation test, whereas other deficiencies can be detected by basal hormones in combination with clinical judgment. Newly developed formulations of replacement hormones are convenient and physiological. Work has shown that many patients with brain damage--such as traumatic brain injury or aneurysmal subarachnoid haemorrhage--are at high risk of (sometimes unrecognised) hypopituitarism. Thus, a much increased true prevalence of this disorder needs to be assumed. As a result, hypopituitarism is not a rare disease and should be recognised by the general practitioner.

In order to study the physiology and pathophysiology of gonadotrophin action, we have produced transgenic (TG) mice overexpressing human chorionic gonadotrophin (hCG) alpha and beta subunits (hCG+ mice) and knockout (KO) mice for the luteinising hormone receptor (LHR; LuRKO mice). The two extremes in LH function, i.e. strong LH/hCG stimulation and total blockade of this action, confirm numerous earlier concepts about LH function, but they also reveal new aspects about gonadal function during excessive LH production and in the absence of this trophic stimulus. The purpose of this review is to summarise the key findings on these two genetically modified mouse models.

A 30-year-old man was investigated for delayed puberty and infertility. These investigations showed a complete absence of circulating luteinizing hormone (LH). Genetic studies revealed a missense mutation in the LHbeta gene (G36D). This mutation disrupts a vital cystine knot motif and abrogates the heterodimerization and secretion of LH. Treatment with hCG was instituted, which led to arise in testosterone and improvement in spermatogenesis. After in vitro fertilization the patient had a son who was heterozygous for the G36D mutation. A second patient with similar clinical and biological presentation has been explored. A non-frame shift deletion of 3 base-pairs was discovered at position 20 which led to the deletion of a lysine residue. The proband and his prepubescent brother were homozygotic for this mutation. These cases illustrate the important physiological role of LH in male sexual maturation and fertility.

During the last 10 years, numerous activating and inactivating mutations have been detected in the genes encoding the two gonadotrophins, luteinising hormone (LH) and follicle-stimulating hormone (FSH), as well as their cognate receptors (R), LHR and FSHR. Because activation of the hypothalamic-pituitary-gonadal axis is a crucial event in the onset and progression of puberty, mutations affecting gonadotrophin action have major influence on this developmental process. Many of the phenotypic effects observed have been expected on the basis of the existing information about gonadotrophin action (e.g. delayed puberty), but also many unexpected findings have been made, including the lack of phenotype in women with activating LHR mutations, and the discrepancy in phenotypes of men with inactivating mutations of FSHbeta (azoospermia and infertility) and FSHR (oligozoospermia and subfertility). Some of the possible mutations, such as inactivating LHbeta and activating FSHR mutations in women, have not yet been detected. Genetically modified mice provide relevant phenocopies for the human mutations and serve as good models for studies on molecular pathogenesis of these conditions. They may also predict phenotypes of the mutations that have not yet been detected in humans. We review here briefly the effects of gonadotrophin subunit and receptor mutations on puberty in humans and contrast the information with findings on genetically modified mice with similar mutations.

Rationale: Due to the proximity of craniopharyngiomas to the hypothalamus and pituitary gland, most children and adolescents presenting with these tumors will exhibit significant endocrine dysfunction. After treatment, these impairments can become a major cause of morbidity and mortality., Methods: The postoperative course of children undergoing surgery for craniopharyngioma is reviewed., Conclusion: Even if hormone levels seem to be adequate in the short term after treatment, deficiencies may develop over years and need to be monitored closely.

Objectives/hypothesis: Males with isolated hypogonadotropic hypogonadism (IHH) fail to undergo normal sexual development, including the lack of masculinization of the larynx. The objective of this study was to measure the mean vocal fundamental frequency (MF0) in IHH patients and determine the impact of androgen treatment. An additional aim was to compare the MF0 between IHH patients and controls., Study Design: Prospective observational study., Methods: Twenty-four patients with IHH were identified along with 30 normal males and females. Voice recordings were obtained on all subjects. Androgen therapy was administered to the IHH patients. The MF0 and serum sex hormone levels were measured before treatment and at intervals during therapy. These results were compared with the pretreatment data within the IHH group. Voice parameters were also compared between the pre- and posttreatment IHH patients and the normal males and females., Results: The MF0 in untreated IHH patients was 229 +/- 41 Hz. This was intermediate between the normal male (150 +/- 22 Hz, P < .001) and normal female patients (256 +/- 29 Hz, P < .01). After treatment, the MF0 in the IHH group decreased to 173 +/- 30 Hz (P < .0001); indeed, their posttreatment MF0 approached that of normal males (P < .08). Serum hormone levels responded to the injected testosterone, but these levels did not directly correlate with MF0., Conclusions: MF0 in IHH patients is intermediate between normal male and female levels. After treatment with testosterone, these values approach the range of normal males. This prospective study details the impact of androgens on the larynx and vocal function in patients with IHH.

Defining the gonadal effects of FSH distinct from those of LH remains difficult. We have characterized and compared the level of Sertoli and germ cell development in three mouse models recently created to isolate FSH activity from LH effects. Two models used LH-deficient hypogonadal (hpg) mice to selectively study either pituitary-independent transgenic (tg) FSH or ligand-independent activated tg FSH receptor (FSHR(+)) expression, and the third model used LH receptor (LHR)-deficient mice to isolate and examine endogenous mouse FSH effects. Stereological evaluation revealed tg-FSH or tg-FSHR(+) activity significantly increased total Sertoli cell numbers per testis in both hpg models relative to control hpg testes. Furthermore, tg-FSH dose-dependently restored hpg Sertoli cells to wild-type (wt) (non-hpg) levels, and LHR-/- testes also exhibited wt Sertoli numbers. Spermatogonial proliferation and meiotic development were enhanced by tg-FSHR(+) or tg-FSH. Despite producing normal Sertoli numbers, isolated tg-FSH activity only increased total spermatogonia and spermatocyte populations to 57 and 44% of wt, which was comparable to spermatogonia and spermatocyte numbers observed in LHR-null testes (45 and 34% of wt). Selective FSH activity initiated round spermatid formation in all three models. However, elongated spermatid formation was detected in tg-FSH and tg-FSHR(+) hpg testes but not in LHR-/- testes, which may reflect even lower intratesticular testosterone levels in LHR-null compared with hpg testes. FSH increased round and elongated spermatid numbers in hpg testes to 16 and 6% of wt without altering intratesticular testosterone levels, but failed to produce spermatozoa demonstrating the inability of FSH to complete spermatogenesis. These findings revealed that full Sertoli cell proliferation can be accomplished by FSH activity without LH requirement, and although postnatal mitotic and meiotic germ cell development can be promoted by FSH alone, LH-mediated effects remain a critical determinant for initiating the full complement of germ cells and final stages of postmeiotic development.

The case of a 62-year-old woman with severe post-menopausal hirsutism is described. Her clinical history revealed regular menstrual periods until menopause at the age of 50, hysterectomy for fibromatosis at 58 years, non-insulin dependent diabetes mellitus, hypertension, obesity, severe hirsutism, which had developed in the previous 3 years, with a deeping of the voice. Examination showed android obesity, hypertension and severe hirsutism involving the face and the trunk. Endocrine evaluation pointed out regular adrenal function, serum total and free-testosterone in the adult male range, with normal androstenedione, DHEAS and 17OHP levels. Estradiol was slightly increased and LH and FSH were inappropriately low for her post-menopausal age. Computed tomography of the abdomen showed regular adrenal glands, and a radio-labeled cholesterol scan was negative. A further pelvic transvaginal ultrasonography revealed a small cystic formation near the right ovary and a slight increase in the size of the left ovary. The patient underwent bilateral ovariectomy. Histological examination showed a lipoid cell tumor within the left ovary. Immunohistochemical studies were positive for inhibin and cytokeratin. After surgery, serum testosterone fell to normal levels, gonadotropins increased to menopausal levels, confirming that the tumor was able to produce both LH, and FSH-inhibiting factors, and hirsutism greatly improved. Periodic hormonal tests remained normal and CT of the abdomen and pelvic ultrasonography did not show alterations at a 3 years follow-up.

(1) The reference ovarian stimulant for women with severe FSH and LH deficiency and pituitary dysfunction is menotropin (postmenopausal urinary human gonadotrophin (hMG)). (2) A recombinant LH, lutropin alfa, has now been licensed for this use, in combination with recombinant FSH (follitropin alfa or follitropin beta). The evaluation file contains no data from trials comparing the follitropin-lutropin alfa combination with menotropin. (3) Two dose-finding studies involving a total of 78 women, and a double-blind trial comparing follitropin + placebo with follitropin + lutropin alfa, have shown that 75 IU/day lutropin alfa yields satisfactory follicular development in two-thirds of women whose plasma LH concentration is below 1.2 IU/I. Efficacy has not been demonstrated in women with higher plasma concentrations of LH. Similar results have been reported with menotropin. (4) The adverse effect profile of the follitropin + lutropin alfa combination is similar to that of menotropin. The main risk is an ovarian hyperstimulation syndrome. Monitoring of plasma estradiol concentrations, pelvic ultrasound findings, and clinical state are required to avoid severe ovarian hyperstimulation. There is no evidence that the risk differs between menotropin and the follitropin + lutropin alfa combination at adjusted doses. (5) In France, the combination of follitropin alfa + lutropin alfa costs about five times more than menotropin. (6) Menotropin remains the first line ovarian stimulant for women with severe deficiency of FSH and LH.

During mammalian testis development distinct generations of fetal and adult Leydig cells arise. Luteinising hormone (LH) is required for normal adult Leydig cell function and for the establishment of normal adult Leydig cell number but its role in the process of adult Leydig cell differentiation has remained uncertain. In this study we have examined adult Leydig cell differentiation in gonadotrophin-releasing hormone (GnRH)-null mice which are deficient in circulating gonadotrophins. Adult Leydig cell differentiation was assessed by measuring expression of mRNA species encoding four specific markers of adult Leydig cell differentiation in the mouse. Each of these markers (3beta-hydroxysteroid dehydrogenase type VI (3betaHSD VI), 17beta-hydroxysteroid dehydrogenase type III (17betaHSD III), prostaglandin D (PGD)-synthetase and oestrogen sulphotransferase (EST)) is expressed only in the adult Leydig cell lineage in the normal adult animal. Real-time PCR studies showed that all four markers are expressed in adult GnRH-null mice. Localisation of 3betaHSD VI and PGD-synthetase expression by in situ hybridisation confirmed that these genes are expressed in the interstitial tissue of the GnRH-null mouse. Treatment of animals with human chorionic gonadotrophin increased expression of 3betaHSD VI and 17betaHSD III within 12 hours further indicating that differentiated, but unstimulated cells already exist in the GnRH-null mouse. Thus, while previous studies have shown that LH is required for adult Leydig cell proliferation and activity, results from the present study show that adult Leydig cell differentiation will take place in animals deficient in LH.