GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

STUDY QUESTION: Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? SUMMARY ANSWER: Both parameters lack the specificity to discriminate CDGP from CHH. WHAT IS KNOWN ALREADY: GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. STUDY DESIGN, SIZE, DURATION: The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. MAIN RESULTS AND THE ROLE OF CHANCE: Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. LIMITATIONS, REASONS FOR CAUTION: As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. WIDER IMPLICATIONS OF THE FINDINGS: Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Adrenal adaptation in potassium-depleted men: role of progesterone?

BACKGROUND: In rodents, the stimulation of adrenal progesterone is necessary for renal adaptation under potassium depletion. Here, we sought to determine the role of progesterone in adrenal adaptation in potassium-depleted healthy human volunteers and compared our findings with data collected in patients with Gitelman syndrome (GS), a salt-losing tubulopathy. METHODS: Twelve healthy young men were given a potassium-depleted diet for 7 days at a tertiary referral medical centre (NCT02297048). We measured by liquid chromatography coupled to tandem mass spectroscopy plasma steroid concentrations at Days 0 and 7 before and 30 min after treatment with tetracosactide. We compared these data with data collected in 10 GS patients submitted to tetracosactide test. RESULTS: The potassium-depleted diet decreased plasma potassium in healthy subjects by 0.3 ± 0.1 mmol/L, decreased plasma aldosterone concentration by 50% (P = 0.0332) and increased plasma 17-hydroxypregnenolone concentration by 45% (P = 0.0232) without affecting other steroids. CYP17 activity, as assessed by 17-hydroxypregnenolone/pregnenolone ratio, increased by 60% (P = 0.0389). As compared with healthy subjects, GS patients had 3-fold higher plasma concentrations of aldosterone, 11-deoxycortisol (+30%) and delta 4-androstenedione (+14%). Their post-tetracosactide progesterone concentration was 2-fold higher than that of healthy subjects and better correlated to plasma potassium than to plasma renin. CONCLUSION: The increase in 17-hydroxypregnenolone concentration after mild potassium depletion in otherwise healthy human subjects suggests that 17 hydroxylation of pregnenolone prevents the increase in progesterone observed in potassium-depleted mice. The unexpected over-response of non-mineralocorticoid steroids to tetracosactide in GS subjects suggests that the adrenal system not only adapts to sodium depletion but may also respond to hypokalaemia.

Oestradiol level, oestrogen receptors, and mortality in elderly men: The three-city cohort study.

CONTEXT: Although endogenous oestradiol, generally considered as the female hormone, has been little investigated in men, it could play a role in men's health, mortality in particular. The influence of oestrogen receptors (ER) genetic polymorphisms on this relationship has never been studied. DESIGN AND PARTICIPANTS: The Three-City cohort study included (1999-2001) 3650 men ≥65 years who were followed for mortality over 12 years. At baseline, total oestradiol (tE2) was measured and ER genotyped in a random subsample of 472 men without hormonal treatment. Free oestradiol (fE2) was estimated using Vermeulen and Södergard algorithms. MAIN OUTCOME: Mortality data were obtained from death certificates. We used inverse probability weighted Cox models to examine the association of oestradiol with all-cause and cause-specific mortality and its interaction with ER genetic polymorphisms. RESULTS: A total of 183 men died over the follow-up (cardiovascular disease (CVD), n = 44; cancer, n = 57; other causes, n = 82). After adjustment, there was a quadratic relationship of all-cause mortality with tE2 and fE2 (P-quadratic = 0.04 and 0.05, respectively), with higher mortality for the top and bottom tertiles compared to the middle one. These associations were stronger for CVD mortality (P-quadratic = 0.01 and 0.02 for tE2 and fE2, respectively) and disappeared for cancer mortality. There was no evidence of an interaction of oestradiol with any ER polymorphisms on all-cause mortality. CONCLUSION: In elderly men, we showed a nonlinear association of tE2 and fE2 with all-cause mortality. These quadratic relationships were stronger for CVD mortality and did not exist for cancer mortality. ER genetic polymorphisms did not modify this association.

Sex hormone-binding globulin and thrombin generation in women using hormonal contraception.

OBJECTIVES: We investigated the impact of serum sex hormone-binding globulin (SHBG) on thrombin generation (TG) in women according to hormonal contraception. PATIENTS AND METHODS: A cross-sectional study of SHBG and TG measured via calibrated automated thrombography was conducted in 150 healthy women, including 75 users of combined oral contraceptives (COC), 22 users of progestin-only contraceptives (POC) and 53 nonusers. RESULTS: COC but not POC-users had significantly higher SHBG levels compared with nonusers. In hormonal contraceptive users, SHBG was positively associated with both activated protein C (APC) resistance and baseline TG, and protein S and prothrombin were important mediators. CONCLUSION: These data provide further evidence that SHBG may be used as a biomarker in assessing prothrombotic profile of hormonal contraception.

Plasma BDNF Level in Major Depression: Biomarker of the Val66Met BDNF Polymorphism and of the Clinical Course in Met Carrier Patients.

AIMS: Despite the involvement of the brain-derived neurotrophic factor (BDNF) in the physiopathology of major depressive disorder (MDD), the coherence between the components of the BDNF pathway and their link with the clinical features of MDD are insufficiently studied. We aimed to assess in Caucasian depressed patients the impact of the BDNF Val66Met polymorphism on plasma BDNF levels taking into account the clinical characteristics of MDD. METHODS: A total of 328 Caucasian adult MDD patients with a current major depressive episode (MDE) were assessed for the BDNF Val66Met polymorphism, plasma BDNF levels and clinical characteristics of the MDD. RESULTS: Plasma BDNF levels were linearly associated with the BDNF Val66Met genotypes (ValVal: 1,525.9 ± 1,183.3 pg/mL vs. ValMet: 1,248.7 ± 1,081.8 vs. MetMet: 1,004.9 ± 952.8; p = 0.04), Met carriers having lower BDNF levels than ValVal ones. Significant interactions between the Val66Met polymorphism and 3 clinical characteristics - age at onset (p = 0.03), MDD duration (p = 0.04), and number of previous MDE (p = 0.04) - were evidenced for plasma BDNF levels. Indeed, in Met carriers, but not in ValVal ones, plasma BDNF levels were negatively correlated with age at onset and positively correlated with MDD duration and number of previous MDE. CONCLUSION: Our results show a measurable, coherent, and functional BDNF pathway based on the BDNF Val66Met polymorphism and plasma BDNF levels in patients with a current MDE. This pathway is related to the clinical course of major depression, plasma BDNF levels being associated with the long-term history of MDD in Met carriers. Further studies assessing central BDNF are needed to understand the underlying mechanisms of this association.

Women Epidemiology Lung Cancer (WELCA) study: reproductive, hormonal, occupational risk factors and biobank.

BACKGROUND: Lung cancer aetiology and clinical aspects have been mainly studied in men, although specific risk factors probably exist in women. Here we present the rationale, design and organization of the WELCA study (Women Epidemiology Lung CAncer) that has been launched to investigate lung cancer in women, focusing particularly on hormonal and occupational factors. METHODS/DESIGN: WELCA is a population based case-control study and planned to recruit 1000 cases and 1000 controls in three years, based on study power calculation. Eligible cases are female patients newly diagnosed with lung cancer, living in Paris and the Ile de France area and aged up to 75 years. Almost all Parisian pneumology and oncology clinical departments are involved. The control group is a random sample of the population living in the same area, frequency-matched on age and additionally stratified on the distribution of socio-professional categories of women residing there. After acquisition of written consent, research nurses administer standardized computer assisted questionnaires to all the subjects in face-to-face interviews and acquire anthropometric measures. Besides usual socio-demographic characteristics, information is gathered about menstrual and reproductive factors, hormonal treatments, lifestyle and leisure characteristics, occupational history, personal and familial medical history. Biological samples are also collected, in order to establish a biobank for molecular epidemiology studies. Molecular characteristics of the tumours will be obtained and patients will be followed up for five years. DISCUSSION: The WELCA study aims to answer key questions in lung cancer aetiology and clinical characteristics specifically in women. The role of hormonal impregnation is investigated, and the interactions with cigarette smoking or body mass index (BMI) will be analyzed in detail. The occupational history of the subjects is carefully reconstructed, focusing in particular on the service sector. The creation of a biobank for collection of serum, plasma, DNA and tumour tissue will allow the genetic and biochemical characterization of both the subjets and the tumours. The follow-up of the patients will help in disentangling the role of hormonal factors and tumour molecular characteristics in survival.

Prevalence of KISS1 Receptor mutations in a series of 603 patients with normosmic congenital hypogonadotrophic hypogonadism and characterization of novel mutations: a single-centre study.

STUDY QUESTION: What is the exact prevalence of Kisspeptin Receptor (KISS1R) mutations in the population of patients with normosmic congenital hypogonadotrophic hypogonadism (nCHH) by comparison with other genes, involved in gonadotrophin-releasing hormone (GnRH) release or action? SUMMARY ANSWER: KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases and were less prevalent than GnRH Receptor (GNRHR) mutations. WHAT IS KNOWN ALREADY: The respective prevalence of each of the genetic causes of nCHH is unclear. Large series of patients are very rare and suffer from heterogeneity of the population of CHH studied. STUDY DESIGN, SIZE, DURATION: Patients with nCHH were consecutively enrolled in a single French referral centre and were gradually tested for KISS1R between January 2006 and April 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 603 patients with nCHH (399 men and 204 women) were diagnosed at the Bicêtre Hospital and underwent KISS1R analysis. The GNRHR, tachykinin receptor 3 (TACR3), gonadotrophin-releasing hormone 1 (GNRH1), tachykinin 3 (TAC3) and KISS1 genes were also sequenced. Functional characterization of KISS1R mutations included a study of signal transduction using a reporter gene (serum response element-luciferase (SRE-Luc) involved in the mitogen-activated protein (MAP) kinase pathway. MAIN RESULTS AND THE ROLE OF CHANCE: We detected 15 KISS1R variants (10 novel), in 12 of the 603 patients (2.0%, 95% CI [0.9-3.1]. KISS1R mutations were less prevalent than GNRHR (4.7%) and TACR3 (2.6%) mutations but more prevalent than GNRH1 (1.5%), TAC3 (1.0%) and KISS1 (0%) mutations. KISS1R mutants were present in the biallelic state in 8 of the 12 patients concerned. Among 5 men with biallelic KISS1R mutations, 4 had either micropenis or cryptorchidism. In vitro analysis of the 5 new variants present in the biallelic state (C95W, Y103*, C115W, P176R and A287E) showed a loss of function. LIMITATIONS, REASONS FOR CAUTION: The prevalence of TACR3, GNRH1, TAC3 and KISS1 mutations was calculated from a smaller number of nCHH patients than KISS1R and GNRHR. This should prompt caution concerning the reported prevalence of mutations in these four genes. WIDER IMPLICATIONS OF THE FINDINGS: We show that KISS1R mutants are responsible for the nCHH phenotype in only a small minority of cases. Together, the genes analysed here were mutated in fewer than 15% of patients, suggesting a role of other genes in nCHH. The presence of cryptorchidism and/or micropenis in the majority of men with biallelic KISS1R mutations strongly suggests that this gene is essential for prenatal GnRH secretion. STUDY FUNDING, COMPETING INTERESTS: This work was supported in part by grants from Paris-Sud University (Bonus Qualité Recherche, and Attractivité grants) to J.B., French Ministry of Health, Hospital Clinical Research Program on Rare Diseases. Assistance Publique Hôpitaux de Paris, Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO) to J.Y. C.P. was supported by student fellowships 'Année Recherche' from Agence Régionale de Santé Provence Alpes Côtes d'Azur. The authors have nothing to disclose.

Premature pubarche before one year of age: distinguishing between mini-puberty variants and precocious puberty.

BACKGROUND: The aim of this study was to facilitate the distinction between the benign "mini-puberty of early infancy" and precocious puberty (PP). MATERIAL AND METHODS: We compared 59 patients (21 boys and 38 girls) seen for pubic hair development before one year of age diagnosed as mini-puberty to 13 patients (2 boys) in whom pubertal development before one year revealed a PP. RESULTS: The boys with mini-puberty presented with pubic hair development and prepubertal testicular volume, with low plasma testosterone concentrations. Their gonadotropin responses to gonadotropin releasing hormone (GnRH) test showed predominant luteinising hormone increase in 9/13. The girls presented with pubic hair development that was accompanied by breast development in 47% of cases, with low plasma estradiol concentrations. Their gonadotropin responses showed predominant follicle-stimulating hormone increase in the 17 evaluated. The patients with PP had organic central PP (5 hypothalamic hamartoma) or idiopathic central PP (n=6), or peripheral PP (one ovarian tumor and one congenital adrenal hyperplasia). The diagnosis was challenging only in 3 girls with idiopathic central PP presenting with prepubertal plasma estradiol concentrations and responses to GnRH test. CONCLUSIONS: The diagnosis of PP was easily determined based on the clinical presentation and the pubertal concentrations of testosterone in boys or of estradiol in girls, as was the diagnosis of central or peripheral origin of PP based on gonadotropin response to the GnRH test. Once PP is excluded, these patients need careful follow-up and physician consultation is needed if clinical pubertal signs progress.

Low testosterone and the risk of dementia in elderly men: Impact of age and education.

OBJECTIVE: The objective of this study was to examine the association of plasma estradiol and testosterone with risk for dementia in elderly men. METHODS: Within the population based Three-City study, including 3650 men age 65 years and older, a case-cohort design was set up after 4-years of follow-up. Baseline plasma levels of total 17-ß estradiol (Total-E2), total testosterone (total-T) and bioavailable testosterone (bio-T) were measured for all cases of incident dementia (n=105) and for a random sample of the cohort (n=413). Cox regression models were used to estimate multivariate steroid sex hormone-associated hazard ratios (HR) and 95% confidence intervals of dementia. RESULTS: There was a reverse J-shaped relationship between total-T and risk for dementia (P=.007). Compared with the median tertile, the HRs associated with total-T in the lower and upper tertile were increased (HR, 2.33; P=.026; HR, 1.9, P=.126; respectively). Low bio-T was associated with a greater risk for dementia (HR for one standard deviation of decreasing log(bio-T), 1.29; 95% confidence interval, 1.03-1.62). An interaction was found between bio-T and age (P<.0001), and bio-T and education (P=.044). Risk for dementia associated with low bio-T was greater in older men (80 years or older) than in younger men (younger than 80 years; HR, 3.11; P=.011 vs. HR, 1.07, P=.715, respectively) and in men with high level of education compared with those with low level of education (HR, 2.32; P=.0002 vs. HR, 0.95; P=.790, respectively). No significant association was found between Total-E2 and dementia. CONCLUSIONS: Low levels of testosterone are associated with a risk for dementia in elderly men. The association between low bio-T and dementia may be more relevant to men 80 years or older and men with a high level of education.

Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications.

Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.

In vitro cellular reprogramming to model gonad development and its disorders.

During embryonic development, mutually antagonistic signaling cascades determine gonadal fate toward a testicular or ovarian identity. Errors in this process result in disorders of sex development (DSDs), characterized by discordance between chromosomal, gonadal, and anatomical sex. The absence of an appropriate, accessible in vitro system is a major obstacle in understanding mechanisms of sex-determination/DSDs. Here, we describe protocols for differentiation of mouse and human pluripotent cells toward gonadal progenitors. Transcriptomic analysis reveals that the in vitro-derived murine gonadal cells are equivalent to embryonic day 11.5 in vivo progenitors. Using similar conditions, Sertoli-like cells derived from 46,XY human induced pluripotent stem cells (hiPSCs) exhibit sustained expression of testis-specific genes, secrete anti-Müllerian hormone, migrate, and form tubular structures. Cells derived from 46,XY DSD female hiPSCs, carrying an NR5A1 variant, show aberrant gene expression and absence of tubule formation. CRISPR-Cas9-mediated variant correction rescued the phenotype. This is a robust tool to understand mechanisms of sex determination and model DSDs.

Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.

We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide-containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.

Endogenous oestradiol as a positive correlate of plasma fibrinogen among older postmenopausal women: a population-based study (the Three-City cohort study).

BACKGROUND: Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. OBJECTIVES: To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin (SHBG) among postmenopausal women. METHODS: We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17ß-oestradiol (E2, pg/ml), total testosterone (T, ng/ml), SHBG (nm) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. RESULTS: E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (ß = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (ß = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m(2) compared with those with normal weight (ß = 0·156, P < 0·001 and ß = 0·092, P = 0·02, respectively, P for interaction = 0·04). CONCLUSION: E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women.

Reproductive Phenotypes in Men With Acquired or Congenital Hypogonadotropic Hypogonadism: A Comparative Study.

CONTEXT: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally. OBJECTIVE: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center. METHODS: We included 172 controls, 668 male HH patients (CHH: n = 201 [age 16.9 ±â€…9.0 years], lesional AHH: n = 467 [age 45.6 ±â€…18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases. RESULTS: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4 ±â€…2.7 mL) but in only 30% of those with AHH (mean TV: 20.8 ±â€…5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH. CONCLUSION: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after treatment for medulloblastoma or posterior fossa ependymoma during childhood.

OBJECTIVE: To evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH). STUDY DESIGN: A total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH; <9 IU/L), or abnormal levels of FSH (>9 IU/L) and luteinizing hormone (LH; <5 or >5 IUL). RESULTS: Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation. CONCLUSION: The plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood.

BACKGROUND: It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done. METHODS: We classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH). RESULTS: Ten (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function. CONCLUSION: The concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.

Small for Gestational Age Preterm Neonates Exhibit Defective GH/IGF1 Signaling Pathway.

Objective: To investigate the impact of fetal growth restriction (FGR) on hormonal regulation of post-natal growth and glucose metabolism [via insulin and growth hormone (GH)/Insulin-like Growth factor 1 (IGF1) axis pathways] in small for gestational age (SGA) neonates. Methods: We conducted a monocentric observational prospective comparative study on 73 singleton babies born with a weight inferior to 2,000 g. We analyzed auxological (weight, height and head circumference), and hormonal (GH, IGF1, and insulin plasma concentrations) data comparing SGA and appropriate for gestational age (AGA) neonates, between day 1 and 60. Results: One third (23/73) of the neonates were SGA. Twenty-five percent (18/73) required insulin for idiopathic hyperglycemia of prematurity and were smaller in weight and head circumference at discharge. In the SGA group compared with the AGA group, GH plasma concentrations were higher at day 3 (70.1 vs. 38.0 mIU/L) and IGF1 plasma concentrations were higher at day 10 (29.0 vs. 18.7 ng/ml). Conclusions: SGA neonates displayed resistance to GH and IGF1, concomitant to insulin resistance. This could partially explain the initial defective catch-up growth and, later in life, the higher prevalence of metabolic syndrome in this population.

Plasma inhibin B and antimüllerian hormone concentrations in boys: discriminating between congenital hypogonadotropic hypogonadism and constitutional pubertal delay.

BACKGROUND: Inhibin B and antimüllerian hormone (AMH) are secreted by the Sertoli cells, stimulated by gonadotropins. We evaluated their use for discriminating between congenital hypogonadotropic hypogonadism (HH) and constitutional pubertal delay. MATERIAL/METHODS: Group 1 (n=39) was diagnosed with constitutional pubertal delay; group 2 (n=15), isolated HH; and group 3, pituitary stalk interruption syndrome (3a with [n=5] and 3b [n=8] without HH). RESULTS: At pubertal age, mean plasma inhibin B concentrations were similar in the groups having the same gonadotropin status. Individual concentrations were normal in groups 1 and 3b, but low in 6 group 2, and 3 group 3a patients. Four group 2, and 1 group 3a, also had low AMH. Among these 9 with low inhibin B, 1 in each group evaluated before puberty had had normal inhibin B and AMH. In contrast, inhibin B increased (P<.03) and AMH decreased (P<.02) in 7 group 3b patients from before to after puberty. There were 20 patients with inhibin B below 100 pg/mL including 4 group 1, 13 group 2, and 3 group 3a. The basal plasma follicle stimulating (FSH) and luteinizing (LH) hormone concentrations were < 1 IU/L in 18%, 36% in group 1, and in 56% and 100% in group 2. CONCLUSIONS: Before puberty, plasma inhibin B and AMH concentrations may be normal despite HH. At pubertal age, both are low in some patients with HH. These hormone values may help discriminate between HH and constitutional pubertal delay together with plasma FSH and LH.