The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband's brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.

Anti-Müllerian hormone in dogs and cats reproduction.

The anti-Müllerian hormone (AMH) is a glycoprotein secreted by Sertoli cells in males and granulosa cells in females. It has first been determined in blood serum of dogs and cats by Place et al. in 2011 with the use of a human-based ELISA test. Meanwhile, different immunoassays have been validated for AMH determination in animals and a variety of studies have demonstrated the clinical significance of AMH. This review summarizes the current knowledge about AMH in dogs and cats and describes future opportunities for its diagnostic use.

Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges.

Body energy stores and metabolic cues influence the onset of puberty. However, the pubertal impact of early nutritional challenges has been only fragmentarily addressed. We evaluated here the consequences, in terms of pubertal timing and hormonal markers, of various nutritional manipulations during pre- or postnatal maturation in rats of both sexes. Males and females were submitted to gestational undernutrition (UNG) or peripubertal (SUB) subnutrition or were raised in large (LL; underfeeding) or small (SL; overfeeding) litters. In addition, groups of UNG, LL, and SL rats were fed on a high-fat diet (HFD) after weaning. Postnatal overfeeding resulted in higher body weights (BWs) during pubertal transition in both sexes, but only SL males displayed overtly advanced external signs of puberty. Postnatal underfeeding persistently decreased BW gain during puberty, yet the magnitude of pubertal delay was greater in LL males. In contrast, regardless of postnatal nutrition, HFD tended to advance the onset of puberty in females but did not alter pubertal timing in males. Likewise, SUB females displayed a marked delay in BW gain and puberty onset, whereas despite similar reduction in BW, SUB males showed normal timing of puberty. These sex divergences were also detected in various hormonal and metabolic indices so that postnatal overnutrition consistently increased LH, FSH, leptin, and insulin levels only in pubertal females, whereas HFD decreased gonadotropin levels in SL females but increased them in SL males. Notably, UNG rats did not show signs of delayed puberty but displayed a striking sex dimorphism in serum insulin/glucose levels, regardless of the diet, so that only UNG males had signs of presumable insulin resistance. Our data disclose important sex differences in the impact of various early nutritional challenges on the timing of puberty, which may help to explain the different trends of altered puberty and related comorbidities between sexes.

The molecular basis of impaired follicle-stimulating hormone action: evidence from human mutations and mouse models.

The pituitary gonadotropin follicle-stimulating hormone (FSH) interacts with its membrane-bound receptor to produce biologic effects. Traditional functions of FSH include follicular development and estradiol production in females, and the regulation of Sertoli cell action and spermatogenesis in males. Knockout mice for both the ligand (Fshb) and the receptor (Fshr) serve as models for FSH deficiency, while Fshb and Fshr transgenic mice manifest FSH excess. In addition, inactivating mutations of both human orthologs (FSHB and FSHR) have been characterized in a small number of patients, with phenotypic effects of the ligand disruption being more profound than those of its receptor. Activating human FSHR mutants have also been described in both sexes, leading to a phenotype of normal testis function (male) or spontaneous ovarian hyperstimulation syndrome (females). As determined from human and mouse models, FSH is essential for normal puberty and fertility in females, particularly for ovarian follicular development beyond the antral stage. In males, FSH is necessary for normal spermatogenesis, but there are differences in human and mouse models. The FSHB mutations in humans result in azoospermia; while FSHR mutations in humans and knockouts of both the ligand and the receptor in mice affect testicular function but do not result in absolute infertility. Available evidence also indicates that FSH may also be necessary for normal androgen synthesis in males and females.

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.

Female gonadal function before and after treatment of acromegaly.

CONTEXT: The menstrual cycle is often abnormal in women with acromegaly. Gonadotropin deficiency may be due to a tumor mass effect (macroadenomas) and/or hyperprolactinemia and/or GH excess. AIM OF THE STUDY: The aim of the study was to analyze the causes of ovarian dysfunction in a large series of patients with acromegaly followed up in a single center. PATIENTS AND METHODS: Gonadal function was assessed on the basis of menstrual status and hormone assays before and after treatment of acromegaly, between 1985 and 2005, in 55 patients aged from 17 to less than 45 yr. RESULTS: Seventeen women (31%) were considered to be eugonadal because they had regular menstrual cycles and/or conceived spontaneously. The remaining 38 women had anovulatory cycles. Of these, 11 had hyperprolactinemia and six had hypogonadism due to a mass effect. The cause of the menstrual disturbances was mixed or unclassifiable in 14 cases. In the seven remaining cases, the gonadal dysfunction was likely related to the GH/IGF-I excess, which exerts a direct effect on the gonadotropic axis. Two had polycystic ovary syndrome, which disappeared after normalization of serum GH/IGF-I levels, suggesting that GH/IGF-I excess may also have a direct effect on the ovary. Thirty-eight women became pregnant, and all had healthy children, despite active acromegaly in 12 cases (31%). CONCLUSION: Gonadal dysfunction is very common in premenopausal women with acromegaly. The potential causes include the lactogenic effect of prolactin, GH, or both on gonadotropic axis. Tumor mass effect or direct effect of GH or IGF-I on the ovary may also participate in ovarian dysfunction.

[Gonadal function in boys prior to treatment for acute lymphoblastic leukaemia]. / Ocena czynnosci gonad u chlopców przed leczeniem ostrej bialaczki limfoblastycznej.

UNLABELLED: The aim of this study was to evaluate the gonadal function in boys with newly-diagnosed acute lymphoblastic leukaemia, prior to therapy. PATIENTS AND METHODS: The analysis was evaluated in 48 boys with acute lymphoblastic leukaemia, at the time of diagnosis; 34 boys were prepubertal - Tanner stage of sexual maturation 1 (group I) and 14 - pubertal - Tanner stage 3-5 (group II). Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, testosterone and testicular volume were determined. RESULTS: In group I no alteration in hormonal status was observed, whereas in group II lower inhibin B was found (68.09 ng/l+/-54.87 vs 152.66 ng/l+/-72.09, p=0.0002). The levels of FSH, LH, testosterone and testicular volume did not differ from healthy adolescents. We did not observe a correlation between inhibin B and FSH concentrations. We did not find the influence of immunophenotype of leukaemic cells, leukocytosis, haemoglobin, platelets levels as well as LDH activity on the values of analyzed hormones. CONCLUSION: In adolescent boys with newly diagnosed leukaemia, lowered inhibin B values may suggest the damage of spermatogenesis even before the start of chemo- and radiotherapy. The small number of examined children requires confirmation on a larger group of patients.

Regulation of circulating leptin and its soluble receptor during pubertal development in the male rhesus monkey (Macaca mulatta).

In humans, circulating leptin levels are low in early childhood and rise until puberty, whereas the reverse occurs for the soluble leptin receptor (sOB-R). In women, leptin remains high and sOB-R remains low, but in men leptin declines after adolescence and sOB-R increases. These observations suggest that leptin may regulate the production of sOB-R, and that the increased testosterone in adolescent boys may be responsible for the gender differences in leptin and sOB-R. To test this hypothesis, leptin was administered continuously to agonadal juvenile male monkeys for 16 days. No change in sOB-R was observed. Intact juvenile male monkeys were given pulsatile doses of gonadotropins for a period of 7 weeks to induce precocious puberty and assess the effect on plasma testosterone, leptin, and sOB-R. By 4 weeks testosterone had reached adult levels. No changes were observed in leptin, but by week 4, sOB-R was higher than pretreatment values and remained higher at week 7. These data suggest that leptin may not play a significant role in regulating the production of sOB-R and that gender differences in sOB-R in humans may be driven by the increased production of testosterone at puberty in males.

Serum anti-Müllerian hormone and inhibin B in disorders of spermatogenesis.

This study investigates circulating concentrations of AMH and inhibin B in men with azoospermia. Serum AMH and inhibin B are significantly lower in the men with nonobstructive azoospermia compared to the controls and the men with obstructive azoospermia, suggesting that these hormones could be markers of nonobstructive azoospermia.

Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's syndrome.

Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushing's syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushing's disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing's syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14-79 years), 12 patients with ACS (4 men, 8 women, aged 32-79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm2), T-score and Z-score referred to the manufacturer's normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76+/-0.03 g/cm2; T-score, -2.78+/-0.28; Z-score, -2.25+/-0.30) while patients with CD (BMD, 0.87+/-0.02 g/cm2; T-score, -1.74+/-0.24; Z-score, -0.99+/-0.32) showed DXA values between the first group and controls (BMD, 1.02+/-0.02 g/cm2; T-score, -0.35+/-0.19; Z-score, 0.33+/-0.16). The difference in BMD at the spine remained statistically significant ( P=0.04) after adjustment for the non-significant differences in age, UFC and fat mass between CD and ACS. Conversely, femoral bone densitometric parameters were not significantly different between patients with ACS and CD, even if they were more reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S levels, expressed as standard score ( Z-score) values referred to a group of 180 healthy subjects stratified by sex and different age groups (<40 years, between 40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age on such hormone (ACS DHEA-S Z-score -0.88+/-1.4 versus CD DHEA-S Z-score 2.25+/-2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar BMD ( r=0.41, P=0.02) and femoral BMD ( r=0.43, P=0.01). DHEA-S Z-score values were also significantly correlated with osteocalcin levels ( r=0.45, P=0.01). Our data suggest that bone loss is greater in ACS than in CD. A plausible explanation comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic actions on bone. However, this hypothesis needs to be confirmed in large, prospective series of patients with Cushing's syndrome of different etiology.

Factors affecting gonadal function after bone marrow transplantation during childhood.

Conditioning for bone marrow transplantation (BMT) may alter viability of germ cells and production of gonadal hormones. We analyzed the risk factors for gonadal failure after 12 Gy total body irradiation (TBI) given as six fractions (n = 31, group 1), 10 Gy (one dose) TBI (n = 20, group 2), 6 Gy (one dose) total lymphoid irradiation (TLI, n = 17, group 3) and chemotherapy alone (n = 7, group 4), given at 7.7 +/- 0.4 (0.6-13.6) years. Among the 34 girls, seven (20.6%) had normal ovarian function with regular spontaneous menstruation and normal plasma follicle-stimulating (FSH) and luteinizing (LH) hormones, five (14.7%) had partial ovarian failure with regular menstruation but increased FSH and/or LH, and 22 (64.7%) had complete ovarian failure. The 24 girls with chronological and bone ages >13 years included similar percentages, with increased FSH or LH in all four groups. There was a positive correlation between age at BMT and FSH (r = 0.54, P < 0.01), but not with lh, and between fsh and lh (r = 0.8, P = 0.0003). Plasma FSH concentrations had returned to normal spontaneously in six cases, and those of LH in two cases. Among the 41 boys, 16 (39%) had normal testicular function and 25 (61%) had tubular failure and increased FSH. Of these, 10 also had Leydig cell failure (three complete and seven partial). The 18 boys with chronological and bone ages >15 years included similar percentages with increased FSH or LH in groups 1 to 3, and testicular volume was significantly lower in group 2 than in group 3 (P = 0.008). There was no correlation between age at BMT and FSH, LH or testosterone, but there was a negative correlation between FSH and inhibin B (rho = -0.87, P < 0.003). we conclude that girls are more likely to suffer ovarian failure the older they are at bmt, and that early ovarian recovery is possible. the negative correlation between fsh and inhibin b in boys suggests that this parameter is an additional indicator of tubular function.

Gonadotropin secretion in prepubertal normal and agonadal children evaluated by ultrasensitive time-resolved immunofluorometric assays.

To analyze a possible gonadal effect on the control of gonadotropin secretion during the prepubertal period, we have measured the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) serum concentrations in children with primary gonadal failure (PGF). We measured them using an ultrasensitive immunofluorometric assay (IFMA) in a single daytime serum sample and compared the results with those obtained with a radioimmunoassay (RIA) technique. The patients were 22 children with PGF (13 girls and 9 boys) aged 0.56-15.4 years and 58 normal children (28 girls and 30 boys) aged 0.08-16 years. In the normal group there were significant changes in serum LH and FSH concentrations in relation to sex and pubertal development. These changes were more evident especially in LH concentrations when using IFMA. We observed that during the prepubertal period the normal LH levels (mean +/- SD) were detectable with this method at concentrations well below the limit RIA could detect (girls 0.026 +/- 0.012 IU/l, and boys 0.025 +/- 0.01 IU/l), while at the onset of puberty these LH levels rose significantly in both sexes (girls 1.0 +/- 0.79 IU/l, boys 1.7 +/- 0.7 IU/l; p < 0.01 vs. prepubertal group), reaching similar values to those observed in FSH concentrations (prepubertal girls 1.9 +/- 0.89 IU/l, boys 0.73 +/- 0.41 IU/l; early pubertal girls 3.1 +/- 0.9 IU/l, boys 2.6 +/- 1.3 IU/l). At prepubertal age, most PGF patients showed normal gonadotropin serum levels (particularly LH) when measured by RIA. However, these same samples-when measured by IFMA-showed LH and FSH levels clearly higher than normal in almost all-10 of 12-patients (PGF girls, n = 8, LH 1.1 +/- 1.0 IU/l, FSH 34 +/- 30 IU/l; PGF boys, n = 4, LH 0.13 +/- 0.12 IU/l, FSH 6.5 +/- 5.7 IU/l). We conclude that, during the so-called 'juvenile pause' when the gonadotropin concentrations could be reliably measured, supranormal gonadotropin levels could be observed during a single daytime serum sample in patients with PGF. These findings suggest that during this period of life the gonads contribute to the negative feedback regulation of gonadotropin levels.

Valores basais de LH e FSH em crianças e adolescentes normais determinados através do método da quimioluminescência / Basal values of LH and FSH in normal children and adolescents determined by chemiluminescence method

Com a finalidade de estabelecer valores referenciais para as concentraçöes basais de gonadotrofinas séricas avaliadas através do método de quimioluminescência, foram dosados o LH e o FSH em 148 crianças e adolescentes nos vários estágios puberais. Para os meninos, o valores de LH e FSH, em UI/L, expressos como média e intervalo de confiança, foram no estágio I 1,00 (0,47-1,53) e 1,78 (1,26-2,30); no estágio II, 1,16 (0,39-1,94) e 3,31 (2,08-4,53); no estágio III 2,28 (1,45-3,12) e 3,71 (2,56-4,85) e, nos estágios IV e V 4,10 (3,25-4,94) e 8,94 (4,48-13,40). Nas meninas, os valores foram no estágio 10,48 (0,34-0,62) e 3,50 (2,58-4,42); noestágio II, 1,92 (-0,12-3,96) e 5,93 (2,34-9,53); no estágio III 4,41 (1,85-6,96) e 8,40 (6,07-10,73) e, nos estágios IV e V 6,39 (4,00-8,78) e 7,57 (5,35-9,80). A porcentagem de valores indetectáveis foi de 9,45 para o LH e 3,37 para o FSH, todos os casos ocorrendo nos estágios I e II da puberdade. Foram observadas diferenças significativas entre os valores pré-puberais e os encontrados a partir do estágio III de puberdade. Constatou-se, no entanto, a ocorrência de sobreposiçäo de valores nos diferentes estágios do desenvolvimento puberal.