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Context: Computed tomography (CT) unenhanced attenuation value of <10 Hounsfield units (HU) has an excellent specificity (98%) to diagnose lipid-rich adrenocortical adenomas (ACAs) with a weaker sensitivity (71%)., Objective: To determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs., Design: This was a retrospective study of cases collected between 2009 and 2012., Setting: This study was conducted in a tertiary-care university hospital., Patients: Seventy-two patients operated on for an ACA (Weiss score ≤ 2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA)., Main Outcome Measure: CT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed., Results: Among the 34 patients with a Cush-ACA a minority (n = 7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (> 10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ∼ 60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content., Conclusions: Unenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs., (© 2015 European Society of Endocrinology.)

Context: Recently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli-Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients., Patients and Methods: A 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-D-aspartate) and the patient serum, with or without leptin., Results: A negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin., Conclusion: Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

Context: McCune-Albright syndrome (MAS) is a disorder caused by a post-zygotic gain-of-function mutation in the gene encoding the Gs-alpha protein. Sexual precocity, common in girls, has been reported in only 15% of boys, and little is known on the long-term evolution of MAS in males., Objective: In a boy with MAS, we studied spermatogenesis, testis histology, and immunohistochemistry with the aim to shed light on seminiferous tubule activity., Design: A boy who presented at the age of 2.9 years with sexual precocity, monolateral macroorchidism, increased testosterone levels, and suppressed gonadotropins was followed up until the age of 18., Results: Throughout follow-up testicular asymmetry persisted and gonadotropin and testosterone pattern did not change. At the age of 18, inhibin B was undetectable while alpha-immunoreactive inhibin was within normal range. Anti-Mullerian hormone level was slightly subnormal. Sperm cells were 3,900,000 per ejaculate. Histology of both testes showed spermatogonia, spermatocytes, and, in some tubes, matured spermatozoa. Sertoli cells were markedly stained with anti-inhibin alpha-subunit antibody in both the testes. There was no immunostaining of Sertoli, Leydig, or germ cells with anti-betaA or anti-betaB antibody. MAS R201H mutation was identified in both the testes., Conclusion: The 15-year follow-up in this boy with MAS demonstrated that autonomous testicular activation and gonadotropin suppression persisted over time. This provides an interesting model of active spermatogenesis despite long-term FSH suppression. It also suggests that FSH is needed for the full expression of the inhibin betaB-subunit gene, an expression previously reported in the germ and Leydig cells of normal adult subjects.

Background: Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation and increased predisposition to various neoplasms. Endocrine manifestations in PJS include gynecomastia due to calcified Sertoli cell testicular tumors usually referred to as large-cell calcifying Sertoli cell tumors (LSCT)., Objective: To evaluate the value of endocrine markers and aromatase inhibitor treatment in children with PJS and LSCT., Design and Setting: Familial cases, followed in a tertiary care center., Patients: Two male siblings aged 7 and 9 years with PJS and LSCT., Intervention: Third generation aromatase inhibitor (anastrozole) in one of the patients., Main Outcome Measures: Longitudinal measurements of sex-steroids, gonadotropins, Sertoli cell markers and auxological evaluation., Results: The two male siblings with PJS had similar bilateral multifocal testicular calcifications and biochemical evidence of Sertoli cell dysfunction manifested by elevated plasma inhibin-alpha levels. Only one sibling had gynecomastia. Estradiol levels were normal in both. During treatment with anastrozole, estradiol levels, growth and skeletal maturation, as well as Sertoli cell markers (inhibin B, inhibin-alpha and anti-Mullerian hormone) decreased., Conclusions: Inhibin-alpha may be considered as a marker for LSCT in children with PJS, pointing to a specific defect in inhibin regulation in this condition. Moreover, the decrease in Sertoli cell markers during aromatase inhibitor treatment suggests that increased estrogen production is a primary event regulating downstream production of Sertoli cell peptides. Anastrozole is efficient in controlling the clinical features of the disease and should be proposed as an alternative to bilateral orchidectomy, which is often performed in this condition.

Objective: Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP., Design: This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly., Methods: Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH > or = 7 IU/l, advanced bone age > 1 year, enlarged uterus (> or = 36 mm) and testosterone level > or = 0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12., Results: GnRH-stimulated peak LH < or = 3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding., Conclusions: The triptorelin 3-month depot efficiently suppresses the pituitary-gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.

Objective: Growth hormone secretion is decreased in obese subjects, and their GH response to stimulation tests is blunted. The mechanisms relating excess adipose mass and GH secretion are unknown. We hypothesized that leptin might be a signal linking adipose mass to GH secretion., Design: We measured serum leptin levels and the GH response to stimulation tests in 42 obese and 40 lean short normal prepubertal children., Results: The mean serum leptin concentrations were 23.8+/-1.7 ng/ml and 3.6+/-0.4 ng/ml in obese and lean children respectively, and were found to be inversely related to GH peak in both groups. After adjusting for body fat data, leptin was still an independent predictor of GH peak. Multiple stepwise regression analysis identified both leptin (regression coefficient = -0.78, P = 0.001), and insulin (regression coefficient = -0.03. P = 0.009) as negative determinants of GH response to the GHRH test in obese children (multiple R = 0.64), and only leptin in lean children (r = -0.51, P = 0.001). No correlation was observed between leptin and IGF-I or IGF binding protein-3., Conclusion: These results are consistent with the hypothesis that leptin could contribute to the regulation of GH secretion.

In ob/ob mice, leptin deficiency results in hypogonadotrophic hypogonadism, impaired sexual maturation and infertility, which are all corrected by leptin administration. In humans, pubertal development and menarche are related to the attainment of a critical amount of body fat. To examine whether changes in circulating concentrations of leptin could be a hormonal signal influencing gonadotrophin secretion, we studied 98 adolescents and young adults of both sexes, aged 13-19 years, whose weight varied from normal to massively obese and whose sexual maturation was between Tanner stages 3 and 5. We measured leptin, sex steroids and circulating gonadotrophin concentrations in the basal state and in response to GnRH. In perimenarchial and young adult girls, we found that the LH and FSH responses to GnRH were negatively correlated with body mass index (BMI: r = -0.45 and -0.47 respectively, P < 0.0025) and circulating leptin (r = -0.53 and -0.49 respectively, P < 0.002). Decreased LH and FSH responses to GnRH were associated with increased adiposity and hyperleptinaemia. Our data do not establish, but are consistent with a direct neuroendocrine negative effect of excess leptin on the central reproductive system of obese girls. In boys of comparable adiposity, we found no influence of BMI or leptin on gonadotrophin concentrations, which is another aspect of the sexual dimorphism characterizing human leptin physiology.

Familial acromegaly is a very rare inherited disorder, characterized by the clustering within a single family of several related cases with somatotroph adenomas and acromegaly. The causes of these dominantly inherited pituitary tumours remain unknown. Although these families have a clinical presentation distinct from that of multiple endocrine neoplasia type 1 (MEN-1), the question of this syndrome as being linked to the MEN-1 locus has remained open. Our aim was to study a three-generation family with cases of acromegaly in a mother and her son, to explore better the clinical presentation of the disease, its pattern of inheritance and to test the hypothesis of a genetic linkage to the MEN-1 locus using closely linked polymorphic genetic markers. The refined analysis of 15 unaffected relatives revealed miscellaneous non-specific endocrine dysfunctions and the presence of multiple lipomata, as noted previously in some cases. Moreover, the notion of acromegalo-gigantism in the maternal grandmother and an incomplete penetrance appeared even more typical, suggesting that familial acromegaly is a specific clinical entity. Finally, under the hypotheses assumed for segregation analysis, no clinical, biological or genetic evidence of linkage to the MEN-1 locus could be retained in this family. However, these conclusions were limited because of incomplete penetrance and uncertain definition of the carrier status. Therefore, we conclude that further identification of the genetic predisposition to familial acromegaly might be obtained from the combined molecular genetic analysis of several families presenting with the same clinical features.

We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight > or = 20 kg, 1.87 mg if body weight < 20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone < 3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.

The purpose of this study was to determine whether gonadotropin-releasing hormone (GnRH) may exert a direct action on human prolactinomas. On a series of 17 adenomas, we studied the effect of GnRH on the in vitro prolactin (PRL) secretion of dispersed and perifused cells of 10 cases and the [125I]GnRH agonist binding on frozen sections of three out of the adenomas studied in perifusion and on the membrane preparations of seven other cases. Two 20-min pulses of GnRH (10(-7) mol/l) stimulated the in vitro PRL secretion of three adenomas out of 10 (increase of 200, 444 and 205%, respectively, above basal levels). The GnRH receptors of three adenomas bound GnRH agonist (Des-Gly10-(D-Ala6)-GnRH ethylamide). The binding was specific, with a high affinity (Kd = 0.60, 0.48 and 0.40 nmol/l) similar to that of two human anterior pituitaries obtained post-mortem (Kd = 0.70 and 0.40 nmol/l). Indirect immunoperoxidase revealed that the majority of the cells (60-90%) in all the adenomas studied contained immunoreactive PRL. Four of them also contained cells immunoreactive to the alpha-subunit of the glycoprotein hormones. In none of the prolactinomas were cells immunoreactive to antiserum of anti-beta-luteinizing hormone, anti-beta-follicle-stimulating hormone or anti-beta-thyrotropin. All the prolactinomas that were responsive to GnRH in perifusion experiments and/or bound specifically to [125I]GnRH agonist were also immunoreactive for alpha-subunit. These results show that GnRH, via GnRH specific receptors, exerts a stimulation on in vitro PRL secretion in a subset of prolactinomas characterized by the presence of alpha-subunit.

To study the sex steroid-gonadotrophin relationship, plasma oestradiol (E2), testosterone and gonadotrophin-releasing hormone (GnRH)-induced (100 micrograms iv) gonadotrophin response were measured in 42 male partners of infertile couples with normal sperm count (group I) and in 21 men with Leydig cell tumour (LCT, group II) in which a basal evaluation was repeated after tumour removal. Plasma free alpha-subunit (FAS), immunoreactive alpha-inhibin and luteinizing hormone (LH) pulse analysis were assessed in 10 LCT before and in six of them after surgery. Testosterone was significantly (p < 0.01) lower whereas E2 was significantly (p < 0.001) higher in group II than in group I. Gonadotrophin data were similar in both groups. The mean FAS was higher in group II than in group I and alpha-inhibin was higher than the normal range in 6/10 LCT. In group II, E2 levels were significantly (p < 0.01) and negatively correlated with testosterone, FSH, GnRH-induced gonadotrophin rise and LH pulse amplitude but not frequency. Significant (p < 0.001) changes were observed after surgery: E2 and alpha-inhibin fell; testosterone, LH and FSH rose; whereas FAS did not change significantly. The LH pulse amplitude but not frequency increased significantly (p < 0.05). In conclusion E2 oversecreted by LCT decreased LH and testosterone levels concomitantly. The GnRH-induced gonadotrophin level rose and the LH pulse amplitude decreased when the plasma E2 level rose, whereas the pulse frequency remained unaffected. A concomitant increase in alpha-inhibin and E2 is likely to be responsible for the drop in plasma FSH levels. These data support an action of excessive amounts of E2 at pituitary level, perhaps by decreasing the sensitivity of gonadotrophs to GnRH.