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Marta Ciaccio, Marco Rivarola, and Alicia Belgorosky

Abstract. An evaluation of the usefulness of determining the decrease in serum sex hormone-binding globulin after exogenous testosterone was studied in 55 prepubertal patients with ambiguous external genitalia or micropenis. The biochemical response (androgen sensitivity test) was compared with the clinical response as judged by signs of androgen stimulation of external genitalia. Patients were divided in two groups according to age. Group I, 11 patients younger than 3 months and Group II, 44 patients older than 3 months. Only in 54% of Group I was there a correlation between the androgen sensitivity test and the clinical response to androgens in either a positive (4 patients) or negative sense (2 patients). On the other hand, the androgen sensitivity test and the clinical response to androgens correlated in 91% of the patients of Group II in either a positive (35 patients) or negative sense (5 patients). Two of the 4 patients with lacking correlation had a negative androgen sensitivity test and micropenis secondary to pituitary deficiency. It is concluded that in prepubertal patients older than 3 months with abnormalities of sex differentiation, the androgen sensitivity test and the clinical response to androgens are useful for evaluating androgen sensitivity. The clinical response to androgens is useful in early life when a positive response is found.

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Marta Ciaccio, Alicia Belgorosky, and Marco A Rivarola

It has been reported that growth hormone modulates serum levels of insulin-like growth factor I (IGF-I) positively and serum levels of sex-hormone-binding globulin (SHBG) negatively. We have measured IGF-I and SHBG concentrations in 24 prepubertal patients with growth hormone deficiency. Twelve of these patients had had intracranial tumors removed (organic growth hormone deficiency) and 12 had growth hormone deficiency of unknown etiology (idiopathic). Fifty-two prepubertal control subjects, admitted for elective surgery, were also studied. All prepubertal patients were divided into two age groups: older and younger than 7 years of age. In both groups there were patients with multiple pituitary deficiencies on hydrocortisone and/or levothyroxine sodium replacement therapy. In the age group younger than 7 years, serum IGF-I was not significantly different between organic and idiopathic growth hormone deficiency (0.28±0.21 versus 0.062±0.071 mU/l) but serum SHBG levels were different (74.6±33.5 versus 173±59 nmol/l, p<0.05). These values were not significantly different from controls (0.47±0.25 mU/l and 132±47 nmol/l, respectively). In the age group older than 7 years, there was no significant difference between organic and idiopathic growth hormone deficiency in serum IGF-I (0.33±0.17 versus 0.16±0.11 mU/l) or serum SHBG (113±72 versus 108±17 nmol/l). These values were significantly different from controls (1.04±0.36 mU/l and 68.7±31.7 nmol/l, p<0.05, respectively). It is concluded that serum IGF-I and serum SHBG are regulated by growth hormone in late puberty. In early prepuberty, however, the effect of growth hormone on these two serum parameters seems to be weak. This phenomenon could be related to an increase in the sensitivity of the cellular response to the biological effects of growth hormone with age.

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Esperanza B Berensztein, Alicia Belgorosky, and Marco A Rivarola

The aim of the present work was to develop a method for maintaining prepubertal human testicular cells in culture. Seven pairs of testes of boys who died of causes unrelated to endocrine or metabolic diseases were obtained at necropsy. Histology of the testes was normal. Testes were digested with collagenase and dispersed cells were seeded in multi-well dishes in the presence of 5% bovine fetal serum. After the first day, cells were cultured for five days in serum-free medium in the presence or absence of 918 pmol/l insulin. At the end of culture, microscopic examination showed healthy looking cells with characteristics compatible with pre-Sertoli cells; peritubular cells were identified by immunocytochemistry. In the presence of insulin, cells were able to secrete either testosterone or estradiol into the medium, as well as to reveal aromatase activity. In order to study the effect of the time elapsed between death and beginning of cultures, steroidogenic activity was related to this post mortem time. It was found that, in the presence of insulin, cells obtained from testes with less than 24 h of post mortem time secreted testosterone (64±7.2 pmol/106 cells·24 h, mean±sd) while cells obtained from testes with more than 24 h of post mortem time did not secrete testosterone. With long post mortem times, aromatase activity under insulin increased from non-detectable to 35 pmol/106 cells·24 h. Time course studies showed that cells with capacity to secrete testosterone increase this secretion gradually up to day 10 of culture, while those with detectable aromatase activity showed increments in this activity during the first week of culture. It is concluded that it is possible to maintain cultures of prepubertal human testicular cells obtained at necropsy. In order to maintain testosterone secretion capacity, the time between death and initiation of culture should not exceed 24 h.

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Renata C Scalco, Vivian Hwa, Horacio M Domené, Héctor G Jasper, Alicia Belgorosky, Roxana Marino, Alberto M Pereira, Carlos A Tonelli, Jan M Wit, Ron G Rosenfeld, and Alexander A L Jorge

Context and objective

GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations.


We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared.


Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of −1.4±0.8 when compared with population-matched controls (P< 0.001).


STAT5B mutations in the heterozygous state have a significant negative impact on height (∼3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.

Open access

Armand Valsesia, Pierre Chatelain, Adam Stevens, Valentina A Peterkova, Alicia Belgorosky, Mohamad Maghnie, Franco Antoniazzi, Ekaterina Koledova, Jerome Wojcik, Pierre Farmer, Benoit Destenaves, Peter Clayton, and the PREDICT Investigator group

Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naïve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: ≤4 μg/l (severe GHD; n=45) and >4 to <10 μg/l mild GHD; n=49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P<0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years −3.3 cm; −0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (+2.7 cm; +0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage.

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Mariana Costanzo, María Sol Touzon, Roxana Marino, Gabriela Guercio, Pablo Ramirez, María Celeste Mattone, Natalia Pérez Garrido, María Marcela Bailez, Elisa Vaiani, Marta Ciaccio, María Laura Galluzzo Mutti, Alicia Belgorosky, and Esperanza Berensztein


Differences/disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical.


The aim of this study is to report the histological characteristics and immunoexpression patterns of gonadal parenchyma in patients with 46,XX testicular and ovotesticular DSD, with a focus on the detection of germ cell malignancies.


Inclusion criteria were SRY-negative 46,XX testicular and ovotesticular DSD with available samples from gonadal biopsy or gonadectomy for the review of histological findings. Gonadal histology was assessed on hematoxylin and eosin-stained sections and immunohistochemical analysis. Histopathological criteria from the last World Health Organization classification of urogenital tumors were used to identify undifferentiated gonadal tissue, gonadoblastoma, and dysgerminoma.


Median age at first histological evaluation of gonadal samples was 1.46 years (range: 0.16–16 years). Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD. Most individuals had bilateral ovotestes (12/15). No histological alterations were found in the ovarian parenchyma, while signs of dysgenesis were seen in all cases of testicular parenchyma. In 4/15 ovotesticular DSD, a prepubertal biopsy failed to identify ovarian parenchyma. We detected early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma).


46,XX disorders of gonadal development are historically considered at a low risk for germ cell cancer, and the need for assessment of gonadal histology has been questioned. The finding of early germ cell malignancies in our cohort brings awareness and needs further research.