A novel variant of DHH in a familial case of 46,XY disorder of sex development: Insights from molecular dynamics simulations.

Objective: Disorders of sex development (DSD) are a heterogeneous group of conditions affecting the differentiation and development of the internal and external genitalia. Here, we aimed at identifying the genetic cause of DSD in two 46,XY sisters from a consanguineous family.

Design: We performed a whole-exome sequencing of two 46,XY female individuals.

Evidence of ERalpha and ERbeta selectivity and partial estrogen agonism in traditional Chinese medicine.

The use of complementary and alternative medicine and herbal products, especially traditional Chinese medicines, is progressively rising for both adults and children. This increased use is based on the popular belief that these medicines are safe and harmless. In this report, we describe the results of a bedside-to-bench study that involved a short-statured 4-year-old boy with deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone due to an ectopic posterior pituitary gland and invisible pituitary stalk.

Increased serum estrogenic bioactivity in girls with premature thelarche: a marker of environmental pollutant exposure?

The aim of the work was to investigate the pathophysiology of isolated premature thelarche (IPT) by determining the impact of pre/postnatal exposure to endocrine disrupting chemicals (EDCs) through evaluation of total serum estrogenic bioactivity (EBA). The pathophysiology remains elusive, although recent investigations suggested the role of EDCs in premature female breast development. We investigated 15 girls with IPT.

Fetal ovarian cysts: an early manifestation of McCune-Albright syndrome?

Objective: Beyond the classic triad of peripheral precocious puberty, café-au-lait skin pigmentation and polyostotic fibrous dysplasia, partial presentation McCune-Albright syndrome (MAS) has been reported, including the association of isolated recurrent ovarian cysts in early infancy. The aims of this study were to determine whether isolated voluminous fetal unilateral ovarian cysts (diameter > 4 cm) may be associated with a Gsα activating mutation, suggestive of MAS.

Design: We followed five female fetuses presenting with voluminous unilateral ovarian cysts by ultrasonography until delivery.

'Idiopathic' partial androgen insensitivity syndrome in 28 newborn and infant males: impact of prenatal exposure to environmental endocrine disruptor chemicals?

Objective: 46,XY disorders of sex differentiation (46,XY DSD) can be due to a testis determination defect, an androgen biosynthesis defect, or androgen resistance (complete or partial androgen insensitivity syndrome (PAIS), or 5α reductase deficiency). We aimed to evaluate the impact of a prenatal contamination by environmental xenoestrogens in 'idiopathic' PAIS-like phenotype.

Subjects: We investigated 28 newborn/infant males with 46,XY DSD, normal androgen production, and no androgen receptor or steroid-5αR type II enzyme (SRD5A2) gene mutations.

Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients.

Context: In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential.

Objective: The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis.

Primary amenorrhea in four adolescents revealed 5α-reductase deficiency confirmed by molecular analysis.

Objective: To determine the genetic cause of primary amenorrhea.

Design: Case series.

Setting: Pediatric endocrinology, endocrinology, and gynecology departments of academic hospitals.

Steroidogenic factor-1 (SF-1) gene mutation as a frequent cause of primary amenorrhea in 46,XY female adolescents with low testosterone concentration.

Background: Primary amenorrhea due to 46,XY disorders of sex differentiation (DSD) is a frequent reason for consultation in endocrine and gynecology clinics. Among the genetic causes of low-testosterone primary amenorrhea due to 46,XY DSD, SRY gene is reported to be frequently involved, but other genes, such as SF1 and WT1, have never been studied for their prevalence.

Methods: We directly sequenced SRY, SF1 and WT1 genes in 15 adolescent girls with primary amenorrhea, low testosterone concentration, and XY karyotype, to determine the prevalence of mutations.

Isolated Cushing's syndrome: an unusual presentation of McCune-Albright syndrome in the neonatal period.

Cushing's syndrome (CS) may develop at any time in childhood. In the neonatal period, the major cause is the overactivation of adrenal cells within the context of McCune-Albright syndrome (MAS). The hypercorticism usually appears with other clinical signs of MAS.

Regulation of activities of steroid hormone receptors by tibolone and its primary metabolites.

This work was undertaken (i) to study deeply the estrogen, androgen and progestative activities of tibolone and its metabolites (ii) to determine whether tibolone and its metabolites present glucocorticoid or mineralocorticoid activity. For this purpose, we used human cell lines bearing a luciferase gene with a responsive element under the control of human estrogen receptor alpha (ERalpha) or estrogen receptor beta (ERbeta) or androgen receptor (AR) or chimeric Gal4 fusion with progesterone receptor (PR), glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). The major tibolone metabolites, the two hydroxymetabolites, bind and activate ER with a preference for ERalpha.

Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta.

Estrogens control transcriptional responses through binding to two different nuclear receptors, estrogen receptor alpha (ERalpha) and beta (ERbeta). Since these two ER subtypes are thought to mediate different biological effects, there is intense interest in designing subtype-selective ER ligands. In this study, we evaluated the ERalpha and ERbeta selectivity of 19 known estrogens and antiestrogens using reporter cell lines previously developed in our laboratory.

Increased serum estrogenic bioactivity in three male newborns with ambiguous genitalia: a potential consequence of prenatal exposure to environmental endocrine disruptors.

In the past 15 years, anomalies of male sexual differentiation have greatly increased in both wildlife and humans in different parts of the world. Environmental endocrine disruptors have been implicated in the dramatic rise in neonatal ambiguous genitalia with variable rates of severity, such as micropenis, cryptorchidism, and isolated or associated hypospadias. Because most environmental pollutants, such as organochlorine pesticides, polychlorinated biphenyls, dioxins and furans, alkylphenol polyetholyethoxylates, and phytoestrogens and phtalates, have estrogenic and antiandrogenic activity, they are able to interfere with normal fetal male sexual differentiation.

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene.

Liver receptor homolog-1 (LRH-1) is a nuclear receptor previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis. Recently, a new role for LRH-1 has been discovered in tumor progression, giving LRH-1 potential transforming functions. In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines.

In vivo bioluminescence imaging to evaluate estrogenic activities of endocrine disrupters.

Reporter gene technology is widely used to measure activity of hormone analogs, and bioluminescent in vitro assays have allowed rapid screening of numerous chemicals either to identify new agonists or antagonists of hormones or to detect the presence of endocrine disrupters in the environment. Stable bioluminescent cell lines have been established and they provide reproducible dose-response curves and accurate determination of in vitro efficiencies of various chemicals. In vivo, however, these molecules can be metabolized, bound by proteins, or stored in fats and thus could display efficiencies different from those observed in vitro.

Evidence that chlormadinone acetate exhibits antiandrogenic activity in androgen-dependent cell line.

Chlormadinone acetate (CMA), like other 17-hydroxyprogesterone derivatives, is thought to be a potential antiandrogen on the basis of its effect on spontaneous benign prostatic hyperplasia (BPH) in dogs. This work was undertaken to find out whether CMA presents antiandrogen activity in human androgen-dependent cell line. For this purpose, we used PALM cells, the PC-3 cell line stably transfected with human androgen receptor and a luciferase gene under transcriptional control of MMTV.

Evaluation of androgenic bioactivity in human serum by recombinant cell line: preliminary results.

Besides the measurement of circulating conjugated metabolites of dihydrotestosterone (DHT), which reflects androgenic activity, only one assay to measure androgenic bioactivity in human serum has been proposed thus far. This recombinant bioassay is based on the androgen-dependent interaction between the LBD and NT domains of AR fused to the Gal 4 DNA-binding domain, but its construction is highly complex. We have developed a mammalian cell (CHO 515) bioassay that measures total androgen bioactivity in human serum.

Phenylphenols, biphenols, bisphenol-A and 4-tert-octylphenol exhibit alpha and beta estrogen activities and antiandrogen activity in reporter cell lines.

We previously demonstrated the interactions of different chemical compounds with estrogen receptors ERalpha and ERbeta and the androgen receptor (AR) using different reporter cell lines. In this study, we characterize the ERalpha, ERbeta and AR activity of different biphenyls using the same tools. We provide evidence that several phenyl derivatives present both estrogenic and antiandrogenic activity.

A new recombinant cell bioassay for ultrasensitive determination of serum estrogenic bioactivity in children.

The evaluation of estrogenic status is necessary for many physiological and pathological conditions in pediatric as well as adult endocrinology. Because current immunoassays exclusively measure E2--and with a sensitivity that is insufficient for prepubertal children--we developed a new recombinant cell bioassay for ultrasensitive determination of serum estrogenic bioactivity. This assay is based on human uterine cervix carcinoma cells, HeLa cells, that do not naturally express E2 receptor.