Effects of chlorocholine chloride on pubertal development and reproductive functions in male rats.

Chlorocholine chloride (CCC), a plant growth retardant, may act as an endocrine disruptor. Our previous study showed that pubertal CCC exposure in rats might decrease testosterone (T) synthesis. This study observed the changes in pubertal development and reproduction of male rats exposed to CCC and its underlying mechanisms. Rats were exposed to CCC (0, 75, 137.5 and 200 mg/kg bw/day) from postnatal day 23 to 60. The results showed that CCC treatment delayed the onset of puberty and reduced the relative organ weight of prostate. Seminiferous tubules with deciduous spermatogenic cells were observed in the 200 mg/kg bw/day group. Sexual behavior was inhibited in the 137.5 and 200 mg/kg bw/day groups. Sperm motility, litter size and normalized anogenital distance (AGD) of male pups were decreased in the 137.5 and 200 mg/kg bw/day groups. Serum kisspeptin level and serum and testicular levels of T were reduced in all CCC treated groups. Crucial hormones in hypothalamic-pituitary-testicular (HPT) axis were reduced subsequently after CCC treatment. Collectively, our results demonstrated that CCC might disturb HPT axis through suppressing the secretion of kisspeptin and subsequently lead to delayed puberty onset and impaired reproductive functions.

Bisphenol S alters development of the male mouse mammary gland and sensitizes it to a peripubertal estrogen challenge.

Humans are exposed to estrogenic chemicals in food and food packaging, personal care products, and other industrial and consumer goods. Bisphenol A (BPA), a well-studied xenoestrogen, is known to alter development of estrogen-sensitive organs including the brain, reproductive tract, and mammary gland. Bisphenol S (BPS; 4,4'-sulfonyldiphenol), which has a similar chemical structure to BPA, is also used in many consumer products, but its effects on estrogen-sensitive organs in mammals has not been thoroughly examined. Here, we quantified the effects of perinatal exposures to BPS on the male mouse mammary gland. In our first study, pregnant CD-1 mice were orally exposed to BPS (2 or 200 µg/kg/day) starting on pregnancy day 9 through lactation day 20, and male mammary glands were evaluated on embryonic day 16, prior to puberty, and in early adulthood. We observed modest changes in tissue organization in the fetal gland, and significant increases in growth of the gland induced by developmental BPS exposure in adulthood. In our second study, pregnant CD-1 mice were orally exposed to BPS (2, 200 or 2000 µg/kg/day) starting on pregnancy day 9 through lactational day 2. After weaning, the male pups were administered either oil (vehicle) or an estrogen challenge (1 µg ethinyl estradiol/kg/day) for ten days starting prior to puberty. After the 10-day estrogen challenge, we examined hormone-sensitive outcomes including anogenital index (AGI), weight of the seminal vesicles, and morphological parameters of the mammary gland. Although AGI and seminal vesicle weight were not affected by BPS, we observed dose-specific effects on the response of male mammary glands to the peripubertal estrogen challenge. Because male mammary glands are structurally less developed compared to females, they may provide a simple model tissue to evaluate the effects of putative xenoestrogens.

Why Do Normal Children Have Acromegalic Levels of IGF-I During Puberty?

CONTEXT: The rapid pubertal height growth is unique to humans, but why do we have it? Although the spurt contributes 13% to 15% to the final adult height, we hypothesized that the biological significance of the high acromegalic levels of GH and IGF-I, which are behind the pubertal growth spurt, might primarily occur to stimulate the reproductive organs. EVIDENCE SYNTHESIS: Animal data have demonstrated that adult Igf1 and Igf2 gene knockout mice that survive show a dramatic reduction in the size of the reproductive organs and are infertile. In humans, case reports of mutations in the genes affecting the GH-IGF axis and growth (GH, GHRH, GH-R, STAT5b, IGF-I, IGF-II, IGF-1R, PAPPA2) are also characterized by delayed pubertal onset and micropenis. Furthermore, GH treatment will tend to normalize the penile size in patients with GH deficiency. Thus, the endocrine effects of high IGF-I levels might be needed for the transition of the sexual organs, including the secondary sex characteristics, from the "dormant" stages of childhood into fully functioning reproductive systems. The peak IGF-I levels, on average, occur 2 years after the peak height growth velocity, suggesting reasons other than longitudinal growth for the high IGF-I levels, and remain high in the years after the height spurt, when the reproductive systems become fully functional. CONCLUSION: We suggest that the serum levels of IGF-I should be monitored in children with poor development of sexual organs, although it remains to be investigated whether GH should be added to sex steroids in the management of hypogonadism for some pubertal children (e.g., boys with micropenis).

El adelanto en la telarquia y edad de la menarquia se relacióna con la malnutrición por exceso en niñas chilenas pero no en varones: estudio de base poblacional / The advance in thelarche and age of menarche is related to malnutrition by excess in Chilean girls but not in boys: population-based study

Introduction: Puberty normally begins after 8 years in girls and 9 years in boys. Objective: To determine the prevalence of signs of precocious puberty (PP), breast development in girls, premature gonadal development (PGD), premature adrenarche (PA), menarche age (MA) and its association with nutritional status (NS). Material and Methods: From a sample of 3.010 children from 5 to 14 years randomly selected in Santiago of Chile were chosen a subsample of 873 kids according to the cutoff to define PP. Survey was applied to obtain MA. Logistic regression were used to evaluate the relationship between PP and NS. Results: In boys the prevalence of PGD and PP was 8.55% and 3.16% respectively, no relationship was found with nutritional status In girls the prevalence of breast development and PA was 8.13% and 0.9% respectively. Only there be association between PP and NS in women: with a prevalence of 1,2%, 13,9% and 21,1% in well-nourished, Overweight and obesity are at greater risk of showing PP compared with eutrophic girls with an OR of 25,5 (IC 95% 3,2-203,0) and 46.93 (IC 95% 6,1-361,5). MA was 12,01 ± 0,94 years in eutrophic girls and 11,40 ± 0,96years in obese girls (p< 0,05). Conclusion: There was a positive correlation in females between overweight and obesity an PP and MA. There is a secular trend in MA, to compare these findings with other national studies. Obesity could have an important role in explaining the advancement observed in pubertal development.

Introducción: El desarrollo puberal se inicia normalmente después de los 8 años en niñas y de los 9 años en varones. Objetivo: Estimar la prevalencia de signos de pubertad precoz (sPP): crecimiento genital (CG) en varones, telarquia en niñas y vello púbico (VP) en ambos sexos; y determinar edad de la menarquia (EM) en una muestra de escolares de Santiago de Chile), y evaluar la asociación de estas variables con el estado nutricional (EN). Material y Métodos: Se examinaron 3.010 escolares de clase media baja de 6 a 14 años, pertenecientes a 10 colegios de Santiago de Chile y seleccionados aleatoriamente. En todos ellos se consignó peso, talla, IMC y desarrollo puberal según Tanner. Se aplicó una encuesta a los padres para obtener la EM a la población total de mujeres (n= 1.433). Para determinar sPP se analizaron por separado los 867 niños (62% mujeres) menores a la edad establecida como puntos de corte para definir PP. Se utilizó regresión logística para determinar la asociación existente entre sPP y el EN. Resultados: En varones la prevalencia de CG y VP fue de 8,55% y 3,16% y no se asocio al EN. La prevalencia de telarquia y VP en niñas fue de 8,13% y 0,9% respectivamente. Se observó una fuerte asociación entre telarquia y EN con prevalencias de 1.2%, 13.9% y 21.1% en eutróficas, sobrepeso y obesas, respectivamente (p< 0,0001) (Gráfico 1). La presencia de sobrepeso y/o obesidad otorgan un mayor riesgo de presentar telarquia, vs comparación con las niñas eutróficas con un OR de 25,5 (IC 95% 3,2-203,0) y 46.93 (IC 95% 6,1-361,5), respectivamente. La EM fue 12,01 ± 0,94 años en niñas eutróficas siendo de 11,40 ± 0,96 años en niñas obesas (p< 0,05). Conclusión: Se observó una correlación positiva solo en el sexo femenino entre malnutrición por exceso, telarquia precoz y EM. Se observa una tendencia secular en la EM al comparar los hallazgos con otros estudios nacionales.

Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up?

OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.

Maternal nutritional restriction during late gestation impairs development of the reproductive organs in both male and female lambs.

Maternal nutritional restrictions during late gestation could lead to fetal hypoglycemia. Glucose levels in the fetal sheep regulate circulating insulin-like growth factor 1 (IGF1) levels, which stimulate cell proliferation and differentiation of reproductive organs after binding to its own receptor or estrogen receptors. The objective of this study was to determine the effects of subnutrition of ewes during the last trimester of gestation on the serum glucose/IGF1 levels and development of reproductive organs in their lambs. Pregnant ewes carrying singletons were randomly assigned to restricted (R ewes, n = 8) or control (C ewes, n = 8) groups (4 lambs of each gender/group) and fed with 50% or 100% of metabolic energy requirements from ∼100 days of gestation to term (∼147 days), respectively. Blood samples from lambs were taken on the first day after born and once at week for serum glucose and IGF1 determination. Lambs were euthanatized at 2 months of age, reproductive organs were weighted and tissue samples were collected from them for histology and to measure mRNA expression of IGF1 and its receptor (IGF1R) by qRT-PCR. Pre-partum glucose levels in R ewes were significantly lower compared to C ewes (p < .05). Compared to lambs born from C ewes, lambs born from R ewes showed lower serum levels of glucose and IGF1 during the first week of age (p < .05). At 2 month of age, these lambs had significant lower uterine and testicular weight and lower ovarian, uterine and testicular mRNA expressions of IGF1 and its receptor (p < .05). Histological findings showed that diameter of secondary and tertiary follicles in ovaries and number of endometrial glands in uterus of females, or number of Sertoli cells and seminiferous tubules and diameter, perimeter and tubular area in testicles of males were significantly lower in lambs born from R ewes compared to the respective organs of lambs born from the C ewes (p < .05). In conclusion, these results demonstrate that maternal subnutrition during late gestation affects IGF1 levels during fetal life and impairs reproductive development in the neonatal lamb, which could have permanent negative consequences in the future reproductive performance of the offspring.

Novel function of LHFPL2 in female and male distal reproductive tract development.

Congenital reproductive tract anomalies could impair fertility. Female and male reproductive tracts are developed from Müllerian ducts and Wolffian ducts, respectively, involving initiation, elongation and differentiation. Genetic basis solely for distal reproductive tract development is largely unknown. Lhfpl2 (lipoma HMGIC fusion partner-like 2) encodes a tetra-transmembrane protein with unknown functions. It is expressed in follicle cells of ovary and epithelial cells of reproductive tracts. A spontaneous point mutation of Lhfpl2 (LHFPL2(G102E)) leads to infertility in 100% female mice, which have normal ovarian development, ovulation, uterine development, and uterine response to exogenous estrogen stimulation, but abnormal upper longitudinal vaginal septum and lower vaginal agenesis. Infertility is also observed in ~70% mutant males, which have normal mating behavior and sperm counts, but abnormal distal vas deferens convolution resulting in complete and incomplete blockage of reproductive tract in infertile and fertile males, respectively. On embryonic day 15.5, mutant Müllerian ducts and Wolffian ducts have elongated but their duct tips are enlarged and fail to merge with the urogenital sinus. These findings provide a novel function of LHFPL2 and a novel genetic basis for distal reproductive tract development; they also emphasize the importance of an additional merging phase for proper reproductive tract development.

Overexpression of Anti-Müllerian Hormone Disrupts Gonadal Sex Differentiation, Blocks Sex Hormone Synthesis, and Supports Cell Autonomous Sex Development in the Chicken.

The primary role of Anti-Müllerian hormone (AMH) during mammalian development is the regression of Müllerian ducts in males. This highly conserved function is retained in birds and is supported by the high levels of AMH expression in developing testes. Mammalian AMH expression is regulated by a combination of transcription factors, the most important being Sry-type high-mobility-group box transcription factor-9 (SOX9). In the chicken embryo, however, AMH mRNA expression precedes that of SOX9, leading to the view that AMH may play a more central role in avian testicular development. To define its role in chicken gonadal development, AMH was overexpressed using the RCASBP viral vector. AMH caused the gonads of both sexes to develop as small and undeveloped structures at both embryonic and adult stages. Molecular analysis revealed that although female gonads developed testis-like cords, gonads lacked Sertoli cells and were incapable of steroidogenesis. A similar gonadal phenotype was also observed in males, with a complete loss of both Sertoli cells, disrupted SOX9 expression and gonadal steroidogenesis. At sexual maturity both sexes showed a female external phenotype but retained sexually dimorphic body weights that matched their genetic sexes. These data suggest that AMH does not operate as an early testis activator in the chicken but can affect downstream events, such as sex steroid hormone production. In addition, this study provides a unique opportunity to assess chicken sexual development in an environment of sex hormone deficiency, demonstrating the importance of both hormonal signaling and direct cell autonomous factors for somatic sex identity in birds.

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters.

This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.

Clinical and molecular aspects of androgen insensitivity.

Androgen insensitivity describes the inability of cells to respond adequately to androgens. The clinical aspects are well characterized and described in the androgen insensitivity syndrome, where underandrogenization occurs despite normal to high levels of androgens. In 46,XY individuals, this is associated with a variable phenotype ranging from completely female to ambiguous genitalia and infertility in males with gynecomastia. Androgen action is facilitated by a single androgen receptor (AR), whose gene is localized on the X chromosome. However, the identification of mutations in the AR gene in patients with androgen insensitivity is variable, and chances are lower the more subtle the phenotype is. Therefore, other currently unknown mechanisms must be hypothesized to lead to the respective phenotype. The AR is a nuclear transcription factor, acting in concert with an array of only partly known cofactors serving as modulators of target gene transcription. The induced transcription pattern is highly tissue and cell specific, and in some tissues may lead to lasting changes of cell programming. Only one regulated gene APOD has currently been identified to serve as a clinical tool for the diagnosis of androgen insensitivity.

Specific morphogenetic events in mouse external genitalia sex differentiation are responsive/dependent upon androgens and/or estrogens.

The objective of this study was to perform a comprehensive morphologic analysis of developing mouse external genitalia (ExG) and to determine specific sexual differentiation features that are responsive to androgens or estrogens. To eliminate sex steroid signaling postnatally, male and female mice were gonadectomized on the day of birth, and then injected intraperitoneally every other day with DES (200 ng/g), DHT (1 µg/g), or oil. On day-10 postnatal male and female ExG were dissected, fixed, embedded, serially sectioned and analyzed. We identified 10 sexually dimorphic anatomical features indicative of normal penile and clitoral differentiation in intact mice. Several (but not all) penile features were impaired or abolished as a result of neonatal castration. Those penile features remaining after neonatal castration were completely abolished with attendant clitoral development in androgen receptor (AR) mutant male mice (X(Tfm)/Y and X/Y AR-null) in which AR signaling is absent both pre- and postnatally. Administration of DHT to neonatally castrated males restored development of all 10 masculine features to almost normal levels. Neonatal ovariectomy of female mice had little effect on clitoral development, whereas treatment of ovariectomized female mice with DHT induced partial masculinization of the clitoris. Administration of DES to neonatally gonadectomized male and female mice elicited a spectrum of development abnormalities. These studies demonstrate that the presence or absence of androgen prenatally specifies penile versus clitoral identity. Differentiated penile features emerge postnatally and are sensitive to and dependent upon prenatal or pre- and postnatal androgen. Emergence of differentiated clitoral features occurs postnatally in either intact or ovariectomized females. It is likely that each penile and clitoral feature has a unique time-course of hormonal dependency/sensitivity.

La autoevaluación es un método poco confiable para establecer el desarrollo puberal en escolares / Self evaluation is not reliable for assessing puberal development in school-aged children

Introduction: Puberal development assessment (PDA) is performed according Tanner's method (TM). Objective: In order establish the coincidence between PDA determined by physicians and the self-evaluation by school-aged children. Material and Methods: 2 980 school children from Santiago, Chile, were assessed by means of TM, the development of the mammary gland (MD), male genitalia (MG) and pubic hair (PH) were assessed. PDA was simultaneously performed by physicians and by the school children. Results: Concordance between physicians and self assessment showed a kappa coefficient (KC) of 0.55, 0.45, and 0.51 in PH, MD and MG respectively, (acceptable KC > 0.61). Self-evaluation of PDA decreased as the age of children increased, with OR of 0.76 (95 percent IC 0.74 -0.79); 0.87 (95 percent IC 0.83 - 0.91) and 0.92 (95 percent IC 0.88 - 0.96) for PH, MD and MG respectively. An inverse relationship between nutritional status (NS) and PDA was observed only in PH, obese school children underscored their PH (OR 0.6; 95 percent IC 0.5 - 0.7). Multivariate analysis for gender and NS showed that only females overestimate their PH, OR of 1.15 (95 percent IC 1-1.32). Conclusions: PDA through self-assessment yields only moderate correlation coefficients, thus it is not reliable for making relevant clinical decisions.

Introducción: La determinación del desarrollo puberal (DDP) se evalúa según el método de Tanner (MT). Objetivo: Determinar la concordancia de la DDP entre médicos con la autoevaluación en escolares. Pacientes y Métodos: Se examinaron 2 980 escolares de Santiago de Chile. Se evalúo desarrollo mamario (DM), genitales masculinos (GM) y vello púbico (VP) mediante el MT. La DDP fue evaluada simultáneamente por un médico y por los escolares. Resultados: La concordancia entre médicos y la autoevaluación mostró un coeficiente kappa (CK) de 0,55, 0,45, 0,51 en VP, DM y GM respectivamente, (CK aceptable > 0,61). La autoevaluación del DDP disminuyo a medida que aumentaba la edad, con OR respectivos de 0,76 (95 por ciento IC 0,74-0,79); 0,87 (95 por ciento IC 0,83-0,91) y 0,92 (95 por ciento IC 0,88 -0,96) para VP, DM y GM. Se observo una relación inversa entre estado nutricional (EN) y DDP sólo en VP, escolares obesos subestimaban su VP (OR 0,6; 95 por ciento IC 0,5-0,7). El análisis multivariado de género y EN mostró que sólo las mujeres sobreestimaban su VP, OR de 1,15 (95 por ciento IC 1-1,32). Conclusiones: La DDP mediante autoevaluación obtiene coeficientes de correlación sólo moderados que no permiten confiar en este para establecer decisiones clínicas relevantes.

A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia.

BACKGROUND: Kisspeptin 1 receptor (KISS1R) gene mutations are rare but have recently become an important etiology of normosmic isolated hypogonadotropic hypogonadism (IHH). OBJECTIVES: To characterize the genetic defect, the phenotype, and response to therapy of three IHH siblings with a novel severe KISS1R mutation. PATIENTS AND METHODS: Three siblings (16- and 22-year-old sisters and their 20-year-old brother) born to consanguineous parents with normal neonatal external genitalia presented with no pubertal development, normosmia, and a low response to GNRH stimulation. Homozygosity mapping, KISS1R gene sequencing, and RNA expression were performed. RESULTS: The females' basal low estradiol level (50 pmol/l) failed to rise in response to human chorionic gonadotropin (hCG). The brother's low testosterone (1.87 nmol/l) responded to combined hCG and human menopausal gonadotropin (hCG) and HMG therapies, but the testes remained small (1-2 ml). Secondary sexual characteristics were attained by exogenous sex steroid replacement. SNP array studies revealed shared homozygosity for a chromosome 19 region encompassing KISS1R. Sequencing revealed a novel homozygous KISS1R mutation at the nt-1 canonical acceptor splice site of intron 1 in affected siblings. The mother (menarche at 14 years) was heterozygous. cDNA sequencing showed that the G>A mutation results in skipping of exon 2 and a premature stop codon at residue 151. CONCLUSIONS: The novel severe N-terminal KISS1R splice site (c.245-1G>A) mutation results in IHH. Heterozygous female carriers may manifest a subtle fertile phenotype. The subnormal gonadal response to hCG in patients may implicate a direct role of KISS1R in gonadal function. The normal neonatal virilization in a male homozygous to this severe mutation challenges the hypothesis that KISS1R is required for fetal development of male external genitalia.

Estrogen dependent signaling in reproductive tissues - a role for estrogen receptors and estrogen related receptors.

Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. The biological effects of estrogens are classically mediated via interaction with cognate nuclear receptors. The relative expression of ER subtypes/variants varies between cells within different tissues and this alters the response to natural and synthetic ligands. This review focuses on the role of estrogen and estrogen related receptors in reproductive tissues.

Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures.

Because bisphenol A (BPA) exposure is nearly ubiquitous, increased knowledge of its potential effects on development will enable better risk assessment and regulatory guidance. Here, Sprague-Dawley rats were reared in low exogenous estrogen environments. After breeding at adulthood, dams were gavaged on gestational days (GDs) 6-21 with vehicle (VEH), 2.5 or 25.0 µg/kg/day BPA, or 5.0 or 10.0 µg/kg/day ethinyl estradiol (EE2). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose the dam received. Relative to the VEH group, dams of both EE2-treated groups weighed less throughout gestation and lactation. PND 1 absolute anogenital distance and anogenital index were unaltered by any treatment. Ages at fur development and eye and ear opening were unaffected by any treatment. Despite a significant treatment effect, no group was significantly different from VEH in PNDs 3-6 righting latencies; although males had shorter latencies and all latencies decreased with age. PNDs 8-11 slant board behavior was unaffected by any treatment; however, males had shorter turning latencies and latencies decreased with age. Preweaning body weights of BPA- and EE2-treated groups as well as naive controls were less than VEH. No treatment affected PND 21 whole or regional brain weights or levels of estradiol, testosterone, corticosterone, T3, T4, luteinizing hormone, ghrelin, or leptin. These results add to the literature indicating that developmental BPA treatment at these doses has no effects on gestational or lactational body weight, offspring anogenital distance, preweaning behaviors or hormone levels, and whole and regional brain weights measured at weaning.

45,X/46,XY mosaicisme: report of five cases and clinical review.

INTRODUCTION: The mosaicism 45, X/46, XY is a gonosomal abnormality characterized by a broad phenotypic spectrum, ranging from women with or without Turner syndrome stigmata, to men apparently normal, passing by the ambiguous phenotypes with variable virilisation of external genitalia. From the histological point of view, several situations may arise. PATIENTS AND METHODS: We analyzed the clinical, hormonal, sonographic, and genitographics data, as well as peroperative and histological findings for five cases of mosaicism 45, X/46, XY, and we discussed treatment performed. RESULTS: The mean age of patients was 6.6 years, two had a female phenotype with clitoral hypertrophy (one of them had Turner syndrome stigmata), one had a normal male phenotype with bilateral cryptorchidism and two had an ambiguity of external genitalia assigned to male. Short stature was noted for four patients. Surgical exploration concluded to the diagnosis of mixed gonadal dysgenesis for four of our patients. No cases of gonadoblastoma have been reported, for girls a prophylactic gonadectomy was performed, for boys the streak gonad was resected and the dysgenetic testis biopsied and preserved, subject for constant monitoring. CONCLUSION: This heterogeneity indicate the importance of an accurate clinical and histological evaluation of any patient presenting with 45, X/46,XY mosaicism.

The pros and cons of phytoestrogens.

Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens.

Indirect development, transdifferentiation and the macroregulatory evolution of metazoans.

It is proposed here that a biphasic life cycle with partial dedifferentiation of intermediate juvenile or larval stages represents the mainstream developmental mode of metazoans. Developmental plasticity of differentiated cells is considered the essential characteristic of indirect development, rather than the exclusive development of the adult from 'set-aside' cells. Many differentiated larval cells of indirect developers resume proliferation, partially dedifferentiate and contribute to adult tissues. Transcriptional pluripotency of differentiated states has premetazoan origins and seems to be facilitated by histone variant H2A.Z. Developmental plasticity of differentiated states also facilitates the evolution of polyphenism. Uncertainty remains about whether the most recent common ancestor of protostomes and deuterostomes was a direct or an indirect developer, and how the feeding larvae of bilaterians are related to non-feeding larvae of sponges and cnidarians. Feeding ciliated larvae of bilaterians form their primary gut opening by invagination, which seems related to invagination in cnidarians. Formation of the secondary gut opening proceeds by protostomy or deuterostomy, and gene usage suggests serial homology of the mouth and anus. Indirect developers do not use the Hox vector to build their ciliated larvae, but the Hox vector is associated with the construction of the reproductive portion of the animal during feeding-dependent posterior growth. It is further proposed that the original function of the Hox cluster was in gonad formation rather than in anteroposterior diversification.

Ultrasonographic patterns of reproductive organs in infants fed soy formula: comparisons to infants fed breast milk and milk formula.

OBJECTIVE: To determine if differences exist in hormone-sensitive organ size between infants who were fed soy formula (SF), milk formula (MF), or breast milk (BF). STUDY DESIGN: Breast buds, uterus, ovaries, prostate, and testicular volumes were assessed by ultrasonography in 40 BF, 41 MF, and 39 SF infants at age 4 months. RESULTS: There were no significant feeding group effects in anthropometric or body composition. Among girls, there were no feeding group differences in breast bud or uterine volume. MF infants had greater (P < .05) mean ovarian volume and greater (P < .01) numbers of ovarian cysts per ovary than did BF infants. Among boys, there were no feeding group differences in prostate or breast bud volumes. Mean testicular volume did not differ between SF and MF boys, but both formula-fed groups had lower volumes than BF infants. CONCLUSIONS: Our data do not support major diet-related differences in reproductive organ size as measured by ultrasound in infants at age 4 months, although there is some evidence that ovarian development may be advanced in MF-fed infants and that testicular development may be slower in both MF and SF infants as compared with BF. There was no evidence that feeding SF exerts any estrogenic effects on reproductive organs studied.

Genetic and clinical spectrum of aromatase deficiency in infancy, childhood and adolescence.

INTRODUCTION: cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported. PHENOTYPE: Phenotype is dependent on sex and age. In newborns, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia. In prepubertal aromatase deficient girls, high levels of ovarian androgens and gonadotropins facilitate the formation of ovarian cysts. Bone mineralization can be affected and bone aging is delayed. In pubertal girls, there is poor sexual development and abnormal virilization. The phenotype may be variable according to enzyme activity level. Insulin sensitivity may be abnormal in both men and women. Finally, aromatase might also play a role in the regulation of testicular cell mass in the newborn testis. CONCLUSION: Adequate interpretation of clinical data should lead to the analysis of the CYP19 gene for diagnostic confirmation and implementation of appropriate management.