An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects. This complexity causes difficulty when a static approach to toxicity through endocrine mechanisms driven by rigid guidelines is used to identify EDC and manage risk to human and wildlife populations. We propose that principles taken from fundamental endocrinology be employed to identify EDC and manage their risk to exposed populations. We emphasize the importance of developmental stage and, in particular, the realization that exposure to a presumptive "safe" dose of chemical may impact a life stage when there is normally no endogenous hormone exposure, thereby underscoring the potential for very low-dose EDC exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote further understanding of complex EDC effects, especially due to developmental exposures.

Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity ABSTRACTAndrogens act through a receptor protein (AR) to mediate sex differentiation and development of the male phenotype. We have isolated the eight exons in the amino acid coding region of the AR gene from a human X chromosome library. Nucleotide sequences of the AR gene intron/exon boundaries were determined for use in designing synthetic

Context:Higher testosterone in black compared with white men has been postulated to explain their higher prostate cancer incidence. Previous studies comparing hormone levels by race might have been limited by size, restricted age variation, or lack of representation of the general population.Objective: Our objective was to compare serum testosterone, estradiol, and SHBG concentrations among non-Hispanic black, non-Hispanic white, and Mexican-American men.Participants, Design, and Setting: A total of 1413 men aged 20ϩ yr and who attended the morning examination session of the Third National Health and Nutrition Examination Survey (NHANES III) in 1988 -1991 were included in this cross-sectional study.Measurement: Serum hormone concentrations were measured by electrochemiluminescence immunoassays.Results: After applying sampling weights and adjusting for age, percent body fat, alcohol, smoking, and activity, testosterone concentrations were not different between non-Hispanic blacks (n ϭ 363; geometric mean, 5.29 ng/ml) and non-Hispanic whites (n ϭ 674; 5.11 ng/ml; P Ͼ 0.05) but were higher in Mexican-Americans (n ϭ 376; 5.48 ng/ml; P Ͻ 0.05). Non-Hispanic blacks (40.80 pg/ml) had a higher estradiol concentration than non-Hispanic whites (35.46 pg/ml; P Ͻ 0.01) and Mexican-Americans (34.11 pg/ml; P Ͻ 0.01). Non-Hispanic blacks (36.49 nmol/liter) had a higher SHBG concentration than nonHispanic whites (34.91 nmol/liter; P Ͻ 0.05) and Mexican-Americans (35.04 nmol/liter; P Ͻ 0.05). Conclusions:Contrary to the postulated racial difference, testosterone concentrations did not differ notably between black and white men. However, blacks had higher estradiol levels. Mexican-Americans had higher testosterone than whites but similar estradiol and SHBG concentrations. Given these findings, it may be equally if not more important to investigate estradiol as testosterone in relation to diseases with racial disparity. (J Clin Endocrinol Metab 92: 2519 -2525, 2007)

ABSTRACT. Objectives. To identify and study adults (21 years or older) who have a 46,XY karyotype and presented as infants or children with genital ambiguity, including a small phallus and perineoscrotal hypospadias, reared male or female.Methods. Participants were classified according to the cause underlying their intersex condition based on review of medical and surgical records. Long-term medical and surgical outcome was assessed with a written questionnaire and physical examination. Long-term psychosexual development was assessed with a written questionnaire and semistructured interview.Results. Thirty-nine (72%) of 54 eligible patients participated. The cause underlying genital ambiguity of participants included partial androgen insensitivity syndrome (n ‫؍‬ 14; 5 men and 9 women), partial gonadal dysgenesis (n ‫؍‬ 11; 7 men and 4 women), and other intersex conditions. Men had significantly more genital surgeries (mean: 5.8) than women (mean: 2.1), and physician-rated cosmetic appearance of the genitalia was significantly worse for men than for women. The majority of participants were satisfied with their body image, and men and women did not differ on this measure. Most men (90%) and women (83%) had sexual experience with a partner. Men and women did not differ in their satisfaction with their sexual function. The majority of participants were exclusively heterosexual, and men considered themselves to be masculine and women considered themselves to be feminine. Finally, 23% of participants (5 men and 4 women) were dissatisfied with their sex of rearing determined by their parents and physicians.Conclusions. Either male or female sex of rearing can lead to successful long-term outcome for the majority of cases of severe genital ambiguity in 46,XY individuals.We discuss factors that should be considered by parents and physicians when deciding on a sex of rearing for such infants. Pediatrics 2002;110(3). URL: http://www. pediatrics.org/cgi/content/full/110/3/e31; intersex, sex assignment, gender, androgen insensitivity, gonadal dysgenesis, psychosexual, genital reconstruction, hormone replacement.ABBREVIATIONS. PAIS, partial androgen insensitivity syndrome; PGD, partial gonadal dysgenesis. D uring fetal sex differentiation, genetic males who are unable to masculinize their sex ducts and external genitalia can be classified into 2 major etiologic groups: 1) the inability of the fetus to produce sufficient amounts of testosterone and dihydrotestosterone or 2) the inability of the fetus to respond to androgens that are present in normal amounts. 1 We previously described a population of 46,XY subjects who presented to the Pediatric Endocrinology Clinic of Johns Hopkins Hospital with varying degrees of undermasculinized genitalia. 2 In this population, the most difficult group to treat in terms of gender assignment is that of individuals who were born with ambiguous genitalia that includes a small phallus and perineoscrotal hypospadias. 3 For this group of patients, there is a lack of agreement about optimal sex ...

At the request of the U.S. Environmental Protection Agency (U.S. EPA), the National Toxicology Program organized an independent and open peer review to evaluate the scientific evidence on low-dose effects and nonmonotonic dose-response relationships for endocrine-disrupting chemicals in mammalian species. For this peer review, "low-dose effects" referred to biologic changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the U.S. EPA for evaluating reproductive and developmental toxicity. The demonstration that an effect is adverse was not required because in many cases the long-term health consequences of altered endocrine function during development have not been fully characterized. A unique aspect of this peer review was the willing submission of individual animal data by principal investigators of primary research groups active in this field and the independent statistical reanalyses of selected parameters prior to the peer review meeting by a subpanel of statisticians. The expert peer-review panel (the panel) also considered mechanistic data that might influence the plausibility of low-dose effects and identified study design issues or other biologic factors that might account for differences in reported outcomes among studies. The panel found that low-dose effects, as defined for this review, have been demonstrated in laboratory animals exposed to certain endocrine-active agents. In some cases where low-dose effects have been reported, the findings have not been replicated. The shape of the dose-response curves for reported effects varied with the end point and dosing regimen and were low-dose linear, threshold-appearing, or nonmonotonic. The findings of the panel indicate that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see whether changes are needed regarding dose selection, animal-model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents.

Controversy concerning the most appropriate treatment guidelines for intersex children currently exists. This is due to a lack of long-term information regarding medical, surgical, and psychosexual outcome in affected adults. We have assessed by questionnaire and medical examination the physical and psychosexual status of 14 women with documented complete androgen insensitivity syndrome (CAIS). We have also determined participant knowledge of CAIS as well as opinion of medical and surgical treatment. As a whole, secondary sexual development of these women was satisfactory, as judged by both participants and physicians. In general, most women were satisfied with their psychosexual development and sexual function. Factors reported to contribute to dissatisfaction were sexual abuse in one case and marked obesity in another. All of the women who participated were satisfied with having been raised as females, and none desired a gender reassignment. Although not perfect, the medical, surgical, and psychosexual outcomes for women with CAIS were satisfactory; however, specific ways for improving long-term treatment of this population were identified. (J Clin Endocrinol

We screened human prostate cancer tissues for the presence of somatic mutations in the hormone binding domain of the androgen receptor (AR) gene. Exons E-H were amplified from genomic DNA using the polymerase chain reaction and analyzed by denaturing gradient gel electrophoresis (DGGE), which separates DNA fragments that differ by only a single base. We detected a mutation in exon E of the hormone binding domain in 1 of 26 specimens of untreated organ-confined stage B prostate cancer. The mutation was not detectable in peripheral blood lymphocyte DNA. Lymphocyte DNA (wild-type AR) migrated in DGGE as a single band. The tumor DNA migrated in DGGE as four bands, consistent with the presence of cells with mutant AR plus cells with wild-type AR and indicating that the tumor contained a somatic mutation. To our knowledge, a somatic AR gene mutation has not been reported previously. Sequencing revealed a G --A substitution in codon 730, changing valine to methionine. Codon 730 is in a region highly conserved among all steroid receptors. The abundance of the mutated fragment (about 50% of the DNA in the specimen) indicates its presence in cells with a growth advantage. A somatic mutation could be detected by DGGE if it represented at least 10% of the sample. Failure to detect mutations in other specimens analyzed may be due to this limit of sensitivity, the presence of mutations in other parts of the AR, or a low frequency of mutations in early stage disease.Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in men in the U.S.(1). Recognition that androgen is required for the development of prostate cancer (2) and its growth (3) has been the basis for continuing interest in the role of the androgen receptor (AR) in prostate cancer (1,(4)(5)(6). The AR is a member of the superfamily of genes that code for the steroid and thyroid hormone receptor family of ligand-dependent nuclear transcription factors, all of which have an N-terminal domain that affects transcription efficiency, a central DNA

The prevalence of obesity among children, adolescents and adults has been dramatically increasing worldwide during the last several decades. The obesity epidemic has been recognized as one of the major global health problems, because its health hazard is linked to a number of common diseases including breast and prostate cancers. Obesity is caused by combination of genetic and environmental factors. While genetic contribution to obesity has been known to be significant, the genetic factors remain relatively unchanged. Recent studies have highlighted the involvement of environmental “obesogens”, i.e. the xenobiotic chemicals that can disrupt the normal development and homeostatic control over adipogenesis and energy balance. Several lines of evidence suggest that increasing exposure to chemicals with endocrine-disrupting activities (endocrine disrupting chemicals, EDCs) contributes to the increased obesity. The cellular and molecular mechanisms underlying obesogen-associated obesity are just now being appreciated. In this paper, we comprehensively reviewed current knowledge about the role of estrogen receptors alpha and beta (ERα and ERβ) in regulation of energy metabolism pathways, including glucose transport, glycolysis, tricarboxylic acid (TCA) cycle, mitochondrial respiratory chain (MRC adenosine nucleotide translocator (ANT) and fatty acid β-oxidation and synthesis, by estrogens and then examined the disturbance of E2/ER-mediated energy metabolism pathways by environmental obesogens; and finally, we discussed the potential implications of disturbance of energy metabolism pathways by obesogens in obesity and pointed out several key aspects of this area that need to be further explored. A better understanding of the cellular and molecular mechanisms underlying obesogen-associated obesity will lead to new approaches for slow down and/or prevention of the increased trend of obesity associated with exposure to obesogens.