Bailliere's clinical endocrinology and metabolism最新文献

Male sexual differentiation is dependent on normal testicular function, including secretion of testosterone from the Leydig cells, and müllerian-inhibiting substance from the Sertoli cells. External factors, such as anti-androgens and oestrogens, that disturb endocrine balance cause demasculinizing and feminizing effects in the developing male fetus. Oestrogens also causes adverse effects in female fetuses, whereas anti-androgens have little influence. A growing number of chemicals have been found to possess either weak oestrogenic, anti-androgenic or other hormonal activities, and these are often referred to as endocrine disrupters. In animals in the wild, abnormal sexual development has been associated with exposure to mixtures of endocrine disrupters. The emerging adverse trends in human reproductive health, such as increased incidences of cryptorchidism, hypospadias and testicular cancer, and the ubiquitous presence of endocrine disrupters in the environment, support the hypothesis that disturbed sexual differentiation could in some cases be caused by increased exposure to environmental endocrine disrupters.

In the human male fetus, testes develop by the 7th week and begin to secrete two hormones: anti-müllerian hormone (AMH) induces the regression of müllerian ducts, the anlagen of the uterus, fallopian tubes and upper vagina, upon binding to a specific membrane receptor, whereas testosterone induces the differentiation of the wolffian ducts into the epididymes, vasa deferentia and seminal vesicles. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for masculinization of the urogenital sinus and external genitalia. Both androgens act upon binding to the same nuclear receptor. In the absence of AMH and androgen action, for example in the female or in abnormal male differentiation, the internal and external genital primordia differentiate following the female pathway, even in the absence of ovaries.

In males, an impaired function of the AMH-dependent pathway results in the persistent müllerian duct syndrome, a disorder characterized by the presence of uterus and fallopian tubes in otherwise normally virilized boys. Several mutations found in the AMH and AMH-receptor genes explain the pathophysiology of this syndrome.

Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase-3 (17β-HSD-3) deficiency and 5α-reductase-2 (5α-RD-2) deficiency provides natural human genetic models to elucidate androgen actions. To date, five 17β-HSD isozymes have been cloned that catalyse the oxidoreduction of androstenedione and testosterone and dihydrotestosterone (DHT), oestrone and oestradiol. Mutations in the isozyme 17β-HSD-3 gene are responsible for male pseudohermaphroditism due to 17β-HSD deficiency. The type 3 isozyme preferentially catalyses the reduction of androstenedione to testosterone and is primarily expressed in the testes. Fourteen mutations in the 17β-HSD-3 gene have been identified from different ethnic groups. Affected males with the 17β-HSD-3 gene defect have normal wolffian structures but ambiguous external genitalia at birth. Many are raised as girls but virilize at the time of puberty and adopt a male gender role. Some develop gynaecomastia at puberty, which appears to be related to the testosterone/oestradiol ratio.

Two 5α-reductase (5α-RD) isozymes, types 1 and 2, have been identified, which convert testosterone to the more potent androgen DHT. Mutations in the 5α-RD-2 gene cause male pseudohermaphroditism, and 31 mutations in the 5α-RD-2 gene have been reported from various ethnic groups. Such individuals also have normal wolffian structure but ambiguous external genitalia at birth and are raised as girls. Virilization occurs at puberty, often with a gender role change. The prostate remains infantile and facial hair is decreased. Balding has not been reported.

The coexistence of both 17β-HSD-3 and 5α-RD-2 gene defects has been identified in a Turkish community. The studies of inherited enzymatic defects involving androgen biosynthesis and action highlight the importance of testosterone and DHT in male sexual differentiation and male physiology.

The congenital adrenal hyperplasias are the commonest cause of ambiguity of the external genitalia at birth, although sexual differentiation in these disorders is strictly normal. The masculinized genetic female is invariably the result of 21-hydroxylase deficiency. The molecular features are well characterized and the phenotypic correlates are generally concordant. Prenatal treatment by maternal dexamethasone administration can successfully prevent virilization of the external genitalia in an affected female fetus. Placental aromatase is a rare and recently characterized alternative cause of a masculinized female which should be considered in the absence of fetal adrenal hyperplasia and maternal androgen-secreting tumours. The investigation of abnormal sexual development requires an initial karyotype analysis and serum 170H progesterone measurement to determine whether 21-hydroxylase deficiency is the likeliest cause. Thereafter, the presence of a 46,XY karyotype determines the mode of investigation according to androgen production and action. Obtaining appropriate samples for DNA, biochemical and immunohistochemical analyses is essential if the diagnostic yield for the investigation of abnormal sexual development is to be improved.

Animal models of gonadal hormone influences on the sexual differentiation of brain and behaviour are reviewed and discussed as a basis for predicting hormonal influences on human neurobehavioural development. Behavioural outcomes in clinical intersex cases, including congenital adrenal hyperplasia, androgen insensitivity syndrome, enzymatic deficiencies and situations in which hormones have been prescribed during pregnancy are reviewed. It is concluded that the prenatal or neonatal hormone environment contributes to the development of human behaviours that show sex differences, particularly childhood play behaviour, sexual orientation and core gender identity. There also is some evidence for influences on aggression and cognition. It is also concluded that additional research is needed to determine why some intersex patients assigned and reared as girls are not successful in this identity and role.

The study of naturally occurring mutations in humans and induced mutations in mice that cause sex reversal has been instrumental in the cloning and functional analysis of genes involved in gonadal differentiation. Several genes required for this complex developmental process have now been identified. The genes LIM1, WT1 and FTZ-F1 have been demonstrated to be involved in the formation of the gonads prior to their differentiation as testes or ovaries. Subsequent sex-specific gonadal differentiation appears to be mediated by the SRY and SOX9 genes in the testis, and the DAX-1 gene in the ovary.

Over the past few years, knowledge of the structure of gonadotropin receptors and their mode of action has rapidly advanced. The cDNA corresponding to the luteinizeng hormone (LH) receptor (LHR) has been cloned, leading to the identification of a novel family of G-protein-coupled receptors. The follicle stimulating hormone (FSH) receptor (FSHR) was thereafter cloned by cross-hybridization with the LHR. Structure—function relationships have been studied by mutagenesis experiments in several laboratories. The cloning and chromosomal localization to chromosome 2p21 of the two human gonadotropin receptor genes has provided insights into their evolutionary relationships. The LHR and FSHR genes are very large and contain 10 and 11 exons respectively.

The obtention of monoclonal antibodies against the receptors resulted in the characterization of the receptor proteins. These antibodies also allowed the study of receptor expression in target cells in physiological and pathological conditions. The internalization of the LHR has been studied by electron microscopy. A mechanism of receptor-mediated transcytosis through the endothelial cells of the testes has been described for the LHR. The polarized expression of receptors has been studied.

The cloning of gonadotropin receptor genes has opened the field of genetic study of the receptors. Inactivating mutations of the LHR have been described in Leydig cell agenesis or hypoplasia. Different phenotypes, including complete pseudohermaphroditism, ambiguous genitalia and male phenotype, have been described. In the case of the FSHR, only one mutation has been reported in familial ovarian dysgenesis with primary amenorrhea. Related males have variable alterations of spermatogenesis and fertility. Constitutive mutations of the LHR have been reported in familial testotoxicosis. One similar mutation has also been described for the FSHR. Such mutations may lead to the development of a model of receptor activation.

Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.