Disorder Of Male Sexual Differentiation Research Articles

Complete Androgen Insensitivity Syndrome: Primary Amenorrhoea of Rare Variety

Androgen insensitivity syndrome is an X linked disorder of male sexual differentiation caused by mutation affecting the androgen receptor gene Xq 11-12 resulting in decreased peripheral responsiveness to circulating androgens, with variable phenotypic expression.

Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia.

Gynecomastia is a benign enlargement of the male breast caused by the proliferation of glandular breast tissue. Determining the various causes of gynecomastia such as physiological causes, drugs, systemic diseases, and endocrine disorders is important. Androgen insensitivity syndrome (AIS) is a rare endocrine disorder presenting with gynecomastia and is a disorder of male sexual differentiation caused by mutations within the androgen receptor gene. All individuals with AIS have the 46 XY karyotype, although AIS phenotypes can be classified as mild, partial or complete and can differ among both males and females including ambiguous genitalia or infertility in males. We experienced a case of partial AIS presenting with gynecomastia and identified the androgen receptor gene mutation.

Physiology, pathology and pharmacology of the male reproductive system

The male reproductive system consists of the testes, a ductal system and sex accessory organs. Production of sperm by the testes combined with fluids formed by the sex accessory organs (e.g. seminal vesicles, prostate and bulbourethral glands) produce a secretion that supports the survival of spermatozoa and provides a medium through which they can move through the reproductive ducts (e.g. epididymis, vas deferens, ejaculatory duct and urethra) for ejaculation of viable sperm into the female reproductive tract. Summarized herein are the essentials of normal male reproductive physiology, disorders of male sexual differentiation, pharmacological therapy of common diseases of the male genitourinary tract and the impact of drugs of abuse on the male reproductive system.

Mutational analysis of Hungarian patients with androgen insensitivity syndrome.

To support the clinical diagnosis of androgen insensitivity syndrome (AIS), we performed mutational analysis of the androgen receptor gene. Clinical, hormonal and molecular genetic data of ten undervirilized genetic male patients living in Hungary were recorded. PCR-based single strand conformation polymorphism (SSCP) analysis was used to study the whole coding region of the androgen receptor gene. Direct fluorescent sequencing was applied when aberrant migration was detected by SSCP. Five different mutations were identified in five unrelated genetic male patients with abnormal sexual differentiation. One of these mutations was novel, while the other four mutations have been described previously in the literature. One of the mutations identified earlier in individuals with sporadic AIS showed a familial inheritance pattern in our study group. No abnormality of the androgen receptor gene was identified in three patients clinically suspected to have partial AIS. Application of molecular techniques helped to clarify the diagnosis in patients with disorders of male sexual differentiation.

Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder of male sexual differentiation caused by mutations in the androgen receptor (AR) gene. A reliable genotype-phenotype correlation in these patients does not exist as yet. Here we report the molecular studies performed on eight individuals with AIS. Exon-specific polymerase chain reaction (PCR), single-strand conformation polymorphism, and sequencing analyses, were performed in exons 2 to 8 of the AR gene. In one case, total cellular RNA was extracted from genital skin fibroblasts and reverse transcriptase-PCR was performed. Six different point mutations leading to amino acid substitutions (P682T, Q711E, G743E, F827V, H874R, D879Y), one splice-junction mutation (g-->c at +5, exon 6/intron 6), and a missense mutation without amino acid substitution (S888S) were identified. All mutations, including a de novo mutation, were previously undescribed on the steroid binding domain. Of the eight mutations identified, four led to a complete female phenotype (codons 743, 827, 874 and the donor splice site +5), two were detected in phenotypic females with partial virilization (codons 682 and 711), and two were present in phenotypic male subjects with undervirilized external genitalia, thus indicating that all of these sites determine AR functional activity.

Environmental xenoestrogens, antiandrogens and disorders of male sexual differentiation

Over the past 20 years, the documented increase in the disorders of male sexual differentiation, such as hypospadias, cryptorchidism, and micropenis, has led to the suspicion that environmental chemicals are detrimental to normal male genital development in utero. Male sexual differentiation is critically dependent on the normal action of androgens, and unbalanced androgen/estrogen ratios can disturb it. Environmental xenoestrogens (such as herbicides, pesticides, PCBs, plasticizers, and polystyrenes) that mimic estrogens or environmental antiandrogens (such as polyaromatic hydrocarbons, linuron, vinclozolin, and pp′DDE) that disturb endocrine balance, cause demasculinizing effects in the male foetus. These environmental chemicals are often referred to as endocrine disruptors: they are thought to mimic endogenous estrogens by entering the cell, binding to the receptor and activating transcription, they may also antagonize normal androgen action. We have established numerous cell lines to assess the estrogenicity and antiandrogenicity of compounds found in the environment and to identify new products present in wastewater effluents that are able to disrupt endocrine functions. Several cell lines responding to estrogens have been obtained in our group, including cells with different enzymatic equipment and cells expressing chimeric receptor or natural estrogen receptors α and β. These cell lines have proved to be useful for assessing the biological activity of pesticides, fungicides, and chemicals found in plastic or discarded in the environment. In order to generate a powerful tool for the investigation of androgen action and the rapid screening of potential antagonists, we developed a new stable prostatic cell line. The PALM cell line is an original cellular model to characterize the response of hAR, and it provides an easy and rapid bioluminescent test to identify new antagonists. We also developed a model based on a fusion protein between the androgen receptor (AR) and the green fluorescent protein (GFP) to study the intracellular dynamics of AR. The GFP–AR model was applied to define the ability of several xenoestrogens and antiandrogens to inhibit the nuclear transfer of AR. The ubiquitous presence of endocrine disruptors in the environment and the increased incidence of neonatal genital malformation support the hypothesis that disturbed male sexual differentiation may in some cases be caused by increased exposure to environmental xenoestrogens and/or antiandrogens.

Wide variation in androgen receptor dysfunction in complete androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a disorder of male sexual differentiation caused by mutations in the androgen receptor (AR) gene. The partial form (PAIS), associated with varying degrees of receptor dysfunction, presents with a range of undervirilization phenotypes. The complete form (CAIS) is characterized by normal female external appearance at birth. In these cases the receptor is often absent or inactive. However, cases have been described where the mutant receptor concerned has considerable residual activity in in vitro assays. Here we describe the effects of five mutations, Gly750Asp, Leu762Phe, Ala765Thr, Asp864Asn and Leu907Phe, identified in complete androgen insensitivity patients. In vitro assays of mutant androgen receptors expressed in a mammalian cell line showed that the Gly750Asp, Leu762Phe and Ala765Thr mutations cause almost complete loss of androgen-binding activity, suggesting that these residues are critical for ligand binding. However, receptors with Asp864Asn and Leu907Phe, although defective, were capable of considerable binding and transactivation activity. Given that some mutations identified in PAIS patients have a more severe effect on androgen receptor function than two CAIS mutations described here, these results provide further evidence that other factors, including genetic background, can have a significant impact on the phenotype associated with a particular AR mutation.

Androgen insensitivity with mental retardation: a contiguous gene syndrome?

We present data to suggest the existence of a mental retardation (MR) locus at Xq11.2-q12 between DXS1 and DXS905, identified in two subjects with complete androgen insensitivity syndrome (CAIS) and...

Anatomical, Morphological and Volumetric Analysis: A Review of 759 Cases of Testicular Maldescent

Undescended testis is the most frequent disorder of male sexual differentiation affecting 0.8% of all boys by age 1 year. Anatomical and descriptive features of undescended testis lack standardization, and often do not reflect intraoperative findings. We review a large cohort of patients treated for undescended testis and analyze anatomical, morphological and volumetric findings at orchiopexy. Of 759 patients 1 month to 9 years old entered into the study between 1985 and 1990 at our hospital 55% underwent surgery between ages 8 months and 4 years, 15.5% had bilateral undescended testis and 27.6% had a nonpalpable gonad. Preoperative physical findings correlated poorly with intraoperative observation with respect to testicular position. An ectopic gonad was diagnosed in 15% of the patients, most of whom had a patent processus vaginalis. Gubernacular attachment was in the scrotum in only a third of all cases studied. Undescended testes were softer and smaller than the contralateral gonad in the majority of cases. To our knowledge ours is the first study to correlate preoperative and intraoperative findings in cases of undescended testis. New anatomical as well as morphological and volumetric data are provided.

Genetic disorders of male sexual differentiation.

There are many complex interactions that contribute to the events that characterize normal sexual differentiation in the male. Although many of the pertinent steps have not yet been defined, recent studies have provided some insights. A review of our current knowledge of these events will serve as a basis for further discussion of the abnormalities in sexual differentiation and their genetic basis.

The Phenotypic Expression of Selective Disorders of Male Sexual Differentiation

Normal male sexual differentiation is the result of a series of individual steps that occur in an orderly fashion: testicular differentiation, mullerian regression, wolffian duct development, differentiation of the urogenital sinus and external genitalia, phallic growth and descent of the testes. Herein we present the pathophysiological mechanism by which selective disorders disrupt these normal events and produce specific phenotypes.