Journal Archives - Volume 7
Sex can be defined in 4 different ways: the genotypic sex determined by the chromosomes: 46,XX for females, 46,XY for males; the gonadal sex, testis for men, ovary for women; the phenotypic sex determined by the external genitalia and the social sex or sex of rearing. A genetic male has 46,XY chromosomes, testes, male external genitalia and is raised as a boy. A genetic female has 46,XX chromosomes, ovaries, female external genitalia and is raised as a girl. The present chapter covers normal development, differential diagnosis of abnormal development, approach of the newborn with ambiguous genitalia and role of medical management. The key feature is the appearance of the external genitalia which are either discordant with the genetic and/or gonadal sex, or ambiguous in appearance.
Abstract: Phenotype sex results from the differentiation of internal ducts and external genitalia under the influence of hormones and transcription factors. When dicordance occurs among these three processes (i.e. chromosomal, gonadal or phenotypic sex determination), then intersexuality develops. Sex differentiation is regulated by more than 50 different genes on both the sex chromosomes and autosomes. These genes encode transcription factors, gonadal steroid, peptide hormones and tissue receptors. The sex determination genetic cascade involves the SRY gene (Sex-determining region on Y) as the testis determining factor, although other upstream (SF-1, WT-1) and downstream (DAX-1, AMH, HOXA10) genes are also likely involved.
Abstract: In case of an intersex child, a paediatric urologist would like to know the best feasible management in a particular case. For acquiring this information and implementing it, a teamwork is required. The role of the radiologist is to provide information about the internal genital anatomy using the currently available imaging modalities.
Abstract: Congenital adrenal hyperplasia (CAH) results from inherited defects in one of the five enzymatic steps required for the biosynthesis of cortisol. These disorders are so named because the adrenal glands are hyperplastic at birth due to unrestrained ACTH stimulation already in foetal life. Indeed, chronic overstimulation of ACTH secretion due to low levels of cortisol results in hyperplasia of the adrenal cortex. A defect in a particular step may be manifested clinically not only because cortisol and other steroid hormones are not synthesized effectively but also because precursor steroids proximal to the blocked step accumulate and can be shunted into other metabolic pathways, particularly that of androgen biosynthesis. Each enzymatic defect produces a distinctive hormonal profile and clinical picture. The two most common CAH, 21-hydroxylase (21-OH) (>90%) and 11b-hydroxylase (11b-OH) deficiencies (~5%), are due to deficient enzymes (P450C21, and P450c11) expressed exclusively in the adrenal glands, while the three other CAHs (<%), due to deficiencies in enzymes (P450scc, 3b-HSD and P-450c17) expressed in the adrenal glands and gonadal tissues, result in decreased biosynthesis of both cortisol and testosterone.
Abstract: Androgen insensitivity syndrome (AIS) is considered to be the most common cause of male pseudo hermaphrodite (MPH). In this condition end organs of patients with AIS are unresponsive to testosterone. Currently, there is considerable controversy regarding the appropriate sex of rearing of 46,XY infants with ambiguous or frankly female genitalia. This controversy arose as a result of patient dissatisfaction with their gender roles, unfavourable results of surgical procedures carried out decades ago and a particularly aggressive AIS advocacy group. In this chapter, the authors dwell on the etiology, pathophysiology and the clinical spectrum in patients with AIS. They also discuss the constraints on decision making as well as options available for the entire spectrum of clinical presentation.
Abstract: Within the main categories of intersex is the group known as male pseudohermaphroditism, in which a genetic male has distinctly female phenotypic features. The general pathophysiology of male pseudohermaphroditism relates to abnormal male differentiation because of a relative deficiency of androgen action on the foetus - with the result being inadequate virilization. This may be due to (1) inadequate testosterone production; (2) an abnormal androgen receptor in target tissues; or (3) defective conversion of androgen precursors to their final active metabolites. The focus of this chapter is the third cause of male pseudohermaphroditism (defective conversion of androgen precursors) and will review the condition known as 5a-reductase deficiency (5ARD). Recent interest in the possibility that less severe disturbances of 5a-reductase activity may be linked to isolated hypospadias has revealed that a SRD5A2 gene mutation may be found in 10% of boys with this condition. Since, this finding explains only a small subset of hypospadias patients, a large group of hypospadias patients still exists with no clear cause for this condition. It remains possible that other, more subtle, disturbances of 5a-reductase type 2 expression may be the cause of hypospadias in those patients for whom no other endocrine abnormality can be identified. This may include a delayed or reduced expression of the 5a-reductase type 2 isoenzyme, decreasing the overall necessary delivery of DHT to the foetal genital tissues during the critical period of urethral development.
Abstract: Sexual ambiguity is a psychosocial emergency. Gender assignment, the process by which the sex of rearing in newborn with ambiguous genitalia is decided requires a complete understanding of pathophysiology of intersex conditions along with chromosomal sex, hormonal profile, anatomy of internal and external genitalia, gonadal functions, potential for fertility and predilection of gonads for malignancy. The present article aims to describe the pathophysiology; clinical picture and management of mixed gonadal dysgenesis and dysgenetic male pseudo hermaphroditism with pure gonadal dysgenesis and persistent mullerian duct syndrome as their important differentials.
Abstract: True hermaphroditism (TH) is a rare condition and makes up less than 10% of all intersex cases. The gonads may be ovotestes, or they may be separate, with an ovary on one side and a testis or ovotestis on the other. The histological examination of the testicular tissue with TH individual should demonstrate distinct tubules, whereas, the ovarian tissue should contain follicles. Although TH is a rare anomaly, it shows considerable genetic heterogeneity and different genetic abnormalities have been proposed. Testicular differentiation requires a highly regulated expression of a series of genes. The role of specific genes in testicular development has been studied by gene cloning, mutation analysis, transgenic mice experiments and gene deletion studies. Point mutations in the sex determining region of the Y chromosome (SRY gene) in 46,XY patients and hidden mosaicism for a Y chromosome on Y sequences in 46,XX patients have been proposed as a cause of the dual gonadal development. Histologically, the two types of gonadal tissue in an ovotestis may show polar or corticomedullary distribution. A 46,XX chromosomal complement is the most common finding in TH. Less than 1% of people with true hermaphroditism have 46,XX/46,XY chimerism or existence of 2 or more cell lines, each of which has a different genetic origin. The presenting features of true hermaphroditism are age dependent. During neonatal period and infancy; it is usually done to help define the child's gender. In an older child, it is usually because of problems of abnormal secondary sexual characters which are inappropriate for the sex-of-rearing like excessive or inadequate phallic growth, breast enlargement or sexuality problems. An early decision on the gender of rearing is essential and it assists the future management of the child.
Abstract: Persistent mullerian duct syndrome (PMDS) is a rare congenital autosomal recessive disorder affecting phenotypic males with 46,XY karyotype and is caused by either a mutation in the gene for mullerian inhibiting substance (also called anti-mullerian hormone; MIS/AMH) or a defect in the putative receptor for MIS/AMH. Those affected have normal development of androgen-dependent structures such as penis, scrotum, epididymis, vas deferens, seminal vesicles and prostate. Deficiency of, or resistance to MIS/AMH, causes failure of regression of the Mullerian ducts, which form the fallopian tubes, uterus, upper one-third of the vagina and the broad ligaments. In addition, PMDS patients always have unilateral or bilateral cryptorchidism. The diagnosis is often made during the surgery for inguinal hernia, cryptorchidism, or at laparotomy for an unrelated cause, or in adulthood while investigating for infertility. Management is largely restricted to orchidopexy and when feasible, salpingectomy and hysterectomy is done preserving the vas and its vasculature.
Abstract: Controversy still exists regarding the timing of reconstructive surgery, namely early versus late. Early correction alleviates some of the apprehension regarding definitive gender assignment and decreases the possibility of social stigmata the child may face in early social situations like daycare and school. This early reconstruction can be a combination of both clitoroplasty and vaginal reconstruction. Alternatively, clitoroplasty can be done in infancy, for the previously mentioned reasons and vaginal reconstruction then delayed until age 3 or 4 when the pelvic anatomy is better defined and more easily accessed. The goals of feminizing reconstructive surgery include genital cosmesis, clitoral preservation, and creation of a functional vagina for both menstruation and intercourse. This chapter illustrates the various procedures of feminizing genitoplasty.
Debate concerning the psychological management of intersex patients relates to both the recent re-appraisal of John Money's work, as well as the lack of long-term data concerning psychosexual development of people affected by syndromes of abnormal sex differentiation. This chapter reviews basic recommendations offered by John Money for counseling intersex patients and their families in his book Sex efforts of the body and related syndromes: a guide to counseling children, adolescents, their families. Recent data from adult 46,XY intersex patient support and advocacy groups are presented, along with the internet addresses for their respective websites.