Approach to Inter Sex Disorders

GR Sridhar, Endocrine and Diabetes Centre, Visakhapatnam-530002

 To Bottom  Article Index  Previous Article  Next Article

When a child is born, and it is not possible to answer in one word the question 'Is it a boy or girl?' that is a psychosocial emergency whether or not it is a medical emergency (1). The concept of sex being immutable is so strong, any ambiguities about it could spark a host of reactions in the family of the child; the treating physician, unless grounded in the mechanics of management, stands the risk of being drawn into a vortex of swirling emotions. This is besides the risk of genial ambiguity being part of a syndrome requiring emergency medical treatment independently, such as salt losing variety of congenital adrenal hyperplasia.

What are inter sex disorders? Ambiguous genitalia or inter sex disorders may not all have a precise definition. The definitions vary from

Overview of normal genial development

A concept of abnormalities can be formed from a review of normal development. In the fetus, the chromosomal sex (XX or XY) directs the development of either ovaries or testes (2), which in turn secrete hormonal signals directing internal and external genial development (4). In the male, sex-determining genes, testis determining factor (TDF) from the short arm of the Y chromosome contribute to testicular differentiation. Testicular Leydig cells synthesize and secrete testosterone, which in turn maintains and virilizes the wolffian ducts, which become the vas deferents, seminal vesicles and epididymis. Besides, mullerian-inhibitory factor (MIF) secreted from the testicular Sertoli cells inhibit the formation of mullerian structures into uterus, fallopian tubes and upper vagina.

The TDF gene, localized to the distal short of the Y chromosome,acts as a master switch for male differentiation. Its gene product then reacts with genes elsewhere on the Y, X and autosomes and on their diverse gene products while proceeding toward male gonadal development. In addition, autosomal factors, in addition to autosomal genes linked to X chromosome are also recognised to regulate testicular differentiation (4). Such information may not be relevant to approaching common disorders of sexual development, yet it gives a flavour of the rich complexity of the layers controlling sexual differentiation. The testosterone in turn is converted into dihydrotestosterone which virilizes the external genitalia.

In the female, ovaries develop when two X chromosomes exist. The external genitalia form spontaneously when a Y chromosome is absent. In both sexes, genial development is completed by 20 weeks of fetal life. In the females, exposure of androgens at critical periods leads to masculinization of the fetus. Genital ambiguity can arise from inappropriate androgen effect. Either too much androgen exposure in a female fetus or lack of appropriate androgen effect in a male fetus will result in incomplete differentiation of the external genitalia. The end result of both can be remarkably similar (4).

Criteria of sex:

Approached from a broad perspective, sex can be characterised by a variety of factors:

A full description of anomalies in each of these factors is impractical, hence the following working definition of inter sex states has been adopted:

How common are anomalies of sexual development ?

We do not have epidemiological studies on the prevalence of inter sex disorders. Genital ambuigity was seen in 2.5% (12/445, EDC Visakhapatnam) to 10% (115/1119, BJ Wadia Hospital for Children, Mumbai) , 12% (118/1001, AIIMS, New Delhi), and 12.5% (38/1001, SGPGI, Lucknow) in various parts of the country. At AIIMS, New Delhi, the categorisation was as follows (5): Male pseudohermaphroditism (60%) -- androgen resistance 15%, 5a reductase deficiency 2%, others 5% and unclassified 77%. Female pseudohermaphroditism (13%) -- congenital adrenal hyperplasia 72%.

Clinical approach to a new born with ambiguous genitalia

History:

Physical evaluation

General examination

Hyperpigmentation (high ACTH), dehydration, hypotension, hyper tension (CAH)

Laboratory investigation

Androgen binding studies

Gender assignment

Gender assignment is often complex. It is best handled by a knowledgeable team of a gynecologist, pediatric surgeon or urologist, pediatric endocrinologist and psychologist. They should agree between themselves, and discuss the issue carefully with the parents.

The decision should rest on the following factors:

  1. Future fertility: In masculinized females, fertility is unaffected. Reproduction is possible with proper treatment. Masculinised females may therefore be reared as females
  2. Projected appearance of genitalia at puberty and penile adequacy for coital function: The aim is to enable the child into a psychologically normal, healthy, well-adjusted adult. The logical aim would be to decide whether the phallus could develop into a penis adequate for coitus. This depends on the erectile tissue. Technically construction of female genitalia is easier, and most western countries opt for a female sex assignment in cases of uncertainty about adequate penile function. However in our country, the situation is likely to be different. It depends on choosing between an infertile female or an impotent male. It may often become a Hobson choice.

Genital reconstruction is ideally done before 18 months of age, though this is the exception in our country.

Suggested management of infant with congenital adrenal hyperplasia (6)

Clinical description of inter sex disorders

Excellent reviews are available in all major textbooks, and are therefore not attempted in this presentation.

In summary

Genital ambiguity is a result of inappropriate androgen effect. Too much androgen exposure in a female or lack of appropriate androgen effect in a male results in genial ambiguity. This medical emergency requires management of potentially lethal metabolic derangement, and also providing prompt sex assignment. Appropriate gender assignment is best done by a multidisciplinary team familiar with the natural course of such disorders.

Future

Future research should increase our understanding of mechanisms of sexual differentiation, including testicular differentiating factor and other regulating genes. Identification of heterozyges for CAH results in prenatal diagnosis and corrective therapy. Improved surgical techniques are to be expected.

References

  1. Pagon RA. Diagnostic approach to the newborn with ambiguous genitalia. Ped Clin North Am 1987, 34:1019-1031
  2. Savage MO. Normal and abnormal sexual differentiation. In Weatherall DJ, Ledingham JGG, Warrell DA (eds). Oxford Textbook of Medicine 3 ed. Oxford Univ Press, Oxford 1996; vol2, pp1689-95
  3. Ghai OP. Ambiguous genitalia. In Essential Pediatrics, Ghai OP. 3ed. Interprint, New Delhi 1993; pp353-4
  4. Damario MA, Rock JA. Diagnostic approach to ambiguous genitalia. In Adashi EY, Rock JA, Rosenwaks Z (eds) Reproductive Endocrinology, Surgery and Technology. Lippincott Raven, Philadelphia 1996; vol 1; pp890-914
  5. Varma IC, Mathew S, Elango R, Menon PSN, Rohatgi M, Mathews AR. Clinical and investigative approach to inter sex disorders - Indian experience. In Desai MP, Colaco MP (eds) Proc 1st Natl Symposium on Pediatric Endocrinology. BJ Wadia Hospital for Children, Bombay, 1986; pp136-45
  6. Lee MM, Donahoe PK. Ambiguous genitalia. In Bardin CW (ed). Current therapy in Endocrinology & Metabolism. 5 ed. Mosby St Louis, 1994; pp242-9


 To Top  Article Index  Previous Article  Next Article