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Genetic Errors of Metabolism.


At about the sixth week, in male embryos, Mullerian Inhibiting Factor prevents development towards a uterus, womb and ovaries. At the same time androgens are produced as the testes begin to be formed.

Until the eighth week, the external genitalia grow identically for either sex. At this time an enzyme, 5alpha reductase, is produced in males, which converts testosterone to dihydrotestosterone. From the eighth week, external genitalia begin to develop from a structure called the genital tubule. At twelve weeks, in females, it becomes the clitoris and vaginal entrance In males, under the influence of dihydrotestosterone, the external genitalia instead develops towards a penis. Meanwhile an area called the labioscrotal swellings becomes either the scrotum or labia.

However genetic errors can cause problems with the metabolic process. In one, testosterone fails to activate the receptors which should produce the male characteristics in male fetuses, one creates androgens inappropriately, and the third creates testosterone, but not the androgen dihydrotestosterone.


Androgen Insensitivity Syndrome.

The first condition, affecting XY fetuses, is sometimes referred to as testicular feminisation, but nowadays, more appropriately, Androgen Insensitivity Syndrome. The primitive testicles produce testosterone in the normal way, but the various receptors around the body are insensitive to it.

The baby usually appears to be a girl, is labelled as a girl and she grows up as one. Since the Mullerian inhibiting factor is produced, the ovaries, Fallopian tubes, womb, uterus and upper vagina do not develop. Usually, the first sign that all is not as it should be is that a swelling is found, the partly developed testes, in the abdominal cavity, groin or labia. Sometimes the first sign of trouble is in puberty, with failure to menstruate.

In popular accounts these people, along with those with an inactive SRY gene are referred to as 'XY women'. Indeed, the diagnosis is often confused. However, while the latter seem to occur randomly, AIS is an inherited defect - an X linked recessive trait.

The undescended testes are usually removed because of a danger that they may become cancerous.

From time to time, there has been speculation that various public figures, from Queen Elizabeth I, and Greta Garbo to, most recently, Mrs. Simpson were 'really men'. The last named gave rise to a particularly offensive caricature, in one newspaper, and the description of her as "an androgynous freak"

In some cases, the condition is less severe, and enough masculinisation of genitals occurs for the baby to be labelled a boy.

 Not all AIS people are happy with the gender role imposed on them, and there is considerable variation. Some are resentful of surgery to 'normalise' them as girls. It appears that, for some, the rise in testosterone levels in puberty, possibly produced by the adrenals, has been enough to partly overcome their insensitivity.

Others have suffered considerably in the male role. Testosterone is sometimes prescribed to assist pubertal changes in the male direction. However, there are some who, in deference, possibly, to their parents and the clinician, but against their better judgment, have experienced attempts in the clinic to force them into manhood, against their will, by administration of massive doses. All it did was make them feel very ill.

Certainly for those with Complete AIS, as one psychiatrist puts it,(1) " You could wham them full of testosterone, give them as much as you like, in forms that would crystallise out in the blood. It still would not express male hormone effects in the body."


Congenital Adrenal Hyperplasia.

Originally called Adrenogenital Syndrome (AGS). By the fifth or sixth month after conception, the external genitals are partially complete. During this time the adrenal glands have been developing. In some cases a autosomal recessive gene defect means that there is a deficiency of the enzyme, 21-hydroxylase. This means, in turn, that the fetus unable to properly produce cortisol from 17-hydroxy-progesterone. Much of it instead becomes converted into androgens.(2)

The pituitary over-stimulates the adrenal cortex and, usually, enough cortisol is produced. The result, however, is hyperplasia of the cortex and even higher levels of androgens.

In some cases, aldosterone, another hormone that regulates the electrolyte balance of the body, that is, the concentration of various salts, may be deficient. This may lead to an Addisonian crisis, often shortly after birth, which may be the first sign that something is wrong.

Nowadays they are given corticosteroids to make up any deficiency, which also has the effect of reducing the adrenal output, and thus the excess androgens.

This condition affects both males and females. In females, while development of the internal genitalia has already occurred, it produces a varying degree of masculine appearance to the external genitals. In males it tends to lead to precocious puberty, as early as three or four years old, with growth of pubic hair an enlarged penis and rapid physical growth. Girls, who have mild CAH experience symptoms at any age even after puberty. Signs include unwanted hair growth, irregular periods, infertility and rapid growth in height.

Girls with slight masculinisation have, in the past, been given corrective surgery and many are now expressing great resentment. Some have been raised as boys. Textbooks generally refer to an 'enlarged clitoris' which may mislead inexperienced practitioners treating mature clients, for fully male-appearing genitals may develop.

 There is a tendency to describe CAH as a syndrome which only occurs with girls. As an autosomal condition, this would appear to be wrong. Presumably puberty at age six in a boy is a cause for admiration rather than pathologisation.

 However, though boys with CAH become interested in sex relatively early, Bancroft(3) suggests that their fantasies tend to be consistent with their social and emotional age, and they do not develop any particular behavioural problems. He takes this as support for the idea that sensitisation is mediated by hormones, but the target is more determined by social learning.


5 alpha reductase deficiency.

By the eighth week, the general levels of testosterone are falling. Under normal circumstances the development of male external genitalia is promoted by dihydroxytestosterone produced within them. This is achieved by an enzyme, 5alpha reductase and in some males this is deficient. The result is that the baby may be labelled as a girl at birth. In puberty the rise of testosterone usually but not always allows development to proceed towards completion.

 One study that has caused a great deal of argument is one by Imperato-McGinley of a number of such boys, mainly from three villages in Santo Domingo, in the Dominican Republic, and we will be returning to these later.



  1. Television Programme, BBC2, (1996) Dark Secrets: XY Women,
  2. Fausto Sterling, A., (1992) Myths of Gender, Biological Theories about Women and Men, (P84), New York: Basic Books.
  3. Bancroft J. (1989) Human Sexuality and its Problems, Edinburgh: Churchill Livingstone.

NEXT The Fetal Environment.

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Bland, J., (2001) About Gender: Genetic Errors of Metabolism.
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Web page copyright 1998-2006 Derby TV/TS Group. Text copyright Jed Bland.
15.05.98 Last amended 12.11.01, 01.05.14