12th April 2024

Contrasexual pubertal development

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia results from deficiencies of enzymes, which play an important role in corticosteroid synthesis. This results in low levels of cortisol and, in turn, result in high levels of ACTH. Elevated level of ACTH promotes hyperplasia of the adrenal glands. See the diagram below, which illustrates corticosteroid synthesis and highlights the relevant enzymes in congenital adrenal hyperplasia.

The most common enzyme deficiency is 21 hydroxylase, which accounts for over 90% of CAH. The second most common enzyme deficiency is 11 ß-hydroxylase. Both enzymes are responsible for the conversion of progesterone and its by-product 17α-hydroxyprogesterone into aldosterone and cortisol eventually. The build-up of 17α-hydroxyprogesterone increases its conversion into testosterone.

Aldosterone is a hormone responsible for sodium and water reabsorption in the renal tubules. Low levels of aldosterone results in salt wasting in the body. Cortisol is responsible for gluconeogenesis in the body and low levels of glucose in the body. In 11 ß-hydroxylase deficiency, the build-up of 11 deoxycortisone – a by-product of progesterone – leads to hypertension.

The third most common enzyme deficiency is 17α-hydroxylase. 17α-hydroxylase is responsible for the conversion of progesterone into cortisol. This leads to low levels of cortisol and androgens. Low levels of androgen lead to poorly developed male genitals and a lack of development of secondary sexual characteristics in males and females. Progesterone is directed more down the aldosterone pathway, leading to a build-up of the precursors of aldosterone – 11 deoxycorticosterone and corticosterone. This build-up leads to an increased effect of aldosterone, leading to hypernatremia, hypokalaemia and hypertension. Due to the hypertensive effect of aldosterone precursors, this also leads to low levels of aldosterone.

Symptoms

In both 21-hydroxylase deficiency and 11 ß-hydroxylase deficiency, there are high levels of androgens. This leads to masculinisation of secondary sex characteristics in females. This results in enlarged clitoris, ambiguous genitalia, acne and hirsutism. High levels of androgen could also cause an early onset of puberty.

In 17α-hydroxylase deficiency, there are low levels of androgens. This leads to ambiguous genitalia development in males and a lack of secondary sexual characteristics in females.

In 21 hydroxylase deficiency, there are low levels of aldosterone, leading to salt wasting, especially in infants. This leads to vomiting, dehydration and hypotension. In 11 ß-hydroxylase deficiency and 17α-hydroxylase deficiency, there are elevated levels of aldosterone precursors. This leads to hypertension.

Cortisol is low in all three enzyme deficiencies and leads to hypoglycaemia.

Management

In classic 21 hydroxylase deficiency, individuals with salt wasting due to low aldosterone levels are given lifelong glucocorticoids such as hydrocortisone and fludrocortisone. The glucocorticoid also inhibits ACTH to prevent hyperplasia of the adrenal glands, which in turn prevents excess androgen production. Response to treatment is done through blood tests to check plasma renin levels and through regular blood pressure measurements. Long-term glucocorticoid treatment can also cause premature ageing of the bones, so it needs to be monitored at least yearly with X-ray to check for premature closing of the epiphyseal plates., Affected individuals with non-classic 21 hydroxylase deficiency do not need glucocorticoids.

In 11 ß-hydroxylase deficiency, spironolactone is the main treatment for females as it blocks mineralocorticoid and androgen receptors to control hypertension and the effects of androgen excess. In individuals who do not desire fertility, contraceptives can be used in combination with spironolactone. In males, amiloride and triamterene are used instead of spironolactone due to its side effects of gynaecomastia and sexual dysfunction.

In 17α-hydroxylase deficiency, glucocorticoid is the main management which will control hypertension induced by metabolites that act as weaker versions of aldosterone. Females may also be given low-dose oestrogen to promote secondary sexual characteristics and progestin to promote cyclic menstrual bleeding. In males, testosterone can be used to promote secondary sexual characteristics.

Androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is a condition with a genetic defect of the androgen receptor. It is inherited in an X-linked recessive pattern. There are three types of AIS – complete with receptors that do not respond to androgens at all, partial with some functioning receptors and mild insensitivity with masculinisation of external genitalia. In most cases, the affected individuals are infertile.

Symptoms

Investigation

Ultrasound of the pelvis would reveal an absence of the uterus and testes that have failed to descend into the scrotum. Blood tests would reveal an elevated level of testosterone.

Management

Treatment includes hormone replacement therapy, which could be male or female sex hormones depending on the gender role that the individual identifies with. Surgery is also done to remove the testes to reduce the risk of cancer. Corrective surgery may also be done to correct the external genitalia.

References

• Congenital Adrenal Hyperplasia. BMJ Best Practice. Last Reviewed 22nd December 2023
• Lissaue, Tom, Will Carroll, Keir Shiels, and Ranj Singh. Illustrated textbook of paediatrics. Amsterdam: Elservier, 2022
• Klatt, Edward C., and Vinay Kumar. Robbins and COTRAN Review of Pathology. London: Elsevier Health Sciences, 2015