Biology of DSDs: Congenital Adrenal Hyperplasia

Description

Congenital Adrenal Hyperplasia, or CAH, is a group of sex development conditions which affect the adrenal glands and hormone production in both males and females. CAH occurs when genetic mutations cause the adrenal glands to produce excess sex hormones known as androgens.

If you want to help improve medical research and psychological support for individuals with these conditions, you can donate to DSDFamilies (https://dsdfamilies.org/donate).

Sources

[1] NIH. (2020). 21-hydroxylase deficiency. Genetics Home Reference, National Library of Medicine.

[2] LOCAH. (2018). The Intersex Masterpost. Medium.

[3] Witchel, S. (2018). Disorders of sex development. Best Practice and Research in Clinical Obstetrics and Gynecology, 48, 3.

[4] NIH. (2019). Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Genetic and Rare Diseases Information Center.

[5] Falhammar, H., et al. (2012). Clinical outcomes in the management of CAH. Endocrine, 41.

[6] Gidlof, S., et al. (2013). One hundred years of CAH in Sweden, a retrospective. Diab & Endocr, 1(1).

[7] Gliban, D., et al. (2014). Health related quality of life of children and adolescents with CAH in Brazil.

[8] Kovacs, J., et al. (2001). Lessons From 30 Years of Clinical Diagnosis and Treatment of CAH. Clinic Endoc.

[9] Nordenstrom, A., et al. (2010). Sexual function and surgical outcome in women with CAH. J Clin Endocrinol.

CAH support groups and foundations:

[1] CARES Foundation (https://www.caresfoundation.org)

[2] Living With CAH (https://www.caresfoundation.org)

Transcript

Congenital Adrenal Hyperplasia, or CAH, is a group of sex development conditions which affect the adrenal glands and hormone production in both males and females. Adrenal glands are located on the top of the kidneys and produce hormones which regulate essential functions in the body. CAH occurs when genetic mutations cause the adrenal glands to produce excess male sex hormones known as androgens.

The condition affects about 1 in 13,000 newborns--a rate of around 0.008% of births. Both males and females with CAH often experience excess androgens and severe salt loss in the body, affecting fluid levels and blood pressure. In females with CAH, the excess androgens often result in virilized (also known as masculinized) genitalia, and in males with CAH, genitalia is usually unaffected. The most common form is known as 21-hydroxylase deficiency, which makes up 95% of all cases of Congenital Adrenal Hyperplasia. For the rest of the video, we will be exploring 21-hydroxylase deficiency in females, using the shorthand, CAH.

At conception, the chromosome set for females with CAH begins with the typical 46,XX. An inherited mutation in the CYP21A2 gene causes a deficiency of the enzyme 21-hydroxylase. This enzyme is found in the adrenal glands, where it helps produce cortisol and aldosterone. Cortisol maintains blood sugar levels, protects the body from stress, and suppresses inflammation, while aldosterone regulates the amount of salt retained by the kidneys. Without enough aldosterone, the body starts to lose too much water and salt. With a lack of the 21-hydroxylase enzyme for cortisol and aldosterone production, substances build up in the adrenal glands, and instead of being converted into cortisol and aldosterone, these substances are converted into more androgens. As the development of the fetus progresses, excess androgen results in sex development differences.

Around the 8th week after conception, the 46,XX fetus undergoes gonadal differentiation. In the absence of SRY, transcription factors FOXL2, WNT4, and RSPO1 initiate and maintain gonadal differentiation into ovaries. With no testes present to activate anti-Mullerian hormone, the Mullerian structure develops uninhibited (forming the fallopian tubes, uterus, cervix, and upper part of the vagina). And with no testes to produce testosterone, the Wolffian structure (which would have formed the epididymis, vas deferens, and seminal vesicle) disintegrates.

While the ovaries and Mullerian structure fully develop, the excess androgen produced from the adrenal glands often masculinizes the external genitalia, a region highly sensitive to androgen exposure. This can result in the growth of the clitoris, atrophy of the vagina, and sometimes a fusion of the labia. However, with no SRY activation and no anti-Mullerian hormone, the fetus still develops anatomy to support the production of large gametes. Thus, newborns with 46,XX CAH are females.

For females, CAH is often recognized immediately at birth due to the masculinizing effects of androgen on genital morphology. Misinformed doctors and parents may think that cosmetic surgery is necessary to make the infant's genitals conform to typical norms, but this is usually not healthy for the child, both physically and psychologically. Unnecessary surgery can affect future sexual function and harm the individual's development. Because of this, such cosmetic surgeries are a violation of the baby's human rights. Surgeries on infants should only occur if it is medically necessary for present and future bodily function.

In the United States and Europe, newborns are screened at birth for the classic salt-wasting and simple virilizing forms of CAH. For those who test positive, additional biochemical and genetic testing is done to confirm the diagnosis. The level of severity relates to the amount of functional 21-hydroxylase enzyme in the body. Approximately 75% of individuals with 21-hydroxylase deficiency have the salt-wasting variety, which is the most severe form, resulting in a completely non-functioning enzyme. This results in a low amount of aldosterone (the salt retention hormone), which in turn causes critically low salt levels in the bloodstream. Without hormone and steroid treatment at infancy, this can lead to severe dehydration and weight loss, and ultimately, the death of the child. This is why the salt-wasting variety of CAH must be treated immediately. On the other hand, for those babies with the simple virilizing form, the genitals are affected, but salt levels remain stable.

Later in life, both males and females with CAH may experience early puberty, excessive hair growth, acne, shorter than average adult height, irregular periods for females, and testicular enlargement and testicular tumors in males. Lifelong hormone replacement therapy is needed to treat adrenal insufficiency and to decrease androgen production so that typical growth and puberty can proceed. Since fertility is usually unaffected, most women with CAH can become pregnant and carry children.

In all, both males and females with Congenital Adrenal Hyperplasia have typical internal reproductive anatomy but may experience unique genital morphology and levels of infertility. Where bodily variation is healthy and non-life threatening, it should be accepted and not stigmatized. Rather than trying to correct differences in appearance, parents of girls and boys with CAH, as well as medical professionals, should model a behavior of love and acceptance so that the child can grow into an adult who is both highly knowledgeable of their own condition and confident in their body.

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