Classic Congenital Adrenal Hyperplasia (CAH)
Genetic disease that prevents natural synthesis of certain hormones
Classic congenital adrenal hyperplasia (CAH) is a rare inherited endocrine disorder caused by a genetic mutation in a crucial enzyme for cortisol synthesis, and is characterized by overgrowth of the adrenal glands, adrenal insufficiency, mineralocorticoid deficiency, and androgen excess. The most frequent form of CAH, responsible for 95% of cases, is a deficiency in the enzyme 21-hydroxylase, which is required for the production of cortisol and aldosterone in the adrenal glands. There are two main types, classic and non-classical CAH. Classic CAH is diagnosed at birth and is characterized by adrenal insufficiency. It can lead to severe virilization in women, testicular tumors in men, and infertility.
Classic CAH has an incidence of 1 in 10,000-15,000 births in North American and European populations1. CAH occurs in both males and females, but its presentation from patient to patient can be quite different. Adrenal crisis, a life-threatening condition that occurs when the body cannot produce sufficient cortisol in response to stress, is a risk in both males and females with classic CAH. For this reason, all newborns in the US and in many other countries are screened for CAH at birth and treated as appropriate with corticosteroid replacement (glucocorticoids and, in many cases, mineralocorticoids) to make up for their inability to synthesize these hormones. CAH also causes hormonal imbalances in adults.
Despite taking corticosteroids, most patients are unable to achieve hormonal balance
Corticosteroids are the current standard of care for classic CAH and are used to address the endogenous cortisol deficiency of CAH patients. Such exogenous cortisol administration, however, has its own complications and side effects, and it is difficult to mimic normal glucocorticoid levels. Elevated ACTH levels can result and cause excess adrenal production of various androgens, including testosterone. In women, these excess androgens cause hirsutism, alopecia, acne, and irregular menstruation. In men, testicular adrenal rest tumors occur at a high rate that, in turn leads to a high rate of infertility. Increasing exogenous corticosteroids is the current means of addressing such issues, but often results in iatrogenic Cushing’s syndrome. The patient and the physician are often trapped between over-treating with corticosteroids and suffering from elevated levels of androgens.
- Speiser PW, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60. (PMID: 20823466)
Vasomotor Symptoms (VMS)
Vasomotor symptoms (VMS) are defined as hot flashes and night sweats in menopausal women. As estrogen levels fall during menopause, the neurons believed to be the key modulators of the heat dissipation response become hyperactive. This leads to VMS, including sensations of heat and/or perspiration that generally last several minutes and are often preceded or followed by sensations of cold and/or shivering.
- Avis, NE, et al. Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition. JAMA Intern Med. 2015 Apr 1; 175(4): 531–539. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433164/
- Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289:3243.