Pathophysiology
Summary
The adrenal cortex is functionally and structurally divided into three zones: the zona glomerulosa, zona fasciculata, and zona reticularis. These zones are responsible for the synthesis of mineralocorticoids, glucocorticoids, and androgens, respectively. The initiation of hormone production in the adrenal cortex is largely regulated by adrenocorticotropic hormone (ACTH), secreted by the anterior pituitary. ACTH stimulates the enzyme desmolase, initiating the rate-limiting step in steroid hormone synthesis by converting cholesterol into pregnenolone.
Pregnenolone is the foundational molecule for all hormones synthesized in the adrenal cortex. It is further converted to progesterone in the zona glomerulosa via the enzyme 3-beta-hydroxysteroid dehydrogenase. In the zona glomerulosa, progesterone undergoes a series of transformations to ultimately produce the mineralocorticoid aldosterone: 21-hydroxylase converts progesterone to 11-deoxycorticosterone, which is converted to corticosterone by 11-hydroxylase. Finally, 18-hydroxylase, stimulated by angiotensin II, converts corticosterone to aldosterone.
In the zona fasciculata, 17-hydroxylase converts pregnenolone to 17-hydroxypregnenolone, which is converted to 17-hydroxyprogesterone and further acted upon by 21-hydroxylase and 11-hydroxylase to produce cortisol, the primary glucocorticoid. The zona reticularis is responsible for androgen synthesis: 17-hydroxypregnenolone and 17-hydroxyprogesterone are converted into the androgens dehydroepiandrosterone (DHEA) and androstenedione via 17-20 lyase. These weak androgens are further converted to testosterone through oxidoreductase.
Congenital adrenal hyperplasia (CAH) is a significant pathology often tied to enzymatic deficiencies in the adrenal cortex. These deficiencies are autosomal recessive in nature and primarily involve 11, 17, and 21-hydroxylase. CAH leads to adrenal gland hyperplasia due to decreased cortisol synthesis, which triggers negative feedback on the anterior pituitary, resulting in increased ACTH. MSH is also increased, as ACTH and MSH share a common precursor (POMC).
In females, severe deficiencies in 11 and 21-hydroxylase can manifest at birth with ambiguous genitalia due to elevated levels of androgens in utero. In adolescence, milder forms of these deficiencies present with clitoromegaly, precocious pubic hair development, or hirsutism, all attributable to hyperandrogenism. Irregular menstrual cycles and infertility may also occur, which are likewise influenced by elevated androgen levels.
In terms of electrolyte imbalances, 21-hydroxylase deficiency can lead to hyponatremia, hyperkalemia, and type IV RTA due to low aldosterone. This can further escalate to hypotension & hypovolemic shock. Increased renin due to compensatory activation of RAAS. Conversely, 11-hydroxylase deficiency presents with low aldosterone but hypokalemia, hypertension, and low renin due to the increased mineralocorticoid effects of increase in 11-deoxycorticosterone levels.
17-hydroxylase deficiency shunts hormone production toward mineralocorticoids, leading to a distinctive clinical picture. The increase in increased aldosterone levels but low cortisol and and low androgen productions. This results in ambiguous genitalia in males due to low testosterone and a lack of secondary sex characteristics and delayed menarche or amenorrhea due to low estrogen levels.
Lesson Outline
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FAQs
The adrenal cortex is divided into three zones: the zona glomerulosa, zona fasciculata, and zona reticularis, each responsible for synthesizing different steroid hormones. The zona glomerulosa produces mineralocorticoids, the zona fasciculata synthesizes glucocorticoids, and the zona reticularis is responsible for androgen production. In CAH, these processes are disrupted, often leading to excessive androgen production and a range of clinical symptoms.
Adrenocorticotropic hormone (ACTH), secreted by the anterior pituitary gland, stimulates the adrenal cortex to produce hormones. ACTH activates the enzyme desmolase, converting cholesterol into pregnenolone, the precursor for all adrenal hormones. In CAH, reduced cortisol synthesis triggers a negative feedback loop on the anterior pituitary, increasing ACTH levels and causing adrenal gland hyperplasia.
21-hydroxylase deficiency, the most common form of CAH, results in decreased aldosterone and cortisol production. This leads to hypotension, hypovolemic shock, and elevated renin levels. Additionally, the deficiency disrupts electrolyte balance, causing hyponatremia, hyperkalemia, and type IV renal tubular acidosis, which can compromise overall health.
11-hydroxylase deficiency leads to decreased cortisol and aldosterone, but increases 11-deoxycorticosterone, resulting in mineralocorticoid side effects such as hypertension and hypokalemia. In contrast, 17-hydroxylase deficiency results in elevated aldosterone levels, causing hypertension and reduced androgen production. This leads to ambiguous genitalia in males and delayed sexual development in females.
In 21-hydroxylase deficiency, decreased aldosterone production leads to hypovolemia, triggering an increase in renin levels as part of the body's compensatory mechanism. In contrast, 11-hydroxylase deficiency results in increased mineralocorticoid effects, leading to decreased renin levels. Altered renin levels can further disrupt electrolyte balance and blood pressure, complicating the clinical picture.
