Adrenal Steroid Hormone Biosynthesis

Introduction

The steroid hormone biosynthesis starts from cholesterol. It is a complex and dynamic process with the participation of various enzymes and their cofactors. The adrenal gland is separated into two parts, the cortex and the medulla. The synthesis of steroid hormones mainly occurs in the adrenal cortex. However, gonads (sex organs), placenta, and brain are the other structures responsible for the production of steroid hormones.

What Are the Different Steroid Hormones?

The steroid hormones are divided into three types, mineralocorticoids, glucocorticoids, and sex hormones. The adrenal gland is surrounded by a connective tissue capsule layer. The capsule divides the gland into three zones:

• Zona glomerulosa.

• Zona fasciculata.

• Zona reticularis.

Zona glomerulosa is the outermost layer of the adrenal gland responsible for mineralocorticoid production. Mineralocorticoids (aldosterone) regulate salt and water balance. Zona fasciculata produces glucocorticoids (cortisol). Cortisol regulates energy levels by increasing the levels of glucose, amino acids, and fats. Cortisol also regulates immunity. Finally, androgens (testosterone and estrogen) are sex hormones produced by the zona reticularis (innermost layer).

What Is the Mechanism of Adrenal Steroid Hormone Biosynthesis?

Pregnenolone is the progenitor of all steroids. Adrenal steroid hormone biosynthesis is done by steroidogenic (steroid-producing) cells. It involves multi-step cholesterol conversion with the use of enzymes. The steroidogenic acute regulatory (StAR) protein plays a vital role in the adrenal cortex for synthesis. It increases cholesterol flow from the outer mitochondrial membrane to the inner mitochondrial membrane (mitochondria are the energy-producing cell organelles). During stress, steroid synthesis is an immediate process. Hence, steroids are released rapidly by the adrenal cortex. StAR is absent in the placenta and brain, leading to slow release from these organs.

What Are the Pathways of Adrenal Steroid Hormone Biosynthesis?

The conversion of cholesterol to pregnenolone is the first and the rate-limiting (slowest) step in steroid biosynthesis. It involves three chemical reactions. Various members of the cytochrome p450 enzyme (CYP) family catalyze different reactions in steroid biosynthesis.

1. Mineralocorticoid Biosynthesis: Pregnenolone undergoes an irreversible conversion into progesterone. Progesterone is then converted into Deoxycorticosterone (DOC). The final step is aldosterone production. Angiotensin-II stimulates aldosterone release for sodium retention in the kidneys. Increased extracellular potassium also triggers aldosterone release.

2. Glucocorticoid Biosynthesis: Adrenocorticotropic hormone (ACTH) regulates cortisol production. It is released by the pituitary gland. Cortisol is also released during stress. Certain structural changes in Pregnenolone and progesterone produce cortisol.

3. Adrenal Androgen Biosynthesis: Pregnenolone is converted into dehydroepiandrosterone (DHEA). DHEA is a precursor of active androgens. A portion of DHEA is also converted into DHEA sulfate (DHEAS). Adrenarche is a rise in androgen production that begins in early childhood in response to increased ACTH and DHEAS. The androgens following adrenarche lead to the development of sexual characteristics such as pubic hair, acne, and body odor.

What Are the Other Organs Producing Adrenal Steroid Hormones?

It is reported that steroid hormones are also synthesized by extra-adrenal organs and tissues. The examples are brain, intestine, lung, skin, spleen, placenta, adipose tissue, and immune system.

• Skin: Cortisol synthesis can occur in the skin. It is because the skin has all the enzymes involved in steroid synthesis. Further, the skin also expresses corticotropin-releasing hormone (precursor of ACTH). Cortisol production in the skin is regulated by CRH, ACTH, ultraviolet radiation (UVR), and inflammatory mediators (interleukin-1 beta). Cortisol affects the skin barrier and has a negative effect on wound healing.
• Thymus: Thymus is a small gland responsible for T-lymphocytes (immune cells) production and maturation. Thymus has also been found to produce glucocorticoids. Epithelial cells of the thymus produce Pregnenolone and DOC.

What Are the Disorders Related to Adrenal Steroid Hormone Biosynthesis?

Disorders of the steroid biosynthesis pathways can occur due to a deficiency in enzymes and their cofactors. Seven inborn errors of steroid hormone biosynthesis are known. However, 21-hydroxylase deficiency, also called congenital adrenal hyperplasia (CAH), is the most common.

• Congenital Adrenal Hyperplasia (CAH): CAH represents a group of inherited conditions. It leads to defective mineralocorticoid and glucocorticoid production. It is also called adrenal insufficiency. Cortisol inhibits ACTH released from the pituitary gland via negative feedback. Defective cortisol production prevents the negative feedback mechanism. The result is adrenal cortex hyperplasia (increased cells). Almost three-fourths of the patients have aldosterone deficiency. Hence, they are prone to fluid depletion and potassium retention (hyperkalemia).

What Are the Chemicals That Interfere With Adrenal Steroid Hormone Biosynthesis?

1. Mitotane: It is an environmental contaminant that particularly interferes with steroid biosynthesis. It is found in DDT (an insecticide). Mitotane specifically affects the zona fasciculata and inhibits glucocorticoid production. It results in severe adrenal insufficiency. The characteristics are a loss of appetite, low body temperature (hypothermia), nausea, weakness, and death. Mitotane is activated by CYP family and causes mitochondrial damage, followed by adrenal cortex death.

2. Polychlorinated Biphenyls (PCBs): PCBs are highly carcinogenic compounds previously used in industries and consumer products. Paint, glue, plastic, transformers, and capacitors are a few materials containing PCBs. It has been found that PCBs inhibit aromatase (the enzyme responsible for estrogen production) activity in human breast cells.

3. Azole Fungicides and Antifungal Drugs: Fungicides are chemicals used in agriculture. Fungicides and antifungal drugs containing the ‘azole’ group (Econazole, Tioconazole, Bifoconazole, Miconazole, Isoconazole, and Clotrimazole) have the capacity to inhibit CYPs involved in steroidogenesis. Further, azole antifungal drugs inhibit aromatase activity in the human placenta.

4. Triazine Herbicides: Atrazine, Simazine, and Propazine are herbicides used to control weeds. Atrazine has been banned in most countries. However, its surface water concentration is high as it is resistant to breakdown. Increased exposure to Atrazine is known to induce ovarian and breast tumors as it stimulates estrogen production.

What Are the Disorders Caused Due to Abnormal Steroidogenesis?

Various conditions are caused due to dysregulation of steroid biosynthesis.

1. Skin Inflammatory Disorders: Steroid synthesis in the skin leads to psoriasis and atopic dermatitis. StAR expression is reduced in psoriasis. Besides, deficient steroid biosynthesis is associated with increased inflammation. Hence, the defective glucocorticoid mechanism contributes to psoriasis pathogenesis.

2. Autoimmune Disorders:

• Lower DHEA levels are found in multiple sclerosis patients.

• It is hypothesized that systemic lupus erythematosus (SLE) patients have dysregulated steroidogenesis. Hence, corticosteroids are prescribed for the same.

• Rheumatoid arthritis is another autoimmune disorder in which steroid biosynthesis may play a role. It is because glucocorticoids regulate many genes responsible for chronic inflammation.

Conclusion

Steroid hormones act by binding to specific receptor proteins regulating gene transcription in target tissues. The steroid hormones contribute to important physiological functions of the body. Recent advances in molecular endocrinology and gene targeting allow scientists to elucidate the molecular mechanisms of steroids that regulate various body functions.