Steroid Biosynthesis Study Notes

Learning Objectives

• List the six classes of steroid hormones

• Describe the role of cholesterol as the substrate for steroid hormone synthesis

• Highlight the key features of steroidogenic cells

• Outline the basic organisation of steroidogenic pathways

• Understand that enzyme profiles determine steroid products of steroidogenic organs

Steroid Hormones

Classes of Steroid Hormones: Steroid hormones are divided into several categories. 

• Sex Steroids: Sex steroids include progestogens, androgens, and oestrogens. 

  • Androgens → Male sex hormones (e.g., testosterone, DHEA).

  • Estrogens → Female sex hormones (e.g., estradiol, estrone).

  • Progestogens → Regulate menstrual cycle & pregnancy (e.g., progesterone).

• Adrenal Steroids: Adrenal steroids include glucocorticoids and mineralocorticoids. 

  • Glucocorticoids → Regulate glucose metabolism & stress response (e.g., cortisol).

  • Mineralocorticoids → Regulate salt/water balance (e.g., aldosterone).

• Vitamin D: Other steroid-related hormones include vitamin D (calcitriol), which is produced in the epidermis of the skin. 

  • Vitamin D Derivatives → Steroid-related, regulate calcium and phosphate (e.g., calcitriol).

Note: One important feature of steroid hormones is the number of carbon atoms they contain, which serves as a classification method and is also relevant for understanding the pathways of steroid catabolism.

Cholesterol as the Precursor: All steroid hormones are derived from cholesterol. 

• Conversion to Pregnenolone: The first step of steroidogenesis is the conversion of cholesterol into pregnenolone, which occurs in all steroidogenic cells. 

• P450 Side Chain Cleavage Enzyme: This reaction is mediated by the enzyme cholesterol side chain cleavage enzyme (P450scc), located on the inner mitochondrial membrane. 

  • P450scc removes the carbon side chain from C22 to C27 of cholesterol, producing pregnenolone, which belongs to the progestogen group. 

• The presence of P450scc and the use of cholesterol as a precursor are therefore defining features of all steroidogenic cells.

Sources of Cholesterol in Steroidogenic Cells: Steroidogenic cells obtain cholesterol through two main pathways:

• Uptake From the Circulation: Via low-density lipoproteins (LDLs). The cells express LDL receptors, internalise LDL particles, and release cholesterol.

• De Novo Synthesis: Cholesterol can also be synthesised from acetyl-CoA within the endoplasmic reticulum (ER).

Key Features of Steroidogenic Cells: Steroidogenic cells display several distinctive structural adaptations to support steroid biosynthesis. 

• Extensive SER: They have an extensive smooth endoplasmic reticulum, reflecting their role in lipid and steroid metabolism. 

• Abundant Mitochondria: Site of initial cholesterol conversion.

• Lipid Droplets: Since free cholesterol is toxic, it is esterified and stored in lipid droplets, which act as cholesterol reserves. 

  • Upon stimulation of steroidogenesis, cholesterol is mobilised from these lipid droplets, transported into the mitochondria, and enters the steroidogenic pathway via the action of P450scc.

Stepwise Pathway of Steroidogenesis

Carbon Classification of Steroids:

• Pregnenolone: Pregnenolone, the first product in the steroidogenic pathway, belongs to the progestogen family and contains 21 carbon atoms (C21). 

• Glucocorticoids and Mineralocorticoids: Both glucocorticoids and mineralocorticoids are also C21 steroids, formed by enzymatic modifications of progestogens. 

• Sex Hormones: Androgens are derived from progestogens and contain 19 carbons (C19), while oestrogens are derived from androgens and contain 18 carbons (C18). 

  • This carbon-based classification reflects the stepwise nature of steroid biosynthesis, which proceeds from cholesterol → progestogens (C21) → androgens (C19) → oestrogens (C18).

Role of Enzyme Profiles: The specific steroid hormones produced by a given tissue are determined by the enzyme profile expressed in its steroidogenic cells. 

• Although gonadal cells (testes and ovaries) and adrenal cortical cells share access to the same core pathway, differences in which enzymes are expressed, and the levels at which they are active, dictate the final products. 

Note: This explains why one tissue primarily produces glucocorticoids, while another produces androgens or oestrogens.

Example - Zona Reticularis vs Testis:

• Zona Reticularis (Adrenal Cortex): The zona reticularis of the adrenal cortex mainly produces the androgen DHEA (dihydroepiandrostenedione). 

  • High P4450C17: This occurs because of high expression of P450C17 (17α-hydroxylase), which converts hydroxypregnenolone into DHEA

  • Low 3β-HSD2: This also occurs due to low expression of 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2), which limits the conversion of DHEA to androstenedione. 

    • As a result, DHEA accumulates as the main product.

• Testis (Leydig Cells): The Leydig cells of the testis primarily produce testosterone. 

  • High 3β-HSD2: DHEA is first formed via P450C17, then high expression of 3β-HSD2 converts DHEA into androstenedione

  • High 17β-HSD3: High expression of 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) converts androstenedione into testosterone. 

    • Thus, the testis produces testosterone as its dominant end product.

General Principle: In all steroidogenic organs, the final steroid hormone product depends on the specific combination and relative activity of enzymes expressed in the cells.