Steroid Hormone Synthesis and Congenital Adrenal Hyperplasia

Biochemical Synthesis of Steroid Hormones

• Steroid hormones are derived from cholesterol
• Synthesis occurs in the adrenal cortex and gonads
• Adrenal glands produce corticosteroids (mineralocorticoids and glucocorticoids) and androgens
• Ovaries secrete estrogens and progesterone
• Testes produce androgens
• Biochemical pathways are similar in all tissues
• Steroid hormones are lipid soluble and not stored
• Steroid hormones are derived from cholesterol
• Cholesterol is converted to pregnenolone

Learning Objectives

• Describe the biochemical pathways for glucocorticoid and mineralocorticoid steroid hormone synthesis from the common precursor cholesterol
• Differentiate between the key enzymes involved in each pathway
• Describe the cellular mode of action of these steroid hormones
• Describe the effects of deficiencies in these steroid hormones
• Explain how hormone deficiencies lead to congenital adrenal hyperplasia (CAH)

Congenital Adrenal Hyperplasia (CAH)

• Inherited autosomal recessive disorders
• Mutations cause enzyme deficiencies in mineralocorticoids, glucocorticoids, or sex steroids synthesis
• Enlarged adrenal glands (hyperplastic adrenomegaly)
• Characterized by reduced cortisol or aldosterone levels with increased androgen production

Clinical Presentation of Classic CAH

• Infants: ambiguous genitalia in females, enlarged genitalia in males, poor weight gain, adrenal crisis (dehydration, vomiting, hypoglycemia, circulatory collapse)
• Children and adults: early onset of puberty, rapid growth during childhood, premature completion of growth (short stature), irregular menstrual cycles, infertility in both sexes

Classification of Steroid Hormones

• Steroids: adrenal corticosteroids (glucocorticoids, mineralocorticoids), sex hormones (male sex hormones, female sex hormones)
• Peptide hormones: insulin, glucagon
• Amino acid derivatives: thyroid hormones

Classification of Steroid Hormones - Functions

• Glucocorticoids (cortisol): regulate metabolism, mood, blood pressure, immunity, pain sensation
• Mineralocorticoids (aldosterone): electrolyte and fluid balance, blood volume
• Androgens (testosterone): male reproductive development
• Estrogens: female secondary sexual characteristics, regulation of the menstrual cycle
• Progestogens: regulation of ovulation, maintains pregnancy

Steroid hormone synthesis summary

• Shortening of the hydrocarbon tail of cholesterol
• Hydroxylation of steroid nucleus
• Enzymes: Cytochrome P450 (CYP) mixed function oxidases
• Requires NADPH and oxygen
• Modification occurs in endoplasmic reticulum (ER) and mitochondria of adrenal gland, ovary and testes

First step in steroid synthesis

• StAR: steroidogenic acute regulatory protein controls the uptake of cholesterol into the mitochondria
• Cholesterol is converted to pregnenolone
• Catalyzed by the enzyme, cytochrome P450 side-chain cleavage (desmolase, CYP11A1)
• NADPH and oxygen are required, occurs in adrenal, ovary and testis

Progesterone synthesis

• Progesterone is synthesized from pregnenolone
• 3-hydroxyl group (OH) is oxidized to 3-keto group
• ▲5 double bond is isomerized to a A4 double bond

Aldosterone synthesis

• Aldosterone is synthesized from progesterone
• 21-hydroxylase, 11-hydroxylase, aldosterone synthase act in sequence causing progressive changes to steroid leading to aldosterone
• Hydroxylation at C-21 and C-11
• Oxidation of C-18

Cortisol synthesis

• Cortisol is synthesized from progesterone
• 17-a-hydroxylase, 21-a-hydroxylase, 11-ẞ-hydroxylase act sequentially affecting steroid structure, leading to cortisol

CAH: Deficiency in 3β-OH dehydrogenase

• Virtually no glucocorticoids, mineralocorticoids, active androgens or estrogens
• Salt excretion in urine
• Affected genetic males (46, XY) have ambiguous genitalia
• Autosomal recessive with incidence 1:10,000

CAH: Deficiency in 17α-hydroxylase (CYP17)

• Virtually no sex hormones or cortisol are produced
• Increased production of mineralocorticoids causes sodium and fluid retention, therefore hypertension
• Genetic males (46, XY) have female-like genitalia

CAH: Deficiency in 21-hydroxylase

• Partial and virtually complete deficiencies are known
• Classic Form: Deficiency in production of mineralocorticoids and glucocorticoids, salt-wasting form is most severe; virtually absent mineralocorticoids and glucocorticoids
• Non-Classic Form: Mineralocorticoids may be normal or only slightly reduced, while glucocorticoids may be deficient to varying degrees
• Overproduction of androgens leads to masculinization of external genitalia in females and early virilization in males

CAH: Deficiency in 11-β-hydroxylase (CYP11B1)

• Decrease in serum cortisol, aldosterone, and corticosterone
• Increased production of deoxycorticosterone causes fluid retention due to sodium retention; hypertension and hypokalemia
• Overproduction of androgens leads to masculinization of external genitalia in females and early virilization in males (early pubic hair development)

Clinical Effects of CAH

• Cortisol deficiency leads to poor response to stress, hypoglycemia, hyperpigmentation
• Aldosterone deficiency leads to hyperkalemia, hyponatremia, disturbed cardiac rhythm, and hypotension
• Combined deficiency can lead to vascular collapse, shock, and death
• No negative feedback to hypothalamus, overproduction of ACTH, adrenal hyperplasia
• Excess androgen production: masculinization of external genitalia in females; no active androgens, female-like genitalia

Treatment for CAH

• Daily glucocorticoid and mineralocorticoid replacement
• Restore volume, electrolyte, and glucose imbalances

Hormone Response Elements

• Regions of DNA containing a consensus sequence
• Typically close (upstream/5') to transcription initiation site
• Associate with activated receptors and nuclear receptor proteins

Cellular Mode of Steroid Hormone Action

• Diffuse across the cell membrane
• Bind intracellular receptor within the cytosol or nucleus
• Bind to segment of DNA, triggering transcription of a target gene to mRNA

Steroid Hormone Functions

• Carbohydrate regulation (glucocorticoids)
• Mineral and fluid balance (mineralocorticoids)
• Reproductive functions (gonadal steroids)
• Role in inflammation, stress responses, bone metabolism, cardiovascular function, behavior, and mood

Metabolic Functions of Glucocorticoids

• Stimulates hepatic gluconeogenesis
• Increases deposition of glycogen in the liver
• Antagonizes the peripheral action of insulin on glucose uptake
• Inhibits amino acid uptake and protein synthesis in extrahepatic tissues
• Increases mobilization of fatty acids
• Stimulates lipolysis in adipose tissue
• Increases deposition of fat in facial and truncal areas

Functions of Cortisol

• Many functions in the human body, such as mediating the stress response, regulating metabolism, the inflammatory response, and immune function

Actions of Mineralocorticoids

• Secreted in response to increased ECF and high K+ concentration
• Stimulates transcription of sodium-potassium ATPase
• Increased numbers of sodium pumps in basolateral membranes of tubular epithelial cells
• Facilitates sodium uptake (with water) from the tubular lumen
• Reabsorbs sodium in the kidney at the expense of potassium and H+

Explore the biochemical pathways of steroid hormone synthesis from cholesterol in the adrenal cortex and gonads. Learn about the key enzymes, hormone deficiencies, and the causes of congenital adrenal hyperplasia (CAH). Understand the production of corticosteroids, androgens, estrogens, and progesterone.