biochemistry of steroid hormones

classification of steroid hormones

corticosteroids (typically made in the adrenal cortex)

• glucocorticoids: cortisol - regulates metabolism, mood, blood pressure, immunity, pain sensation

• mineralocorticoids: aldosterone - electrolyte and fluid balance, blood volume

sex steroids (typically made in the gonads or placenta)

• androgens: testosterone - male reproductive development

• estrogens: female secondary sexual characteristics, regulation of the menstrual cycles

• progestogens: regulation ovulation, maintains pregnancy

steroid hormone synthesis overview

sites of synthesis

• adrenal cortex: produces corticosteroids and androgens

• ovaries: secrete estrogens and progesterone

• testes: primarily produce androgens

similar biochemical pathways are shared across adrenal cortex, ovaries and testes

tissue specific enzymes: located in mitochondria and ER

steroid hormones are lipid soluble and freely permeable to cell membranes so they are not stores within cells

regulation of adrenal gland hormones

hypothalamic hypophysiotropic hormones: CRH stimulates ACTH release from the anterior pituitary, which regulates adrenal hormone production

feedback by target gland hormones: cortisol provides negative feedback to the hypothalamus and pituitary, maintaining hormonal balance

steroid hormones are derived from cholesterol

steroid hormones: derived from cholesterol, syhtesized in the liver

structure: unique lipid structure

• four linked hydrocarbon rings

• hydrocarbon tail

• hydroxyl group

amphipathic molecule (hydrophilic and hydrophobic)

steroid hormone synthesis key steps

cholesterol modifications

• shortening the hydrocarbon tail

• hydroxylation of steroid nucleus: addition of OH group modifies the 4 ring structure to produce functional hormones

key enzymes

• cytochrome P450 oxidases: require NADPH and oxygen. located in ER and mitochondria of adrenal glands, ovaries and testes

step 1: steroid sythesis

StAR: steroidogenic acute regulatory protein controls the uptake of cholesterol into the mitochondria

cholesterol is converted to pregnenolone by the cholesterol side chain cleavage

catalyzed by the enzyme, cytochrome P450 side chain cleavage (also called desmolase or CYP11A1)

this is a rate limiting step. NADPH and oxygen are required, occurs in adrenal, ovary and testis

progesterone is synthesized from pregnenolone

converts the 3 hydroxyl group (OH) to a 3 keto group

enzymes:

• 3 beta -OH dehydrogenase

• 5,4 delta isomerase

cortisol is synthesized from progesterone

progesterone → 17-hydroxyprogesterone

• enzymes: 17 alpha hydroxylase (CYP17A1)

17 hydroxyprogesterone → 11 deoxy cortisol

• enzymes: 21 alpha hydroxylase (CYP21A2)

11 deoxy cortisol → cortisol

• enzyme: 11 beta hydroxylase (CYP11B1)

glucocorticoid synthesis (cortisol)

1. cholesterol → pregnenolone by CYP11A1 (cholesterol desmolase)

2. pregnenolone → 17 hydroxyprogesterone by CYP17A1 (17 alpha hydroxylase)

3. 17 hydroxyprogesterone → cortisol by CYP21A2 (21 alpha hydroxylase) and CYP11B1 (11 alpha hydroxylase)

functions of cortisol:

• metabolism: increases blood glucose via gluconeogenesis

• immune response: suppresses inflammation

• stress response: helps the body manage stress

aldosterone is synthesized from progesterone

progesterone → 11 deoxycorticosterone

• enzyme: 21 alpha hydroxylase

11 deoxycorticosterone → corticosterone

• enzyme: 11 beta hydroxylase

corticosterone → aldosterone

• enzymes: 18 hydroxylase, 18 hydroxy dehydrogenase (aldosterone synthase)

mineralocorticoid synthesis (aldosterone)

1. Cholesterol → Pregnenolone by CYP11A1 (Cholesterol Desmolase).

2. Pregnenolone → Progesterone by 3β-HSD (3β-Hydroxysteroid Dehydrogenase).

3. Progesterone → 11-Deoxycorticosterone by CYP21A2 (21α-Hydroxylase).

4. 11-Deoxycorticosterone → Aldosterone by CYP11B2 (Aldosterone Synthase).

functions of aldosterone

• salt and water balance: promotes sodium reabsorption in kidneys

• blood pressure regulation: increases blood volume and pressure

examples of steroids cellular response

cortisol: enhances glucogenesis, suppresses immune response

aldosterone: increases sodium reabsorption in kidneys

testosterone: promotes muscle growth and male characteristics

estradiol: regulates menstrual cycle and reproductive tissues

glucocorticoid deficiency

condition: Addison’s disease

causes: insufficient cortisol production

symptoms: fatigue, low blood pressure, weight loss, hyperpigmentation of the skin

mineralocorticoid deficiency

condition: hypoaldosteronism

causes: insufficient aldosterone production

symptoms: dehydration, low blood sodium levels (hyponatremia), high potassium levels (hyperkalemia), hypotension (low blood pressure)

disorders of adrenal gland insufficiencies

autosomal recessive disorders of cortisol biosynthesis

failure to secrete cortisol - loss of negative feedback to HPA axis

depending on the specific enzyme step involved there may be distinct symptoms and lab findings

classification:

• 3 beta dehydrogenase deficiency

• 17 alpha hydroxylase

• 21 hydroxylase deficiency

• 11 beta hydroxylase deficiency

congenital adrenal hyperplasia (CAH)

inherited autosomal recessive disorders

mutations in the genes encoding enzymes in mineralocorticoids, glucocorticoids or sex steroids synthesis

enlarged adrenal glands

results in reduced levels of cortisol or aldosterone with overproduction of androgen