Molecular structure of Reproductive Steroids (Sex hormones)

What are sex hormones (def, main functions, Origin, male and female hormones produced)

• Def: Steroid (Fat soluble compound) synthesised from cholesterol

• Main functions: Control sexual maturity and reproduction

• Origin: mainly by gonadal glands (males testis and female ovaries) (small amount from suprarenal gland)

• Males produce: mainly androgens (mainly testosterone)

• Females produce: estrogens and progesterones

Gonads 2 functions ( female ovaries and male testes)

1. Production of germ cells (Female ova , Male spermatozoa)

2. Production of sex hormones (Female oestrogen & progesterone, Male testosterone)

Sex hormone metabolic pathway (Which pathway and why, male vs female sex hormones, other hormones in that pathway)

Sex hormones are steroid hormones so they bind to intracellular receptors

1. They are lipophylic (derived from cholesterol)

2. Need transport proteins to reach target tissues

3. long plasma ½ life (hrs to days).

4. Action mediated by forming hormone-receptor complex.

Male sex hormones: Androgens (e.g., testosterone).

Female sex hormones: Estrogens and progestins (eg:progesterone)

Other hormones include: Glucocorticoids and Mineralocorticoids

Mechanism of action of the metabolic pathway

1. Hormones diffuse across plasma memb of its target cell

2. Binds to specific like steroid hormone receptor → forms hormone-receptor complex

3. Complex accumulates, dimerises and binds to HRE (hormone response element is a specific regulatory DNA seq)

4. Causes promoter activation/inhibition & ↑/↓ targeted gene transcription depending on hormone

Male sex hormones Synthesis of testosterone (rate limiting step and immediate precursor) and conversion to potent compound

Testosterone (Prohormone) → DHT (Dihydrotestosterone) is potent compound

Rate limiting step of testosterone synthesis: Cholesterol → pregnenolone by side chain cleavage (incl the enzyme)

Immediate precursor of testosterone: Androstenedione

Biosynthesis of sex steroid hormones simplified version

1. Cholesterol (27C cholestane) → Progestogens (21C pregnane)

2. Progestogens → Mineralcorticoids (21C pregnane) ← Corticosteroids

2. Progestogens → Glucocorticoids (21C pregnane)

2. Progestogens → Androgens (19C androstane) ← Gonadosteroids

3. Androgens (19C Andostane) — Aromatase → Estrogens (18C estrane) [is aromatic]

Biosynthesis of sex steroid (Estrogen , Testosterone, Progesterone)

To Pregnenolone

1. Cholesterol → Pregenolone (in Theca cells stimulated by LH)

To Androstenedione

2a. Pregnenolone → Progesterone → 17a Hydroxyprogesterone

→ Androstenedione (Synthesis in theca cells)

2b. Pregnenolone → 17aHydroxypregnenolone→ DHEA → Androstenedione

(Extra Note: 17aHydroxypregenenolone → 17aHydroxypregrosterone. → …)

To Estrogens

3a. Androstenedione → Testosterone (by 17β‑HSD, reductase activity in theca cells)

—(Aromatase)→ 17B estradiol [E2] ( by FSH stimulation in granulosa cells)

→ Estrone [E1] (by oxidation)

→ Estriol [E3] (by Reduction /16a hydroxylation)

3b.Androstenedione → E1 (by adipose)

(Extra Note: Estrone [E1] → 17b Estradiol E2 by reduction)

Transport of testosterone (bound form vs free form)

• Testosterone bing to specific plasma protein called Sex binding globulin (SHBG) & albumin (small amount) produced in liver

• 97-99% bound form circulating testosterone

• Only small fraction of hormone circulating is free (bio active) form

Testosterone metabolism (Active metabolites vs excretory metabolites)

Active metabolites: DHT & Estradiol

Excretory metabolites: 17-ketosteroids. (primarily excreted in urine >90%)

6-8% testosterone converted to DHT by 5a reductase in androgen target tissue like testis skin and prostate

Testosterone & androstenedione converted to oestrogen by aromatase primarily in adipose tissue (Male&Female) cuz of high conc of aromatase in this tissue.

Plasma testosterone level and conversions to Estradiol, DHT,17ketosteroid,Polar metabolites and conjugates

Plasma testosterone (5mg/day)

• Plasma testosterone —[Aromatase 0.3%]—> Estradiol

• Plasma testosterone —[5a reductase 6-8%]—> DHT

• Plasma testosterone —[17B-OH-steroid dehydrogenase 40%]—> 17 Ketosteroids

• Plasma testosterone —[Hydrolases, conjugating enzymes 50%]—>Polar metabolites and conjugates

Female sex hormones (incl types of estrogens)

Ova produces 2 hormones

1. Estrogens: Family of hormones including

a. Estradiol E2: produced by ovary granulosa cells or peripheral aromatisation of testosterone

b. Estrone E1: aromatisation of androstenedione in post menopausal women. (from adrenal gland)

c. Estriol E3: Formed during pregnancy in placenta

2. Progesterone: Produced & secreted by corpus luteum

Simplified Testosterone and androstenedione to estrogen

1. Testosterone — [Aromatase]—> 17b Estradiol (E2)

2. Androstenedione —[Aromatase]—> Estrone (E1) —[16aHydroxylase] → Estriol (E3)

Transport and metabolism of female sex hormones

Transport

Estrogens & progesterone bind to plasma protein

a. Estrogen binds to SHBG

b. Progesterone binds to Corticosteroid binding globulin

Metabolism

• Estrogens & progestins actively metabolised by liver

• E1 & E2 → E3 that is conjugated with glucuronide or sulfate. Conjugated steroids are water soluble & excreted in bile feces & urine

Congenital adrenal hyperplasia CAH (Adrenogenital syndrome)

1. Deficient cortisol production (controls pituitary gland)

2. Leads to ACTH overproduction → Adrenal hyperplasia

3. Overproduction adrenal androgens (DHEA & androstenedione) →

4. —> ↑ testosterone in peripheral tissue → ↑ body growth (Virilization) & ambiguous genitalia (Female)

Treatment: Cortisol replacement