Gonadal hormones such as testosterone, estradiol, and progesterone are produced by the testes, ovaries, and adrenal cortex. They are derived from cholesterol and produced through various enzymatic pathways involving the mitochondria and endoplasmic reticulum. Testosterone production involves either the Δ4 or Δ5 pathway. Estradiol is produced from testosterone and androstenedione through aromatization. These hormones act through intracellular receptors to regulate sexual differentiation, reproduction and other biological processes. Their levels are controlled by the hypothalamic-pituitary-gonadal axis.

1. Gonadal hormones
Binaya Tamang
UCMS-TH

2. Introduction
• Cholesterol: produces or precursor of all classes of steroid hormones.
o Glucocorticoids ( e.g. cortisol)
o Mineralocorticoids( e.g. aldosterone)
o Sex hormones
• Androgens
• Estrogens
• Progestins
• Produced by
• small quantities by adrenal cortex ( zona reticularis).
• Testes, ovary and corpus luteum

3. Relation betn adrenal androgen and gonads
• Adrenal androgens are weak.
• Are carried by binding proteins to peripheral tissue.
• sex hormone binding protein
• albumin.
• Converted into a stronger androgens testosterone estrogen
• Estrogen from androstenedione and testosterone by aromatization. Rxn
by aromatase ( CYP 19).
• testes,
• ovaries,
• placenta,
• adrenal cortex

4. Secretion of steroid hormone from gonads
• From: testes & ovaries
• Aim: sexual differentiation & reproduction.
• ↑↑ GnRH: hypothalamus
• ↑↑ LH & FSH: anterior pituitary gland
• Binds to receptor ↑ cAMP
LH: A) Testes ↑ Testosterone
• B) Ovaries ↑ estrogen & progesterone ( corpus luteum)
• FSH: growth of ovarian follicles & stimulates testicular spermatogenesis

5. Testes, male
Ovaries, female

6. Isolated
estrogen (1929).
Progesterone ( 1934)
testosterone ( 1935).

7. ANDROGENS
Androgens are C19 steroids capable of producing certain masculinizing
effects
o maintain the normal structure and function of genital tract
o secondary male sex characteristics,
Natural androgens
 Testosterone ( its active form is dihydrotestosterone-DHT)
 Androstenedione
 Dehydroepiandrosterone (DHEA) and its sulfate ( DHEA-S)
Testosterone is the main androgen secreted by Leydig cell increases
during puberty
Women produce about 5-10% as much as man do.

8. FUNCTIONS OF TESTOTERONE
• Growth of genitals
• Growth of beard, body hair
• Skin thickening Acne problems
• Increased muscle strength and mass
• Deepening of voice
• Growth of spermatogenic tissue in testicles, male fertility
• Increased libido
• Growth of jaw, brow, chin, nose, and remodeling of facial bone contours,
in conjunction with human growth hormone
• Completion of bone maturation and termination of growth.
• Protein synthesis anabolic ( use by gymer too)
• Positive N2 balance
• Increase erythropoietin
• Mental: More aggressive, active attitude.

9. ESTROGENS
• The naturally occurring estrogens in humans are
a) β-Estradiol
b) Estrone
c) Estriol
• β-estradiol: The principal circulation and most active
• Estriol: late stage of pregnancy
• Estrone : urine of pregnant woman & placenta.
• Essential Features:
• Aromatic character of ring A (three double bonds)
• Absence of –CH3 group at C10
• All are C18

10. ESTROGENS-function
• for the development and maintenance
• female sex organs and female secondary sex characteristics.
• In conjunction with progesterone (C21, corpus luteum, placenta &
adrenal gland)
• the regulation of menstrual cycle
• breast and uterine growth
• maintenance of pregnancy
• Also effect calcium homeostasis and have beneficial role in bone mass.
• decrease bone resorption
• Post menopausal osteoporosis.

11. Other Actions of Estrogens and Progestins
High circulating levels of estrogen can cause mild glucose intolerance.
Estrogens increase the synthesis of many liver proteins, including:
• transferrin, Sex Hormone Binding Globulin, corticosteroid-binding
globulin, and proteins involved in blood clotting (Increases blood
coagulability).
Estrogens lower serum cholesterol levels by stimulating the formation of
HDL and reducing LDL.

12. PROGESTERONE (C21)
• Progesterone is the hormone of the corpus luteum, the structure which
develops in the ovary from the ruptured graafian follicle.
• It is also formed by the placenta, which secretes progesterone, during the
later part of pregnancy.
• Progesterone is also formed in the adrenal cortex
• an intermediate in the biogenesis of adrenocortical hormones and of
androgens
• MOA : It is similar to estrogen

14. Biosynthesis
• All steroid hormones are formed from cholesterol via pregnenolone
• mitochondria
• Smooth endoplasmic reticulum.
FIRST,
• cholesterol into mitochondria  by stAR transport protein
• Inner mitochondria: cytochrome P450 side chain cleavage enzyme
(P450scc) or desmolase  cholesterol to pregnenolone.
• removal of the side chain give 21-carbon steroid

15. 1st : ANDROGEN SYNTHESIS
• produced in
• testes (Leydig cells),
• adrenal cortex,
• ovary and placenta.
• precursor:
• acetate
• Cholesterol
• General step
• Cholesterol pregnenolone ( inner mitochondria, rate limiting
step) carried to smooth ER  testerone.

16. Two pathways
five enzyme activities in 3 proteins
• 3β-hydroxysteroid dehydrogenase (3β- OHSD) and ∆5,4-isomerase:
single protein
• 17α-hydroxylase and 17,20-lyase: single protein
• 17β-hydroxysteroid dehydrogenase (17β-OHSD)
Two pathways
• progesterone (or ∆ 4) pathway
• dehydroepiandrosterone (or ∆ 5) pathway
Lets explain the process after pregnenolone is formed.

17. ∆ 4 pathway∆ 5 pathway
Single proteinsingle protein
side chain
is lost
Reduced at
C17
hydroxylation
C17

18. Androstenedione: immediate precursor
•Active form: testosterone is converted
•To Dihydrotestosterone( DHT) in
In simple

19. Androgen transport & metabolism
Transport
Testosterone + DHT:
• 2-3% free
• bound with plasma protein
Protein:
• sex hormone binding protein (SHBG)
• Non specific albumin.
• For biological activity: Both free + disassociated from protein
Metabolism
• Testosterone converts into
• Active metabolites:
• Estradiol ( aromatase)
• DHT ( 5 ⍺ reductase)
• Excretory metabolites ( > 90% in urine)
• 17 keto steroids: Androsterone+ etiocholanolone( 17β0H-SD)
• Polar metabolites: diols , triols and conjugates ( hydroxylases, conjugating
enzymes)

20. Dihydrotestosterone (DHT)
• Is Formed From Testosterone in Peripheral Tissues.
• The most significant/potent form: Active form
• 400 μg of DHT / daily vs about 5 mg of testosterone
• About 50–100 μg of DHT : testes
• Remaining by peripheral conversion.

21. Some knowledge of adrenal androgens
• The major androgen or androgen precursor produced by the adrenal
cortex is dehydroepiandrosterone (DHEA).
• DHEA is really a prohormone,  convert the weak DHEA into the
more potent androstenedione.
• Androstenedione reduces testosterone
• Small amounts of testosterone are produced in the adrenal by this
mechanism, but most of this conversion occurs in the testes.

22. 2nd Estrogen: Biosynthesis
• primary estrogen of ovary: β-Estradiol
• In pregnancy(from the placenta): estriol
Site:
• In ovary by maturing graffian follicles ( major)
• Also adrenal cortex testes in small amount
• Late pregnancy: estriol is predominant
• Transport in plasma : SHBG and Albumin.
Steps:
• The general pathway in the early steps are the same as in androgen
biosynthesis
• Precursor: testosterone and androstenedione.
• C19C18 ( by removal of CH3 at C10 and aromatization)

24. Metabolites of estrogen
• Estradiol and estrone are reversible.
• Estradiol
• Estrone
(2-hydroxylation )
Methoxy derivatives
(16⍺ hydroxylation)
estriol
In liver
conjugation with glucuronic acid
urine

25. Mechanism of action
Free testosterone enters the target cells
In the cytoplasm converted to ‘active’ DHT
hormone-receptor complex
binds to the ‘hormone-responsive element’ (HRE) on gene
induces the transcription
↑↑ respective proteins
• Similar for estrogen too: ER-⍺ and ER-β are its receptor

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