Sex Hormones

Dr. Lotfi S. Bin Dahman MD, PhD

Clinical Biochemistry
HUCOM
 Sex Hormones
• The function of the gonads are controlled by the
peptide hormones, follicle stimulating hormone (FSH)
and luteinizing hormone (LH), which are secreted by
cells in the pituitary gland called gonadotrophs.
• In both males and females, LH and FSH secretion are
controlled by secretion of the hormone gonadotrophin
releasing hormone (GnRH), secreted by the
hypothalamus.
• In women they are the steroid hormones, estradiol and
progesterone, and in men the steroid hormone,
testosterone
 Gonadotrophin Releasing Hormone
• GnRH is a peptide of ten amino acid residues.
It is secreted by neurons in the hypothalamus
into the pituitary portal circulation and acts on
the gonadotrophin secreting cells of the
pituitary to promote LH and FSH release.
• It acts on cell surface receptors and rapidly
degraded by circulating peptidases
 LH and FSH
• They are glycoprotein hormones with MW of 30,000 Da.
• They act on specific cells within the ovary via G-protein
coupled cell surface receptors.
• Both LH and FSH consist of two polypeptide chains (α and β)
held together by non-covalent linkage.
• In addition, the molecules are stabilized by intra-chain
disulphide bonds within the β chain, providing the molecule
with three-dimensional stability.
• Both LH and FSH have high homology with thyroid
stimulating hormone (TSH) and human chorionic
gonadotrophin (hCG), with whom they share the common α
subunit.
 Glycosylation of LH and FSH
• All the pituitary glycoprotein hormones are
glycosylated (a single glycosylation site on the beta-
chain and two glycosylation sites on the alpha-chain).
• One function of glycosylation is to inhibit
degradation of the hormone and to increase its
circulating half-life. Most importantly, glycosylation is
required for biological activity.
• hCG (8–12 h), LH (20–30 minutes), and FSH
(approximately 8 hours).
LH and FSH
 Protein Hormones
(cAMP second messenger)
LH

Receptor G Plasma Membrane

Adenylate Cyclase
cAMP
Testosterone
ATP
R cAMP
cAMP
R Protein Kinase A
S-ER C (PKA)
Steroid Synthesis
C
(+ PO4)
Mitochondria
Pregnenolone Cholesterol

Histones
Cholesterol
Nucleus
DNA
Protein
R-ER
Synthesis
mRNA
Protein Synthesis
(Enzymes) 7
 Biosynthesis
• Sex hormones are produced in
adrenal cortex, testes and ovaries
• All sex hormones are derived from
cholesterol and differ only in the
ring structure and side chains
attached to it
• Enzymes which produce sex
hormones are located in the
mitochondria and smooth ER of
the cell
 Biosynthesis
• Common metabolic pathway for biosynthesis of all
sex hormones
• The first step is the conversion of cholesterol into
pregnenolenone
• This reaction is the rate limiting step in
steroidogenesis and occur in the mitochondria
• This reaction is activated by ACTH (adrenal cortex)
• Needs enzyme called cytochrome P-450 side chain
cleavage enzyme
• Requires NADPH and oxygen
Synthesis of Ovarian Sex Hormones
• Most circulating oestradiol is produced by the granulosa cells of the
developing dominant follicle in the early part of the menstrual cycle
and from luteinized granulosa cells in corpus luteum after ovulation.
• Within ovary, FSH acts on the granulosa cells to induce aromatase,
converts locally testosterone to estradiol.
• Testosterone and its immediate precursor androstenedione are
produced in the ovary principally by the theca cells (stimulated by LH).
• Both progesterone and estradiol are produced by the corpus luteum
under the influence of LH.
• In normal women, both testosterone and androstenedione are
produced in, and secreted in measurable quantities by the ovary and
the adrenals.
 Synthesis of Estrogens

C18

• Estrogens are formed by aromatization of androgens

• Aromatase is a complex endoplasmic reticulum enzyme found in the
ovary and in numerous other tissues in both males and females
• Its action involves hydroxylations and dehydrations that culminate in
aromatization of the A ring of the androgens
Synthesis of Progesterone
Progesterone (C21) produced
directly from pregnenolone

•It is similar to those of male hormones

•Estrogens are formed by the aromatization of
androgens in a complex process that involves 3
hydroxylation steps by theca and granulosa cells of
the ovaries

•LH acts on the theca cells of the ovary to produce

androgens

•Androgens are transferred from the theca cells

into granulosa cells where converted into estrogens
by the enzyme aromatase under the effect of FSH

•After ovulation, granulosa cells secrete estrogens

and progesterone directly into the blood stream
under influence of FSH
Male Sex Hormones Synthesis
Testosterone (C18)

Produced from progesterone

• The Critical step is the cell activity in
mobilizing cholesterol stored in a droplets,
transport of cholesterol to mitochondrion

• The first enzymatic step is the conversion of

cholesterol to pregnenolone by CYP450, which
occurs in the mitochondria

• This step occurs in adrenal, ovary and testes

• But in ovary and testes, the reaction is
promoted by LH rather than ACTH

• Testosterone can be converted to

dihydrotestosterone (DHT)

• DHT is the most potent of the male steroid

hormones, with activity that is 10 times that of
testosterone
 Male Sex Hormones
• Testicular androgens are synthesized in the
interstitial by Leydig cells and the Sertoli cells (FSH
dependent) of the testes
• Ovaries produce also androgens in small amounts
and the remainder from the adrenal cortex
• Sertoli cells also produce androgen binding protein
(ABP) which binds testosterone and DHT
• ABP is secreted into lumen of seminiferous tubules
which binds testosterone and transports it in very
high concentration to the site of spermatogenesis
 Male Sex Hormones (Androgens)
Testosterone Structure:
• Ketone group at C₃
• Double bond between C₄ & C₅
• 2 methyl group at C₁ₒ & C₁₃
Testosterone (C18)
• OH at C₁₇

Dihydrotestosterone (DHT) Structure:

• Has the same structure without double bond between C₄ & C₅
• It is the active form of testosterone
 Female Sex Hormones
Types: estrone (E1), estradiol (E2) and estriol (E3)
Structure:
• Hydroxyl group at C₃
• Methyl group at C₁₃
• Ketone group at C₁₇ (E1), hydroxyl group at C₁₇ (E2) &
2 hydroxyl groups at C₁₆ & C₁₇
 Progesterone
Structure:
• Ketone group at C₃
• Double bond between C₄ & C₅
• Methyl group at C₁ₒ & C₁₃
• Methyl ketone at C₁₇
Site of Production:
C21
• Ovary and placenta in female
• Adrenal cortex in both male and female
Plasma Transport of Testosterone
• In the circulation, 97% of testosterone is protein bound
1. Principally to sex hormone-binding globulin (SHBG)
2. Lesser to albumin
• Testosterone concentrations in the plasma are very low
before puberty (reach to normal adult values rapidly)
• A slight decline in concentration may be seen in the elderly
 Plasma Transport of Estrogen and
Progesterone and Metabolism
• Estrogens are bound to testosterone-estrogen binding
globulin (TEBG)
• Progesterone is bound to corticosteroid binding
globulin (CBG)
• Liver converts estradiol and estrone to estriol which
conjugates with sulfate or glucuronic acid before
excreted in urine or bile
• Liver converts progesterone into a compound called
pregnandiol