Anna Belen Ignacio-Alensuela, MD
FPOGS, FPSREI
Assistant Professor, Junior Consultant
Department of Biochemistry & Nutrition
Assistant Section Chief, Section on Repro Endo & Infertility
Department of Obstetrics & Gynecology
FEU-NRMF Medical Center
Section Chief, Section on Repro Endo & Infertility
JRRMMMC
HORMONES: Classification
Group I Group II
Type Steroid, Polypeptides, proteins,
iodothyronines glycoproteins
calcitriol, retinoids catecholamines
Solubility lipophilic Hydrophilic
Transport CHON yes No (Except IGF-I)
Plasma half life Long (hours to days) Short (minutes)
Receptor Intracellular plasma membrane
Mediator R-H complex cAMP, cGMP, Ca,
Metabolites of complex
phosphoinositols, Kinase
cascade
The Biochemistry of Hormones, AIA, SY 2007-2008
HORMONES: Group I
Overview Fat soluble / Steroid Hormones
Part 2: Biosynthesis and modification
Hormones
Storage & secretion
that bind to
intracellular Metabolism
receptors
(Fat soluble,
Transport Proteins
steroid Receptors
hormones)
Hormone-Receptor interaction
Hormone Action / Target tissue
response
The Biochemistry of Hormones, AIA, SY 2007-2008
Group I Hormones
1 Cholesterol Estrogens Glucocorticoids
Progestins Mineralocorticoids
Androgens
2 Cholesterol Calcitriol
derivatives
3 Tyrosine T3, T4 Cathecholamines
Retinoic
acid
The Biochemistry of Hormones, AIA, SY 2007-2008
STEROID HORMONES
Structure and Basic structure:
classification Cyclopentanoperhydrophenanthrene
Classification
A B Origin (natural vs synthetic)
C D Metabolic stage (agents vs
metabolites)
Endocrine effect (sex hormones vs
corticosteroids)
Speroff L, et al. Clinical Gynecologic Endocrinology and Infertility, ed 6,
Lippincott Williams & Wilkins, Baltimore, 1999
The Biochemistry of Hormones, AIA, SY 2007-2008
STEROID HORMONES
CHOLESTEROL Basic building block in
steroidogenesis
Major source from
blood/plasma Acetyl
CoA
Small portion
synthesized from
acetate by all steroid-
producing organs
except placenta
Speroff L, et al. Clinical Gynecologic Endocrinolgy and Infertility, ed 6,
Lippincott, 1999
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Steroid
Hormones
from
Cholesterol
The Biochemistry of Hormones, AIA, SY 2007-2008
STEROIDOGENESIS
Pathway common for all
steroid-producing endocrine
organs
Number of carbon atoms in
steroid molecule can be
reduced but never increased
Mediated by members of
cytochrome P450 group of
oxidases
Speroff L, et al. Clinical Gynecologic Endocrinolgy and Infertility, ed 6,
Lippincott, 1999
The Biochemistry of Hormones, AIA, SY 2007-2008
Steroid Hormone Producing Glands
ORGAN MAIN HORMONES OTHER HORMONES
Ovaries Estradiol (follicle), Pregnenolone,
progesterone (corpus 17-hydroxyprogesterone,
luteum), testosterone, DHEA,
androstenedione (stroma) estrone
Testis Testosterone (Leydig DHEA-S, DHEA,
cells) androstenedione, estrone,
estradiol
Adrenals Mineralocorticoids,
glucocorticoids, DHEA-S,
DHEA, androstenedione
RATE LIMITING STEP: delivery of cholesterol to the
inner membrane of the mitochondria by the transport protein
STAR (Steroidogenic Acute Regulatory protein).
The Biochemistry of Hormones, AIA, SY 2007-2008
STEROID
HORMONES
Cholesterol
3 main groups (27 carbons)
according to
number of carbon
Pregnane derivatives Progestins
atoms (21 carbons) Corticoids
pregnane (21 C)
androstane (19 C)
Androstane derivatives Androgens
(19 carbons)
estrane (18 C)
Speroff L, et al. Clinical
Gynecologic Endocrinology
and Infertility, ed 6, Lippincott
Williams & Wilkins, Baltimore, Estrane derivatives Estrogens
1999 (18 carbons)
The Biochemistry of Hormones, AIA, SY 2007-2008
STEROIDOGENIC ENZYMES
ENZYME CELLULAR REACTIONS
LOCATION
P450scc mitochondria cholesterol side chain cleavage
P450c11 mitochondria 11β
β-hydroxylase, 18-
hydroxylase, 19-methyloxidase
P450c17 endoplasmic 17-hydroxylase, 17,20-lyase
reticulum
P450c21 Endoplasmic 21-hydroxylase
reticulum
P450arom Endoplasmic aromatase
reticulum
Speroff L, et al. Clinical Gynecologic Endocrinology and Infertility, ed 6, Lippin-
Cott Williams & Wilkins, Baltimore, 1999 Gonadal Hormones
The Biochemistry of Hormones, AIA, SY 2007-2008 Adrenal Hormones
GONADAL STEROIDOGENESIS
Speroff L, et al.
Clinical Gynecologic
Endocrinolgy and
Cholesterol Acetate
Infertility, ed 6, Lip-
pincott, 1999
P450scc
∆5 pathway ∆4 pathway
Pregnenolone
DHEA Progesterone 3β
β-OHSD
P450c17 pathway pathway
17αOHlase ∆5,4 isomerase
17-Hydroxypregnenolone Progesterone
P450c17, 20 lyase P450c17
17αOHlase
Dehydroepidandrosterone 17-Hydroxyprogesterone
3β
β-OHSD P450c17
5,4
∆ isomerase 17, 20 lyase
17β
β-OHSD
Androstenedione Testosterone
P450arom P450arom
17β
βHSD
The Biochemistry of Hormones,Estrone
AIA, SY 2007-2008 Estradiol
P450 scc Side chain cleavage enzyme
LH
The Biochemistry of Hormones, AIA, SY 2007-2008
Testosterone Metabolism
1 Oxidation (17 Many tissues 17-ketosteroids
position) including the liver (estradiol,
androstenediol)
2 Reduction of Target tissues DHT
the A ring Dihydro-
double bond testosterone
& 3-ketone
5 α REDUCTASE
NADPH
Testosterone
The Biochemistry of Hormones, AIA, SY 2007-2008
DHT Dihydrotestosterone
Most significant Active form of testosterone in the skin,
metabolic prostate, external genitalia, skin
product of Plasma content: 1/10 of testosterone
testosterone
Daily production: Testes: 50-100
400 µg /day
(testosterone:
µg /day
5 mg/day) peripheral
conversion
The Biochemistry of Hormones, AIA, SY 2007-2008
Testosterone is a Pre-hormone
Testosterone is Converted to DHT
considered as a
pre-hormone Conversion occurs in the
testes
DHT is the active MORE POTENT than
form of testosterone
testosterone Androgen receptor has higher
affinity for DHT
DHT-Receptor complex has
higher affinity for Androgen
Response Element
The Biochemistry of Hormones, AIA, SY 2007-2008
DHT Dihydrotestosterone
Most significant metabolic product of
testosterone
Skin, prostate, external genitalia, Active form
skin
Plasma content: 1/10 of testosterone
Daily production: 400 µg /day (testosterone: 5
mg/day
Source: testes = 50-100 µg /day
peripheral conversion
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Subcellular Compartmentalization of Gonadal Hormone Synthesis
Acetate
Storage
Cholesterol
Vacoules
Cholesterol
Cholesteryl
Mitochondrion Esters
Cholesterol
P450scc Fatty Acids
Pregnenolone
Endoplasmic Pregnenolone
Reticulum
3β
β-HSD
estradiol
androstenedione Progesterone
17αOHlase
Testosterone 17, 20 lyase
17-OHprogesterone
The Biochemistry of Hormones, AIA, SY 2007-2008
OVARIAN STEROIDOGENESIS
Theca cell
Two-cell two- Cholesterol
gonadotropin L
H
hypothesis Andros- Testos-
tenedione terone
Compartmentalization
of steroid hormone
Granulosa
synthesis in the cell Andros- Testos-
tenedione terone
developing follicle F
Speroff L, et al. Clinical S Aromatization
Gynecologic Endocrinology H
and Infertilty, ed 6, Lippincott Estrone Estradiol
Williams & Wilkins, Baltimore,
1999
The Biochemistry of Hormones, AIA, SY 2007-2008
Graafian follicle showing arrangement of
follicle cells around the Oocyte
Hormone production in
the graafian follicle
Theca Androstenedione
cells Testosterone
Granulosa Estrone
cells
Estradiol
Corpus Progesterone
luteum
The Biochemistry of Hormones, AIA, SY 2007-2008
OVARIAN STEROIDOGENESIS
Follicular phase
THECA
Acetate GRANULOSA
Acetate ANTHRUM
Cholesterol
LH P450scc
Pregnenolone
17-OH pregnenolone
X
Cholesterol
Pregnenolone
DHA Androstenedione
aromatase FSH
Androstenedione Estrone
Testosterone Estradiol
The Biochemistry of Hormones, AIA, SY 2007-2008
OVARIAN STEROIDOGENESIS Luteal phase
LH LDL
THECA
FSH GRANULOSA
Acetate Acetate LH LDL
Cholesterol
Cholesterol
Pregnenolone
Pregnenolone
17-OH pregnenolone Progesterone
Estradiol
DHA Estrone
Androstenedione
Androstenedione
Testosterone
The Biochemistry of Hormones, AIA, SY 2007-2008
Estrogen Metabolism
Estrone (E1) Estradiol (E2) Estriol (E3)
Menopause / Pregnancy
peripheral conversion
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Significant amounts of Estrogen are produced by
peripheral aromatization of androgen
In pregnant 50% of estradiol comes
women from adrenal androgens
In post Almost ALL of estrone
menopausal comes from
women androstenedione
The Biochemistry of Hormones, AIA, SY 2007-2008
Steroid Metabolism by the feto-maternal unit
FETUS PLACENTA MOTHER
Cortisol
A
D L
Progesterone Estriol (E3) Estriol (E3)
R I
E Pregnenolone + V
N E
Glucuronide
A DHEA / DHEAS
R
Estriol (E3)
L
DHEA / DHEAS E 3 Glucuronide
16α OH DHEA K
L
DHEA I
I
E 3 Glucuronide D
V + 16α OH DHEA
N
E 16α OH lase E
R
Y
E 3 Glucuronide
The Biochemistry of Hormones, AIA, SY 2007-2008
Significant amounts of Estrogen are produced by
peripheral aromatization of androgen
In Men 80 % of estradiol comes from
peripheral aromatization of
testosterone
Aromatase: adipose Cirrhosis
tissue, liver, skin, etc
Hyperthyroidism
Aging
Obesity
The Biochemistry of Hormones, AIA, SY 2007-2008
Cholesterol ADRENAL STEROIDOGENESIS
C17,20 lyase
α OH lase
P450scc
DHEA
Pregnenolone 17-OH pregnenolone
17α
3β
β-OHSD ∆5,4 isomerase
P450c17
P450c17
Progesterone 17-OHprogesterone Androstenedione
21-OH lase 17β
β-HSD
11 deoxycortisone (DOC) 11 deoxycortisol
Testosterone
11β
β-OH lase
Corticosterone Cortisol
18-OH lase, 19-OHdehydrogenase
Aldosterone
The Biochemistry Harding
of Hormones, BW:
AIA, SY In: Endocrinology, vol 2 De groot LJ
2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Ca ACTH receptor
Adrenal steroid ACTH G protein
Adenylate cyclase Extracellular side
hormone
synthesis:
PI cycle
DAG protein Cytosolic side
kinase
Ca
Influenced by ATP
cAMP
ACTH from the IP3
Protein kinase A
Pituitary gland
Protein
Phosphorylation
+ Cholesterol esters
esterase
+
Cholesterol
STAR
Ca
+ Side chain
cleavage enzyme
Secretion from
the zona to the STEROID
∆ 5- Pregnenolone
blood stream HORMONE
Mitochondrion
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Cellular specificity of adrenal steroidogenesis
Zona Mineralocorticoids Na – K balance
glomerulosa
Zona Glucocortocoids stress adaptation
fasciculata
Zona Androgens
reticularis
The Biochemistry of Hormones, AIA, SY 2007-2008
Mineralocorticoid Synthesis
Enzymes present in the 18-OH lase
zona glomerulosa only (aka aldosterone synthase)
19-OH-dehydrogenase
Enzyme absent 17-αOHlase
11- Deoxycortisone Active, Na+ retaining
(DOC)
Cortisone (+) Glucocorticoid activity
Weak mineralocorticoid (,5%
of the potency of
aldosterone
Aldosterone Na-K balance
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
RAAS
Angiotensin I
Estrogen
+
Renin substrate
(angiotensinogen)
1 Increased plasma volume
2 Increased blood pressure in susceptibles
3 Water retention-related symptoms (edema, Angiotensin II
bloating, weight gain, breast tension)
Renin
J-G cells
Renal afferent
arteriole Na+/water retention
K+ elimination
Oelkers W. Mol Cell Endocrinol. 2004;217:255. Pitt B, et al. N Engl J Med. 1999;341:709.
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Angiotensinogen
J-G cells
Renin Renal afferent
arteriole
Angiotensin I
CONVERTING ENZYME
ANGIOTENSIN II
AMINOPEPTIDASE
Angiotensin III
ANGIOTENSINASES
Degradation
The Biochemistry product
of Hormones, AIA, SY 2007-2008
Glucocorticoid Synthesis
Enzymes present only in 17α OH lase Rapid,
the Fasciculata and the 21-OH lase smooth ER
reticularis Zones
11β-OH lase Slow,
mitochondria
Cortisol Most potent natural
glucocorticoid in humans
The Biochemistry of Hormones, AIA, SY 2007-2008
The Biochemistry of Hormones, AIA, SY 2007-2008
Subcellular Compartmentalization of Glucocorticoid Biosynthesis
Acetate
Storage
Cholesterol
Vacoules
Cholesterol
Cortisol Cholesteryl
Esters
Cortisol
Cholesterol
11βOHlase P450scc Fatty Acids
11 deoxycortisol Pregnenolone
Mitochondrion
Pregnenolone
3β
β-HSD
Endoplasmic Progesterone
11 deoxycortisol
Reticulum 17αOHlase
21 OHlase
17-OHprogesterone
The Biochemistry of Hormones, AIA, SY 2007-2008
