FEMALE

REPRODUCTIVEs
HORMONES
BIOCHEMISTRY DEPARTMENT

Molecular medicine case studies :

Mutations of the FSH and LH receptors

(which have similar structure)
Primary ovarian failure caused by a
point mutation in the FSH receptor
gene.
Chromosome 2p C to T in nucleotide 566
of exon 7 of the FSH receptor gene.
Alanine to Valine substitution at residue
189 of the protein.

Pituitary Hormones
Posterior pituitary
Stores and releases 2 hormones that are
produced in the hypothalamus:
o Antidiuretic hormone
(ADH/vasopressin):
o Oxytocin:

Oxytocin
9 amino acid peptide, produced primarily
by paraventricular nucleus and small
amount by supraoptic nucleus
Targets: Uterus and mammary glands
Contraction of pregnant uterus
Stimulates contractions of the mammary
gland alveoli.

Milk-ejection reflex.

Pituitary Hormones
Anterior pituitary
Prolactin
Growth Hormone (GH)
Thyroid Stimulating Hormone (TSH)
Adrenocorticotropic Hormone (ACTH)
Follicle-stimulating Hormone (FSH)
Luteinizing Hormone (LH)

PROLACTIN
Protein consist of 199 amino acids.
In females: stimulates milk production in the
mammary glands.
Release: inhibited at non-pregnant women.
As estrogen and progesterone levels rise
late in pregnancy, it stimulates prolactin
release.
Hyperprolactinaemia can cause menstrual
problems in females and breast
enlargement in males.

Hypo-Pit-Gonadal Axes

HORMONAL CONTROL OVER GONADAL FUNCTION

An Overview
estrogens
GnRH

Hypothalamus
(synthesizes
Gonadotropin
releasing
hormone)

LH+FSH

androgens

Gonads Anterior pituitary

synthesize
(synthesizes
gonadal hormones
Gonadotropins:
luteinizing hormone
follicle stimulating hormone)

RESEPTOR
Reseptor Hormon umumnya di membran
plasma atau didalam sitoplasma.
Interaksi H-R
signal
transduction kedalam sel.
Reseptor mengalami up and down
Regulation
Reseptor Angiotensin II terlihat akan
meningkat atau menurun bergantung pada
tipe sel yang dipengaruhinya.
TRH,TSH dan T3-T4 : regulasi melalui
reseptor masing-masing dalam mekanisme
negative feedback.

RESEPTOR
Hal ini dipengaruhi oleh a.l.
1. jumlah hormon tsb yang
disekresikan, misalnya reseptor
Insulin akan up regulate bila
Insulin sedikit
2. pengaruh dari hormon lain,misalnya
reseptor LH akan meningkat oleh
sekresi FSH
Struktur reseptor LH mirip dengan
reseptor FSH, hCG sel luteal dan TSH
Reseptor-reseptor tersebut dapat
bermutasi
timbul kelainan.

RESEPTOR
Beberapa obat dapat berinteraksi dengan
reseptor tersebut
Efek yang timbul : agonist (menyerupai
efek ligand yang sebenarnya) atau
antagonist (berlawanan dengan efek
ligand nya, misalnya menghambat
transduksi signal)
Reseptor juga dipunyai oleh banyak
molekul lain, seperti Interleukin,
Interferon, Antigen, Neurotransmiter,
LDL dll.

Action of GnRH
GnRH action A system stimulation of
phosphatidylinositol
GnRH binds to receptors at the cell membrane of the
gonadotrope
Phospholipase C is activated, catalyzes the hidrolysis of
PIP2 to DAG and IP3
DAG activates protein kinase C (PKC), which
phosphorylates specific protein
It participate in the resulting secretory process to
transport LH and FSH to cell exterior
IP3 stimulates Ca2+ from calcium stroge particle and
cause increased stimulation of PKC
participates in exocytosis of LH and FSH from the cell

Action of GnRH

GONADOTROPINS
Follicle-stimulating hormone (FSH)
Target: Ovaries and Testis
Stimulates the maturation of sperm and
egg.
In the females causes the release of
estrogen

GONADOTROPINS
Luteinizing Hormone (LH)
Target: Ovaries and Testis
Male: Production of testosterone

In the females: LH and FSH caused

follicle development and then LH
independently is responsible for
ovulation.

Sex Hormones
Gonad and Adrenal
Estrogen
Progesterone
Dihydrotestosterone
Testosterone

Ovarian hormones
Steroids
o Estrogens
o Androgens
o Progesterone
Peptides

OVARIAN STEROID HORMONES

Produced in both interstitial and
follicular cells
Derivatives of cholesterol (LDLlipoproteins and de novo synthesis)

SYNTHESIS

ESTROGEN
Chemical structure: C18
Source:
o follicular cells
o corpus luteum
o placenta
o adrenal cortex
o adipose tissue (DHEA androstenedione
E1)

SYNTHESIS
First step: in mitochondria
The rest: in smooth ER
Reduction in number of carbon atoms
Estrogens are primarily synthesized in
granulosa cells
Androgens are primarily synthesized in
thecal cells

Ovarian Steroid Hormones

Three types of steroid hormones :
Progestogens, Androgens and Estrogens
Estrogen biosynthesis :
1. C19 Androgens (thecal cells) will be
aromatized (granulosa cells) to obtain
Estrogens
2. LH stimulates Androgen production
and aromatized within the thecal cells.
Also are available for aromatization in
the granulosa cells

Ovarian Steroid Hormones

Estrogen produced by thecal cells : the
major steroid in the circulation
Estrogen synthesized by granulosa cells :
a local role, possibly related to ovum
maturation
FSH regulate production and subsequent
induction and activation of Aromatase in
the granulosa cells
Estradiol (E2) is oxidized to Estrone
within the liver and Estrone hydrated to
Estriol (E3).

Ovarian Steroid Hormones

These three estrogens are excreted in
the urine as glucuronides and sulfates
Placenta, Adrenals, Adipose tissue can
produce significant quantities of
Estrogens from steroid precursors
Aromatization of Androstenedione and
Testosterone within tissue is a major
source of Estrogens in the male and post
menopausal female.

Estrogens in circulation
Estradiol (E2)
Secreted by the ovary
Estrone (E1)
Derived from peripheral conversion of
estradiol and androstenedione
Estriol (E3)
Liver metabolite of estrone

ESTROGENS
Transport in blood
Mostly carrier-bound (albumin, sex
hormone-binding globulin)
Two peaks
o Before ovulation
o Mid-luteal peak

Levels : much higher in the follicular

fluid than in the plasma!

Mechanisms of Action
Cytoplasmic receptor binds to steroid
hormone.
Translocates to nucleus.
DNA-binding domain binds to specific HRE
of the DNA.
Dimerization occurs.

Process of 2 receptor units coming

together at the 2 half-sites.
Stimulates transcription of particular genes.

Mechanisms of Action

Mechanism of action of Ovarian

Steroid Hormones
E2 and Progesterone interact with
cytoplasmic and/or nuclear protein
receptors.
Release of the two receptors subunits
with attached steroid hormones from
association with a heat-shock protein.
Either identical subunits singly or
possibly together interact directly with
the DNA hormone responsive element to
activate transcriptional events leading to
translation of a cell-specific protein.

Steroid/thyroid
hormone
retinoic acid

Peptide or
peptidergic

second-messenger
regulated kinase or
receptor kinase

Transcription
factor(TF)

steroid/thyroid hormone/retinoic
acid receptor

PO4-TF
nucleus

Gene A
HREs

mRNA A

mRNA A

cytoplasm
Protein A

Metabolism
Metabolized to glucuronides and
sulfates
Recycled in enterohepatic circulation
Excreted in the urine

Physiological
Reproductive system
o Development and maintenance of uterus,
uterine tubes,vagina, external genitalia
and breasts
o Cyclic changes in the endometrium,
cervix, vagina
o Growth of the ovarian follicles
o Motility of the uterine tubes

Physiological
Reproductive system
o Pregnancy: uterine muscle mass ,
excitability , breasts
o Female secondary sex characteristics
(fat deposits, etc)
o Estrous behavior in animals, increased
libido in humans

Progesteron
The most distinctive hormone between
males and females
Chemical structure: C21
Source:
c. luteum
placenta
follicles (small amount)
adrenal cortex

Progesteron
Progesterone biosynthesis :
FSH promotes the growth of the follicle
by acting through receptors on the
granulosa cells and inducing the
Aromatase enzyme to convert Androgens
to Estrogens.
The Androgens originate from the theca
which is stimulated by LH through its
receptors initially on theca cells and
appear in the granulosa cells and are
probably coupled to the same second
messenger (cAMP) as FSH receptors

Progesteron
Progesterone biosynthesis :
Progesterone synthesis is an early step in
the biosynthesis of androgen and
estrogen within the thecal cell.
But circulating progesterone is produced
by corpus luteum
Androgens :
Androstenedione and Testosterone as a
precursors of estrogens are secreted by
ovaries in the beginning of Puberty.
Development of secondary sexual
characters almost totally by the actions
of estrogens.

Ovarian Steroid Hormones

Androgens :
Androgens of ovarian origin may be
influenced at a puberty.
Acne, results from sebaceous gland
activation by ovarian androgens.
Pubic and axillary hair growth are also
attributed to androgens of ovarian
and/or adrenal origin.
Changes in enzymic (3-hydroxysteroid
dehydrogenase, 1-hydroxylase and
17,20-desmolase) activity, increased
production of adrenal androgens

Transport
2% free
80% albumin-bound
18% corticosteroid-binding protein
(transcortin) -bound

Physiological
Cyclic changes in the endometrium,
cervix, and vagina
Breasts: supports the secretory function
during lactation
Inhibits LH secretion
Responsible for preparing the reproductive
tract for implantation and the maintenance
of pregnancy

Physiological

OVARIAN PEPTIDE HORMONES

Relaxin
Relaxes pelvic joints
Softens and dilates cervix
Sperm mobility - in males
Inhibin
Selective inhibitory control of FSH
Activin
Selective stimulaton of FSH
Cell differentiation

OVARIAN PEPTIDE HORMONES

Follistatins
Inhibit FSH secretion
Gonadotropin surge attenuating factor
Prevents premature LH surge
POMC hormones
Vasopressin and oxytocin (in
luteal cells)

Intrafollicular Polypeptide
Regulatory Factors
Several peptides have been isolated
from ovarian follicles and regulate
oocyte maturation :
1.
2.
3.
4.

Oocyte Maturation Factor

Ovarian Growth Factors
Inhibins
Activins

Intrafollicular Polypeptide
Regulatory Factors
1. Oocyte Maturation Inhibitor :
Low molecular weight-peptide
Its concentration in antral fluid decreases as the
follicle maturates
Gap junctions, present between cells of the
corona radiata and the oocyte
structural
pathway for cell-to-cell communication.
Cumulus cell extensions project through the zona
pellucida to the oocyte
OMI may exert its action indirectly through an
action on cumulus cells
LH induced oocyte maturation may result from an
uncoupling between the cumulus cells and the
oocyte

Intrafollicular Polypeptide
Regulatory Factors
2. Ovarian Growth Factors :
Induction of LH receptors is a critical
aspect of granulosa cell differentiation
and ovarian follicular development
Pituitary FSH functions as the inducer
of granulosa cell LH receptor
acquisition
This FSH-dependent LH receptor
induction is inhibited by EGF and FGF

Intrafollicular Polypeptide
Regulatory Factors
3. Inhibin :
Inhibin is present in follicular fluid,
ovarian and granulosa cell extracts
Inhibin exerts a suppressive action on
both basal and GnRH-stimulated
pituitary FSH secretion
Circulating levels of Inhibin are
inversely related to plasma FSH levels.
Inhibin can be detected in the plasma
of women given FSH, but not in
castrated subjects.

Intrafollicular Polypeptide
Regulatory Factors
3. Inhibin :
Inhibin composed of two subunits that
are linked by disulfide bridges
The two subunits (, ) encoded by
separated genes
Antibodies to inhibin confirm its
presence in the plasma of men and
women.
The control of inhibin biosynthesis is
at the level of transcription.

Intrafollicular Polypeptide
Regulatory Factors
4. Activin :
Purified fractions of follicular fluid
exhibited stimuli rather than inhibitory
effects on FSH release from pituitaries
invitro.
Subunits of inhibin and transforming
growth factor (TGF) were similar.
Dimers of the subunits of inhibin, AB,
AA and B B were named Activin, Activin A
and Activin B
Activin can enhance basal secretion of FSH
in a dose-dependent manner in vitro without
affecting the secretion of LH.