FEMALE REPRODUCTIVE

HORMONE
BIOCHEMISTRY DEPARTMENT

Pathophysiology of the
Reproductive Cycle

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 hormone of 199 amino acids.
In females it stimulates milk production by
the mammary glands..
Release is inhibited in 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
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
A system stimulation of phosphatidylinositol is GnRH
action
GnRH binds to receptors in the cell membrane of the
gonadotrope
Phospholipase C is activated, catalyzes the hidrolysis of
PIP2 to form 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 of Ca2+ from calcium stroge particle,
cause increased stimulation of PKC
participates in exocytosis of LH and FSH from cell

Action of GnRH

GONADOTROPINS
Follicle-stimulating hormone (FSH)
Target: Ovaries and Testes
Stimulates the maturation of sperm and
egg, in the females causes the release of
estrogen

GONADOTROPINS
Luteinizing Hormone (LH)
Target: Ovaries and Testes
Male: Production of testosterone
In females works with FSH to cause
follicle development, and then
independently is responsible for ovulation.

Sex Hormones
Gonad and Adrenal
Estrogen
Progesterone
Dihydrotestosterone
Testosterone

Ovarian hormones
Steroids
o Estrogens
o Androgens
o Progesterone
Peptides

A Steroid Molecule

OVARIAN STEROID HORMONES

Produced in both interstitial and
follicular cells

Derivatives of cholesterol (coming

from LDL-lipoproteins and de novo
synthesis)

Stimulasi sintesis hormon steroid

SYNTHESIS

ESTROGEN

o
o
o
o
o

Chemical structure: C18

Source:
follicular cells
corpus luteum
placenta
adrenal cortex
adipose tissue (DHEA androstenedione
E1)

SYNTHESIS
First step happens in mitochondria
All the rest in smooth ER
Reduction in number of carbon atoms
Estrogens are primarily synthesized in
granulosa cells
Aromatization of Androstenedione and
Testosterone within tissue is a major source
of Estrogens in the male and post
menopausal female.

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).

Estrogens in circulation
Estradiol
o Secreted by the ovary
Estrone
o Derived from peripheral conversion of
estradiol and androstenodione
Estriol
o Liver metabolite of estrone

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

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

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

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

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

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

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

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

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.

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.

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

OVARIAN PEPTIDE HORMONES

o
o
o
o
o
o

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
o Inhibit FSH secretion
Gonadotropin surge attenuating factor
o Prevents premature LH surge

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

Oocyte Maturation Inhibitor

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.
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
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.