Reproductive Hormones and Their

Therapeutic Uses
By
Dr. Atef Abdel-Hai Khalil Selmi
Professor of Obstetrics, Gynecology, & A.I.
Faculty of Veterinary Medicine
Zagazig University

Neuro-endocrine Regulation of Reproductive Hormones

Cerebrum
Hypothalamus

Third Ventricle

Pituitary Stalk
Optic chiasm
Pituitary
Gland

Medulla
Oblongata

Cerebellum

Pineal
Body

I - Hypothalamic hormones
Hypothalamus secretes neurohumoral substance called
neurohormones or releasing hormones that influence
pituitary synthesis and secretion of the corresponding
hormone such that:
1.Gonadotropin hormonereleasing hormone (GnRH)
affect synthesis and release of gonadotropin hormones
(FSH and LH) from anterior pituitary gland.
2.Thyroid stimulating hormone releasing hormone
(TSHRH) affect synthesis and release of Thyroid
stimulating hormone (TSH) from anterior pituitary
gland.

3. Adrenocoticotropic hormone releasing hormone

(ACTHRH) affect synthesis and release of
Adrenocoticotropic hormone (ACTH) from
anterior pituitary gland.
4. Prolacten inhibiting hormone (PIH) affect
synthesis and release of prolactin hormone from
anterior pituitary gland.
5. Somatostatin affect synthesis and release of
somatotropin or growth hormone from anterior
pituitary gland.
6. Oxytocine hormone that stored in posterior
pituitary gland.

1- Gonadotropin Releasing Hormone (GnRH(

Chemistry:
GnRH is a decapeptide neurohumoral substance
(composed of 10 amino acids) secreted by neurons
located in the arcuate nucleus of the hypothalamus,
then transported axonally to be stored in the median
eminence until appropriate stimulation which causes
its release into the hypothalamo-hypophyseal portal
circulation.
Biological effect:
The portal circulation carries the releasing hormone to
their receptors (pituitary gonadotrophs) in
the
anterior lope of pituitary gland, where it stimulates
synthesis and secretion of gonadotropic hormones,
Follicle stimulating hormone and luteinizing hormone
(FSH &LH ).

Commercial Preparations :
Receptal (5 ml IM) and Fertagyl (2.5 ml IM) are the
preparations mostly available that can be used in
cows as a single IM injection to stimulate a surge like
release of FSH and LH from the anterior pituitary.
Therapeutic Uses:
1-Ovarian inactivity.
2-Delayed ovulation.
3-Cystic ovary (twice the dose).
4-Improve conception rate.
5-Synchronization of ovulation and resumption of
normal estrous cyclicity in postpartum cows.
6-Minimize incidence of cystic ovary in postpartum
cows.

2- Oxytocin Hormone
Chemistry:
It is a peptide neurohumoral substance synthesized
by neurons located in supraoptic nucleus of the
hypothalamus and transported axonally to be stored
in the posterior pituitary.
It is released from posterior pituitary to the
general circulation following appropriate nervous
stimuli (neural reflex) coming either from pelvic
plexus during parturition or from other sense (visual,
tactile, or auditory) during lactation.

Biological effect:
It stimulate smooth muscle contraction in both the
genital tract (must be primed by estrogen) and
mammary system (myoepithelial cells around milk
acini and lactiferous ducts). Therefore, oxytocin has a
definite functions in parturition, milk let-down,
ovulation, transportation of sperm and ova in genital
tract, and implicated in the control of luteal
regression.
Adrenalin block the contractile effect of oxytocin on
uterine muscle and myoepithelial cells in mammary
tissue. Therefore, widely exited females would develop
nervous inhibitory impulse during parturition and
would not likely to give a good milk let-down.

Commercial Preparations:
Oxytocin, Cyntocinon, hypophesin or posterior pituitary
extract are the preparations mostly available that can be
used as a single IM or IV injection (10-15 iu for small or
15-25 iu for large animal, respectively) to stimulate milk
let-down or to stimulate uterine contraction.
Therapeutic Uses:
1.Stimulates milk let-down.
2.Stimulates uterine contraction:
A.In parturient females during weak or abolished birth
pain to overcome uterine inertia, hasten placental drop,
and to hasten uterine involution.
B.In open pyometra to get- red uterine contents.
C.In uterine prolapse to reduce size of the prolapsed
uterus.

oxytocin

GnRH

Reproduced
from
Reproductive
endocrinology
Edited by Samuel S.C and Robert B. Jaffe
( W.B. Saunders Company, Philadelphia)

II - Pituitary Gonadotropin Hormones

Chemistry:
Gonadotropins are glycoprotein in nature
(carbohydrates-containing proteins), that are secreted
from pituitary gonadotrophs under the stimulatory
effect of hypothalamic GnRH.
They are composed of two polypeptide subunits,
and that are bound in non-covalent association of
very high affinity.
Both FSH and LH within the same species have a
common subunit that possess the same amino acids
sequence (species specific), but subunit is a hormone
specific subunit that has a different amino acids
sequence.

 Carbohydrate groups located in both subunit

influence the stability and ability of the hormone
to combine with and activate their receptor sites
in testis and ovary.
The half-life of gonadotropin hormones in
circulation depends upon their sialic acid content
(see next table).

Characteristics of gonadotropic hormones

Hormone

Molecular
weight

Carbohydrate

Sialic
acid

Half-life

LH

34000 - 28

24- 12
%

FSH

37000 - 32

% 25

%5

.hr 2

HCG

38000

32%

% 8.5

.hr 11

PMS (eCG)

68000

% 48

% 10.4

.hr 26

2% 1 .min 30>

1 - Follicle stimulating hormone (FSH )

Biological effect:
1.Stimulate folliculogenesis: It reach the specific
receptor sites on the granulosa cells surrounding the
primordial follicle and stimulate their mitosis with a
consequent proliferation and follicular fluid
formation that result in increased follicular size and
development.
2.Stimulate follicular maturation that ocurrs under a
certain balance between FSH, LH, Estrogen,
Progesteron, and Androgen hormones.
3.Stimulate luteinization : by increasing LH receptors
on both thecal cells and granulosa cells.

4. Stimulate steroidogenesis: the steroidogenic

activity of the follicle depends upon FSH and LH
that acting synergistically on both thecal cells
(androgen) and granulosa cells (estrogen) with a
consequent increase in follicular estrogen
production (two cell theory).

Steroid cocentration in follicular fluid in relation to

follicular development and atresia:
Follicular diameter (mm)

Estradiol
(Pmol/ml)

Progesterone
(Pmol/ml)

Testosterone
(Pmol/ml)

2-3mm (small, nonatretic) 140

40

280

3-6 mm (large, nonatretic)

100

150

70

3-6 mm (large, atretic)

860

120

190

Commercial preparations:
Anteron, Prolan A, Gestyl, and Folligon.
Biological preparations:
Anterior pituitary extract, Pregnant mare serum
gonadotropin
(PMS)
Or
equine
chorionic
gonadotropin
(eCG), and Menopausal urine
gonadotropin (MUG).
Therapeutic dose:
A.200 - 500 i.u. for Small animal.
B.500 -1500 i.u. for large animal.
NB: Over dosing causes super-ovulation.

Therapeutic uses:
1.It is used mainly to activates the ovary in
cases of ovarian inactivity or to induce
follicular growth either for super-ovulation
purposes or for out-of-seasone breeding.
2.Repeated injections are required owing to
short half-life, but repeated administration
has a refractory results due to antibodies
formation that neutralize the injected
hormone. Moreover, anaphylactic reaction
may be developed in treated cases.

2 - Luteinizing hormone (LH)

Biological effect:
1.Stimulate
follicular
steroidogenesis:
the
steroidogenic activity of the follicle depends upon FSH
and LH that acting synergistically on both thecal cells
(androgen) and granulosa cells (estrogen) with a
consequent increase in follicular estrogen production
(two cell theory), since androgen well be aromatized to
estrogen during diffusion through granulosa cells
(aromatase enzyme).
2.Stimulate follicular and ovum maturation through
increased progesteron production by granulosa cells in
antral follicle.

1. Induce ovulation by increasing intrafollicular

concentration of proteolytic system ( proteolytic
enzymes, collagenase-like enzyme, plasminogen ).
2. Stimulate CL formation and maintain its
steroidogenic activities.
Commercial preparations:
Premogenyl, Prolan B, and Pregnyl.
Biological preparations:
Human chorionic gonadotropin(HCG).
Therapeutic dose :
500-1000 i.u. for small animals.
1000-5000 i.u. for large animals.

Therapeutic uses:
1. Luteinization of follicular cysts (cystic ovary).
2. Induction of ovulation.
3. Delayed ovulation.
NB: Repeated administration has a refractory
results due to antibodies formation that neutralize
the injected hormone.

3 - Prolactin or Leutotrophic hormone(LTH(

Biochemistry:
Its molecules are very similar to growth hormone.
It is composed of single polypeptide chain that
contains 198 amino acid with a molecular weight of
27000.
It have specific receptor sites on the ovary, liver,
adrenal gland, and mammary gland.
The wide spread of prolactin receptors and wide
range of action (osmoregulation, metabolic, and
reproduction) classify prolactin as a metabolic rather
than a gonadotropic hormone.

Biological effect:
It inducing mammary growth (mammogenic
action).
It initiates milk secretion after parturition
(lactogenic action).
It stimulates continuation of established milk
secretion (galactogenic action).
It has luteotropic action and increased number of
LH receptors on the ovary.
It maintain CL function with consequent cessation
of estrous cycle in high lactating cows.
It stimulate maternal behavior in nursing females.

III Ovarian Hormones

A Ovarian Steroid Hormones
Biochemistry: The ovary, among the steroid
synthesizing glands, has the unique capacity to secrete
significant amount of estrogens.

Plasma cholesterol is the precursor of steroid nucleus

(cyclopentano-perhydro-phenantherin nucleus).
Conversion of cholesterol in the ovarian tissues to
steroid hormone is accelerated by LH through cAMP.

1- Estrogen
It is generally accepted that follicular estrogen is
synthesized by collaboration of two cell layers (theca
interna cells and granulosa cells) through what is
called two cell theory.
LH stimulate theca interna cells to synthesize and
secrete androgens. Whereas, FSH stimulate the
granulosa cells to aromatize the diffused androgens
into estrogen with a cosequent rise in concentration of
estrogen in intrafollicular fluid.

Biological action:
1. Growth of sexual organs through its anabolic
effect.
2. Development of secondary sexual characters in
females.
3. Induce the clinical and behavioral signs of estrum.
4. induce proliferation of the duct system of the
udder.
5. Favors calcium deposition and closure of epiphysis
in long bones.
6. Prepare receptors on uterine muscle to oxytocin.
7. Favors deposition of glycogen in endometrial
glands.
8. Anabolic steroid.

Commercial preparations:
Diethyl stibesterol, Premarine, Cyren B,
Triphynyl etheline, Hexesterol, and Folone 1&5.
Therapeutic dose:
The preparations are oily and injected IM or SC
(Average dose is 30 mg).
A.Small animals Up to 20 mg.
B.Large animals Up to 50 mg.
Therapeutic uses:
1.To induce abortion in cases of unwanted pregnancy.
2.To open cervical canal to get red of uterine contents
during treatment of closed pyometra or mummified
fetus.

3. To induce hormonal castration and

fattening of males.
4. To treat ovarian inactivity through
multiple injection of small minute doses to
initiate FSH secretion.
5. To help in treatment of vaginal prolapse.
NB: Estrogen treatment may lead to
hypocalcaemia. Therefore,
calcium
preparation should be injected together
with estrogen.

Disadvantages of estrogen application:

1. Reduce milk yield and lactation may be inhibited
or even stopped.
2. Excessive amounts causes relaxation of the pelvic
ligaments and may leads to vaginal or rectal
prolapse together with development of genital
tract infection.
3. Prolonged use might causes nymphomania,
cassation of estrous cycle and atrophy of the
ovary due to its inhibitory effect on FSH secretion
and release.

2-Progesterone
Biological action:
1.Play an important role in follicular maturation,
ovulation, fertilization, and implantation.
2.Necessary to maintain pregnancy.
3.Favors deposition of glycogen in endometrial glands
and stimulate uterine milk secretion
4.Proliferate the alveolar system of mammary gland.
5.Anabolic steroid .
6.Inhibit folliculogenesis.

Commercial preparations:
1.Methyl acetoxyprogesterone (MAP).
2.Chlormadinone acetate progesterone (CAP).
3.Medroxy progesterone acetate (MPA).
Therapeutic doses:
Small animals 10-20 mg.
Large animals 50 mg.
Therapeutic uses:
1.To prevent or control habitual abortion.
2.Synchronization of estrous.
3.To counter act the effect of estrogen in cows suffer
cystic ovary (nymphomania).
4.In cases of vaginal prolapse .

B - Ovarian Protein Hormones

1 Inhibin
It is a protein hormone made by the ovary
(granulosa cells) and testis (Sertoli cells) that is
secreted into the blood stream to control (inhibit) the
secretion of follicle stimulating hormone by the
pituitary gland. It also limits the release of
gonadotropin-releasing hormone.
There are two functional forms of inhibin, A and B
forms. Both inhibin A and B has two protein subunits,
(an A and a A subunits & B subunit and a B
subunit).
The two forms and subunits are almost of the same
size and are held together by covalent linkages.

 Inhibin A is secreted by the granulosa cells of the

dominant follicle as it grows, causing blood
inhibin A levels to gradually increase toward
midcycle, with the main peak occurring after
ovulation.
Inhibin B is produced by small follicles at the
start of the cycle, with minimal secretion during
the luteal phase. Elevated levels of follicle
stimulating hormone in menopause women may
be due to reduced inhibin B owing to decreased
follicular reserves.

 Serum inhibin levels fell during gonadotropin

suppression and were partially and approximately
equally restored by either FSH or LH treatment.
However, bilateral ovariectomy decreased plasma
immunoreactive inhibin and increased plasma FSH
significantly.
These findings indicates that the ovary is the main
source of inhibin secretion and that the inhibin is a
major regulator in the follicular development
through FSH secretion.
FSH presumably acts directly on the Sertoli cell to
increase inhibin secretion in males, whereas LH
may act via increased intratesticular Testosterone
levels and/or other factor(s).

The relationship between inhibin and

follicle-stimulating hormone represents a
typical negative feedback servomechanism

2 - Activin
It is a polypeptide hormon produced in the gonads,
pituitary gland, placenta, and other organs.
It has an action in the body opposite to that of
inhibin.
Levels of these two hormones tend to fluctuate in
both males and females in response to a number of
cues (include changes in hormone levels triggered by
natural biological processes, environmental pressure,
and other factors).
In the ovarian follicle, activin increases FSH
binding and FSH-induced aromatization.
It participates in androgen synthesis, enhancing LH
action in the ovary and testis.

3 - Bradykinin
It is a polypeptide hormone.
It is found in the follicular fluid of Graffian follicle
of bovine, rabbit and human.
It reaches the fallopian tube after ovulation and
help in trapping the ovum by infundibulum.

4 - Relaxin
It is a polypeptide in nature secreted from CL in
late pregnancy, and by the placenta and uterus.
It aids in the dilatation of the cervix and causes
relaxation of the pelvic ligaments, separation of the
symphysis pelvis thereby preparing the birth way for
the act of parturition.

Mechanism of Hormonal Control

1. Neurohumoral mechanism:
A neurohumoral substance reaching the
endocrine gland through circulating blood
such as Gonadotropin releasing hormone
secreted from the hypothalamus and
reaching anterior pituitary gland through
hypothalamo-hypophysial portal circulation
to stimulate synthesis and secretion of
Gonadotropin.

Neurohumoral mechanism

2. Nervous mechanism:
An appropriate nervous impulse is necessary
to release the hormones such as nervous
impulse necessary to release oxytocin from
posterior pituitary gland following visual
or tactile or auditory stimulation during
milking. Vaginal stimulation in conditioned
ovulators (she camel and female rabbit) is
necessary to induce surge-like release of
LH to induce ovulation.

Nervous mechanism

3. Feed-back mechanism (servo-mechanism):

Such that reported between FSH and inhibin
hormone. FSH stimulate follicular growth and
stimulate steroidgenesis. FSH secretion will be
decline or inhibited as the follicle reaching the
mature size and secrete high amounts of inhibin
hormone ( negative feed back regulation), but
high level of estrogen will stimulate release of high
amounts of LH necessary to induce ovulation
(positive feed back regulation).
Therefore, a negative feed back is found between
inhibin and FSH, but a positive feed back is
developed between estrogen and LH.

In another wards, inhibin will feed back to

anterior pituitary gland to inhibit secretion
of FSH (negative feed back) and estrogen
stimulate secretion of LH (positive feed
back).
Whereas, high level of progesterone will
inhibits FSH secretion and stop estrous
cycle.
NB: Typical negative feedback mechanism is
recorded for FSH and Inhibin.

Feed-back mechanism (servo-mechanism)

Reproduced
from
Reproductive
endocrinology
Edited by Samuel S.C and Robert B. Jaffe
( W.B. Saunders Company, Philadelphia)

Capillary
Protein
Hormone

Hormone
Receptor

Adenylate
Cyclase
Enzyme
Released
from cell

ATP

ATP = Adenosine Triphosphate

cAMP = Cyclic Adenosine Monophosphate
FSH
PP = Pyrophosphate

cAMP + PP

Caffeine inhibits
enzyme and allows
prolonged activation

Cytoplasm
Estrogen Protein
synthesis Kinase
DNA
Protein
Steroid
enzymes
mRNA

Phosphodiesterase

Inactivates
by conversion
AMP 5

Nucleus

Granulosa
Cell

Mode of Action of Protein/Peptide Hormones

Bilaminar Cell Membrane

Capillary

Steroid

Release from blood

circulation

Progesterone

Mode of Action of Steroid Hormones

Diffuses in cytoplasm
DNA
Steroid

Rough
Endoplasmic
Reticulum

Nucleus
Chromatin
mRNA
Receptor

Protein
Synthesis

Bilaminar Cell

Uterine
Glandular
Epithelial
Cell
Secretion into
uterine lumen

IV-Endometrial hormones
Prostaglandin
Biochemistry:
Arachidonic fatty acid is the precursor of all
Prostaglandin series ( A, B, C, D, E, F, G, H).
Biosynthesis of Prostaglandin (PG) is mediated by a
complex of microsomal enzymes (prostaglandin
synthetase enzymes).
These enzymes are demonstrated in a wide number of
organs, but the rate and type of prostaglandin
biosynthesis differ widely among organs.
Prostaglandin E (PGE) is the predominant product in
many tissues, but PGF is the product frequently
identified in the genital tract.

 PGF often display the opposite biologic activity to that

of PGE, but PGF can be converted directly to PGE
and vice versa. The consequent biologic activity can
also be reversed or modified by direct conversion.
Synthesis and secretion:
Progesterone stabilize phospholipase enzyme that is
responsible for hydrolysis of phospholipids. However,
estrogen labilize this enzyme.
Thus, decline in progesterone concentration in the
plasma and ascendance of estrogen during the
terminal period of pregnancy are responsible to
induce release of such enzyme to induce hydrolysis of
phospholipids and produce the precursor of PG
(arachidonic fatty acid).

 Increased estrogen concentration during the last

15 days of pregnancy was associated with
increased PGF2 concentration in both fetal fluid
and endometrial caruncles.

Mode of action on smooth muscle:

PGF (smooth muscle contraction) often display the
opposite biologic activity to that of PGE (smooth
muscle relaxation).
PGF can be converted directly to PGE and vice versa.
The consequent biologic activity can also be reversed
or modified by direct conversion.
PGF2 has an ecopolic effect and luteolytic effect.
It increases calcium release from sarcoplasmic
reticula, and calcium-induced activation of glycogen
phosphorylase system through cAMP with cosequent
formation of glucose (nessesary to support the
metabolic needs of the contractile muscle).
PGE2 induce smooth muscle relaxation through
Guanilate cyclase activity (inhibition) through cGMP.

Commercial preparations:
Estrumate (2 ml IM), Lutalyse (5 ml IM), Illerine (2.5
ml IM), Prosolvine (2 ml IM), Equamate (2 ml IM for
mares).
Therapeutic uses:
1.Estrus synchronization (Three programs or
regimens):
A-Clinical examination, detection of CL, single dose,
breeding for responders.
B-Single dose, heat,
followed by another dose after 12 days from the first
injection for refractory cases.
C-Two successive
injection with 12 days intervals, then application of
two successive insemination.

2. Induction of parturition.
3. Induction of abortion.
4. Opening the cervix and get red uterine
contents in cases of closed pyometra,
endometritis,
and
mummified
or
macerated fetus.
5. Reduce length of estrous cycle, with a
consequent induction of recurrent estrous
during a short period.