1. Neuroendocrine Regulation of
Reproduction
By
Dr. Atef Abdel-Hai Khalil Selmi
Professor of Obstetrics, Gynecology, & A.I.
Faculty of Veterinary Medicine
Zagazig University
( 1 )

2. Neuroendocrine Regulation of
Reproduction
Endocrinology: the branch of science dealing with
the study of hormones and their receptors.
Neuroendocrinology: A branch of Science dealing
with the implication of nervous system in regulation of
the endocrine gland functions and many biological
activities inside an individual. In neurobiology, the
neuron have the unique capacity to transmit
information rapidly and reliably over a long distances
through a nerve impulse. Such that oxytocin release
from posterior pituitary is controlled by sensory nerve
impulses derived either from mammary gland or from
pelvic plexus. However, pituitary function is regulated
through feed back control by neurohormones secreted
directly from nerve cells located in the hypothalamus.

3. Mammalian hormones
Metabolic hormones: These hormones are
necessary for metabolism, growth and development
as well as to maintain the general health condition and
state of wellbeing of an individual (sense, respirate,
feed, move, grow, excrete etc…). They are indirectly
involved in some aspects of mammalian reproduction
such as GH , Thyroxin, Insulin, Glucagon, etc…..
Reproductive hormones: These hormones are
derived primarily from the areas of the hypothalamus,
pituitary, gonads, placenta, and uterus. They are
involved directly in various aspects of reproduction
such as oogenesis, spermatogenesis, ovulation,
sexual behavior, fertilization, implantation,
maintenance of gestation, parturition, lactation, and
development of maternal behavior.

4. Neuro-endocrine Regulation of Reproductive Hormones
Cerebrum
Cerebellum
Medulla
Oblongata
Pituitary Stalk
Third Ventricle
Pineal Body
Optic chiasm
Pituitary Gland
Hypothalamus

6. 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 hormone–releasing 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

8. 1- Gonadotropin Releasing Hormone)HRnG(
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

9. 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-Improvement of conception rate.
5-Synchronization of ovulation and resumption of
normal estrous cyclicity in postpartum cows.
6-Minimize incidence of cystic ovary in postpartum
cows.

10. 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 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.

11. Biological effect: It stimulate smooth muscle
contraction in both the genital tract (must be
primed by estrogen) and mammary system.
Therefore, oxytocin has a definite functions
in parturition, milk let-down, 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

12. Commercial Preparations: Oxytocin and
Cyntocinon are the preparations mostly available
that can be used as a single IM or IV injection (10-
15iu or 15-25 iu for small or 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.
B- to overcome uterine inertia.
C- to hasten placental drop.
D- to hasten uterine involution.
E- to get- red uterine contents in open pyometra.
F- to reduce size of the prolapsed uterus.

13. 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,α and β that bound in noncovalent association of
very high affinity. Both FSH and LH wthin the same species
have a common α subunit that possess the same amino acids
sequence (species specific), but β subunit is a hormone
specific subunit that has a different amino acids sequence.
Whereas, 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.
However, half-life of glycoprotein hormones in circulation
depends upon their sialic acid content.

14. Characteristics of gonadotropic hormones
Half-lifeSialic
acid
Carbo-
hydrate
Molecular
weight
Hormone
< 30 min.1 – 2%12 -24
%
28 - 34000LH
2 hr.5 %25 %32 - 37000FSH
11 hr.8.5 %32%38000HCG
26 hr.10.4 %48 %68000PMS
(eCG)

15. A- Follicle stimulating hormone (FSH(:
Biological effect:
1-Stimulate folliculogenesis: It reach the specific
receptor sites on 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 luteinization : by increasing LH receptors
on both granulosa cells and thecal cells.
3- Stimulate steroidogenesis: the steroidogenic activity
of the follicle depends on FSH and LH that acting on
both granulosa cells (estrogen) and thecal cells
(androgen) with a consequent increase in follicular
estrogen production (two cell theory).
4- Stimulate follicular maturation: a certain balance

16. Steroid cocentration in follicular fluid in relation
to follicular development and atresia
Testosterone
(Pmol/ml)
Progesterone
(Pmol/ml)
Estradiol
(Pmol/ml)
Follicular diameter
(mm)
280401402-3 (small, nonatretic)
701501003-6 (large, nonatretic)
1901208603-6 (large, atretic)

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

18. :Therapeutic uses
- 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. Repeated injections are required owing to
short half-life.
- Repeated administration has a refractory results
due to antibodies formation that neutralize the
injected hormone. Moreover, anaphylactic reaction
may developed in treated cases.

19. (LH):B- luteinizing hormone
Biological effect:
1- Stimulate follicular steroidogenesis: the
steroidogenic activity of the follicle depends on
FSH and LH that acting on both granulosa cells
(estrogen) and thecal cells (androgen) with a
consequent increase in follicular estrogen
production (two cell theory), since androgen well
be aromatized to estrogen during diffusion through
granulosa cells.
2- Stimulate follicular and ovum maturation.
3- Induce ovulation by increasing intrafollicular
concentration of proteolytic system ( proteolytic
enzymes, collagenase-like enzyme, plasminogen

20. Commercial Biological preparations :
-Premogenyl - Human chorionic gonadotropin(HCG)
-Prolan B
-Pregnyl
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.
4-Repeated administration has a refractory results due to
antibodies formation that neutralize the injected hormone.

21. C- prolactin or Leutotrophic hormone(LTH(:
Chemistry:
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 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 metabolic
rather than gonadotropic hormone.

22. Biological effect:
It has mammogenic action: inducing mammary
growth.
It has lactogenic action: initiates milk secretion
after parturition.
It has galactogenic action: stimulates
continuation of established milk secretion.
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 mature
females.

23. Ovarian Steroid hormones
1-Estrogen :
Chemistry:
Plasma cholesterol is the precursor of steroid nucleus
(cyclopentano-perhydro-phenantherin nucleus) . Conversion
of cholesterol to steroid hormone is accelerated by LH
through cAMP.
Biological action:
Growth of sexual organs through its anabolic effect.
Development of secondary sexual characters in females.
Induce the clinical and behavioral signs of estrum.
induce proliferation of the duct system of the udder.
Favors calcium deposition in long bones.
Prepare receptors to oxytocin.
Favors deposition of glycogen in endometrial glands.

24. Commercial preparations:
-Diethyl stibesterol
-Premarine.
-Cyren B .
-Triphynyl etheline.
-Hexesterol.
-Folone.
They are oily preparations and injected i.m. or s.c.
Therapeutic dose:
-Small animals Up to 20 mg.
-Large animals Up to 50 mg.
-Average dose 30 mg.

25. Therapeutic uses:
1. Induce abortion in case of unwanted pregnancy.
2.To open cervical canal to get red of uterine
contents during treatment of closed pyometra or
mummified fetus.
3.To treat ovarian inactivity through injection of
small minute doses to initiate FSH secretion.
4. To induce hormonal castration and fattening.
5- To help in treatment of vaginal prolapse.

26. Disadvantages of estrogen application:
1- Reduce milk yield and even stop its secretion.
2- Excessive amounts causes relaxation of the pelvic
ligaments and may leads to vaginal or rectal prolapse.
3. Prolonged use might causes nymphomania,
cassation of estrous cycle and atrophy of the ovary
due to stopping FSH secretion and release.

27. 2-Progesterone
Biological action:
1- Inhibit folliculogenesis.
2- Proliferate the alveolar system of
mammary gland.
3- Necessary to maintain pregnancy.
4-Favors deposition of glycogen in
endometrial glands and stemulate uterine
milk secretion.
5-Anabolic steroid .

28. Commercial preparation:
Methyl acetoxy progesterone (MAP).
Chlormadinone acetate progesterone (CAP).
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. In cystic ovary (nymphomania) to counter effect of estrogen.
4. Vaginal prolapse .

29. 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 trapping of the ovum by
infundibulum.

30. 4-Relaxin:
It is a polypeptide in nature secreted from C.L. in the
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.

31. 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.
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

32. 3-Feed-back mechanism (servo-mechanism): such
that reported btween Gonadotropin hormones
and estrogen hormone. FSH stimulate follicular
growth and stimulate steroidogenesis. FSH
secretion will be decline or inhibited as the follicle
reaching the mature size and secrete high
amounts of estrogen 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 estrogen and FSH, but a positive
feed back is developed between estrogen and
LH. In another wards, estrogen will feed back to
anterior pituitary gland to inhibit secretion of FSH

34. Mechanism of Hormonal
Action
Hormone: An organo-chemical substance
produced by certain specialized cells (endocrine
gland), reach their receptors sites on the target
organ or tissues through circulation (blood or
lymph), with the resultant stimulation as follows:
1-Hormone binds to its specific receptors located
on the plasma membrane of the target cell (1st
messenger to plasma membrane.
2- Then activates Adenylat Cyclase Enzyme that
change cATP to cAMP (2nd messenger to nuclear
DNA).
3-Nuclear DNA transcript the message and produce
mRNA (3rd messenger to cytoplasm) that
activates protein kinase enzyme involved in the
physiological function of the target cell (produce
hormone or enzymes or secretions).

35. Protein/Peptide Hormones
ATP = Adenosine Triphosphate
cAMP = Cyclic Adenosine Monophosphate
PP = Pyrophosphate
Granulosa
Cell
FSH
Enzyme Cytoplasm
DNA
Steroid
enzymes
Estrogen
synthesis
Phosphodiesterase
Inactivates
by conversion
Caffeine inhibits
enzyme and allows
prolonged activation
Capillary
Protein
Hormone
Hormone
Receptor
Adenylate
Cyclase
ATP cAMP + PP
Protein
Kinase
5’AMP
NucleusmRNA
Protein
Released
from cell
Bilaminar Cell Membrane

36. Steroid Hormones
Uterine
Glandular
Epithelial
Cell
Progesterone
Diffuses in cytoplasm
Secretion into
uterine lumen
Steroid
Capillary
Release from blood
circulation
Steroid
DNA
Nucleus
Receptor
mRNA
Rough
Endoplasmic
Reticulum
Protein
Synthesis
Bilaminar Cell Membrane
Chromatin

37. Endometrial hormones
Prostaglandin
Chemistry:
Arachidonic fatty acid is the precursor of
Prostaglandin series ( A, B, C, D, E, F, G, H).
Biosynthesis of Prostaglandin (PG) is mediated by a
microsomal complex of 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.

38. :Synthesis and secretion
 Progesterone stabilize phospholipase enzyme that
is responsible for hydrolysis of phospholipids.
However, estrogen labilize this enzyme. Thus, decline
in progesterone cocentration in the plasma and
ascendence 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
PGF2α concentration in both fetal fluid and
endometrial caruncles.

39. :Mode of action on smooth muscle
PGF (smooth muscle contraction) often display the
opposite biologic activity to that of PGE (smooth
muscle relaxation), but PGF can be converted directly to
PGE and vice versa. The consequent biologic activity
can also be reversed or modified by direct conversion.
PGF2α 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.

40. :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-Treatment of pyometra, endometritis, and mummified or
macerated fetus (opening the cervix and repeated estrum).