Reproductive Hormones

Gonadotropin Releasing Hormone (GnRH)

GnRH is a neuropeptide (a decapeptide) that is produced in the hypothalamic

surge and toniccentres. In the male and the female, the target tissue is the anterior pituitary
gland, specifically Gonadotroph cells. In males and females, secretion of GnRH results in the
release of Follicle Stimulating Hormone (FSH) and Leutinising Hormone (LH) from the
anterior pituitary gland.

GnRH-producing neurons are stimulated into production in response to spontaneous rhythms

and by sensory impulses from sensory inputs derived from the external environment.
Alterations in the internal conditions of the body can also result in altered GnRH production. For
example in some species such as the sheep, there is seasonal sexual activity and the cerebral
cortex, hypothalamus, pituitary and testes interact to regulate functions further along the
signalling chain.

In females when the oestrogen concentration prior to ovulation reaches a certain threshold,
large quantities of GnRH are released in the form of a surge. This results in a corresponding peak
in LH that stimulates ovulation. In females this surge centre is often called the preovulatory
centre. In males this surge centre becomes inactivated during fetal life due to the brain
maturation effects of estradiol being able to pass through the blood brain barrier in males,
please see the reproductive development of the brain for more details. In males there are
between 4-12 GnRH peaks per day. Plasma concentrations of LH peak approximately 10mins
post GnRH surge.

Although the hypothalamus via GnRH stimulates the secretion of LH and FSH, it cannot regulate
LH and FSH independently. Therefore another hormone produced from the developing ovarian
follicle in the female and sertoli cells in the male acts as a negative feedback mechanism for FSH.
Sex hormones also alter the level of production of GnRH from the hypothalamus via a negative
feedback system. High concentrations of progesterone or testosterone will reduce the secretion
of GnRH and also therefore the secretion of LH and FSH.
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 Luteinizing Hormone (LH)

LH is a type of glycoprotein that is produced in the anterior pituitary via gonadotroph cells and
serves to regulate the function of the gonads. In males LH stimulates the production and
secretion of testosterone from the testes via leydig cells. In females LH stimulates the
production of oestrogens and progesterone from the ovary via theca interna cells and luteal
cells. Concentrations of LH increase during ovulation and with the formation of the corpora
lutea with progesterone secretion. The secretion of LH is regulated via the secretion of GnRH
(see earlier section).

As shown previously, in males there are between 4 to 12 GnRH pulses per day and this therefore
means that LH also peaks throughout the day. During these peaks, the production and secretion
of testosterone increases. Testosterone secretion also is pulsatile.

Follicle Stimulating Hormone (FSH)

FSH is a type of glycoprotein that is produced in the anterior pituitary via gonadotroph cells.
FSH secretion is regulated by GnRH from the hypothalamus. The target tissue of FSH in males
are the sertoli cells within the testes and in the female the granulosa cells of the ovary. FSH
stimulates the maturation of germ cells within the testes and ovaries. In the female it also
stimulates follicular development and oestradiol synthesis.

In the male FSH also stimulates the secretion of inhibin which has a negative feedback directly
to the anterior pituitary. Although GnRH is released in a pulsatile fashion and the other
gonadotropic hormone LH is therefore also pulsatile, FSH concentrations do not fluctuate as
much as that of LH. This is because of the added regulatory feedback mechanism of inhibin
within the regulatory pathways for FSH secretion.

Prolactin (PRL)

Prolactin is a protein that is produced from by the anterior pituitary via lactotroph cells. This
hormone exerts a stimulatory effect on milk synthesis within the mammary glands. It has also
been shown to have some degree of gonadal function in some domestic species and rodents. In
birds increased concentrations of prolactin have been linked with brooding behaviours and the
associated metabolic changes that birds undergo during brooding.

Prolactin secretion is regulated by the hypothalamus which produces several neurohormones

that affect prolactin concentrations. The most important within this is dopamine (or prolactin
inhibitory hormone, PRL-IH) which exerts a totally dominant inhibitory action on prolactin
synthesis. The hypothalamic regulation of prolactin secretion is via signals from the central
nervous system. Prolactin synthesis is increased when the mother is suckling via a reflex
stimulation of the teats. This stimulation reflex reduces the secretion of dopamine and increases
the hormone prolactin releasing hormone (PRL-RH). Once prolactin binds to it's target
receptors within the mammary gland cells, it activates an intracellular tyrosine kinase. When
this occurs in the developing animal this binding can also cause the differentiation of mammary
epithelial cells during pregnancy. The half-life of prolactin is approximately 20mins.

Estradiol can also have an effect on the prolactin producing cells within the anterior pituitary
and is responsible for increased concentrations of prolactin in females undergoing puberty and
may also contribute to the increased concentrations during late pregnancy.

Oxytocin (OT)

OT is a neuropeptide (a octapeptide) which is synthesised in the hypothalamus and stored in

the posterior pituitary. OT is primarily involved in upregulating the activity of smooth muscle
cells in the uterus and the smooth muscles surrounding the alveoli ducts of the mammary
glands. At parturition, OT causes strong contractions from the myometrium. OT is also essential
for 'milk let-down' in most domestic species.

OT binds to receptors in the membrane of target cells which activates phospholipase C. OT

facilitates the generation of the driving pressure behind pushing the milk towards the large
excretory ducts and the teats.

Estradiol (E2)

Estradiol (E2) is a steroid hormone and is part of the oestrogens group of hormones and is the
principle oestrogen in females. Estrone and estriolare chemically similar to estradiol but are
found in lower concentrations and have a lower estrogenic activity. Production of oestrogens
occurs in the ovary via granulosa cells, the placenta and the Zona reticularis of the adrenal
cortex. In males in it is produced in sertoli cells found in the testes. Estradiol is synthesised from
cholestrol.

Oestrogens have a number of functions related to reproduction and other areas of physiology. In
relation to the reproductive role of oestrogens, they stimulate follicular growth and maturation,
induce the female to begin displaying oestrous behaviour to facilitate mating, prepare the
external genitalia for copulation and create favourable conditions for the development of
fertilised egg cells. Oestrogens also contribute to the growth and development of mammary
tissue and prepare the uterus for parturition.
Effects on reproductive organs:
Vagina: slight mucous secretion, hyperaemia, oedema
Cervix: relaxation, liquification of mucous plug (causing the bull string)
Uterus: stimulates uterine gland development, sensitization of the endometrium to oxytocin,
immune activation (local), leucocyte infiltration, secretion of PGF2a and PGE2
Fallopian tube: increased motility and cilia activity
Mammary gland: stimulates mammary duct development
Corpus luteum: Luteolytic (bovine and ovine) but luteotrophic (equine and porcine)

Where oestrogens stimulate growth of follicles in the ovaries, oestrogens secreted from the
ovary in the follicular phase (proestrous and oestrous) lead to hypertrophy of the epithelium
and the endometrium. Secretory glands within the uterus enlarge and secretion is initiated
leading to thickening of tissues. The blood vessels supplying the uterus and external genitalia
dilate and blood flow to these areas increases significantly. Oedema occurs within the uterus
and surrounding connective tissues. Oestrogen also causes increased uterine muscle tone. In the
cervix oestrogens stimulate increased mucus secretion and the vaginal epithelium becomes
keratinised.

In males the target tissue is the brain where it causes maturation of the brain during
development. This maturation process ensures the appropriate development of male sexual
behaviours. E2 in the male also inhibits long bone growth.

Progesterone (P4)

Progesterone is a steroid hormone that along with oestrogens is based on a cholesterol molecule
produced by the corpus luteum and the placenta using cholesterol as the base molecule.
Progesterone is produced by the corpus luteum as well as by the feto-placental unit and in the
zona reticularis of the adrenal cortex (to a lesser extent). More detailed information regarding
corpus luteum formation and regression please use the links. Progesterone prepares the uterus
for reception of fertilized oocytes and is transported via the blood bound to plasma proteins.
Progesterone also prepares the mammary tissues for milk production as well as inhibiting
female reproductive behaviours associated with oestrous.
Effects on reproductive organs:
Vagina: slight mucous secretion, paleness, exfoliation
Cervix: closure, formation of the mucous plug
Uterus: stimulates uterine gland secretions, sensitization of the endometrium to oxytocin,
decreases uterine motility, immunosuppression, inhibition of PGF2a and PGE2
Fallopian tube: increased secretion, decreased motility
Mammary gland: stimulates lobulo-alveolar development

The concentration of progesterone increases after ovulation increasing the growth of glands
found in the endometrium resulting in increased secretion. These secretions include mucin,
carbohydrates and specific proteins that are designed for nourishment of the embryo prior to
implantation. Progesterone also stimulates the growth of the endometrium and stabilises
smooth muscle cells to ensure that they do not contract during foetal development. Once near
term, the concentration of progesterone decreases, altering the ratio between progesterone and
oestrogen. This stimulates myometrial activity and prepares the uterus for parturition.
Progesterone During Pregnancy
During pregnancy the plasma concentration of progesterone is maintained at an elevated level.
Progesterone also inhibits secretion of FSH and LH (negative feedback at hypothalamic level by
inhibiting GnRH) and thus also prevents the ovulation of follicles during the luteal phase and
during pregnancy. In most domestic species the corpus luteum persists for the entire length of
gestation.
The exception to this rule is the mare in which the progesterone concentration falls during the
later stages of pregnancy. This is due to the regression of the corpus luteum around day 180 of
the 330-340 day gestation period.

It is possible to use the relative concentration of progesterone as an aid to pregnancy diagnosis,

for example in cattle. However, for a definitive diagnosis a high level of progesterone is required
on two separate samples due to the overlap between the luteal phase and pregnancy.

Testosterone (T)
The male sex hormone is called testosterone and this hormone is required for spermatogenesis.
Testosterone is a steroid hormone that is produced in the leydig cells within the testes. A
relatively high concentration of testosterone is maintained within the testicular tissue and
testosterone is circulated around the body by diffusion of the hormone from the spermatic cord
into the testicular veins and arteries. The primary action of testosterone is anabolic growth,
spermatogenesis promotion and promotion of secretion from the accessory sex glands.

Male sex hormones are regulated by negative feedback systems that operate at various levels
within the male sex hormone system. The starting point for the production of testosterone (and
therefore the production of spermatozoa)is the hypothalamus. The hypothalamus contains
neuroendocrine cells that are capable of secreting a substance called Gonadotropin-releasing
hormone or GnRH. GnRH stimulates basophilic cells in the adenohypophysis, via the "portal
system" to secrete two intermediate hormones within the male sex hormone cycle; Luteinizing
hormone (LH) and Follicle-Stimulating Hormone(FSH).

The secretion of GnRH is pulsatile and can vary greatly throughout the day and/or year, and
therefore the secretion of LH and FSH are also pulsatile (although the plasma concentration of
FSH does not fluctuate as much as LH due to the effect of Inhibin, see below). The activity of
GnRH neuroendocrine cells is determined by spontaneous rhythms and by sensory impulses.
Cycles such as seasonal sexual activity are controlled by this pulsatile system. In male animals
there are generally 4 to 12 GnRH pulses per day.
Testosterone Regulation
When LH binds to the Leydig cells, it stimulates the cellular messenger cAMP to activate
protein kinase A. Protein kinase A undergoes a series of phosphorylations that in turn activate
a series of enzymes that synthesis testosterone from the cholesterol base molecule. A portion of
the testosterone produced in the Leydig cells diffuses into the Sertoli cells that are positioned
adjacent to the Leydig cells in the testes but seperated by a basal lamina. This secreted
testosterone is converted to to the female sex hormone estradiol in the Sertoli cell and as with
the testosterone, a proportion diffuses into the blood, becoming part of the negative feedback
system for LH.

Testosterone inhibits the secretion of GnRH from the hypothalamus and therefore secretion of
LH from the pituitary gland. If the testes are removed via castration, blood concentrations of LH
and FSH will increase as there is only limited negative feedback.
Effects of Male Sex Hormones
Testosterone plays a crucial role in the development of male sex organs during fetal growth
where increased production of testosterone causes penis growth and development of accessory
sex glands during puberty. Testosterone also affects a number of other characteristics of the
male, often called the "secondary sex characteristics". Testosterone is able to bind to receptors
in the cytosol of cells in the same manner as other steroid hormones and these hormone-
receptor complexes are then able to bind to DNA in the nucleus resulting in alterations in the
level of transcription of specific genes.

Testosterone has a number of anabolic effects stimulating the development and growth of the
skeleton and skeletal muscles. Muscle masses show a general increase and in certain body
regions such as the neck of stallions or bulls there is obvious hypertrophy. Testosterone also
alters behaviour in terms of increasing the degree of sex drive and as a result of the action in
several areas of the brain, behaviour can become more aggressive. The larynx of males also
enlarges during puberty and the vocal cords lengthen resulting in a deeper and stronger voice.

Testosterone also causes an increase in the level of pheromones to be secreted by glands in the
skin which attract and evoke sexual behaviour in females. Glands use in scent marking and
territorial marking are also activated by testosterone. In certain species, tusks, antlers and horns
are also stimulated to develop.

Inhibin

Inhibin is a type of glycoprotein that is synthesised within the granulosa cells of ovarian follicles
in females and in sertoli cells located in the seminiferous tubules within the testes in the male. In
both males and females the target organ for inhibin is the adenohypophysis, specifically the
gonadotroph cells (basophilic cells).

In the male inhibin production is stimulated via androgens. Inhibin inhibits FSH secretion, which
together with decreased concentrations of LH and testosterone results in decreased
spermatogenesis and therefore decreased sperm output and quality.

In females some studies have suggested that inhibin may also be produced by the placenta. In
females inhibin inhibits FSH secretion. It does however not have any effect on the secretion of
LH. When inhibin is secreted, a relatively higher concentration of LH is secreted from the
anterior pituitary gland than FSH. Therefore during follicle development, the increased LH
concentration causes cessation of the recruitment of further follicles under the effect of FSH. The
hormonal changes resulting from the production of inhibin cause some of the previously
recruited follicles to undergo atresia.

Inhibin in the female can also be diminished by GnRH and enhanced by insulin-like growth
factor-1 (IGF-1).

Activin
Activin is a glycoprotein that is produced within granulosa cells in females and sertoli cells in
the male. Activin is thought to play an almost directly opposite role to that of inhibin and is
involved in many physiological functions including stimulation of FSH synthesis and other roles
including cell proliferation, cell differentiation, apoptosis and homeostasis.

The target tissue for activin in the male is the epididymis where it enhances spermatogenesis via
increased FSH secretion. Activin also enhances the effect of LH on the testes.

In the female activin has an effect on the anterior pituitary gland, specifically on gonadotroph
cells, resulting in increased FSH secretion. The increased concentrations of activin results in
increased FSH binding on the female follicle and FSH-induced aromatisation (increased
synthesis of oestrogens). Activin also enhances the action of LH in the ovary.

A further non-reproductive role of activin is it's role in skin lesions where it is thought to
stimulate keratinocytes.
 Prostaglandin F2α

Prostaglanin is a C2O fatty acid and is produced within the uterine endometrium and vesicular
glands. Estradiol stimulates prostaglandin synthesis while progesterone inhibits it. The target
tissue in the female is the corpus luteum, uterine myometrium and ovulatory follicles. In the
female PGF2α cause luteolysis and can also cause the induction of tone and contractions within
the uterus. It plays an important role in partuition in ruminants.

If a pregnancy is to remain viable then luteolysis needs to be avoided and this is achieved where
concentrations of PGF2α remain below a threshold level allowing the corpus luteum to continue
to secrete progesterone and thus maintain pregnancy. There are two main factors involved in
the regulation of uterine secretions of PGF2α; oxytocin secretions from the corpus luteum and
molecules secreted by the developing embryo that facilitate the maternal recognition of
pregnancy.

Oxytocin secretion via the corpus luteumstimulates endometrial production of PGF2α and by the
end of the luteal phase the concentration of oxytocin and the number of oxytocin recptors
within the endometrium allow the production of enough PGF2α to breach the threshold level and
cause luteolysis. During pregnancy the embryonically produced pregnancy
recognitionmolecules inhibit the secretion of PGF2α from the endometrium ensuring that
luteolysis cannot occur.

Normally the concentration of PGF2α in arterial blood is relatively low due to extensive
metabolism by PGF2α-dehydrogenase (in especially the lungs). These levels are below the
threshold required to cause luteolysis as PGF2α production in early gestation is low.

The ovarian artery is wrapped around the uterine vein. This creates a countercurrent
mechanism by which the lipid soluable prostaglandins are able to diffuse from the uterine vein
into the ovarian artery. During the latter stages of the luteal phase as PGF2α production increases
luteolysis will occur as PGF2α Is able to reach its target in the ovary before being metabolized in
systemic circulation.

Horses and pigs do not poses this countercurrent mechanism. In these spp. the [PGF2α-
dehydrogenase] in systemic circulation is much lower in order to induce luteolysis when
Prostaglandin concentration rises.

Prostaglandin (PGE2)
PGE2 is another form of prostaglandin that is produced by the ovary, uterus and embryonic
membranes. This form of prostaglandin also has other important roles including vasodilation,
smooth muscle relaxation, and inhibition of the release of noradrenaline from sympathetic
nerve terminals.

In females it’s target tissue is the cervix (it is a potent cervical dilator), corpus luteum and the
oviduct where it helps induce ovulation and the secretion of progesterone from the corpus
luteum. PGE2 also plays an important role during labour where it aids the softening of the cervix
in animals with a soft-type cervix(equine and human) and aids stimulation of uterine
contractions. It can thus be used to prepare the tract for parturition.
 Human Chorionic Gonadotrophin (hCG)

hCG is a form of glycoprotein that is synthesised within the trophoblast cells of a blastocyst. hCG
is particularly important in primate reproduction where it has a similar effect to LH in
stimulating the continued production of progesterone and oestrogens. This represents part of
the system involved in foetal-maternal communication and pregnancy recognition. Primate
blastocysts therefore produce hCG in relatively high concentrations during the first 3 months of
pregnancy. hCG has also been suggested to play a role in defence of the embryo from the
maternal immune system during the initial stages of pregnancy. In males hCG increases the
growth of the foetal testes.

As hCG is only produced by embryonic cells, the presence of this hormone within maternal
blood can be used for pregnancy confirmation.

Equine Chorionic Gonadotrophin (eCG)

eCG is a form of glycoprotein that is produced from chorionic girdle cells. Chorionic tissues in
horses as well as primates also form hormones. eCG is formed in foetal endocrine cells and is
found within the maternal circulation. eCG is thought to play a similar role in horses to hCG in
primates in terms of pregnancy recognition. Foetal production of eCG is highest between 30-70
days of pregnancy. The primary target of eCG are the ovaries where they faciliate the formation
of the accessory corpora lutea and ensure that progesterone production is maintained.

eCG is also thought to stimulate follicular growth and ovulation in the horse. If eCG is given to
other species it acts in a similar manner to FSH and therefore eCG is often used to induce super-
ovulation in species where a large number of oocytes are required for embryo transfer.

Placental Lactogen (PL)

Placental lactogen is a form of protein that is produced by the placenta and is chemically close in
composition to growth hormone. The primary target tissue of PL are the mammary glands
where they stimulate the growth of alveoli during pregnancy.

PL is also referred to as Chorionic Somatomammotropin (CS).

Relaxin

Relaxin is produced mainly by the corpus luteum in most species and in the placenta(main
contributor in the equine) and ovaries throughout pregnancy. During pregnancy relaxin
prevents the initiation of uterine contractions, together with progesterone. Relaxin
accumulates troughtout pregnancy and is released in lare amounts a few days before partus.
Its target organs are the cervix, vagina, pubic symphesis and related structures. Relaxin is
responsible for the softening and relaxation of connective tissues in the cervix, muscles and
ligaments in the pelvis prior to parturition. Estradiol priming is required for this. This
relaxation of tissues via relaxin is performed in conjunction with prostaglandin.