The hormones which stimulate the ovaries and testis

The reproductive system in males and females are
dependent on the accurate functioning of a few hormones. The Hypothalamic-Pituitary Gonadal (HPG) axis
lays out the key pathways taken by these hormones to maintain and control
reproductive function. (Kanasaki et al., 2017) Gonadotrophin-releasing hormone (GnRH) is a hypothalamic peptide which stimulates the pituitary causing
the release of gonadotrophins, hormones which stimulate the ovaries and testis resulting
in the release of sex steroids. This regulated axis is prone to pathology
depending on age, race or genetic cause. Due to this susceptibility to disease
lead to the discovery of GnRH analogues, agonist and antagonist, which aided in
the treatment of hormone related pathology.  These analogues functioned by shutting down
the HPG axis preventing the release of gonadotrophins which stimulate gonads
for the release of androgens and oestrogen. The gonadal hormones allow for
sexual maturation, when this prematurely occurs, GnRH analogues are able to
offset the early active axis allowing for puberty to be delayed till an
appropriate age. Additionally, the lack of sex steroids as a result of HPG shut
down will help maintain hormone-related cancers such as prostate cancer.

As a key regulator of this system, the Gonadotrophin-releasing hormone, located
on chromosome eight is synthesised as a pre-pro hormone by a small group of
neurons located in the arcuate nucleus and preoptic area in the hypothalamus. (Tsai,
2005) This version of the hormone contains a signal peptide, a 23-amino acid
sequence that allows it to be secreted from cells. (Figure 1.)  It is then cleaved off to form a pro hormone,
derived of 69 amino acids containing: GnRH, the
GnRH-associated peptide (GAP) and the three amino acids that join the two
together. After another processing to form the GnRH decapeptide, the hormone is
then transported in granules to the median eminence of the hypothalamus. (Doctr,
2018) The neuronal axons terminate near the pituitary and release the final
deca-peptide hormone, co-secreted with GAP, into the portal circulation in a
pulsatile fashion where it reaches the gonadotrophic cells in the anterior
pituitary. (Tsai, 2005) The function of GAP is still
unknown.Once the hormone has
reached its destination it binds to its 
G-coupled protein receptors of the cell membrane, linked to Gaq. (Doctr, 2018) This results in the
activation of phospholipase C which cleaves a phospholipid, during this process
 phosphatidylinositol
4,5-bisphosphate (PIP2)  is
cleaved into diacyl glycerol (DAG) and  inositol
1,4,5-trisphosphate (IP3). DAG continues to be bound to the membrane
while IP3 is released into the cytosol. Within the cytosol IP3 moves to bind to
its receptors on calcium channels causing an intracellular rise in calcium. (Reuters, n.d.) The intracellular rise in calcium
provokes the release of the gonadotrophins Luteinizing
hormone (LH) or Follicle-Stimulating
hormone (FSH). (Kanasaki et al., 2017) As DAG continues its
stimulation of Protein Kinase C, it goes
and indirectly causes the upregulation of FSH or LH production resulting in an
increase of gonadotrophins. LH and FSH are released in a pulse-like fashion due
to the fact that GnRH is pulsatile. In females, FSH is responsible for
follicular growth where it primarily affects the granulosa cells to convert
androgens from the theca into estradiol. LH
stimulates the theca cells of the follicle to produce androgens which aids in
estrogen production, also in females, a sustained high levels of estrogen releases
negative feedback on GnRH resulting in a mid-cycle surge of LH causing ovulation.

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 In males, FSH affects the serotolli
cells to secrete androgen binding protein which binds testosterone to stimulate
spermatogenesis. LH stimulates the leydig cells
to produce the androgens: testosterone, androstenedione and
dehydroepiandrosterone. (Mcb.berkeley.edu, n.d.) When measuring GnRH
levels, LH is often used since it mirrors the GnRH pulse. GONADOTROPHINS            GnRH pulse frequency determines whether the
gonadotrophic cells will produce LH or FSH. When the pulse rate of GnRH
is high it promotes the synthesis of LH, whereas a slow pulse rate will
stimulate FSH production. (Thompson and Kaiser, 2014) These gonadotrophins
are glycoproteins synthesized in the same gonadotrophic cells and are structurally
related to human chorionic gonadotrophin
(hCG) and thyroid stimulating hormone
(TSH). Both, LH and FSH are heterodimers containing one alpha chain and one
beta chain. (Cooke, Mullen and Crowe, 2018)
Between the two hormones and other glycoproteins, the amino acid sequences of
the alpha subunits are similar due to the fact that it arises from the same
mRNA strand. Studies conducted present that the alpha subunit sequencing is similar
between varying species. The cysteines within the sequence are universally
conserved implying that the di-sulphide bonds that forms are also common
amongst species; indicating that the folding of the peptides are identical. (Cooke, Mullen and Crowe, 2018) The beta
subunit is known to give specificity to the hormone and therefore has different
sequencing between gonadotrophins. Around 115 amino acids long of different
sequencing, the beta subunit determines between FSH or LH. LH and hCG have a
similar beta-chain sequence due the fact that they bind to the same receptors,
however, hCG has an additional 24 amino acids and carbohydrates at the C-terminus.

(Doctr, 2018) The GnRH pulse controls the
production of the beta-chain, it has no effect on the alpha-chain which is
being produced at all times. (Thompson and Kaiser, 2014)

Since the time of its
discovery, GnRH and its analogues are in clinical use as treatment for many
reproductive disorders. Naturally, with the understanding of the amino acid
sequencing of the peptide (Figure 2), lead to the development of antagonists
and agonists; analogues of GnRH.  (Kumar
and Sharma, 2014) The two forms of analogues act to supress the HPG axis. A
GnRH agonist activates the GnRH receptor causing the flare effect, where an initial surge of FSH and LH are secreted,
followed by the downregulation of these gonadotrophins by detaching the
signalling pathway from its receptor in approximately two weeks. A GnRH
antagonist directly inhibits the GnRH receptor to immediately prevent the
secretion of FSH and LH. (Tarlatzis and Bili, 2004)

The development of GnRH analogues is conducted through the alteration of the
native structure; exchanging L-isomers with D-isomers. (Padula, 2005) To increase the half-life of
native GnRH the Glycine at position 6 is replaced by a D-
amino acid to form an agonist.  (Magon,
2011) For example, the addition of D-Tryptophan increases the potency by 100
times whereas the addition of D-Serine causes a ten times increase. Within an
antagonist the first three amino acids from the carboxyl end, the glycine at
position six and the terminal alanine are altered, allowing increased affinity
and tight binding of the peptide to the receptor. (Miller et al. 2004,) Furthermore,
the Arginine at position eight determines receptor specificity and therefore
also altered in antagonists.

 

 

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