The hormones which stimulate the ovaries and testis

The reproductive system in males and females aredependent on the accurate functioning of a few hormones.

The Hypothalamic-Pituitary Gonadal (HPG) axislays out the key pathways taken by these hormones to maintain and controlreproductive function. (Kanasaki et al., 2017) Gonadotrophin-releasing hormone (GnRH) is a hypothalamic peptide which stimulates the pituitary causingthe release of gonadotrophins, hormones which stimulate the ovaries and testis resultingin the release of sex steroids. This regulated axis is prone to pathologydepending on age, race or genetic cause.

Due to this susceptibility to diseaselead to the discovery of GnRH analogues, agonist and antagonist, which aided inthe treatment of hormone related pathology.  These analogues functioned by shutting downthe HPG axis preventing the release of gonadotrophins which stimulate gonadsfor the release of androgens and oestrogen. The gonadal hormones allow forsexual maturation, when this prematurely occurs, GnRH analogues are able tooffset the early active axis allowing for puberty to be delayed till anappropriate age. Additionally, the lack of sex steroids as a result of HPG shutdown will help maintain hormone-related cancers such as prostate cancer. As a key regulator of this system, the Gonadotrophin-releasing hormone, locatedon chromosome eight is synthesised as a pre-pro hormone by a small group ofneurons 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 acidsequence 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, theGnRH-associated peptide (GAP) and the three amino acids that join the twotogether. After another processing to form the GnRH decapeptide, the hormone isthen transported in granules to the median eminence of the hypothalamus. (Doctr,2018) The neuronal axons terminate near the pituitary and release the finaldeca-peptide hormone, co-secreted with GAP, into the portal circulation in apulsatile fashion where it reaches the gonadotrophic cells in the anteriorpituitary.

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(Tsai, 2005) The function of GAP is stillunknown.Once the hormone hasreached its destination it binds to its G-coupled protein receptors of the cell membrane, linked to Gaq. (Doctr, 2018) This results in theactivation of phospholipase C which cleaves a phospholipid, during this process phosphatidylinositol4,5-bisphosphate (PIP2)  iscleaved into diacyl glycerol (DAG) and  inositol1,4,5-trisphosphate (IP3).

DAG continues to be bound to the membranewhile IP3 is released into the cytosol. Within the cytosol IP3 moves to bind toits receptors on calcium channels causing an intracellular rise in calcium. (Reuters, n.d.) The intracellular rise in calciumprovokes the release of the gonadotrophins Luteinizinghormone (LH) or Follicle-Stimulatinghormone (FSH). (Kanasaki et al., 2017) As DAG continues itsstimulation of Protein Kinase C, it goesand indirectly causes the upregulation of FSH or LH production resulting in anincrease of gonadotrophins. LH and FSH are released in a pulse-like fashion dueto the fact that GnRH is pulsatile.

In females, FSH is responsible forfollicular growth where it primarily affects the granulosa cells to convertandrogens from the theca into estradiol. LHstimulates the theca cells of the follicle to produce androgens which aids inestrogen production, also in females, a sustained high levels of estrogen releasesnegative feedback on GnRH resulting in a mid-cycle surge of LH causing ovulation. In males, FSH affects the serotollicells to secrete androgen binding protein which binds testosterone to stimulatespermatogenesis. LH stimulates the leydig cellsto produce the androgens: testosterone, androstenedione anddehydroepiandrosterone.

(Mcb.berkeley.edu, n.d.) When measuring GnRHlevels, LH is often used since it mirrors the GnRH pulse.

 GONADOTROPHINS            GnRH pulse frequency determines whether thegonadotrophic cells will produce LH or FSH. When the pulse rate of GnRHis high it promotes the synthesis of LH, whereas a slow pulse rate willstimulate FSH production. (Thompson and Kaiser, 2014) These gonadotrophinsare glycoproteins synthesized in the same gonadotrophic cells and are structurallyrelated to human chorionic gonadotrophin(hCG) and thyroid stimulating hormone(TSH). Both, LH and FSH are heterodimers containing one alpha chain and onebeta chain. (Cooke, Mullen and Crowe, 2018)Between the two hormones and other glycoproteins, the amino acid sequences ofthe alpha subunits are similar due to the fact that it arises from the samemRNA strand. Studies conducted present that the alpha subunit sequencing is similarbetween varying species.

The cysteines within the sequence are universallyconserved implying that the di-sulphide bonds that forms are also commonamongst species; indicating that the folding of the peptides are identical. (Cooke, Mullen and Crowe, 2018) The betasubunit is known to give specificity to the hormone and therefore has differentsequencing between gonadotrophins. Around 115 amino acids long of differentsequencing, the beta subunit determines between FSH or LH. LH and hCG have asimilar 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 theproduction of the beta-chain, it has no effect on the alpha-chain which isbeing produced at all times. (Thompson and Kaiser, 2014) Since the time of itsdiscovery, GnRH and its analogues are in clinical use as treatment for manyreproductive disorders. Naturally, with the understanding of the amino acidsequencing of the peptide (Figure 2), lead to the development of antagonistsand agonists; analogues of GnRH.  (Kumarand Sharma, 2014) The two forms of analogues act to supress the HPG axis.

AGnRH 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 thesignalling pathway from its receptor in approximately two weeks. A GnRHantagonist directly inhibits the GnRH receptor to immediately prevent thesecretion of FSH and LH. (Tarlatzis and Bili, 2004)The development of GnRH analogues is conducted through the alteration of thenative structure; exchanging L-isomers with D-isomers. (Padula, 2005) To increase the half-life ofnative 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 100times whereas the addition of D-Serine causes a ten times increase. Within anantagonist the first three amino acids from the carboxyl end, the glycine atposition six and the terminal alanine are altered, allowing increased affinityand tight binding of the peptide to the receptor.

(Miller et al. 2004,) Furthermore,the Arginine at position eight determines receptor specificity and thereforealso altered in antagonists.   

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