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GnRH is the fundamental hypothalamic hormone regulating reproduction. GnRH is a decapeptide that was first isolated from a mammalian hypothalamus in 1971 by R.Guillerman and A.Schally. GnRH is sometimes referred to as the "master" hormone has an influential role to play in puberty, reproduction and the pituitary-gonadal axis. Two isoforms of GnRH have been identified in the mammalian central nervous system, GnRH-I and GnRH-II.
GnRH is synthesized in specialized GnRH neurons of the hypothalamus as a prohormone and after appropriate enzyme processing; GnRH is packaged in storage granules that are transported down axons to the external zone of the medial eminence (Fink 1988). GnRH neurons are found in the area surrounding the olfactory placode during prenatal development, and then the GnRH producing cells migrate through the nasal system into the medio-basal-hypothalamus (Bless et al 2005).
The hormone is released in rhythmic pulses from the nerve endings of the GnRH neurons into the hypophyseal portal system every 60-90 minutes. While GnRH neurons are likely to have an intrinsic pulsatile secretory pattern, many neurotransmitters including dopamine and NPY may modify the GnRH secretory pattern. The mechanism behind the pulsatile nature of GnRH release is believed to be the GnRH pulse generator and primate studies have shown the potential location to be the medio-basal hypothalamus, however further studies are required to confirm this.
In humans, two isoforms for GnRH receptors exist; a receptor for GnRH I and a receptor for GnRH II. The receptors are both members of the G-protein coupled receptor (GPCR) family. Activation of the G-protein pathway occurs upon GnRH binding to its corresponding receptor on the pituitary gonadotropes. Receptor binding activates Gq, which stimulate increased phosphoinositol turnover by activating phospholipase C. This enzyme leads to the generation of several secondary messengers, such as diacylglycerol which leads activation of protein kinase C and inositol tris-phosphate which releases intracelluar Ca2+. Both events results in gonadotrophin synthesis which is realised across the stimulation of the steroidogenic factor 1 (111,112 Schenider et al), followed by secretion of LH and FSH. LH and FSH are released into the systemic circulation, travelling to the target reproductive organs where both gonadal hormone and gamete production are controlled.
GnRH regulates the synthesis and secretion of gonadotrophins and this is highlighted with its involvement in the menstrual cycle. The frequency of pulses is highest at the ovulatory LH surge and lowest during the luteal phase of the ovarian cycle is all of a result from changes in GnRH frequency. Moreover, LH is stored and largely dependant on GnRH for secretion, while FSH tends to be constitutively secreted and more dependant on biosynthesis for secretion (Millar 2005). An interesting phenomenon known as "self priming" also induces the release of LH and FSH, whereby GnRH increases the potential pituitary LH and FSH responsiveness to its own action (DeKoning J et al 2001).
Human chorionic gonadotrophin (hCG) is another type of gonadotrophin but exclusively synthesised in the synctiotrophoblast. hCG is released into the maternal circulation where it binds onto the LH/hCG receptors of the luteal cells in the ovary stimulating progesterone release that itself actively promotes luteal survival by autocrine stimulation.
LH, hCG and FSH are heterodimers and glycoprotein hormones, each consisting of an Î± and a Î² subunit. The Î±-subunit is identical in all of the gonadotrophins whereas the Î² subunit confers the specificity to the hormone. It is the Î² subunits that confers the hormones bioactivity, half life, specific biologic action and is responsible for the specificity of the interaction with its cognate receptor. Interstingly hCG's Î² subunit shares a 80% homology to LH and can bind onto LH receptors.
Gonadorelin is a synthetic decapeptide that has been developed for clinical use, which has the same amino acid sequence as GnRH. With Gonadorelin having the same amino acid structure, its pharmacological and toxicological profile is identical to that of GnRH. Gonadorelin hydrochloride has been used for diagnostic testing, to distinguish between primary and secondary hypogonadism, hypogonadism being defined as impaired gonadal function with resultant decreased sex steroids.
To distinguish between the two forms of hypogonadism, systemic levels of LH and FSH are measured before and after Gonadorelin administration. Upon Gonadorelin administration an increase in the levels of gonadotrophins LH and FSH would be indicative of a patient with secondary hypogonadism. Secondary hypogonadism is characterized by inappropriately low concentrations of gonadotrophins due to a defect involving either the hypothalamus or pituitary gland. Secondary hypogonadism involving defects at the hypothalamus are known as hypogonadotrophic hypogonadism (HH). The results of this test should be interpreted with caution and considered along with results of other clinical and laboratory evaluations.
Clinical manifestations of HH depend on the stage of development at which the deficiency in the reproductive axis occurred. Signs of gonadotrophin deficiency may occur at birth and manifest as micropenis and cryptochidism in infant boys. Cryptochidism occurs when one or both testes fail to descend through the inguinal canal to the scrotum, which can potentially lead to testicular tumour formation and infertility. Despite the primary treatment being surgery, hormonal therapies have also been used with native GnRH given intranasally. Native GnRH given intranasally stimulates the pituitary gonadotropes to produce gonadotrophins. LH secretion stimulates Leydig cells to produce testosterone which is believed to have some involvement in testicular descent.
At puberty, individuals with HH have incomplete development of secondary sexual characteristics due to lack of gonadotrophins which are vital for oestrogen and androgen production in females and testosterone in males. Delayed puberty is defined as the lack of secondary sexual characteristics in girls by the age of 14 and boys by the age of 15. Pulsatile release of GnRH elicits pulsatile LH and FSH release thereby stimulating oestrogen and androgen production in females and testosterone in males. Upon LH stimulation of the Leydig cells in males, cholesterol is converted to testosterone in a series of reactions with increased activity of the regulating enzymes such as cholesterol desmolase. In females, LH binds to theca cells of the ovary where like men cholesterol is converted to testosterone and another androgen androstenedione which is converted to oestradiol, via aromatase. The rise of sex hormones levels is essential for puberty progression and pulsatile gonadotrophins are also required to stimulate spermatogenesis in men and folliculogenesis in women.
GnRH must be administered in a pulsatile manner as with activation of most GPCRs causes desensitization where the response wanes despite constant and excess stimulation. This occurs during G-protein phosphorylation causing uncoupling between receptor and its relevant pathways. Upon receptor activation the hormone-receptor complex migrates to specialized areas of the cell surface called "coated pits", where they are internalised. Once inside the cell GnRH is degraded by peptidase and the receptor is recycled back to the cell surface or degraded by lysosomes. The regulation of GnRH receptors is an example of homologous regulation but it is also important that receptor recycling occurs as it promotes resensitisation. Therefore it is vital that GnRH is administered in a pulsatile fashion, which is also discontinuous and that internalisation occurs, so that it allows time for the receptors to recover from desensitisation. Constant GnRH stimulation would cause discontinuous gonadotrophin secretion due to receptor desensitisation.
Gonadorelin acetate is an approved therapy for inducing ovulation for those women that are infertile due to HH. The aim is to induce the growth of a single dominant follicle. This is achieved by administering gonadorelin acetate as a subcutaneous injection but also delivered through a pump set for pulsatile dosing. It is essential that gonadorelin acetate is administered in this manner in order to mimic normal cycle dynamics resulting in ovulation. This therapy offers a clear advantage over traditional treatment with exogenous gonadotrophins, which involves higher rates of both multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) (Carl PJ et al 2006). Side effects for using gonadorelin include headache, light-headedness, nausea and abdominal discomfort.
Native GnRH is rapidly degraded by peptidases, with a half life of 2-4 minutes. To increase the potency and duration of GnRH, analogues were created which are synthetic derivatives of native GnRH with alterations in their chemical structure that result in changes in biologic activity (Casper 1991). Two types of analogues have been distinguished, agonists and antagonists.
The production of GnRH agonists (GnRH-ag) involves at least two alterations in chemical structure that serve to enhance the biologic activity compared to native GnRH. These alterations include substitution for glycine at position 6 for a D-amino acid and deletion for glycine at position 10, usually replaced by N-ethylamide group (Casper 1991). These substitutions make the GnRH-ag resistant to degradation and increase its affinity for the GnRH receptor. Such agonists that have become clinically available are Triptorelin, Leuprolide, Buserelin, Desorelin and Histrelin.
Further crucial functions for GnRH exist on positions 1, 2, 3 and 8. Substitutions at these positions as well as at 6 and 10 have resulted in antagonistic qualities which were represented by its potency and physical-chemical characteristics. The first generation of GnRH antagonists (GnRH-ant) synthesized two decades ago had the disadvantage of being mediocre at their suppressive potential. The second generation of antagonists had great potency but had the main disadvantage of histamine release inducing anaphylactic reactions in some patients, which were later found out to be due to Arginine substitution. This side effect was greatly reduced in the third generation by substituting the appropriate combination of amino acids at position 5, 6 and 8. Such examples of the third generation GnRH-ant are Cetorelix, Ganirelix, Abarelix and Degarelix.
Increasing the lipophilicity of amino acid substitutions are also used in recent GnRH agonist and antagonist preparations which work by increasing the retention of the drug in the body and to the prolong the duration of action (Padula AM 2005).
Before the introduction of GnRH-ag and GnRH-ant in controlled ovarian hyper-stimulation (COH) treatment, the premature LH surge was an undesired event encountered in up to 30% of hyper-stimulation cycles for in-vitro fertilisation (IVF), leading to cycle cancellation before oocyte retrieval was possible (Kiesel 2002). GnRH-ag and GnRH-ant desensitize the pituitary gonadotropes causing gonadotrophin levels to fall. This leads to the prevention of the premature LH surge associated with premature ovulation and lutenisation, which allows a greater flexibility in the timing of ovum pick up (Porter et al 1984).
GnRH agonists bind to the same receptors that native GnRH binds to in the pituitary gonadotropes and hence activate the same G-protein pathway which involves phospholipase C activation. After receptor binding, an internalization of the receptor-peptide complex occurs leading to biological inactivation and receptor recycling. An initial up-regulation of receptors causes an intense release of LH and FSH, also known as the "flare up effect". The resistance of the GnRH-ag to degradation by peptidase markedly prolongs the recycling time (Casper 1991) and as a result, fewer GnRH receptors are present on the cell surface after subsequent injections leading to down-regulation of GnRH receptors which desensitizes the pituitary gonadotropes.
GnRH antagonists also bind to the same receptors that native GnRH binds to in the pituitary gonadotropes but does so in a competitive fashion. GnRH antagonists inhibit gonadotrophin secretion by competitively blocking GnRH receptors without receptor down-regulation. There is no "flare up" effect and an unaltered pituitary responsiveness after cessation of treatment.
IVF treatment currently uses GnRH-ag such as goserelin and buserelin and GnRH-ant such as cetorelix and ganrelix for different protocols for COH. The flare up effect, which is seen as a disadvantage of GnRH-ag in different clinical uses, is actually taken advantage of with the short protocol. The increased FSH secretion during the initial flare up response at the beginning of the cycle prevents the LH surge during stimulation. The occurrence of ovarian cysts is the most common complication of this protocol. Either continuing GnRH-ag or GnRH-ant administration until spontaneous subsidence or draining the cysts with hCG are potential treatment options (Marcus SF et al 2001).
The long protocol is most widely used method use in IVF treatments. The aim is to desensitize the pituitary using GnRH-ag and GnRH-ant at least 2 weeks prior to hMG or FSH administration. However the flare up effect seen with GnRH-ag use may trigger the growth of an increased amount primordial follicles leading up to OHSS which is life threatening in severe cases (MacDougall et al 1992). The use of GnRH-ant can severely reduce the potential of OHSS as no flare up effect is seen.
OHSS is the most serious complication of superovualtion, occurring in around 5% of IVF cycles. In a severe form complications may include deep vein thrombosis, respiratory distress and death (Shenker et al 1978). Careful monitoring and supportive treatment such as heparin may be used until the condition spontaneously resolves.
The immediate reversibility of pituitary suppression after withdrawal of the antagonist provides opportunities for other stimulation strategies with reduced risk for OHSS. This can be achieved with GnRH agonist used for its flare up effect, rather than hCG for the final stage of follicular maturation which may reduce the risk of OHSS (Olivennes et al 1996).
The use of GnRH-ag and GnRH-ant in the ultra long protocol, which was suggested for endometriosis sufferers, is administered 2-6 months prior to ovarian stimulation to minimize endometriotic foci as much as possible during the time of egg retrieval and embryo transfer (Kim et al 1996)
The use of GnRH-ant however shows slightly lower pregnancy and implantation rate than the established GnRH-ag protocols. Low oestradiol patterns preceding oocyte retrieval due to the rapid effect of GnRH-ant (Coccia ME et al 2004) seem to be the most likely reason. There is also a role for GnRH analogues in ovulation induction for those patients with polycystic ovarian syndrome (PCOS) which is characterized by amenorrhea and elevated levels of androgens and LH leading to infertility. Pretreatment with GnRH-ag and GnRH-ant is thought to reduce early pregnancy losses which are usually caused by elevated LH levels. Subsequent gonadotrophins are administered to achieve ovulation induction.
Endometriosis is a disease with an unclear pathogenesis and defined by the presence of endometrial glands and stroma located ectopically outside the uterine cavity. GnRH analogues suppress FSH and LH levels which cause a decrease in oestrogen levels which have been used to relieve pain and reduce the size of the steroid responsive endometriosis. However decreased oestrogen levels induce menopausal type symptoms such as hot flushes, amenorrhoea, vaginal dryness and over time may lead to osteoperosis. To alleviate some of these symptoms appropriate "add-back" therapy is issued which usually is a small amount of oestrogen and progesterone or progesterone alone.
Uterine fibroids are smooth muscle tumours, that are almost always benign, that grow in the wall of the uterus. It is known that oestrogen receptors on fibroids cause the tumour to respond to oestrogen stimulation which induces growth of fibroids. GnRH-ag leuprolide and GnRH-ant cetorelix can help relieve the symptoms of uterine fibroids such as menorrhagia and help in pre-surgical procedure of the removal of the fibroid. GnRH analogues are usually administered several months prior to surgery and as in endometriosis causes a decrease in oestrogen and progesterone levels, which will reduce the size of the fibroids making it easier to remove the fibroids by surgery. GnRH analogues induce a state of amenorrhoea which helps alleviate anaemia that is caused due to menorrhagia.
Approximately 30-40% of human breast cancers grow as sex steroid dependant cancers. LH stimulates the ovaries to produce oestrogens which include oestradiol and this process is responsible for producing up to 90% of circulating oestradiol (Robertson JF et al 2003). The use of GnRH-ant goserelin is to decrease LH production, providing a potential and reversible therapy for breast cancer. The combination of GnRH analogues and tamoxifen, a selective oestrogen receptor modulator blocker, showed more effectiveness than GnRH analogues or tamoxifen alone in advanced breast cancer therapy.
Prostate cancer is also a steroid dependant cancer which relies on testosterone for growth. Using GnRH analogues causes down regulation which ultimately suppresses LH production and therefore testosterone production. When GnRH-ag is used the initial flare up effects lead up to an initial surge in testosterone levels which can cause increased bone pain. However pre-treatment with anti-androgens such as flumatide counteracts these effects and inhibits adrenal androgens. With both GnRH-ag and GnRH-ant levels of testosterone ultimately falls causing loss of libido, impotence and weight gain.
Other cancers such as ovarian and endometrial cancers are believed to produce GnRH and express its receptors. GnRH analogues can be used to inhibit tumour cell growth mainly by blocking cell cycle progression in G0/G1 phase and inducing apoptosis (Kim et al 1999). There is further evidence for direct growth inhibition of GnRH analogues by a GnRH receptor mediated mechanism.
The protection of ovarian function in women undergoing cytotoxic treatment is another clinical use being developed for GnRH analogues. The mechanism by which chemotherapy causes ovarian damage is not completely understood. A protective effect of GnRH analogues administered simultaneously to cytotoxic therapy seems to reduce chemotherapy induced ovarian failure and infertility (Blumenfeld 1996). The flare up effect seen with GnRH-ag use may induce the growth of hormone dependant tumours by production of its cognate steroids.
With most ART protocols prior to stimulation of multiple follicular developments in a technique known as controlled ovarian hyper-stimulation (COH), pituitary down regulation with a GnRH agonist or antagonist to prevent premature lutenisation has become standard.
Human menopausal gonadotrophin (hMG) that was used in the early days of ART contained both LH and FSH, was extracted from the urine of post-menopausual women. High levels of LH were noted to negatively impact fertilization and implantation, leading to the development of gonadotrophins containing predominantly FSH (WD Latash et al 2004). Despite advances leading to purified urinary FSH contamination of urinary proteins remained a problem (Donini P et al 1966).
Commercial gonadotrophins are available via genetically engineered mammalian cell lines. Unlike urinary hMG, which provides a fixed ratio of FSH:LH activity without any possibility to differentially adjust the FSH or LH dose, the use of recombinant gonadotrophins allow maximal flexibility in relation to timing and dose of supplementation (Ludwig et al 2005). Furthermore pharmaco-economic studies indicate that urinary gonadotrophins are no more cost effective than the recombinant products (Balasch et al 2001).
Recombinant FSH (rFSH) and LH (rLH) are produced in Chinese hamster ovary cells (CHO). CHO cells are transfected with a genomic clone containing the complete FSH or LH Î±, Î² coding sequences. The resultant protein product closely mimics FSH or LH in the body and specifically homogenous with no contamination with urinary proteins. Purified urinary FSH and LH and more recently rFSH and rLH have been used for COH.
With the addition of FSH folliculogenesis can occur, starting with antral follicle development which is FSH dependant. FSH causes an increase in granulosa cell proliferation as well as inducing and maintaining LH receptors. FSH also stimulates aromatase allowing conversion of androgens, produced by theca cells, into oestradiol, produced by the granulosa cells.
Follicles will become atretic unless exposed to tonic levels of FSH and LH, so expanding antral follicles will also die unless exposed to LH. hCG administration recreates the LH surge which coincides with the appearance of LH receptors on the outer granulosa cells. hCG used in various clinical applications are usually extracted from urine of pregnant women. In assisted reproduction techniques (ART) purified urinary hCG preparations, such as Pregynl, have been used for decades as a surrogate LH in COH protocols. Within a couple of hours of hCG administration dramatic changes occur in the oocyte. Meiotic and cytoplasmic maturation of the oocyte is stimulated by the hCG surge, despite no hCG/LH receptors existing on the oocyte. Its effect must be mediated by via the cumulus cells of the follicle, where it is thought to act by suppressing cAMP levels.
hCG also directly affects the growth and endocrinological activity of the follicle cells with pre-ovulatory growth in follicular size correlating with the pattern of steroid secretion. Within a couple of hours of the hCG surge, there is a transient rise in the output of follicular oestrogens and androgens and this rise coincides with distinctive changes in the thecal and granulosa cell layers. The changes in these layers no longer convert androgen to oestrogen, but instead induce progesterone production via the newly acquired LH/hCG receptors. However egg retrieval around 35 hours after hCG administration occur just prior to ovulation as if ovulation occurs the eggs cannot be retrieved.
With slight differences in their receptor affinities and half lives, the hCG surge is prolonged two times with that of the LH surge that naturally occurs (Howles 2000). It has been suggested that this prolonged period of stimulation may be a contributory factor in the development of OHSS. Evidence from recent studies has suggested that it may be possible to use rLH instead of hCG to induce ovulation in women undergoing ART (Gurgan T et al 2005).
Studies in humans have found the pharmokinetic profile of rLH to be virtually similar to that of circulating LH suggesting that it may be more appropriate than hCG for inducing the LH surge (Howles 2000). No differences were found in terms of oocyte retrieval or the proportion of fertilized oocytes.
LH supplementation in patients undergoing ovarian stimulation with FSH is controversial. In general it can be concluded that in most patients FSH alone is sufficient to achieve optimal results in ovarian stimulation for assisted reproduction. It is believed that endogenous LH concentrations caused by the down regulation with GnRH agonists should be greater than the threshold concentration of 2.5 IU/L which is sufficient to maintain adequate androgen and aromatase activity for follicular steroidogenesis (Merviel P et al 2004). LH concentrations this low are required as only less than 1% of follicular LH receptors need to be occupied to permit normal steroidogenesis (Chappel 1991).
Patients that are poor responders to an FSH-only protocol can be rescued by rLH supplementation (Laml et al 1999). It was suggested that the poor ovarian response to rFSH only, seen mostly in young normogonadotrophic patients, is due to profound depression of LH after down regulation with GnRH agonists (De Placido et al 2005). Studies concluded that rLH supplementation in the late follicular phase in ovarian stimulation showed increased numbers of mature oocytes, implantation and pregnancy rates compared to rFSH alone.
With older patients the decreasing number of functional LH receptors and ovarian responsiveness has been suggested as a possible mechanism behind the beneficial effects of LH supplementation (Vikho et al 1996). GnRH antagonist's cetorelix and ganirelix, like GnRH agonists, have shown to prevent premature LH surge with minimal dosage. However the physiological LH concentrations during the early follicular phase show a rapid decrease after GnRH antagonist initiation in the later stages of the follicular phase (Caglar 2005). The decrease in some cases takes the concentration below the threshold value to maintain adequate androgen and aromatase activity for follicular steroidogenesis and hence LH supplementation may need to be given.
The gonadotrophins can also be used in a similar manner to induce ovulation in women that are infertile due to HH, the major difference being that circulating levels of gonadotrophins are originally much lower than that of IVF patients hence GnRH-ag and GnRH-ant are not required. FSH and LH are required for optimal stimulation of follicle growth and development is based on the data that in the absence of LH, FSH stimulated follicle growth results in diminished oestradiol concentrations, which are necessary for endometrial growth for implantation (Caglar et al 2005).
Most patients with HH do not have the threshold concentration of LH required to achieve optimal follicular growth and oestrogen synthesis. Many studies concluded that women with HH required the combination of 75 IU/day rLH and 150 IU/day rFSH, which is administered as intramuscular or subcutaneous injections, is required for optimal follicular development, adequate serum oestradiol concentrations, endometrial thickness and ability to luteinize after hCG administration (Caglar et al 2005). hCG is given with the same intentions as with IVF patients to induce oocyte maturation but also to cause ovulation. As discussed before, upon the hCG surge various changes in the thecal and granulosa cell layers lead to progesterone production. Progesterone is required for the inhibiting the growth of less mature developing follicles and is essential for ovulation. hCG also directly influence collagenase and gelatinase activity which is integral in the bio-chemistry of ovulation.
Ovulation induction in this manner can be achieved patients with PCOS which is the most common cause for anovualtory infertility. In terms of PCOS, excess LH and androgen levels may individually or collectively play a direct or indirect role in augmenting steroidogenesis but arresting follicular growth. So in this instance FSH would be administered alone, and hCG to be administered appropriately.
Complications associated with the use of gonadotrophins for ovulation induction and IVF is the possibility of OHSS. OHSS as described before involves abdominal pain; enlarged ovaries and fluid build up in the abdomen. Also multiple pregnancies are another potential disadvantage for this particular use of gonadotrophins for ovulation induction. Other side effects of using rLH and rFSH include headaches, abdominal pains and nausea.
Gonadotrophins may also be used to treat male infertility. Treatment consisting of rFSH and rLH is administered to increase spermatogenesis in men that are infertile due to HH. LH stimulates Leydig cells to produce testosterone, but also binds to androgen receptors within the Sertoli cells thereby supporting spermatogenesis. However for complete restoration and maintenance of spermatogenesis, LH stimulation of Leydig cells is not sufficient, FSH is required which binds to receptors on the basolateral surface of Sertoli cells. The FSH receptor levels vary with the cycle of the seminiferous tubule, but do so in opposite fashion to the androgen receptors. FSH and testosterone oscillate to act synergistically on the Sertoli cell to allow spermatogenesis to go onto completion. Hence there is a need to administer both rFSH and rLH to successfully induce spermatogenesis in infertile men.
Other uses of hCG include the detection of pregnancy with a semi quantitative test with a urine sample. Urine samples from pregnant women around 2 weeks after fertilisation are found to contain rising levels of hCG and is considered a useful and reliable test for pregnancy. hCG is also used clinically as specific marker for various diseases and cancers. hCG is especially specific for trophoblastic tumours of placental and germ cell origin, thus treatment of relapsing choriocarcinomas is often initiated on the basis of rising hCG levels (Stenman UH et al 2004). While these tumours produce the full heterodimeric hormone, many non trophoblastic tumours such as ovarian and cervical cancer express hCGÎ² where elevated levels are a sign of an aggressive disease (Stenman UH et al 2004).
In summary, native GnRH and GnRH analogues for clinical use are based upon the knowledge of their physiology and molecular biology. Despite acting on the same receptors opposing effects are achieved, with native GnRH promoting gonadotrophin release and GnRH analogues down regulating gonadotrophin release. The uses therefore will differ, with native GnRH being used in either deficient GnRH or gonadotrophin settings and GnRH analogues being used for excess GnRH secretion or gonadotrophins. However the use of GnRH and its analogues both intertwine with its use for ovulation induction, with GnRH analogues being supported by gonadotrophin use.
The use GnRH-ant offers several potential advantages over GnRH-ag for the use in clinics. The use of GnRH-ant for IVF shows no "flare up" effect, rapid action and shorter treatment regime. This will therefore reduce the incidence of OHSS and the number of injections needed which will reduce the mild transient local injection site reactions. The flare up effect of GnRH-ag is a further disadvantage upon the use of treatment in various cancers, where the effect can aggravate the tumour. The flare up effect however is taken advantage of and used in the short protocol of IVF.
However the use of GnRH-ant in some clinical scenarios such as the protection of ovarian function in women undergoing cytotoxic treatment and prostatic cancer has little clinical data and in general has limited licenses available for wider use. Also GnRH-ant with its potent and immediate action may reduce LH concentrations below the threshold value, hence causing the need for LH supplementation for particular patients undergoing IVF.
It is believed that GnRH plays a paracrine role in the placenta and gonads as well as acting as a neurotransmitter in the central and peripheral nervous system (Millar 2005). GnRH is also thought to play an autocrine role in GnRH neurons, immune cells, breast and prostate cancer cells which could give native GnRH future roles to play (Millar 2005).
The safety aspects of GnRH analogues, related to direct effects on the extra pituitary structures such as ovary, oocytes and granulosa cells is a matter of debate (Huirne JAF et al 1999). Based on the lower implantation rates of the higher dose groups in a study, the possibility of direct effect of antagonists on human embryos is of concern. Also only open trials have been conducted in terms of comparing GnRH-ag or GnRH-ant for IVF and there is a need to conduct double blinding trials in order for unbiased comparisons to be made (Huirne JAF et al 1999).
Future developments may employ high thorough-put screening of large chemical libraries to identify orally active small molecule agonists of human LH or FSH receptors that might prevent the need to inject gonadotrophins (Perlman S et al 2003). Also rFSH being developed (FSH-CTP) now with a longer half life has been engineered by adding amino acids and carbohydrate residues (Fares et al 1992). This significantly increase the half life compared to other rFSH compounds, which will reduce the need for daily gonadotrophin injections (Fares et al 1992).
To add or not to add LH for ovulation has been a debate even discussed today, with the belief that hCG can play an important positive role if administered in the follicular phase in IVF cycles (Filicori et al 2005). As of yet not single, sufficiently large prospective randomized trial supports the assumption that the addition of the LH activity to rFSH leads to higher ongoing pregnancy rates. Furthermore there seems to be a relation between low LH concentrations and a higher implantation and pregnancy rate.
In conclusion it can be seen that GnRH and its analogues and gonadotrophins have many important roles to play in terms of clinical use which was achieved by the knowledge of the relevant physiology and molecular biology. Overall it appears that with ongoing developments about further functions of GnRH and it analogues and gonadotrophins, further roles in the clinics can be achieved. Also trials need to be conducted which will see the inevitable replacement of current clinical management.