Gnrg drugs. Pharmacological group — Anticancer hormonal agents and hormone antagonists

Some practical aspects of the use of GnRH agonists in IVF cycles. Discussion.

Gonadotropin-releasing hormone (GnRH) and its analogues. As an introduction.

The repetitive periodicity of the change of day and night over millions of years of evolution has formed a special life cycle highly organized living organisms, many of which have adapted to this cyclical periodicity by acquiring an "innate circadian pacemaker", the so-called circadian clock. The main function of the circadian pacemaker is to synchronize and organize in time all the main biochemical, physiological and behavioral processes of a living organism. The main conductor of the circadian rhythm is the nervous and endocrine systems, the central structures of which are not only in close proximity to each other, but are sometimes represented by one group of cells that have both the ability to generate and process a nerve signal and the ability to synthesize biochemically highly active hormonal compounds.

The circadian pacemaker is located in the suprachiasmatic nuclei of the hypothalamus. The light signal recognized by the retina through the optical-hypothalamic pathway excites neurons in the suprachiasmatic nuclei and, through norepinephrine, corrects the rate of melatonin production by the pineal gland, regulating the activity of the underlying hypothalamic endocrine structures under control. The activation of the reproductive system occurs due to the gonadotropin-releasing hormone (GnRH) of the hypothalamus, the only target of which is the adenohypophysis gonadotrophs capable of synthesizing follicle-stimulating (FSH) and luteinizing (LH) hormones, and GnRH activity models the levels of both gonadotropins. Neurons capable of producing a neurotransmitter similar in chemical structure to GnRH, called GnRH-II, are found outside the boundaries of the hypothalamus (in the limbic system, hypocampus, olfactory region, etc.), representing probably also intermediary mechanisms that provide, in particular, gendered behavioral responses ( Sealfon SC, 1997; Millar RP et al., 2004). GnRH-secreting (GnRH-I) and GnRH-II neurons have different embryonic origins. GnRH-I neurons are formed in the region of the olfactory plate outside the brain, only after that, during the period of embryonic development, they migrate to the arcuate nuclei of the mediobasal parts of the hypothalamus, the bottom of the third ventricle, and GnRH-II neurons originate from the embryonic tissues of the midbrain.

In 1971, a group of scientists from the laboratory of the New Orleans Institute, led by Andrew Schally, managed to unravel the chemical structure of GnRH (Schally AV et al., 1971). In isolation, Roger C. L. Guillemin was able to synthesize and describe the chemical formula of GnRH, for which both scientists, together with Rosalyn Sussman Yalow, were awarded the Nobel Prize in Physiology or Medicine in 1977.

By itself, GnRH is the main central endocrine regulator of the reproductive system, controlling the entire complex process of follicular growth, ovulation, luteal activity in women and spermatogenesis in men, in addition, ensuring the interaction of the central nervous and reproductive systems. Interestingly, GnRH loses its importance during pregnancy, passing the reins of power to hormonally active compounds synthesized by elements of the fetal egg. It can be neatly noted that there is something symbolic in this.

GnRH has a fairly simple chemical structure of 10 amino acids (decapeptide), is synthesized intracellularly, and then transported along axons to synapses. Secretion of GnRH occurs in a pulsed mode by the terminal sections of neurosecretory neurons in the preoptic area of ​​the hypothalamus initially, as well as a number of other neuropeptides in the form of a much more complex compound, a 92-amino acid peptide prohormone, which combines a signal peptide and a GnRH-associated peptide (Sealfon SC, 1997). Through the portal circulatory system, GnRH enters the adenohypophysis every 71-216 minutes. Modulation of plasma concentrations of FSH and LH is produced by changing the frequency of GnRH impulses, which is ultimately realized through complex hypothalamic-pituitary-ovarian interactions in the monthly reproductive cycle in women (Backstrom CT et al., 1982; Reame N et al., 1984; Crowley WF Jr, Filicori M et al., 1985). Given the asynchrony of changes in FSH and LH levels during the menstrual cycle, it has long been assumed that each gonadotropin should have its own releasing hormone. However, later it was noticed that the pituitary response in terms of the secretion of gonadotropins is provided by GnRH alone, but the nature of the secretion of gonadotropins has some differences, which explains the difference in the behavior of the graphs of plasma concentrations of FSH and LH during the cycle. So each impulse of GnRH is characterized by the release of LH, but to a lesser extent FSH, in turn GnRH in more provides tonic synthesis of FSH than LH. Consequently, the lower frequency of GnRH impulses ensures the prevalence of FSH over LH and is recorded in the late luteal and early follicular phases of the menstrual cycle. While an increase in the frequency of GnRH pulses is associated with an increase in the plasma concentration of LH over FSH, it is therefore easy to imagine that the most intense frequency of GnRH peaks is precisely during the period of preovulatory LH surge (Jayes, Friederike C. Lking, Jack H. Britt and Kenneth L. Esbenshade, 1997 ).
Interestingly, in men, GnRH, which is responsible for the synthesis of the same gonadotropins, is also secreted in a pulsed mode, but with a constant pulse frequency.

The second tool for regulating GnRH activity is the change in the affinity and number of receptors for it on gonadotrophs, for example, the number of receptors changes 2-3 times during the physiological menstrual cycle. The unique GnRH receptor is represented by a transmembrane complex with seven sites penetrating the cell membrane, as well as extracellular hormone-binding and intracellular protein-binding sites. The regulation of gonadotropin synthesis occurs after GnRH binds to its I-type receptor, predominantly through the activation of the Gq-protein system as an intracellular mediator (Stanislaus D et al., 1997). Interestingly, the second form of GnRH, GnRH-II, despite having its own receptor, also transmits the signal mainly through GnRH-I receptors. It has been shown that the number of GnRH receptors in the pituitary depends on a variety of endocrine and paracrine factors. So almost all participants in the hormonal hypothalamic-pituitary-ovarian relay are able to influence the number of GnRH receptors. Gonadotropins and progesterone inhibit the synthesis of GnRH receptors, and estrogens are able to exhibit both stimulating and suppressive effects. The high activity and readiness of gonadotrophs, for example, before the LH peak, is characterized by an increased density of GnRH receptors, which is probably due to the increasing activity of the releasing hormone itself.

It was found that to ensure the secretory activity of gonadotrophs, it is precisely the pulsating mode of GnRH release that is necessary (Neill JD et al., 1977; Levine JE et al., 1982; Levine JE et al., 1985). It has been experimentally revealed that a change in the rhythm of GnRH pulsation, with the maintenance of a high frequency (more than three impulses per hour) or prolonged tonic activity with constant binding of receptors, is realized in a paradoxical effect, characterized by a decrease in the number and affinity of receptors, respectively, a decrease or complete abolition of the synthesis of gonadotropins . This effect is known as receptor desensitization (Belchetz PE et al. 1978; Gharib SD et al. 1990; Nillius SJ et al. 1972; Millar R.P. et al. 2004).
For objectivity, it should be noted that the mechanism of desensitization is not yet fully understood, for example, it has been established that the loss of receptors occurs only at the first stage (Conn PM et al., 1994). Obviously, at later stages, post-receptor mechanisms of suppression of the secretory activity of gonadotrophs are already involved. One way or another, but the empirically found feature of the behavior of gonadotrophs to exogenous tonic administration of GnRH, called desensitization, drug-induced castration or drug-induced hypophysectomy, quickly found its application in practical endocrinology and reproductive medicine (Andreyko JL et al., 1987), occupying a niche in the treatment of premature sexual development, some forms of neoplasms and conditions sensitive to sex steroids (Conn PM et al., 1991; Klijn JGM, 2003), as well as protocols for assisted reproductive technologies (ART). In contrast, the primary clinical use of GnRH agonists in infertility was originally thought to be the treatment of anovulation by prolonging gonadotropin secretion.

Subsequently, a large number (thousands) of chemical compounds were synthesized that can actively and efficiently bind to GnRH-I type receptors. Most of which caused a relatively short release of FSH and LH (7 to 14 days) prior to a desensitization plateau, seven of which were approved for clinical trials and practical use. These medicinal compounds were grouped together as GnRH agonists. A distinctive feature from GnRH itself is that the modified GnRH formula does not allow peptidases of the adenohypophysis to quickly destroy the molecule, which prolongs the effect of the administered drug, allowing you to significantly reduce the number of injections required for the course of treatment. By the way, currently commercially available drugs allow injections no more than once every 3 months or 12 weeks or 84 days, which is generally impressive.

Other compounds, on the contrary, almost instantly blocked the secretion of FSH and LH, so GnRH antagonists were named. The drugs of this series have been presented to the medical community quite recently, moreover, they are not so numerous, which is explained by the complexity of the synthesis and selection from the proposed prototypes due to the tendency of these chemical compounds to frequent side effects in the form of an allergic reaction, as a side effect of histamine-releasing effect on mast cells, and in addition, poor solubility (Reissmann T et al., 1994; Gordon K et al., 1992). Therefore, only two chemical compounds of the third generation of GnRH antagonists: Cetrorelix (Cetrotide / Cetrotide) and Ganirelix (Orgalutran / Orgalutran) are currently used for assisted reproduction, a number in other areas of medicine and many others are under research (Huirne JA et al, 2001 ).

This discussion focuses on the practical use of GnRH agonists in reproductive medicine.


The main modifications of GnRH, which made it possible to prolong the effect of the administered drug while ensuring a high affinity of the exogenous molecule and the GnRH-I receptor, are the replacement of amino acids in the 6th and 9th positions, as well as the removal of the amino acid glycine in the 10th position. When combined, these changes significantly enhance the biological activity of the synthetic hormone molecule, providing a higher binding affinity for GnRH receptors. The introduction of amino acids with higher lipophilicity in the 6th position provides an extension of the half-life of the drug, which is associated with a slowdown in renal excretion and an increase in the ability to deposit in adipose tissue (Karten MJ et al., 1986)

Distinguish:

  • Agonists with two substitutions: leuprorelin (Lucrine depot), buserelin (Buserelin depot, Buserelin long), goserelin (Zoladex), gistrelin and deslorelin.
  • Agonists with one substitution in the 6th position: nafarelin and triptorelin (Decapepil, Decapeptide)

GnRH agonists with two substitutions:


Leuprorelin
Buserelin


goserelin


Histrelin



Deslorelin

Agonists with one substitution in the 6th position:


Nafarelin



Triptorelin

Philosophy of clinical application of GnRH agonists in IVF cycles

Practical issues of using GnRH agonists in IVF cycles

Depot or Daily?

Great demand and years of active use of GnRH agonists have allowed scientists to develop and test various regimens for the administration of specific drug compounds. Daily, monthly (every 28 days), and quarterly (every 84 days) formulations are commercially available. From the point of view of simple logic, both the doctor and the patient, while maintaining the result, a reduction in the number of injections is always welcome. And if with the second part of the postulate, everything is very clear: the depot form implies a significant reduction in the frequency of necessary injections, then with efficiency everything is not so straightforward. It turns out that the effect of the administered depot drug is difficult to predict from the standpoint of not only the depth of desensitization, which remains obviously stronger, but also the duration, often overlapping the early stages of pregnancy (Broekmans FJ et al., 1992). In other words, the effect of the administered drug lasts much longer than is actually necessary.
Devreker F et al., 1996, in their study noted that the use of depot versions of GnRH agonists in IVF not only lengthens the stimulation phase, forcing the use of more inducer, but, importantly, is associated with a lower pregnancy rate, due to the drug's effects on activity of the corpus luteum in the post-transfer phase.
And despite the fact that the reduction in the frequency of pregnancy when choosing a depot instead of a daily remains the subject of ongoing discussions (Albuquerque LE et al., 2003), the fact of lengthening the induction interval and increasing the need for gonadotropins, as a result of deeper desensitization, no longer causes anyone doubt. In addition, in the context of the continued activity of the drug in early pregnancy, the question arises of the possibility of a direct teratogenic effect on the embryo, which is still little studied, but in any case is not useful.
Therefore, despite the fact that the depot versions of GnRH agonists are more attractive at first glance, they are still not acceptable in everyday IVF practice, except in cases where a longer and deeper preparation for the treatment cycle is required, which is so far especially important in some forms. endometriosis.

Subcutaneous or intranasal routes of administration?

What is the best GnRH agonist to use in IVF protocol?

Options for stimulation protocols using GnRH agonists

Long protocol.
Perhaps the most commonly used approach. The long protocol with GnRH agonists and the classic protocol with GnRH antagonists account for more than 90% of all cycles of controlled induction in IVF. Assumes the stimulation of superovulation against the background of already achieved desensitization of the pituitary gland.


Preliminary administration of a GnRH agonist can be performed both from the beginning of the follicular phase (long follicular protocol options) and the luteal phase (long luteal protocol options). The duration of the general administration of a GnRH agonist also varies greatly, depending on the chosen tactics and can last from 7 days (long protocols with a short desensitization phase) to two months (long protocols with depot forms of the GnRH agonist). It is important to note that in terms of superovulation stimulation productivity, assuming the GnRH agonist will be used prior to the day of trigger injection, the mid-luteal phase of the previous cycle is the most optimal for initiating GnRH agonist administration, compared to the follicular, early, or late luteal phases (Pellicer A et al., 1989; Kondaveeti-Gordon U et al., 1996; San Roman GA et al., 1992). This is partly due to a reduced risk of unwanted side effects. For example, it is known that when a GnRH agonist is introduced into the follicular phase, the incidence of an induction luteal cyst increases in response to the initial gonadotropin-activating action of the GnRH agonist. There is an opinion that induction cycles against the background of a luteal cyst are characterized by significantly more modest rates of pregnancy (Keltz MD et al., 1995). That is why this approach, as a rule, involves pre-treatment with high-dose combined oral contraceptives (COCs), which prohibit ovulation, and hence the formation of a cyst (Biljan MM et al., 1998). Also, the preliminary use of COCs makes it easy to program the treatment cycle, which is especially important, for example, in relation to donors in direct oocyte donation programs. But here it is still important to find a middle ground, since the presumably long-term use of COC preparations may have a detrimental effect on the readiness of the endometrium for implantation in the subsequent induced cycle.

A feature inherent in the philosophy of the long protocol is the profound suppression of endogenous synthesis of gonadotropins, which, as you know, translates into an increased need for exogenous gonadotropins. This important feature may become critical in some groups of patients, for example, with initially low follicular reserve and high basal FSH levels on days 2-3 of the natural follicular phase. Deep desensitization of such patients definitely threatens not only economic losses, but also the risk of failure of an adequate ovarian response to stimulation in general. For such patients, as an alternative to the short protocol and the protocol with GnRH antagonists, it was proposed to apply a special long protocol with a short desensitization phase (7-12 days). The conclusions of studies regarding the effectiveness of this approach diverged diametrically, but in general, especially given the availability of solid alternatives, currently practicing reproductologists do not favor this approach. There is an opinion that this variant of induction cannot reliably protect against the harmful effects of LH (Fujii S et al., 1997). Despite the fact that in the group of patients with a low follicular reserve, a significantly higher number of oocytes was received and a significantly lower amount of gonadotropins wasted, there was no increase in the frequency of implantation and live births (Dirnfeld M et al., 1999; Garcia-Velasco JA et al. ., 2000).

As a summary of the description of the flare-up approach, it can be noted that the short protocol is already more of a historical than a practical version of induction, and there are the following justifications for this:

  1. In the group of "standard" patients, the short protocol of induction is significantly inferior in the effectiveness of treatment to the long one (Tan SL et al., 1994; Daya S et al., 2000).
  2. In the group of patients with excessive follicular reserve, the short protocol is inferior in efficacy and safety to the protocol with GnRH antagonists.
  3. Finally, in the poor response group, the short protocol was never shown to be superior to other stimulation approaches (Shanbhag S et al., 2007).
In other words, at the current stage of development of reproductive medicine, the short protocol simply does not have a target audience of patients.

Modes of administration of gonadotropins in IVF cycles with GnRH agonists

One way or another, but all variants of protocols with a GnRH agonist involve induction with gonadotropins only. There are three principles of prescribing gonadotropins to stimulate superovulation:

  • Fixed dose regimen. It implies the selection of the dose of the inductor, which will remain unchanged throughout the entire protocol, as it will provide the optimal follicular response in terms of quantity and growth. It is generally accepted that a well-chosen dose of gonadotropins that does not require changes up or down is the key to a better treatment prognosis. Most often, a fixed-dose gonadotropin regimen is applied to patients with an average follicular reserve.
  • Step up mode. It implies not high doses of gonadotropins in the first days of stimulation, with the possibility of a significant increase in the amount of inductor when registering an insufficient follicular response. This mode provides maximum control of stimulation in terms of preventing the risk of developing OHSS, which is why it is most often used in a group of patients with an expected excessive response to ongoing stimulation. It should be noted here that another preventive step in terms of the risk of OHSS, which involves delaying the onset of stimulation until 3-6 days of the menstrual cycle, which is quite often used in protocols with GnRH antagonists, is clearly not available in long protocols with GnRH agonists, since each day following the first day in a state of desensitization is characterized by the same endocrine characteristics, which do not allow antral follicles to be recruited, and therefore compete with each other, reducing the size of the available cohort.
  • Step down mode. The direct opposite of the previous approach. Assumes a relatively high dose of the inducer at the start, with a decrease in the administered dose after 3-6 days of administration of gonadotropins. An overly high dose of gonadotropins ensures the maximum number of stimulated follicular cohort, which makes it difficult to use this approach in a group of patients with excessive follicular reserve and a potential risk of developing ovarian hyperstimulation syndrome (OHSS) and, on the contrary, is suitable for ovulation induction in a group of patients with low follicular reserve. It should be noted that in protocols with GnRH agonists, the step down principle is always practiced when registering an excessive follicular response to induction, since in such a situation it remains the only option for preventing the development of OHSS. At the same time, as an extreme step within the framework of the step down regime, it was proposed to completely abandon the introduction of gonadotropins into last days stimulation, but with continued administration of a GnRH agonist to desensitize and prevent early LH surge. This tactic has been called "coasting" or "coasting" stimulation. In their papers, the authors (Sher G et al., 1995; Fluker MR et al., 1999) noted that this approach avoids the development of severe OHSS. However, this induction regimen has relatively few supporters, since, on the one hand, prevention of the risk of developing OHSS still leaves much to be desired, on the other hand, there is evidence to date of a decrease in the incidence of pregnancy in coasting induction cycles.
Need for LH induction cycles with GnRH agonists

The real story of direct ovulation induction dates back to the discovery of the possibility of using urinary gonadotropins, which, as is known, basically represent an equal ratio of both pituitary gonadotropins LH and FSH (1:1). For a long time, preparations of this series were the only available means of preparing a multifollicular cohort in the ART cycle, which, on the one hand, contributed to the formation of the belief about full-fledged induction, as a process that is possible only with a complex of gonadotropins, on the other hand, did not contradict the accepted ideas of the theory of two cells postulated in scientific circles, two gonadotropins (Fevold et al., 1941; Short et al., 1962)

Everything has changed since the advent of recombinant gonadotropins, first FSH (rFSH), and then LH (rLH) and GnRH antagonists. The availability of new drugs made it possible to simulate induction cycles, changing not only the amount of the mixture of gonadotropins, as it was before, but also varying the active units of each gonadotropin separately, for example, reducing the amount of LH administered up to its complete rejection. These possibilities have led to controversy about the optimal strategy and divergent approaches to ovarian induction (Filicori, 1999).

Everyone is well aware of the role of LH in the formation of ovulation processes, which is impossible without the implementation of LH effects (Weiss et al., 1992; Latronico et al., 1996; Toledo et al., 1996). On the other hand, a detailed consideration of clinical situations where LH is completely absent or completely inactive provides the necessary data to explain the role of LH in the process of development of the dominant follicle using examples. Thus, the use of only purified or rFSH in patients with hypogonadotropic hypogonadism, although it provides the growth of dominant follicles, is characterized by a significant decrease in the frequency of pregnancy, when compared with patients who received an equilibrium mixture of FSH:LH (Shoham et al., 1991; Schoot et al., 1994 ; Balasch et al., 1995; Kousta et al., 1996). Which, of course, was associated with a decrease in estrogen saturation, but was not compensated by the exogenous addition of estradiol to the therapy regimen (Hull et al., 1994; Balasch et al., 1995), proving the fact that the contraceptive defect realized its action not at the level of processes transformation of the endometrium. It turns out that some LH activity is necessary for the normal development of the oocyte-cumulus complex of the follicle.

Most clinical studies comparing FSH+LH stimulation protocols with purified FSH or rFSH in patients in IVF programs have not identified the need to include LH (in the form of hMG or rLH) in long protocols with GnRH agonists (Daya et al., 1995; Loumaye et al. , 1997). Probably, the reason for this is the background activity of LH, which persists even against the background of desensitization of the pituitary gland by GnRH agonists. It can be assumed that the amount of active LH to ensure normal folliculogenesis is probably very low (Catt and Dufau, 1977; Doerr, 1979; Chappel and Howles, 1991). However, it is possible that some normogonadotropic women after profound suppression by GnRH agonists may need LH-containing drugs. In addition, it should be taken into account that just as there are individual variations in the depth of the standard suppression of endogenous secretion of gonadotropins, there are also individual requirements for the amount of background LH necessary to stabilize the processes of folliculogenesis. So far, it is impossible to unequivocally indicate the truly optimal approaches. Apparently, we have a long way to follow the discussions on this issue. But, in an attempt to objectively review, the following theses can already be proposed regarding the need for induction protocols against the background of GnRH agonists in LH:

  • It is likely that sufficient background LH threshold can be crossed in cycles with deeper desensitization, which can be observed as an individual effect on GnRH agonists, but will certainly occur in cycles with prolonged desensitization, when the duration of administration and total doses of the drug taken are significantly higher, for example , during the super-long protocol, as well as in patients approaching the decline of reproductive function.
  • Given the clinical observations of induction cycles in patients with hypogonadotropic hypogonadism, namely the reduction in the number and growth rate of the follicular cohort, with stimulation of FSH alone compared with a mixture of gonadotropins, it can be argued that the addition of LH to the stimulation protocol can be justified when registering an inadequately low (as according to quantity and rate) of the follicular response to a sufficient dose of the inducer
  • And the most important. The choice of gonadotropin in the standard population of patients does not affect the result of treatment, therefore, the attending physician has the right to add LH-containing drugs to the protocol at his discretion, in other words, based on his clinical experience and intuition, which may already be sufficient justification for the need to use LH.
Post-transfer support in cycles with GnRH agonists

The well-known axiom of reproductive medicine:
"ovarian stimulation improves IVF efficiency",
actually made me agree with one more fact:
"Ovarian stimulation suggests the need for hormonal support for the luteal phase."
The thing is that due to the presence of several active corpus luteum, the luteal phase of the induced cycle is characterized by superphysiological concentrations of sex steroids. This, according to the principle of negative feedback, inhibits the gonadotropin secretory activity of the pituitary gland and results in a reduction in the period of functioning of the corpus luteum, with an earlier and transient decrease in their activity, resulting in a truncation of the luteal phase of the induced cycle by 1-3 days. This feature of the stimulated cycle in itself significantly reduces the effectiveness of IVF, affecting the success of implantation of a normal embryo. GnRH agonists that appeared in IVF practice even more exposed the potential problems of inferiority of the luteal phase, adding to the described processes a direct central inhibitory effect of agonists on the synthesis of gonadotropins (primarily LH), due to the desensitization effect of pituitary receptors (Daya S et al., 2004). ;.Pritts EA et al., 2002; Fatemi HM et al., 2007).

Right Understanding The harmonious endocrine status of the luteal phase, meanwhile, suggests that the defect in phase II of the induced cycle consists not only in a deficiency in the plasma concentration of progesterone, but also in estradiol, which is also known to be vital for a normally developing pregnancy. In any case, the mandatory replenishment of only these (estradiol and progesterone) two hormones in cycles of total HRT with embryo transfer, under conditions of induced or natural menopause, was sufficient for normal endometrial preparation, implantation and pregnancy (De Ziegler D et al., 1991; Navot D et al., 1986).
It is thanks to the balanced replenishment of progesterone and estradiol during the period of embryo implantation that hCG preparations, which are known to realize their positive effect through the activation of the secretory activity of the corpus luteum, demonstrate greater efficiency in terms of the frequency of pregnancy. In comparative studies, hCG therapy has been shown to be more effective than progesterone supplementation alone (Soliman S et al. 1994; Gelbaya TA et al. 2008). On the other hand, the possibility of using hCG in the post-transfer period is limited by the risk of progression of OHSS. Which simply does not allow this approach to be applied in most induction protocols.
That is why, taking into account the obvious failure of the luteal phase of the induced cycle against the background of GnRH agonists, especially under conditions of deep desensitization of the long and super-long protocols, there is a need to add both progesterone and estradiol. By the way, some comparative studies weighing the effectiveness of progesterone monotherapy and progesterone-estrogen combination therapy in cycles with GnRH agonists also showed higher rates of pregnancy (40% vs. 26%) and implantation, as well as relatively low rates of pregnancy loss. in the integrated approach group (Farhi J et al., 2000; Gorkemli H et al., 2004; Daya S et al., 2004).

As for the duration of substitution therapy, there is still no consensus on this issue. From the standpoint of understanding the logic of the negative action of all aspects of the foreseeable induction, pathological links are broken at the moment when the fetal egg begins to synthesize hCG into the peripheral blood in a volume capable of activating prematurely fading corpus luteum, that is, from the moment pregnancy is determined. Proctor Al et al., 2006, in their study confirm that this approach, although characterized by an increase in pregnancy losses at an earlier date, does not affect the most important indicator - the frequency of live birth.

GnRH agonist as an alternative trigger in cycles with GnRH antagonists

Deciphering the aria of GnRH agonists with the awareness of the inevitability of the primary flare-up effect led researchers not only to bypass it, layering on COCs or the luteal phase of the previous menstrual cycle in a long protocol, but also to use an unusual feature in medicinal purposes. This is how, in general, not a bad idea for the practical application of a short IVF protocol was born. But, as usual, inquisitive minds did not stop there. It turned out that GnRH agonists, due to their rapid activating effect on the production of gonadotropins and primarily LH (this is especially important here), can be used to trigger follicles instead of the usual hCG (Emperaire JC m et al., 1991; Lanzone A et al., 1994) , ideally modeling the treatment cycle in the likeness of the natural one. However, the theoretical calculations were not reliable. And the first analysis of the experience of using such tactics turned out to be a failure (Breckwoldt M et al., 1974; Crosignani PG et al., 1975).
And soon GnRH agonists found their use in IVF as a means to desensitize the pituitary gland and for many decades remained the only drugs used for this purpose. What distracted the attention of researchers from the topic of their use as a trigger for the final maturation of follicles, since the drug used to suppress the pituitary gland cannot be prescribed for the opposite purpose in the same ART cycle.

Real interest in the topic of the alternative trigger has emerged since the widespread use and practical availability of GnRH antagonists. But a more methodical approach still paid off.
In general, on this moment a large number of studies have been conducted on the use of a GnRH agonist as a follicular trigger (Lanzone A et al., 1989; Imoedemhe D and et al., 1991; Gonen Y et al., 1990; Itskovitz J et al., 1991; Kulikowski M et al. ., 1995; Griesinger G et al., 2006; Engmann L et al., 2008). And despite the fact that the opinions of researchers on this issue often do not coincide, some theses were nevertheless postulated:

  • the use of a GnRH agonist as an ovulation trigger is associated with a reduced risk of progression to moderate to severe OHSS (Itskovitz-Eldor J et al., 2000; Engmann L et al., 2008).
  • the use of a GnRH agonist as an ovulation trigger makes it possible to obtain an adequate (Fauser BC et al., 2002), although a relatively smaller number of good quality oocytes and embryos is possible.
  • the use of a GnRH agonist as an ovulation trigger is characterized by a decrease in the frequency of pregnancy in the fresh cycle due to a violation of the endocrine characteristics of the luteal phase. This makes it necessary to adjust the support of the post-transfer period by adding estrogen preparations (Engmann L et al., 2008) and/or hCG, or to abandon the transfer of embryos in the cycle of obtaining oocytes, with cryopreservation and their subsequent use (Griesinger G et al., 2006).
Recognition of the described features did not allow the introduction of the practice of using a GnRH agonist as a trigger in the general population of patients, leaving behind this tactic only a group of patients demonstrating an excessive follicular response to the ongoing induction and threatened by the development of OHSS.

Maternal and child health

GnRH agonists have traditionally been considered relatively safe drugs, with the main possible negative effects being mediated through a state of induced hypoestrogenism. It is the drop in serum concentration of estradiol that explains the most frequent undesirable systemic manifestations of GnRH agonists:

  • tides
  • vaginal dryness
  • decreased libido
  • hair loss
  • breast size reduction
  • emotional lability
  • decrease in bone mineral density, also likely on the basis of postmenopausal osteoporosis
Those main negative manifestations that disappear after the cessation of the biological action of the administered drug.

However, the question of a possible teratogenic effect still needs to be considered in detail. Understanding that the leverage for the application of GnRH agonists is located in the deep central neuro-endocrine structures of the brain, it is not difficult to assume that its use can have a detrimental effect on the developing embryo. Especially bearing in mind that the activity of the administered GnRH agonist often has a long-term tailing character, capturing the first weeks of pregnancy. But, fortunately, studies conducted on this issue, although they agreed with the fact of placental transmission of the GnRH agonist to the fetus, did not reveal teratogenic manifestations in primates (Sopelak VM et al., 1987; Brogden RN et al., 1990). Similarly, no adverse health effects have been reported in human offspring following the inadvertent administration of GnRH agonists during the first weeks of pregnancy (Golan A et al. 1990; Dicker D et al. 1989; Weissman A et al. 1993). However, when it comes to the health of children born, we should not forget about the risks, even if they are not proven, even if they are purely theoretical. In any case, if there is a choice, it is probably still worth giving preference to short-acting daily drugs. Moreover, there are works demonstrating some features in the behavior of children, in particular attention deficit hyperactivity disorder, after accidental prolonged desensitization of the pituitary gland during early term pregnancy (Lahat E et al., 1999).

Conclusion

Aside from the dry medical lyricism, alternatively summarizing this discussion, GnRH agonists can be compared to the "good road". As you know, the road is often unpredictable. Unexpected turns, potholes, ice, traffic lights, speed control, those unpleasant associations that inevitably pop up at the mention of this concept. With the advent of gonadotropins, we learned how to drive well, choose the right vehicle from the garage of available drugs and control the speed. But, as you know, a bad road can cross out everything, on it you can not only lose most of the advantage, but also not reach your destination at all. The most important quality of GnRH agonists is that they make almost any road clear, free and comfortable, one where black cats are not allowed, and the wind is always in the back. In addition, to a certain extent, they allow you to choose the type of coverage and plot your route. Of course, there are also drawbacks here, so the process may turn out to be somewhat longer, much more moral and financial resources will be spent on overcoming it, and for someone it’s not at all on the way. But, ultimately, the long-tired wanderer has the best chance of achieving his goal, and not just moving along the ring or taking another flight to nowhere. That is why, in their main characteristics, GnRH agonists have combined all the advantages of a good road.

It is no secret that many patients are not very disposed to the use of drugs based on hormones, but these substances are very important in the treatment of a variety of pathological conditions. Gynecological diseases are no exception. In this case, the use of gonadotropin agonists, which have the ability to regulate the function of reproduction, is recommended.

Hormonal preparations are necessary if a patient has uterine fibroids, endometriosis, endometrial hyperplasia. Gonadotropin antagonists are also very often used in IVF regimens and before surgery on the uterus, which is aimed at reducing its size.

Releasing hormones have the ability to influence the work of the endocrine glands, affect the growth and development of the whole organism, and the correct interaction of the central nervous system and endocrine.

Gonadotropin-releasing hormone agonists can restore communication between the pituitary, hypothalamus, and ovaries in women diagnosed with endometriosis.

When using this group of drugs, the following occurs:

  • artificial menopause develops;
  • pituitary cells lose sensitivity;
  • less gonadotropin compounds are released;
  • after the end of use, the regulation of the hypothalamus is restored.

These effects occur because gonadotropin binds to GnRH receptors, which is located in the adenohypophysis. With the constant introduction of drugs, the release of gonadotropin stops, which provokes the absence of menstruation.

Medications

Gonadotropin agonists

Clinical studies have shown that these substances help to reduce fibroids by half. It also turned out that in extremely rare cases they do not show such activity or are not effective at all. In the presence of more than one tumor, therapeutic measures depend on how old the patient is and the location of the fibrous and smooth muscle components in the myoma.

The effect of the treatment can last about four months, it will fade for another six months. Doctors reported that there were situations of re-growth of education.

Negative reactions

The instructions that come with drugs based on antigonadotropins describe that when they are used, such negative reactions can develop:

  • depression;
  • decrease in sexual desire;
  • hot flashes;
  • removal of minerals from bone tissue.

These drugs have proven themselves on the positive side in the treatment of fibroids without the use of surgery during menopause. When performing the operation, drugs facilitate its implementation. In case of detection of anemia and metrorrhagia, GnRH antagonists can restore blood counts to normal.

Relapse: prevention

Gonadotropin antagonists are drugs used in the absence of the effect of the use of other drugs. These include: Danazol and Gestrinone.

Antigonadotropins are used extremely rarely, since they smooth out the manifestations of fibroids, but do not contribute to its growth. A negative reaction after the introduction of these drugs can be the formation of acne, hypertrichosis, and in some cases even the voice changes.

When using drugs, it is possible to achieve a decrease in the release of gonadotropins by the pituitary gland. They can stop further progression of endometriosis, although their therapeutic effects are rather limited.

This group of drugs can be used for no more than 6 months. Main indications:

  • infertility;
  • prevention of recurrence of endometriosis.

It should be noted that self-selection of drugs is prohibited due to the occurrence of negative reactions. Most often occur:

  • weight gain;
  • hirsuntism;
  • excessive sweating;
  • osteoporosis;
  • depression and nervousness;
  • vaginitis.

Gonadotropin

This is a hormone that is synthesized in the pituitary gland and has the ability to influence not only the egg, but also the entire reproductive and reproductive systems. Its main effects on the body:

  • stimulates the rupture of the follicle;
  • induce ovulation;
  • increase the concentration of androgens and progesterone;
  • promotes the attachment of a fertilized egg to the uterine mucosa.

Before starting therapy with this drug, you must make sure that there is no pregnancy, since the main component has a negative effect on the fetus. It is important to understand that only a doctor can recommend such drugs. He also prescribes the dose, frequency of administration and course of treatment. If necessary and individual characteristics body, the doctor can make adjustments. After carrying out the necessary tests, it will be possible to talk about the effectiveness of the treatment.

Experienced specialists have concluded that gonadotropin antagonists have an advantage over agonists. It is expressed as follows:

  • the therapeutic effect comes faster;
  • the release of gonadotropins is suppressed, which provokes the reversibility of the effect;
  • there are no problems with the choice of dosage, which contributes to the evaluation of the treatment.

It is important that each patient understands that only an experienced specialist prescribes hormonal drugs, because their uncontrolled and independent use can lead to a negative effect on the body.

Men can also take these drugs to improve testosterone synthesis and normalize the functioning of Leiding cells. The drugs help the boys to lower the testicles into the scrotum. In men, when exposed to gonadotropin antagonists, spermatogenesis is restored and secondary sexual characteristics develop. Also undergoes infertility therapy in men, while controlling the concentration of testosterone in the blood and the quality of spermatozoa.

Gonadotropin-releasing hormone (GnRH) is produced in the hypothalamus and affects the pituitary gland, triggering the production of sex hormones and making conception possible. It is used in the scheme of stimulation of ovulation in the natural cycle and in IVF (in vitro fertilization). Also, due to the ability to regulate the production of other hormones, it is successfully used in the treatment of many diseases of the genital area, especially those caused by the onset of menopause.

Application

GnRH agonists were originally developed as fertility drugs. But after the research, it turned out that they have a large number of properties. Currently, chemical compounds of GnRH, one of the representatives of the releasing hormones of the hypothalamus, are prescribed in the treatment of serious diseases in the female reproductive system, namely:

  • Endometriosis is a pathology in which the cells of the inner lining of the uterus spread outside of it.
  • infertility. It is used in stimulation schemes and in IVF.
  • Myoma of the uterus - a benign tumor that occurs in the muscular layer of the uterus.
  • Hyperplasia of the endometrium is a pathological condition of the mucous layer of the uterus.
  • Polycystic ovaries.

These compounds are also used before surgery, for example, to reduce tumor volume in the uterus, reduce intraoperative blood loss, which allows the surgeon to perform a planned intervention without consequences and with fewer complications.

The mechanism of action of the drugs is as follows: gonadotropin-releasing hormone (aGnRH) agonists can easily establish communication in the hypothalamus-pituitary system (located in the brain and responsible for regulating the functioning of the endocrine glands) in patients with uterine fibroids, endometriosis. In the process of influence of substances on the glands, the sensitivity of the cells of the pituitary gland itself begins to decrease, the release of gonadotropic hormones, which regulate the function of the gonads, decreases. As a result, drug-induced maximum androgenic blockade occurs, or a state of reversible hypoestrogenism.

After cessation of use medicinal product the process of hypothalamic control of reproductive function by the pituitary gland returns to normal.

Therapy for endometriosis

Endometriosis (overgrowth of the endometrium) is a disease that usually occurs in women of childbearing age and has a number of characteristic symptoms: pelvic pain and dyspareunia.

Diagnosing this pathology is quite difficult, since the discomfort is similar to the sensations that the patient may experience during menstruation. Many women with this diagnosis are infertile.

It was found that aGnRH is able to suppress the secretion of hormones by the ovaries, thereby causing regression of endometriotic lesions, and this helps to reduce pain in patients with this pathology.

Some of the most effective GnRH adrugs are:

  • Danazol - medicine, a synthetic androgen, which has a pronounced reversible antigonadotropic effect.
  • Buserelin is a drug against tumors, a synthetic model of natural GnRH. The use of therapeutic doses leads (after about 2 weeks) to a complete blockade of the function of the pituitary gland.
  • Gestrinone - reduces the secretion of gonadotropin, the production of gestagens and estrogens. Before starting therapy, pregnancy must be excluded.
  • Triptorelin is a hormonal agent against tumors, somatostatin gonadotropin-releasing hormone. It blocks the release of gonadotropic hormones - luteotropin, follicle-stimulating hormone (FSH) by the brain appendage, reduces the amount of androgens and estrogens in the blood. Triptorelin is more active than the natural hormone.
  • Nafarelin is a follicle-stimulating agent that affects the secretion of pituitary gonadotropins.

Treatment for uterine fibroids

Uterine fibroids is a diagnosis that becomes known after an ultrasound diagnosis. This disease accounts for 30% of all gynecological pathologies. Patients are given recommendations that are aimed at preventing further tumor growth and regulating the hypothalamic-pituitary-ovarian relationship.

Treatment with medications is based on the choice of those drugs that will reduce the growth and existing size of fibroids, reduce blood loss during menstruation, and restore hemoglobin levels.


Non-surgical therapy is started when the tumor size is more than 2 cm, which corresponds to the volume of the uterus at the 12th week of pregnancy. In order to inhibit the growth of fibroids, the following drugs are prescribed:

  • Zoladex is an anticancer agent, a depot form containing goserelin. Registered in 100 countries around the world.
  • Leuprorelin is an anticancer drug, a synthetic analogue of the hormone. It has more activity than the natural hormone. Together with gonadorelin receptors in the pituitary gland, it causes their fleeting stimulation followed by long-term desensitization.
  • Diphereline is a synthetic decapeptide analog of natural GnRH. With prolonged use, it blocks the secretion of the hormone with inhibition of ovarian function.

Adverse reactions

Typical side effects of using GnRH-a drugs are:

  • hot flashes and fever;
  • conjunctivitis, impaired vision and hearing, tinnitus;
  • headache and dizziness;
  • loss or disturbance of sleep;
  • slight memory impairment (according to research results - up to 44%);
  • if the drug is used for more than six months, a temporary decrease in bone density is possible, which can lead to fractures;
  • sense of anxiety;
  • depressive state;
  • dryness of the vagina;
  • disruption of the intestines;
  • vaginal bleeding;
  • allergy;
  • irritability and lethargy;
  • weight fluctuations;
  • dyspareunia - a sexual disorder characterized by pain before, during and after sexual intercourse in women;
  • arthralgia - a symptom of joint pain, characteristic of one or several joints at the same time;
  • myalgia - discomfort in the muscles;
  • peripheral edema;
  • increased sensitivity of the mammary glands;
  • increase or decrease in lower pressure;
  • sweating;
  • sometimes - violation of the patency of the urinary ducts, dysuria;
  • on the part of the gastrointestinal tract - a decrease in appetite or an increase in it, changes in tastes, dry mouth, increased salivation, thirst, swallowing failure, nausea, diarrhea or constipation, flatulence;
  • cough, shortness of breath, nosebleeds, pleural effusion, fibrous formations in the lungs, infiltrates in them, respiratory disorders;
  • dermatological reactions - dermatitis, dry skin, irritation, rash, hemorrhages in the skin, baldness, intense staining in some areas, brittle nails, acne, hypertrichosis.

To stop these symptoms, the so-called reverse treatment (add-back) is additionally used with the use of agents for hormone replacement therapy, which are prescribed 3 months after the start of the use of GnRH agonists.

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Gonadotropin-releasing hormone (GnRH) agonists were originally created as drugs with greater activity and duration of action compared to endogenous GnRH. However, it turned out that long-term continuous administration of GnRH agonists provides only a short-term increase in the level of gonadotropins, and then the synthesis and secretion of FSH and LH decrease. This paradoxical effect, called desensitization, has proven to be useful in the treatment of many hormone-dependent gynecological diseases, as well as in the treatment of infertility.

Mechanism of action and pharmacological effects

GnRH is a decapeptide. When binding to its membrane receptors, the P-type of phospholipase C is activated, under the action of which inositol triphosphate and diacylglycerol are formed from membrane phospholipids. Inositol triphosphate stimulates the rapid release of calcium ions from intracellular depots and leads to rapid increase its level in the cytoplasm. Diacylglycerol and calcium ions activate protein kinase C, which leads to the activation of mitogen-activated protein kinase, followed by stimulation of the synthesis of arachidonic acid. As a result, the synthesis and secretion of FSH and LH increase.

Endogenous GnRH is secreted in a pulsatile (circhoral) rhythm with a frequency of 60–90 pulses/hour. Long-acting GnRH agonists bind competitively to GnRH receptors and transiently increase the secretion of LH and FSH, and then cause desensitization and a decrease in the number of GnRH receptors on gonadotropic pituitary cells, which leads to a decrease in the synthesis and secretion of gonadotropins. However, when administered in a pulsatile regimen, GnRH preparations mimic the action of endogenous GnRH and stimulate the synthesis of LH and FSH.

Pharmacokinetics

Due to their polypeptide structure, GnRH agonists are destroyed in the gastrointestinal tract, so they are not used orally. Currently, drugs are available for daily s / c administration (triptorelin, leuprolide), intranasal spray (buserelin acetate and nafarelin acetate), as well as the so-called depot drugs, or long-acting drugs that allow you to administer drugs once every 4 weeks: depot -implants for s / c injection (goserelin) and depot suspension for i / m administration (triptorelin and leuprolide). Gonadorelin acetate is administered intravenously in a pulsating mode using a special device.

GnRH is rapidly hydrolyzed by endopeptidase and carboxyamide peptidase. Its half-life is 4-6 minutes. GnRH agonists are obtained synthetically from endogenous GnRH by introducing a D-amino acid into the 6th position, which protects against proteolysis, and modifying the C-terminus, which increases the affinity of these substances for receptors by 100-200 times due to the stabilization of the bioactive conformation. At the same time, the duration of action of GnRH agonists is longer than that of endogenous GnRH. The half-life of GnRH agonists with s / c and intranasal administration is 3 hours.

Place in therapy

GnRH gonadorelin acetate is used to treat hypothalamic amenorrhea. It is administered using an IV pump in a pulsed mode at a frequency of 90 pulses / h, which mimics the endogenous secretion of GnRH. Treatment begins with 2.5 mcg/pulse and gradually increases to 10 mcg/pulse until ovulation occurs, which usually occurs after 2 weeks of treatment (sometimes longer treatment is required; in the absence of ovulation after 3 weeks, an increase in the dose of drugs is necessary).

Long-acting GnRH agonists are used to treat infertility in polycystic ovary syndrome with high LH levels, as well as in schemes (so-called protocols) of controlled hyperstimulation as part of assisted reproductive technologies. Various treatment protocols are used. In long protocols (used most often), desensitization with GnRH agonists is performed prior to the 21st day of the previous cycle to prevent premature ovulation, and then stimulation with gonadotropins is performed against the background of ongoing GnRH therapy. To induce ovulation, 5,000-10,000 units of human chorionic gonadotropin are administered, and follicles are punctured 33-34 hours later. IN short protocols treatments resort to a transient increase in the secretion of LH and FSH, while GnRH agonists are administered daily in the follicular phase starting from the 2nd-3rd day of the cycle, and gonadotropins are added the next day. In the ultra-long treatment protocol, GnRH agonists are prescribed 2-6 months before ovulation induction with gonadotropins. In general, pregnancy rates are highest with the long protocol compared to other protocols.

GnRH agonists are used to treat many gynecological diseases: endometriosis, endometrial hyperplasia, uterine fibroids, premenstrual syndrome. This uses the ability of GnRH agonists to cause "drug castration", or pseudomenopause, in the case of continuous administration. Treatment is carried out for 3-6 months, with amenorrhea occurring.

After 4-10 weeks after the abolition of drugs, menstruation is restored. For chronic pelvic pain, dysmenorrhea, and dyspareunia associated with endometriosis, GnRH agonists are the drugs of choice. However, the positive effect of GnRH agonists on the restoration of fertility in patients with endometriosis has not been proven. After stopping treatment, relapses of the disease are also possible. Therefore, for the treatment of infertility in endometriosis, surgical methods remain the method of choice. GnRH agonists can be given as preoperative preparation. The use of GnRH agonists in uterine fibroids leads to a significant reduction in its size, however, 6-12 months after discontinuation of treatment, the previous dimensions are restored. On average, after 6 months of treatment, the size of fibroids decreases by 51-61%. This allows the use of GnRH agonists as a preoperative preparation, and also facilitates the removal of fibroids during surgery.

The use of GnRH agonists has proven effective in the treatment of the central form of precocious puberty. In this case, the so-called depot preparations, or long-acting drugs, or daily intranasal injections of buserelin are most often used.

Side effects and warnings

The most common adverse reactions when using gonadorelin acetate in pulsed mode are pain and the occurrence of superficial thrombosis at the injection site of the IV pump.

The main side effects of long-acting GnRH agonists are identical to postmenopausal symptoms (headache, sleep disturbance, emotional mobility, depression, decreased libido, hot flashes, vaginal dryness or atrophy, decreased bone mineral density). Due to these side effects, the duration of use is limited to 6 months. To stop these disorders, the so-called recurrent therapy is additionally used using drugs for hormone replacement therapy, which are prescribed 3 months after the start of treatment with GnRH agonists.

Contraindications

Contraindications to the use of GnRH agonists include hypersensitivity to the active substance or to the constituent components of the drug, pregnancy and lactation. In the treatment of the hypothalamic form of amenorrhea with gonadorelin in pulsed mode, contraindications are ovarian cysts and all other forms of amenorrhea.

IN AND. Kulakov, V.N. Serov

The work of the ovaries and reproductive function is controlled through the hypothalamic-pituitary axis. In special areas of the brain, neuronal cells synthesize hormones that stimulate or suppress the work of other organs.

How does gonadotropin work

In accumulations of specific neurons of the hypothalamus, gonadotropin-releasing hormone (GnRH) is synthesized - this is a large protein compound that stimulates the synthesis of the corresponding hormones. This group of releasing factors also includes such biological substances:

  • cotricotropin-releasing hormone;
  • somatoliberin;
  • thyreoliberin.

They affect the cells of the anterior pituitary gland, where the tropic hormones of the same name are produced (ACTH, somatotropic, thyrotropic).

Under the influence of GnRH, follicle-stimulating and luteinizing hormones are produced. The release of the hormone into the blood occurs impulsively once an hour. This ensures sensitivity to the effects of pituitary receptors and the normal functioning of the genital organs.

Increased or continuous intake of releasing hormone leads to a loss of sensitivity to its receptors and, as a result, menstrual irregularities. Rare intake leads to amenorrhea and lack of ovulation.

The secretion of gonadotropin depends on the effects of other biologically active substances - norepinephrine, serotonin, acetylcholine, gamma-aminobutyric acid, dopamine.

That is why the state of stress, emotional oppression, chronic lack of sleep adversely affect the state of the reproductive system. At the same time, a healthy daily routine, positive emotions and a balanced state of mind support the reproductive system.

The use of GnRH in medicine

Previously, natural GnRH was used in medical practice. Studies to increase the half-life of the drug have led to the creation of analogues of gonadotropin-releasing hormone. They are available in various forms and are intended for administration intramuscularly, subcutaneously, as a spray in the nose and in the form of capsules to create an intradermal depot.

Popular drugs - analogues of gonadotropin-releasing hormone include:

  • Buserelin;
  • Zoladex.

The scope of gonadotropin-releasing hormone preparations is very wide and depends on its type and method of administration.

Diferelin is prescribed for the treatment of:

  • different degrees;
  • hyperplastic processes of the endometrium;
  • at ;
  • cancer (BC);
  • in artificial insemination programs.

In men, its use is limited to prostate cancer with hormonal sensitivity. The drug is used in children to treat premature puberty. The drug in various dosages is injected under the skin.

Buserelin nasal spray and solution for injection into the muscle is effective for the treatment of:

  • fibroids;
  • breast cancer.

It is prescribed before and after surgery for endometriosis to reduce pathological foci. Also used during IVF.

Zoladex capsules are used in men and women. Implantation under the skin of the anterior abdominal wall provides a constant supply of the hormone. The action is manifested in a decrease in testosterone in men and estrogen in women, providing a temporary reversible chemical castration.

  • The prostate tumor is regressing.
  • Gonadotropin-releasing hormone in estrogen-sensitive breast cancer reduces tumor size after 3 weeks.
  • Justified his appointment for the treatment of endometriosis, uterine fibroids.

Gonadotropin-releasing hormone agonists

Separately, drugs are isolated that, according to the mechanism of action, are gonadotropin-releasing hormone agonists. This means that their effect on the pituitary gland causes the same effect as their own hormone. Under the action of gastric juice, the active substance breaks down, so all drugs are injected into the muscle, under the skin or intranasally.

Members of this group:

  • Lucrin Depot;
  • Sinarel;
  • Gonapeptyl.

Gonadotropin-releasing hormone agonists are used before and after surgical treatment of endometriosis, fibroid therapy, before hysterectomy (removal of the uterus), for the treatment of infertility.

Gonadotropin-releasing hormone antagonists

Preparations Orgalutran, Firmagon, Cetrotide are antagonists of gonadotropin-releasing hormone. Their action is aimed at inhibiting the production of luteinizing and follicle-stimulating hormones. This effect is used in IVF programs.

Modern methods of artificial insemination provide for the stimulation of ovulation, in which medically achieve the maturation of several eggs at the same time, which is called superovulation. For this, GnRH agonists are administered according to a certain scheme.

This process is accompanied by an increase in estradiol, which can lead to a premature peak release of luteinizing hormone. Ovulation occurs prematurely, some of the eggs are lost, so they cannot be used for fertilization.

Gonadotropin-releasing hormone antagonists bind to GnRH receptors. The action develops a few hours after administration. The duration should be such that the follicles can enter their final growth phase and early ovulation does not occur. Already 13 hours after its administration, the pituitary gland is again open for stimulation with GnRH agonists, which leads to superovulation and the formation of a large number eggs.

The use of this scheme for preparing for fertilization reduces the risk of development, which often developed against the background of long-term use of GnRH agonists. This condition is characterized by an increase in the size of the ovaries, the development of ascites, effusion in the pleural cavity, thickening of the blood and the formation of blood clots.

The introduction of a GnRH antagonist begins 5-6 days after the start of the use of follicle-stimulating hormone or after the follicle reaches a size of 12-14 mm according to ultrasound. When several follicles reach a size of 17-19 mm, the antagonist is canceled and stimulation is continued according to the selected scheme.

Usage hormonal drugs associated with various side effects. Their severity depends on general condition patients' health. The choice of the optimal medicine remains with the attending physician.

Yulia Shevchenko, obstetrician-gynecologist, specially for the site

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