Gonadotropin-releasing hormone agonists. Treatment with GnrH Gonadotropin releasing hormone agonists GnrH
For quotation: Tikhomirov A.L. Gonadotropic releasing hormone agonists in the treatment of uterine fibroids // Breast Cancer. Mother and child. 2010. No. 4. P. 188
According to modern concepts, uterine fibroids are a monoclonal hormone-sensitive proliferation consisting of phenotypically altered myometrial smooth muscle cells.
The monoclonal characteristics of uterine fibroids made it possible to refute the theory that uterine fibroids develop as a result of systemic hormonal changes, designating this formation as a local pathology of the myometrium.
There are two theories of the origin of the precursor cell of uterine fibroids: one implies the appearance of a cell defect during the ontogenetic development of the uterus, due to a long unstable period of formation of embryonic smooth muscle cells, the second suggests the possibility of cell damage in the mature uterus. The fact that, according to pathological studies, the prevalence of uterine fibroids reaches 85%, allows us to consider the second theory of the origin of the progenitor cell more obvious.
The formation of a “growth bud” of a myomatous node most likely occurs in the following way. During each ovulatory menstrual cycle during the first phase, under the influence of estrogens, receptors for sex hormones and various growth factors (EGF, TGF beta, bFGF, etc.) accumulate on the surface of myometrial cells. After ovulation, under the influence of progesterone produced by the corpus luteum, the process of myometrial hyperplasia occurs. Progesterone has both a direct effect on myometrial cells, by binding to its specific receptors, and indirectly, through the expression of various growth factors. Myometrial hyperplasia occurs evenly; this, in particular, is realized due to the balanced expression of two types of progesterone receptors (A and B). A-type receptors are blocking, and B-type are effector. The uniform distribution of these receptors ensures a uniform increase in myometrial tissue.
If pregnancy does not occur, the concentration of progesterone in the blood drops and the process of apoptosis is activated in the myometrial tissue, due to which excess smooth muscle cells are eliminated. It is thanks to this mechanism that the uterus does not increase in size from cycle to cycle.
It can be assumed that during repeatedly repeated cycles of myometrial hyperplasia followed by apoptosis, accumulation of smooth muscle cells occurs in which the apoptosis process is disrupted, and these proliferating cells are exposed to various damaging factors. The damaging factor may be ischemia caused by spasm of the spiral arteries during menstruation, an inflammatory process, traumatic effects due to medical manipulation, or a focus of endometriosis.
With each menstrual cycle, the number of damaged cells accumulates, but their fate may be different. Some cells are sooner or later eliminated from the myometrium, while others begin to form “rudiments” of myomatous nodes with different growth potential. The “active growth bud” in the first stages develops due to physiological fluctuations in hormones during the menstrual cycle. Subsequently, the resulting cooperation of cells activates autocrine-paracrine mechanisms caused by growth factors, forms local autonomous mechanisms for maintaining growth (local production of estrogens from androgens and the formation of connective tissue), and as a result, the importance of physiological concentrations of sex hormones for the formation of a myomatous node ceases to be the main one .
Based on the data of a genetic analysis of myomatous nodes, the proliferative activity of uterine fibroids is caused by dysregulation of the genes of highly mobile protein groups (HMGIC and HMGIY), located on chromosomes 12 and 6, respectively, that is, in the loci of the most common chromosomal dysregulations characteristic of this formation. The product of expression of the HMGIY and HMGIC genes are proteins assigned to various families of the high mobility group proteins, which are chromatin-associated non-histone proteins. These proteins play an important role in regulating chromatin structure and function. In addition, they are responsible for the correct three-dimensional configuration of the DNA-protein complex, that is, they participate in cellular processes such as DNA transcription. Aberrant expression of HMGIC and HMGIY proteins most often characterizes the malignant process. Dysregulation of these proteins due to chromosomal rearrangements is most often detected in various benign mesenchymal formations, such as lipoma, pulmonary hamartoma, endometrial polyp, as well as in leiomyoma. These proteins are expressed in almost all organs and tissues during ontogeny (adrenal glands, aorta, bones, brain, heart, intestines, kidney, lung, liver, muscle, ovaries, placenta, skin, spleen, stomach, testes and uterus), while while in the adult body the expression of these proteins is detected only in the lungs and kidneys. In addition, HMG proteins are expressed when grown
in vitro cell cultures of the above tissues. A similar pattern of expression of HMGIC and HMGIY proteins indicates their participation in the rapid growth of embryonic tissues and tissues in culture.
The monoclonal proliferation of myometrial smooth muscle cells, in which the program of clonal tissue proliferation is activated due to the dysregulation of HMG genes, increases in size against the background of normal hormonal levels, while the cells of the unchanged myometrium are in a state of relative rest.
The importance of hormonal levels for the growth of a myomatous node to a certain stage is critical. With an increase in its size, the formation of autocrine-paracrine regulation of growth and the establishment of local autonomous mechanisms makes the growth of fibroids relatively independent.
The study of the system of interaction between the hypothalamus, pituitary gland and ovaries has contributed to the expansion of ideas about the etiology and pathogenesis of a number of gynecological diseases. It became obvious that their correction requires the possibility of exogenous administration of various hormones that determine the functioning of the hypothalamic-pituitary-ovarian system (HPO). Its main regulators are gonadotropic releasing hormones (GnRH). In the early 80s of the last century, it was possible to synthesize their chemical analogues; this fact was regarded as one of the revolutionary achievements in medicine. Indeed, the emergence of a drug opportunity to “correct” the work of the GnRH and eliminate the effect of sex hormones on the main targets allows us to consider the use of GnRH analogues as a truly pathogenetic therapy, in particular, for such common gynecological nosologies as uterine fibroids and endometriosis.
As is known, the mechanism of action of GnRH agonists (GnRHa) is as follows: after GnRH binds to receptors on the surface of gonadotropic cells, an intense release of LH and FSH occurs. However, prolonged exposure to GnRH on the pituitary gland for several hours leads to a loss of sensitivity of gonadotropic cells and a rapid decrease in the intensity of secretion and biosynthesis of gonadotropins, especially LH. In this desensitized state, gonadotropic cells can remain as long as continuous exposure of the pituitary gland to high doses of agonists continues.
This results in a progressive drop in estrogen concentrations to levels seen during menopause. Levels of testosterone, androstenedione and prolactin decrease parallel to the decrease in LH concentrations. After discontinuation of the drug in the blood, the concentration of FSH and estradiol gradually begins to rise, but the level of LH remains suppressed for another 4 weeks.
Gonadotropin-releasing hormone analogues, which can cause a reversible hypogonadotropic/hypogonadal state, have long been used to treat uterine fibroids. Multiple studies have shown that GnRH therapy can reduce the size and involution of uterine fibroids. It has been suggested that the reduction in fibroid size is associated with a hypogonadal state caused by GnRH agonists. However, different myomatous nodes in the same uterus, due to their proven monoclonality, have different sensitivity to GnRH therapy. The reduction in fibroid size is caused not only by the hypoestrogenic state, but also by other additional factors.
One alternative mechanism of action of GnRH may be a direct effect of GnRH on leiomyoma cells.
GnRH receptor mRNAs, as well as GnRH itself, are transcribed in both normal myometrium and leiomyoma tissue. Growing normal myometrial and leiomyoma explants in culture revealed that normal myometrial explants grow in the form of hills and valleys, while leiomyoma explants form ball-like aggregates. In vitro analysis showed that GnRHa can cause significant morphological changes in the structure of spherical leiomyoma aggregates, but at the same time have no effect on normal myometrial explants. When assessing the nature of the effect of GnRH on the expression of gene products associated with the G1 phase of the cell cycle, such as cyclin D1, cyclin E, p33cdk2 and p34cdk4, it was revealed that GnRH have a dose-dependent biphasic effect on the expression of cyclin E and p33cdk2 in tissue culture from leiomyoma ( 2).
Using FITC-labeled GnRH, it was shown that GnRH directly binds to the cytoplasmic membrane of myometrial and fibroid smooth muscle cells, interacting with its specific receptor.
GnRH of hypothalamic origin is destroyed quite quickly in the pituitary gland and is present in fairly low concentrations in the peripheral bloodstream. Therefore, it is unlikely that the hypothalamus is the main source of GnRH affecting the growth of leiomyomas in the uterus. Thus, the presence of both GnRH receptor mRNA and GnRH mRNA in the myometrium and fibroids suggests that GnRH or GnRH-like peptides are involved in the autocrine and/or paracrine regulation of myometrial and leiomyoma proliferation in vivo.
Thus, smooth muscle cells cultured from myometrium and leiomyomas express GnRH receptor and GnRH mRNA. Their treatment with GnRH leads to morphological changes in spherical aggregates obtained by in vitro growth of leiomyoma explants, as well as changes in the expression of genes associated with the G1 phase of the cell cycle. These changes are absent in the myometrium. These results suggest that GnRHa may act on leiomyoma cells through its membrane receptors, resulting in decreased expression of cyclin E and p33cdk2 genes.
GnRH agonists also have a significant effect on the extracellular matrix of fibroids, which plays an important role in its growth and regression. Tissue remodeling, including rearrangement of the extracellular matrix (ECM), is regulated by the combined action of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Leiomyomas have been shown to express both MMP and TIMMP mRNA and their expression is inversely altered during fibroid growth and during regression induced by GnRH agonists. GnRH-mediated fibroid regression is accompanied by an increase in MMP expression with a concomitant decrease in TIMMP-1 expression, which may provide a favorable environment for ECM degradation.
As a result of a study of the effect of GnRH therapy on uterine fibroids, no significant differences are found in the histological picture of myomatous nodes of treated and untreated patients, while immunohistochemical studies reveal a significant decrease in the cellular proliferative index (by 85%) under the influence of agonists, and the inhibitor label index bcl-2 apoptosis does not have significant differences among the compared groups of patients. Thus, therapy with GnRH agonists leads to a significant decrease in the number of cells in the cell cycle. There is also a significant decrease in the expression of estrogen and progesterone receptors.
The result of conservative therapy for fibroids may be insufficient if the patient has large fibroid nodes. In such cases, it is impossible to avoid surgical intervention, however, the use of GnRH agonists in operated patients also significantly improves the final results of treatment. This is due to the ability of GnRH agonists to reduce the severity of the adhesive process by reducing the activity of formation of thrombin, fibrin, plasminogen activator inhibitor by 25%, the level of fibrin degradation products by 35%, as well as reducing the immune activity of NK cells and thereby reducing the body’s inflammatory response. However, the duration of the operation increases significantly in those patients in whom the myomatous node after therapy with GnRH agonists acquired pronounced hypoechogenicity during preoperative ultrasound examination due to significant softening of the fibroid tissue, which complicated the isolation of such a node from the uterus. On the other hand, the administration of GnRH agonists after conservative myomectomy makes it possible to suppress the microscopic regenerative rudiments of fibroids in the myometrium and thereby reduce the existing level of recurrence of the disease, as well as to use the direct antiproliferative and proapoptotic properties of GnRH agonists on possible hidden foci of endometriosis (internal and external).
Currently, a wide range of different forms of GnRH a is available to gynecological specialists, one of which is Diferelin®. Our clinical observations of the use of Diferelin in 46 patients aged 32 to 52 years in recent years have shown the high effectiveness of this drug in relation to the regression of myomatous nodes with adequate administration of the drug.
The initial size of the uterus of patients included in the study did not exceed 10 weeks of pregnancy, and the diameter of the dominant nodes did not exceed 3 cm. On average, after 3 months of conservative therapy with Diferelin, the size of the uterus decreased to 5-6 weeks, and myomatous nodes decreased by 30-80% . Such a scatter in treatment results is explained by the heterogeneity of myomatous nodes, which probably determines their different sensitivity to the drug.
Thus, Diferelin® is an effective drug for complex conservative treatment of small uterine fibroids. Its use is especially important for combined gynecological pathologies: uterine fibroids, endometriosis and endometrial hyperplasia. This is due to the fact that in many respects the treatment of uterine fibroids, endometriosis and endometrial hyperplastic processes is carried out using virtually the same therapeutic approaches. Diferelin® is also used in postoperative anti-relapse treatment of these diseases. At the same time, when using Diferelin® there are no progestogenic and androgenic side effects, or a negative effect on the lipid profile. It can be used for concomitant diseases: fibrocystic mastopathy, hypercoagulation, polycystic ovarian syndrome, dyslipidemia. Diferelin® is much better tolerated than antigonadotropins, which contributes to greater patient adherence to treatment, and at the present stage is a drug for pathogenetic therapy of benign uterine hyperplasia and endometriosis of all localizations.
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In the female body, the work of the ovaries and the main nodes of reproductive function are controlled exclusively by the brain, through the tissues of the hypothalamic-pituitary axis. The synthesis of special hormones occurs in a certain part of the brain with the help of neuron cells. These hormones can stimulate or suppress the functioning of other organs.
Action of gonadotropin
In the area where the hypothalamus is located, there is a cluster of neurons, where the synthesis of gonadotropin-releasing hormone (their abbreviated name is GnRH) occurs. They are fairly large protein compounds that stimulate the production of substances such as:
- thyroid hormones;
- somatoliberins;
- releasing hormones.
Such hormonal compounds have an effect on the pituitary gland and its work, where the production of tropic hormones of the same name occurs.
Through the action of GnRH, follicle-stimulating and luteinizing hormones are produced, which enter the blood in the form of impulses (every 60 minutes). This ensures a certain threshold of sensitivity to the action of receptors located in the pituitary gland, as well as the normal functioning of the reproductive organs.
If the produced hormone enters the blood more frequently, or even continuously, then the woman’s body begins to work a little differently. An excess of a hormone such as gonadoliberin in the blood leads to the loss of receptor sensitivity to its composition. The result is irregular menstruation.
In the case when the hormone enters the blood a little less frequently than necessary, the chain of processes leads to the appearance of amenorrhea and the cessation of ovulation manifestations. Follicle production slows down or stops altogether.
The production of a hormone such as gonadotropin depends on the action of such substances:
- dopamine;
- gamma-aminobutyric acid;
- serotonin;
- norepinephrine;
- acetylcholine.
This can explain the effect on the body of stress, emotional oppression or chronic lack of sleep. They negatively affect the female body, the production of hormones, and the state of the nervous and reproductive systems.
On the other hand, maintaining a healthy lifestyle, daily positive emotions, maintaining a calm mental state - all this supports the production of the necessary hormones and the functioning of the body.
What are antagonists and agonists used for?
The use of GnRH in the treatment of pathologies associated with infertility is necessary in order to control the functioning of the ovaries. This occurs by stopping the production of hormones by the pituitary gland.
Today there are proven drugs that are successfully used when problems arise. These include Burselin, Decapeptyl, Zoladex and other drugs.
They apply:
- in order to extend the ovulation period during fertilization procedures;
- to stimulate the work of the ovaries, the purpose of using the medicine is to restore the production of high-quality eggs so that fertilization occurs;
- if necessary, control the ovulation process, with auxiliary procedures aimed at reducing the rate of hormone production by the pituitary gland.
It is hormonal drugs such as Lucrin or Diferelin that can affect the ovulation process, as well as non-menstrual processes. It is worth noting that when comparing the use of agonists and antagonists, it is recommended to use agonists for more time compared to the latter.
In order to qualitatively control the maturation of eggs, doctors can prescribe long-term courses of agonists, this makes it possible to obtain good results, increasing the chance of pregnancy and trouble-free bearing of the baby.
Hormonal drugs that are used today
When considering the scope of application of GnRH, we can conclude that it is quite wide, it all depends on the individual characteristics of the body, the method of administration, and the pathological processes that occur in the female body.
Experts prescribe Diferelin when it is necessary to treat:
- uterine fibroids;
- infertility (this drug is also prescribed for artificial insemination);
- breast cancer;
- hyperplastic processes in the structure and tissues of the endometrium;
- infertility in women.
- endometriosis of varying intensity;
Men are prescribed the use of such hormonal drugs for prostate cancer. Children are prescribed medication when they experience puberty too early. The drug is administered subcutaneously.
The use of Buserelin nasal spray is effective for the treatment of diseases such as:
- breast cancer;
- endometrial hyperplasia;
- uterine fibroids.
The drug is administered intramuscularly and works more effectively after a slight muscle release. It is mainly prescribed before and after operations. For example, in the treatment of endometriosis. The use of the medicine occurs with the aim of reducing the foci of disease development. Buserelin is used in IVF.
Zoladex is produced in capsule form and is used to treat prostate cancer and various pathologies in women. Specific capsules must be implanted under the skin in the place where the anterior abdominal wall is located.
Thus, the necessary hormones can be supplied constantly, in the required dosage. The action of the drug is aimed at reducing the level of estrogen in women and testosterone in the male body.
When to use the medicine:
- with uterine fibroids;
- with endometriosis;
- for prostate tumors in men and its regression;
- As cancer progresses, gonadotropin-releasing hormones reduce tumor size.
In any case, the prescription of medications should be carried out exclusively by a specialist.
Modern technology and pregnancy
Today, methods are provided to stimulate the ovulation process; with the help of medications, it is possible to achieve the effect of maturation of even two high-quality eggs at the same time. This is called superovulation. To achieve this effect, gonadotropin-releasing hormone agonists must be used according to a specific regimen.
Drugs such as Firmagon, Orgalutran, Cetrotide are antagonists of gonadotropin-releasing hormones. Their effects are aimed at inhibiting the production of latinizing and follicle-stimulating hormones. These drugs are used in practice when performing an IVF program.
Gonadotropin-releasing hormone antagonists can bind to a specific type of GnRH receptor. Actions occur some time after the administration of drugs.
The duration of use should be such that the follicles complete their development and ovulation does not occur ahead of time - this increases the likelihood of a positive fertilization effect.
The level of estradiol increases in the body. This helps to achieve the peak release of latinizing hormones ahead of time. It turns out that the ovulation process occurs ahead of time because of this. Such methods are used in medical practice.
The use of such preparation regimens does not allow the development of hyperstimulation syndrome in the ovaries. It often occurs with prolonged use of hormones (they increase in size, ascites or effusion into the pleural cavity, or the appearance of formations in the form of blood clots may develop).
What side effects can there be when using drugs?
Almost all hormonal medications have side effects. It all depends on the individual characteristics of the body. It happens that there are no side effects from the use of GnRH at all, but it happens quite the opposite.
The likelihood of an unwanted process occurring can be discussed with a specialist before the appointment. Often, possible side effects are described in the instructions given when purchasing the medicine.
When considering the benefits of using a hormonal drug, you can turn a blind eye to the manifestation of side effects. They always disappear after stopping the medication. In any case, all hormonal medications should be supervised by the attending physician.
Side effects of hormonal medications include:
- the appearance of unpredictable bleeding between menstruation;
- the occurrence of anxiety, depression and other mental changes;
- the appearance of severe pain in the joints and muscles;
- the occurrence of a rapid pulse.
There are other side effects that can occur in the body when using a hormonal drug. It all depends on individual characteristics.
Introduction
Introduction to drugs and protocols
Finally, four drug compounds with a combination of adequate anti-GnRH activity and safety have been developed and have undergone adequate preclinical and clinical testing in ovarian stimulation protocols for the treatment of infertility:
- Nal-Glu
- Antid
- Cetrorelix (“Cetrotide”).
- Ganirelix (“Orgalutran/Orgalutran/Antagon”).
GnRH antagonist administration regimen
Cetrotide Available in two different doses:
- Cetrotide 0.25 mg
- Cetrotide 3 mg
- Orgalutran 0.25 mg. The minimum therapeutic dose was derived empirically from a multicenter clinical trial (The Ganirelix Dose-finding Study Group. Adouble-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone ntagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon). Hum Reprod, 1998)
- A single administration of a large dose (3 mg), with a continuing effect of the drug for up to 96 hours. If necessary, after 96 hours, maintenance daily doses of 0.25 mg are administered. The minimum therapeutic dose of 3 mg was derived empirically from the findings of several clinical studies (Olivennes F et al., 1995, 1998, 2001)
- Daily administration of a minimum dose of 0.25 mg, exactly the same as Orgalutran. The minimum therapeutic dose has also been derived empirically from the findings of several clinical studies (Diedrich K et al., 1994; Felberbaum R et al., 1996; Albano C et al., 1997)
Gonadotropin administration regimen
The classic protocol under the guise of a GnRH antagonist implies that the administration of gonadotropin begins from 2-3 days of the menstrual cycle until the day of introduction of the ovulation trigger, with adjustment of the daily dose as required. Moreover, from the moment of administration of the GnRH antagonist, with good dynamics of follicle growth, increasing the dose of FSH does not improve the prognosis of treatment (Propst AM, Bates GW et al., 2006)
In general, there are three possible principles for using gonadotropins to stimulate superovulation:
- Fixed mode, implies maintaining a constant dose of gonadotropins throughout the entire period of stimulation. It is believed that a well-chosen dose of the inducer, which does not require upward or downward adjustment, provides the best treatment prognosis in terms of the number of high-quality oocytes, embryos and the incidence of clinical pregnancy. Despite the fact that this opinion cannot yet be considered objectively verified, it is still adhered to by the largest number of reproductive specialists.
- Buck mode(“step down”), implies a high dose of an ovulation inducer at the start, with a downward adjustment of the administered dose, if necessary. This stimulation mode provides the maximum follicular response in terms of number and synchrony of development due to ultra-high concentrations of FSH, which makes it possible to recommend the approach in groups of patients with reduced follicular reserve.
- Boost mode(“step up”), on the contrary, involves relatively low doses of gonadotropins at the start of the induction protocol, with the possibility of significantly increasing the dose within the framework of a poor follicular response. This approach provides maximum control over the cohort of dominant follicles, therefore, maximum opportunities for the prevention of excessive response and OHSS. The disadvantage of the lowering mode is a reduction in the number of high-quality oocytes suitable for fertilization and an increase in the number of small-diameter follicles on the day the ovulation trigger is prescribed.
Use of combined oral contraceptives (COCs) to prepare for an induction cycle
When comparing cycles with the use of GnRH antagonists, started in the spontaneous menstrual cycle or after discontinuation of COCs, it was noted that in the COC group it was possible
to achieve better synchronization of the follicular cohort with a large number of dominant follicles and less variability in average diameters from follicle to follicle, which required an increase in the average duration of ovarian stimulation, with a later start of administration of the GnRH antagonist, as the follicles reached the desired diameter (in this work > 13 mm) much later (Fanchin R et al., 2003). However, data from another study demonstrated comparable clinical pregnancy rates regardless of the use of COCs before the ART protocol (Shapiro DB, 2003).
It should be noted that patients with PCOS are a separate topic in this issue. As is known, a number of studies have previously noted the damaging effect of excess LH concentrations in such women (Chappel, Howles, 1991; Shoham et al., 1993). It is believed that LH helps trigger
- atresia, through the accumulation of excess androgen concentrations
- premature resumption of meiotic maturation of the oocyte
- luteinization of granulosa cells and disruption of their interaction with the oocyte, disruption of oocyte maturation
In this regard, it seems logical to discuss the need for preliminary preparation for the ART cycle of patients with PCOS not only with drugs from the group of insulin synthetizers, but also with COCs, since the latter reliably contribute to a decrease in LH levels at the start of a new menstrual cycle, hence the harmful effects of high concentrations of endogenous LH .
Dependence on LH activity during the period of stimulation of superovulation
Background LH activity is a voluminous topic that combines not only clarifying the understanding of the consequences of suppressing the production of endogenous LH, but also weighing the feasibility and number of additional injections of drugs with LH activity during controlled induction of ovulation.
In this discussion, it is first of all useful to recall a number of clinical situations where PH is either absent or biologically ineffective. In particular, with hypogonadotropic hypogonadism syndrome, although patients are in a state of chronic anovulation, the development of the dominant follicle can be stimulated by exogenous administration of gonadotropins. It has been noted that the administration of only purified or rFSH to such patients, although it provides a multifollicular response, is characterized by disproportionately low concentrations of estradiol in plasma, a decrease in endometrial thickness, ovulation frequency, fertilization, and the number of embryos available for embryo transfer or cryopreservation, when compared with patients receiving HMG ( Shoham et al., 1991; Schoot et al., 1994; Balasch et al., 1995; Kousta et al., 1996). At the same time, the addition of estradiol in the FSH group did not improve the prognosis for the likelihood of pregnancy (Hull et al., 1994; Balasch et al., 1995), which clearly indicates that the main defect of such tactics is not realized in violation of the qualitative characteristics of the processes of endometrial proliferation , namely, the failure of the mechanisms for the correct preparation of a mature oocyte. Another illustrative example is clinical cases with primary amenorrhea and infertility caused by a homozygous mutation of the LH receptor gene. At the same time, low concentrations of estradiol are also recorded, and during histological examination of the ovaries, all stages of follicle development are found up to large antral follicles (Latronico et al., 1996; Toledo et al., 1996).
In light of such arguments, it is no longer surprising why the need for the presence of luteinizing hormone during the period of recruitment and development of the dominant follicle is considered a dogma of reproductive endocrinology (Fevold, 1941; Short, 1962), and therefore, historically, ovarian stimulation protocols included both LH and FSH .
However, the question of a comfortable amount of LH in the blood plasma to ensure adequate folliculogenesis remains unclear to this day. Thus, in the publication there are works where it is indicated that in total<1% рецепторов ЛГ в фолликулах необходимо связать для обеспечения нормального стероидогенеза (Catt, Dufau, 1977г; Doerr, 1979г; Chappel, Howles, 1991г). В одном показательном исследовании по подбору дозы рЛГ авторы сопоставляли различные дозы препарата рЛГ, который добавлялся к рФСГ в протоколах контролируемой индукции овуляции у пациенток с гипогонадотропным гипогонадизмом (Recombinant Human LH Study Group, 1998г). Пациентки, получавшие дозы в 75 и 225 МЕ/день рЛГ, характеризовались достоверно большем количеством доминирующих фолликулов, более высокими концентрациями эстрадиола в пересчете на фолликул, большей частотой наступления клинической беременности, чем в двух других группах (0 или 25 МЕ/день рЛГ). Интересно, что ЛГ в плазме крови выявлялся только в группе пациенток, получавших 225 МЕ/день рЛГ. Авторы пришли к выводу, что несмотря на очевидное существование индивидуальных вариаций в минимальных дозах ЛГ, необходимых для обеспечения нормального развития фолликула, у большинства пациенток, получавших 75 МЕ/день рЛГ, отмечен адекватный ответ. Таким образом, становится понятно, что концентрации остаточного эндогенного ЛГ, вероятно, также должны быть достаточны для адекватного созревания когорты доминирующих фолликула в процессе стимуляции яичников очищенным человеческим мочевым ФСГ или рекомбинантным ФСГ в протоколах с антагонистами ГнРГ. В особенности принимая к сведению, что в условиях адекватного подавления синтеза эндогенного ЛГ путем введения антагониста ГнРГ, практически всегда удается фиксировать пороговые концентрации гормона в плазме крови. Между тем, признание потребности в эндогенном ЛГ ставит под сомнение логику протоколов с псевдо-депо антагонистом ГнРГ, так как при единовременном введении большой дозы препарата (Цетротид 3мг) происходит заметно более глубокое угнетение выработки ЛГ. Однако имеющееся на сегодняшний день клинические данные отрицают подобные опасения, показывая, что применение Цетротида в импульсной дозе 3мг в сочетании с рФСГ-препаратом без какой либо ЛГ активности, практически также эффективно в сопоставлении на частоту наступления беременности, как и длинный протокол с агонистом ГнРГ (Roulier R и соавт., 2003г). Важной особенностью данного исследования является однако то, что начало введение цетрореликса производилось по гибкому протоколу, при достижении лидирующим фолликулом диаметра 14мм, что возможно позволяет проскочить критичный для развивающихся доминирующих фолликулов период потребности в эндогенном ЛГ, хотя это во многом и противоречит сегодняшним представлениям, что фолликулы до стадии больших антральных могут развиваться без значимой биоактивности ЛГ и при отсутствии высоких концентраций эстрадиола. При оценке влияния высоких доз ганиреликса, напротив было зафиксировано статистически значимое снижение частоты имплантации (1,5%) и клинической беременности (3,8%) и более высокой частоты выкидыша (13%), что безусловно может быть связано непосредственно с используемым препаратом и его дозой, но еще и с тем, что введение ганиреликса, в отличие от предыдущего исследования производилось на фиксированной основе всегда в один и тот же день лечебного цикла (The Ganirelix Dose-finding Study Group. Adouble-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone 1998г). Другой оценочный подход был использован в работе Bosch E и соавт., 2003г. Авторы проанализировали показатели гормонограммы в части плазменных концентраций ЛГ в процессе ведения протокола ВРТ 96 пациенток. Уровни ЛГ оценивали на 3 день цикла, в день старта антагониста ГнРГ, еще через 2 дня и в день введения триггера овуляции. Выводом исследования был отчет об отсутствии различий в результатах цикла лечения в отношении уровней эстрадиола в день ХГЧ, количества ооцитов, имплантации и частоты наступления клинической беременности, что довольно демонстративно указывает на отсутствие негативного эффекта глубокого подавления выработки ЛГ.
However, the inconsistency of the information we have, including that obtained in clinical trials, although in general does not deny the need for LH as such, does not clearly indicate the logic of the additional use of drugs with LH activity.
It has already been shown that the widespread use of LH in the general population of patients is characterized by rather negative consequences on the prognosis of treatment (Balasch J et al., 1996).
Also, the tactics of additional administration of r-LH within the framework of protocols on GnRH antagonists in the general population of patients undergoing ART cycles cannot be considered justified (Ludwig M et al., 2003; Cédrin-Durnerin I et al., 2003), however, for objectivity It should be noted that the comparison here involved only recombinant LH preparations, and not HMG, which are known to have LH activity not only, but to be honest, not so much because of the LH contained in the composition, which theoretically could also have some significance.
Despite the objective complexity of the question posed, in the absence of the proper amount of analytical information, most experts still agree that the approach should be differentiated, depending on the individual characteristics of the patient (age, follicular reserve, ovarian response to induction, general endocrine status, etc.). d.).
In practice, many fertility specialists are in no hurry to completely abandon LH drugs, both in long and antagonist protocols, leaving their own individual niche behind them. Most often, drugs with LH activity are recommended for patients with a meager and non-intense follicular response, and for patients approaching the end of their reproductive activity. By the way, these recommendations cannot yet be considered sufficiently objective.
Determining the day of introduction of the ovulation trigger
Replacing hCG with a GnRH agonist
When considering in detail the possibilities of GnRH antagonists, it is imperative to mention additional possibilities for triggering follicles, namely, replacing hCG with a GnRH agonist. This approach involves inducing the release of one’s own LH—the surge effect. When formulating this concept, it was assumed that thereby the cycle of artificial induction of follicular growth would come very close in biochemical processes to natural folliculogenesis. Obviously, in the early days, when GnRH agonists ruled the roost, such an algorithm was not permissible in principle.
Over the years, a large number of discussions have accumulated regarding this point in the induced cycle. The conclusions of publications often differ, but in general, it was possible to formulate some general ideas on this issue. Thus, most researchers agreed that the practice of using a GnRH agonist is characterized by a reduction in the risk of developing moderate and severe OHSS, ensuring the receipt of an adequate number of oocytes of good quality, although the last remark remains a controversial point, since other studies have recorded that the number of mature oocytes and embryos of good quality under agonist trigger conditions still tend to decrease. An even more important disadvantage, identified in the process of widespread practice, which is perhaps most rarely discussed, is the reduction in the incidence of clinical pregnancy (Griesinger G et al., 2006). Awareness of this fact did not allow the introduction of the universal use of a GnRH agonist as an ovulation trigger in cycles under the guise of a GnRH antagonist, leaving behind this approach only a small segment of those at risk for OHSS from the total mass of patients undergoing IVF treatment. It is understood that the logic of managing such patients involves a step-by-step algorithm, including not only replacing the ovulation trigger with a GnRH agonist, obtaining oocytes, but also subsequent cryopreservation of developing embryos, using them in final-stage cryo-cycles. In their work, Griesinger G et al., 2007, demonstrated the adequacy of this approach with a good cumulative pregnancy rate.
Dwelling in more detail on the possibilities of preventing the risk of developing OHSS in patients undergoing superovulation induction with GnRH antagonists, it is necessary to recall a number of innovations. Thus, there are studies in which the authors suggest increasing the dose of the GnRH antagonist (de Jong D et al., 1998), explaining that a deeper suppression of gonadotropin production may be more useful in reducing the risk of developing moderate and severe OHSS. In other studies, the authors suggest continuing the administration of the GnRH antagonist for a long period (up to 7 days) after the introduction of the ovulation trigger in cycles followed by cryopreservation of the embryos. However, such approaches seem controversial from the point of view of the effectiveness/cost balance, since eliminating the risk of progression of OHSS in patients in the anti-GnRH protocol is almost guaranteed by replacing the trigger with a GnRH agonist, providing in itself adequate prevention of the risk of moderate and severe OHSS, without increasing the cost and cycle duration.
Support of the luteal phase of cycles with ovulation induction covered by a GnRH antagonist
Awareness of the inferiority of the second phase of the induced cycle, with an understanding of the main pathological mechanisms associated with supraphysiological levels of sex steroids in response to excessive stimulation of the follicles, as well as a sharper and earlier decrease in estradiol levels mediated through the direct effect of drugs for desensitization of the pituitary gland and according to the principle of negative feedback and progesterone after embryo transfer, prompted in practice to recommend maintenance hormonal therapy to absolutely every patient undergoing IVF treatment. The appearance in practice of GnRH antagonists, drugs without a long-term trailing effect on pituitary and ovarian activity, promised tempting prospects for reducing the required volume of maintenance hormonal treatment, ideally with a complete abandonment of it without loss of cycle efficiency. However, medical practice has made its own adjustments here too, putting everything in its place. Very soon it became clear to everyone that the thesis asserting the absence of deep inferiority of the second phase of the induced cycle when using GnRH antagonists is more of a marketing than a clinical statement. The fact is that antagonists really do not cause long-term suppression of the pituitary gland, and therefore do not have a direct negative effect on the function of the corpus luteum, since they do not cause a long-term decrease in LH production after their withdrawal. But, as it turned out, this alone is not enough, since in the middle luteal phase there is still an earlier and transient decrease in the activity of the corpus luteum through a negative feedback mechanism, due to abnormally high levels of sex steroids in the early luteal phase of the induced cycle. Studies conducted in this context have also confirmed the need for hormonal support during the post-transfer period of the superovulation induction cycle using GnRH antagonists (Albano C et al., 1998, 1999).
Alternative protocols for ovulation induction using GnRH antagonists.
Dependence on body weight
It is known that the required therapeutic dose of many drugs is determined by body weight. It is quite natural that after taking the minimum therapeutic dose, research minds asked the question: “What role can the patient’s body weight play in choosing the optimal dose?” After all, theoretically it would not be surprising if it turns out that the minimum therapeutic dose of 0.25 mg per day may turn out to be inadequate for a woman with excess body weight and, at the same time, unnecessary for a woman with underweight, especially considering that between these two women there is a satisfied large weight difference and approaches to stimulation, in particular the need for gonadotropins.
Studies conducted on the pharmacokinetics of cetrorelix have shown that the drug practically disappears from the blood plasma and follicular fluid after just a few hours (Ludwig M et al., 2001), demonstrating values at the limit of sensitivity of the assessment method. However, clinical studies weighing the dependence of the effectiveness of treatment on body weight within the approved dosages did not reveal a correlation (Engel J et al., 2002).
As for ganirelix, for this medicinal compound a dependence of real effectiveness on body weight was identified, and a clinical recommendation was made to increase the recommended dose above the minimum therapeutic dose in overweight patients.
Agonists or Antagonists?...That is the question!
The most powerful introduction of antagonists into the practice of ART began at the turn of the century. Felberbaum R.E. et al., 2000, were one of the first to publish extensive results of their experience with the use of GnRH antagonists (Cetrotide in a daily dose of 0.25 mg) in different groups of patients undergoing infertility treatment as part of IVF technology. A prospective multicenter study included more than 300 patients who underwent follicular puncture. Based on statistically worthy achievements of efficiency (the proportion of MII oocytes is 75%, the fertilization rate is 59.2%, the treatment cycle ended with embryo transfer in 92.2%, the incidence of clinical pregnancy after embryo transfer is 23.6%), the authors actually summarized that this approach to managing ART cycles is not only acceptable, but also completely acceptable.
However, it is still not enough for a practicing physician to know that the drug is approved for use; it is important for him to understand its real effectiveness, especially in relation to other commercially available analogues. As for the objective utility of new compounds, it could only be weighed in terms of direct comparison with currently available drugs. And it is logical that the comparison compared new protocols with GnRH antagonists and established protocols with GnRH agonists, in particular with the gold standard for the preparation of dominant follicles, the ubiquitous long “C” protocol against the background of GnRH agonists.
Maternal and child health
The end result of treatment with ART methods in clinical human reproduction is considered to be not even conception and the pregnancy rate, but the birth of a healthy child. It is quite natural that the assessment of any recommendation, including pharmacological ones, is ultimately made from the standpoint of not only effectiveness, but also safety for the patient and the fetus, and subsequently the mother and child. Fortunately, there were no surprises here and for both GnRH antagonists, widely used in everyday practice, no negative effect on the health of mother and child was identified (Ludwig M et al., 2001; Olivennes F et al., 2001; Boerrigter PJ and al., 2002; Kiminami A et al., 2003).
Conclusion
GnRH hormone in women.
Gonadotropin-releasing hormone, which is also called gonadotropin-releasing hormone, takes part in the synthesis of a number of other hormonal substances:
1. Luteinizing hormone (LHRH).
2. Foliberin.
This biologically active substance belongs to the group of peptide hormones with a tropic orientation. Gonadotropin-releasing hormone is synthesized and released by nerve cells that are localized in the tissues of the hypothalamus. Once released from the hypothalamus, GnRH stimulates the endocrine-active tissues of the pituitary gland. This stimulus includes the production of gonadotropic hormones: follicle-stimulating and luteinizing hormone, as well as prolactin. The synthesis of gonadotropin-releasing hormone occurs in a pulse mode, on average this period is 120 minutes. Secretion of GnRH in women occurs in short peaks that follow each other in a strictly defined time sequence. Time intervals differ in the male body and in the female body.
Normally, the female body releases hormonal molecules every 15 minutes in the follicular phase of the menstrual cycle and every 45 minutes in the luteal phase, as well as during pregnancy. In the male body, gonadotropin-releasing hormone is released every 90 minutes.
GnRH regulation
Regulation of GnRH is carried out according to the following scheme. If for some reason the concentration of sex hormones in the bloodstream drops, then the hypothalamus receives a signal to initiate the production of more gonadotropin-releasing hormone. This, in turn, turns on the mechanism due to which increased production of gonadotropic hormones occurs. These hormones subsequently enter the bloodstream from the anterior pituitary gland. Hormones synthesized by the anterior lobe of the pituitary gland - FSH, luteinizing hormone in women LH and prolactin - have a stimulating effect on the sex glands (ovaries and testes), as a result, the secretion of sex hormones sharply increases.
If the opposite picture is observed, characterized by an increased level of sex hormones in the bloodstream, then the hypothalamus produces less GnRH, and the secretion of gonadotropic hormones (FSH, LH and prolactin) by the pituitary gland also declines. Because of this, the gonads produce fewer sex hormones. This process is called the feedback principle. It is inherent not only in the female body, but also in the male body.
The GNRH1 gene, which is a precursor of gonadotropin-releasing hormone, is located on chromosome eight. The synthesis of the normal, final decapeptide occurs from amino acid precursors of hormonal substances in the tissues of the hypothalamus, in the amount of 92 units, in its anterior preoptic section. The hypothalamic-pituitary-adrenal axis system tries to influence decapeptide through regulatory mechanisms. These mechanisms are needed to suppress chemical reactions during increased estrogen synthesis in the body.
The main hormonal substance that has a direct effect on the production of GnRH is testosterone. In addition, the production of the presented biologically active substance is influenced by the metabolic products of the hormone testosterone in women. Such products are 5a-dihydrotestosterone and estradiol. Substances produced by nerve endings - neurotransmitters - have a significant influence on the production of gonadotropin-releasing hormone:
· Norepinephrine and dopamine have a stimulating effect.
· Serotonin and endorphin have an inhibitory effect.
Functions of gonadotropin-releasing hormone
The presented biologically active substance enters the pituitary blood flow of the portal vein in the projection of the median eminence. From the portal vein, GnRH travels through the bloodstream to the pituitary gland, which contains a considerable number of gonadotropic cells. In the pituitary gland, the hormone activates its own receptor cells. In addition to their receptors, activation of transmembrane receptors occurs, of which there are 7 varieties. Transmembrane receptors are combined into groups of G proteins and are involved in the stimulation of the beta isoform of phosphoinositide phospholipase C. This process activates proteins involved in the production and subsequent release of gonadotropins LH and follicle-stimulating hormone FSH in women. The enzymatic breakdown of GnRH does not take long, usually ending within a few minutes. Thus, the process of inactivation of this liberin is very fast.
The activity of this hormone has been low since early childhood. It increases only during puberty, when the body experiences an increased need for it. With the onset of reproductive age, pulsating activity has a positive effect on reproductive function. This process is regulated through a feedback loop. But after pregnancy, GnRH activity does not matter, and it becomes monotonous rather than cyclical.
In some pathological processes in the hypothalamus and pituitary gland: suppression of the functional processes of the hypothalamus, traumatic injury, neoplasm, pulsatory activity may be disrupted.
If the concentration of prolactin exceeds the norm, then the activity of gonadotropin-releasing hormone is inhibited, and a high level of insulin in the blood leads to an upward jump in pulsating activity, this provokes the pathological activity of luteinizing and follicle-stimulating hormones. This can be observed with polycystic ovary syndrome. The production of gonadotropin-releasing hormone is completely excluded in Kallmann syndrome, a hereditary condition in which, in addition to reproductive and menstrual disorders, olfactory disorders are also observed (a person cannot distinguish odors).
Relationship with follicle-stimulating and luteinizing hormonal substances
Gonadotropin-releasing hormone stimulates the production of gonadotropins - follicle-stimulating and luteinizing hormone - in the pituitary tissues. Important components for the regulation of this process are the length and frequency of the pulses observed during the release of the described biologically active substance. Feedback through the production of androgens and estrogens also takes part in regulation. Pulses of low-frequency release of gonadotropin-releasing hormone have a stimulating effect on the synthesis of follicle-stimulating hormone, while pulses of high frequency lead to the production of luteinizing hormone. The frequency of impulses differs in the female and male body: in men, the hormone is synthesized at a constant frequency, while in the female body the frequency of impulses varies depending on. The highest GnRH pulsation occurs before ovulation. Gonadotropin-releasing hormone is involved in the regulation of several complex processes:
1. Participates in the growth of follicles.
2. Regulates the ovulation process.
3. Supports the process of formation and development of the corpus luteum in women.
4. In men it also supports the processes of spermatogenesis.
Relationship between gonadotropin-releasing hormone and nerve cells
GnRH belongs to the group of neurohormones. This means that the hormone is produced in specific nerve cells, and the release process is carried out from the nerve endings.
The main zone of GnRH production is the hypothalamus, or rather its preoptic zone. This area contains a large number of nerve cells - neurons, where hormone synthesis occurs. Neurons involved in the production of this hormonal substance originate in the tissues of the nasal cavity and then grow into the structures of the brain. In the medulla, neurons are distributed by the medial plate and tissues of the hypothalamus and are united due to detritus. Neurons are grouped into bundles, and as a result, one common synoptic input is formed. The regulation of neurons involved in the production of GnRH is carried out by sensitive neurons thanks to transmitters: norepinephrine, GABA, glutamate, etc. The activity of GnRH synthesis depends on their concentration.
The influence of gonadoliberin on the organs and systems of the female body
As a result of the research, gonadotropin-releasing hormone was found not only in the reproductive organs of the female body. It has been proven that this biologically active substance affects the gonads and placenta. Hormonal cells and their receptors are found in the tissues of the mammary gland; when mastopathy is diagnosed, the cells in this case are localized in the tumor formation of the gland tissue. GnRH is also found in neoplasms of the ovaries, prostate and endometrium, but the role of the hormone in these clinical situations has not yet been studied.
Previously, specialists prescribed natural GnRH in the form of drugs such as:
· Gonadorelin hydrochloride (Factrel).
· Gonadorelin diacetate tetrahydrate (Cystorelin).
Modern medicine has invented a number of analogues of the presented biologically active substance, which either inhibit the production of gonadotropins (GnRH antagonists) or, on the contrary, stimulate them (agonists). These synthetically bred analogues have completely replaced the natural hormone. Pharmacological companies produce the following synthetic preparations of this hormone:
· Goserelin.
· Leuprolein.
· Triptorelin.
· Buserelin.
· Nafarelin.
Leuprolein, for example, is used for the therapeutic treatment of breast and prostate carcinoma, as well as endometriosis. Also recently, this drug began to be used for the treatment of premature puberty.
Goserelin is indicated for prostate cancer in men, but more often for breast cancer in women, endometriosis, and uterine fibroids. The drug is used as an adjuvant after surgery.
Mastopathy after 40 years
Nafarelin is available in the form of a nasal spray. This form is very convenient for the patient, because eliminates the need for outside help. Indications for taking this drug are endometriosis and uterine fibroids.
Any of the above medications is not recommended to be taken while carrying a child, because the likelihood of miscarriage increases, or there is a risk of developing fetal anomalies. Also, the drugs are not prescribed to nursing mothers and children.
GnRH-based drugs are poorly absorbed from the gastrointestinal tract, so the drug is available in the form of injections and intranasal sprays. The half-life of the drug is 10 - 40 minutes. The substance disintegrates in the blood plasma, after which it is excreted through the urinary canal in the form of inactive metabolites along with urine.
Side effects
Therapy with synthetically derived drugs eliminates the disease of hormones and hormonal status in women, but can have a negative effect on other organs and systems of the patient. In the medical library you can find the clinical and pharmacological reference book of P.P. Denisenko, where these effects are described:
1. If the treatment regimen is chosen incorrectly, this can lead to suppression of the hypothalamus-pituitary-ovarian axis.
2. Men may experience hot flashes and decrease potency.
3. In both men and women, the mammary gland may swell. If you palpate it at this moment, it will cause pain.
4. Headaches and bone pain appear.
5. The general condition worsens: nausea and diarrhea appear.
6. An allergic reaction may develop, accompanied by Quincke's edema.
Any drug from the group of GnRH agonists causes a condition similar to menopause. Therefore, these drugs are not prescribed for longer than 6 months without a break.
Control of ovarian performance and reproductive function occurs through the combination of structures such as the hypothalamus and pituitary gland. Neuronal cells located in a special area of the brain are responsible for the production of hormones that stimulate or, conversely, inhibit the performance of internal organs and systems. This hormone has the name - gonadoropin - releasing hormone, which is produced directly in the hypothalamus and is a very massive mixture of proteins responsible for stimulating the production of luteinizing and follicle-stimulating hormone. The group of releasing factors includes the following biological components, such as:
- Corticotropin – releasing hormone;
- Somatoliberin;
- Thyroid hormone.
All of the substances described above have an effect on cells that are located in the anterior lobe of the pituitary gland, where the synthesis of the tropic hormones of the same name directly occurs.
The release of the GnRH hormone into the bloodstream occurs once every 60 minutes. This phenomenon provides sensitivity to the influence of pituitary receptors and promotes the favorable functioning of the organs of the reproductive system. When any failure occurs and an increase in the amount and frequency of gonadorelin entering the blood occurs, there is a loss of sensitivity to the effects of receptors and, as a result of this phenomenon, the monthly cycle is disrupted. In the case of a very rare entry of GnRH into the bloodstream, the ovulatory process does not occur in the woman’s body, and menstruation does not occur for a long period of time.
The release of gonadotropin-releasing hormone depends on the influence of such biologically active substances as:
- Norepinephrine;
- Serotonin;
- Acetylcholine;
- Gamma-aminobutyric acid;
- Dopamine.
Frequent stress, emotional depression, and poor sleep have a negative impact on the functioning of the reproductive system, but in addition to negative factors, there are also positive ones that have a beneficial effect on the performance of the genital organs. The main ones are:
- healthy lifestyle;
- balanced diet;
- positive emotions;
- absence of stressful situations.
The following medications are antagonists of gonadotropin-releasing hormone, such as:
- Orgalutran;
- Firmagon;
- Cetrotide.
The drugs described above have an effect on the human body, inhibiting the production of luteotropin and follicle-stimulating hormones. Most often, these medications are used during preparation for in vitro fertilization. Today, the use of medications makes it possible to stimulate ovulation, during which the maturation of not just one egg ready for fertilization occurs, but several at the same time. This phenomenon in medical practice is called superovulation.
To achieve this state, gonadotropin-releasing hormone agonists are used, which must be administered according to a specially designed regimen. As a result of the administration of such drugs, estradiol concentrations increase and an early LH surge may occur. As a result of this, the ovulation process begins prematurely, eggs begin to be lost and they cannot be used for further artificial insemination.
In turn, when antagonists enter the human body, they begin to actively bind to GnRH receptors and their effect begins a couple of hours after direct administration. The duration of these medications should be such that full growth and development of follicles occurs, and premature ovulation does not occur. 12 hours after the administration of the antagonists, the pituitary gland is again ready to use this drug, which will allow the onset of a state of superovulation and the maturation of several female germ cells. When using this regimen, the risk of ovarian hyperstimulation, which can develop with very long-term use of GnRH agonists, is reduced.
This condition is accompanied by a significant increase in the volume of the ovaries, as well as the appearance of abdominal dropsy, pathological accumulation of fluid in the pleural cavity, as well as thickening of the blood and the formation of blood clots. Taking gonadotropin-releasing hormone antagonists begins 5 or 6 days after starting to use follicle-stimulating hormones. When the follicles increase to a size of 17–19 mm, stop using antagonists.
Administration mode
Drugs that are gonadorelin antagonists have undergone a huge amount of research and are safe drugs that are used to treat infertility.
The widely known and most frequently used gonadotropin-releasing hormone antagonist drugs are Cetrotide and Orgalutran. It is these two medications that have been registered and can be purchased in pharmacies in the Russian Federation.
Cetrocid
Drawing from Medside
The drug Cetrocid is produced in the form of a powder intended for the preparation of an injection solution, which has a dosage of 0.25 mg or 3 mg. Orgalutran is also available as a solution for subcutaneous administration, the dosage of which is 0.25 mg.
Due to the fact that the drug Cetrotide has two different dosages, it can be administered in two different ways. The first is a single administration of the drug in an amount of 3 mg. The therapeutic effectiveness of this medicine after administration lasts for 96 hours. At the end of this period, a maintenance dose of 0.25 mg can be administered. The second way to use Cetrotide is to administer a minimum amount of 0.25 mg daily. The drug Orgalutran is also administered every day using a dosage of 0.25 mg.
A huge advantage with a single administration of a large amount of the drug Cetrotide is the reduction in the number of injections, and the introduction of an additional dosage of 0.25 mg occurs once every 10 induction cycle. The disadvantage of using such an amount is the increased risk of developing a negative effect on follicles that are actively growing and developing. This is caused by the fact that there is a strong decrease in the production of luteinizing hormone.
According to the results of a huge number of studies in which the two protocols were compared, it was found that the pregnancy rate was the same in both the first and second cases.
Start of introduction
The effect after using the drug occurs as soon as possible. In this regard, long preparation is not required to stimulate the ovaries. During the period of preparation for stimulation, it is very important to choose the appropriate tactics and determine the time during which it is necessary to suppress the synthesis of gonadotropins, with the preventive purpose of preventing the peak of luteinizing hormone.
Application protocols
There are two methods of introducing protocols during which the GnRH antagonists will change, which are not similar to each other and are the complete opposite of each other.
Flexible protocol
The essence of this method is to administer the first injection of gonadotropin-releasing hormone antagonist drugs, depending on the concentration of estradiol in the blood or on the degree of follicle maturation and its size.
Fixed protocol
The first administration of the medicine is performed on the specified day of the cycle (often these days are the sixth or seventh).
The protocols described above using GnrH antagonist drugs have been tested using specially designed tests. According to the results of these studies, it was revealed that, despite the same number of ultrasound examination visits, women who received therapy according to the first type, or more precisely, according to a flexible protocol, needed fewer injections and a lower dosage of medications - gonadotropin-releasing hormone antagonists. In addition, they also had a higher number of mature oocytes.
Positive effects
In other words, adapting a particular protocol to the personal characteristics of the response of a woman’s follicular apparatus throughout the entire period of stimulating the maturation of more than one egg makes it possible not to use injections that are not necessary, as well as to optimize the ovarian response to the stimulation process. Stimulating the onset of superovulation on a flexible schedule makes it possible to save the use of at least one ampoule of a gonadotropin-releasing hormone antagonist, as well as about 100 Megonadotropins. But at the same time, it was noticed that if antagonists are administered later than the 8th day, the chance of achieving the desired pregnancy decreases.
Gonadotropin-releasing hormone antagonists are special medicinal compounds that are safe for the human body and actively help stimulate superovulation and subsequent pregnancy. And, despite the fact that for a very long period of time there have been only two units of these medicines, they continue to be in great demand. The development of gonadotropin-releasing hormone antagonists made it possible to make a small revolution in the field of reproductive medicine. The use of these medications makes it possible to individually select therapy for each patient personally during the period of preparation for artificial insemination. The huge advantages of using these substances, in addition to the individually selected amount and method of administration, is also an alternative approach to controlling the onset of superovulation. As a result, the risk of developing an increased follicular response is reduced.
Negative phenomena
Despite this, there are also negative aspects that scientists are working on to eliminate them. In some cases, the use of protocols in conjunction with gonadotropin-releasing hormone antagonist drugs is characterized by a slight increase in the risk of missing the onset of a premature peak of luteinizing hormone. In this regard, there is a tendency to reduce the frequency of pregnancy. In this case, the woman needs to be removed from the cycle of assisted reproductive technologies, and an ovulation trigger must be introduced, which leads to a decrease in the number of mature oocytes.
To this day, research is still being conducted to improve gonadotropin-releasing hormone antagonists in order to achieve maximum results in the treatment of infertility and increase the chances of pregnancy.