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.

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.

Receiving eggs

For stimulation, injections of follicle-stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (HCG), and gonadotropin-releasing hormone (GnRH) blockers are used.

The maturation of eggs cannot be directly determined by non-invasive methods. Therefore, the maturation of eggs is judged indirectly by the growth of ovarian follicles. The growth of follicles is observed using ultrasound machines. When the dominant follicle reaches a certain size (16-20 mm), an egg retrieval procedure is prescribed - puncture of the ovarian follicles. Puncture of the follicles is carried out under general (more often) or local (less often) anesthesia, the needle is passed transvaginally, the course of the needle is monitored with an ultrasound machine. The purpose of the puncture is aspiration (suction) of the contents of the follicle (follicular fluid). The resulting liquid is examined using a microscope to detect eggs.

Usually, the use of hormonal drugs and follicular puncture does not cause negative reactions in the patient, but sometimes complications can occur. A complication of superovulation stimulation is ovarian hyperstimulation syndrome (OHSS), which can develop several days after the end of stimulation. OHSS occurs when a large number of follicles mature, which, transforming into corpus luteum, secrete a large amount of estrogens. In severe cases of OHSS, the patient may require hospitalization. A complication of follicle puncture may be an ovarian hematoma.

If it is impossible to obtain eggs from a patient (absence of ovaries, menopause, etc.), it is possible to use donor eggs (that is, eggs from another woman). The egg donor can be a selfless donor (relative, friend) or a paid donor. The conditions for working with an egg donor are regulated by Order N67 of the Ministry of Health of the Russian Federation.

Receiving sperm

Fertilization in vitro

Direct IVF is carried out by embryologists in an embryological laboratory. Fertilization itself is carried out in one of two ways:
1) insemination in vitro;
2) intracytoplasmic sperm injection (ICSI, ICSI).
In the first, simpler method, a suspension of sperm is added to the eggs that are in a nutrient medium. Spermatozoa are added at the rate of 100-200 thousand per egg. Within 2-3 hours, one of the sperm penetrates the egg and thereby fertilizes it. In the second method (ICSI), the sperm is introduced into the egg “manually” using microsurgical instruments. ICSI is used when sperm quality is very poor, when fertilization cannot be obtained even in a dish.

Embryo transfer to the uterus

The embryo is transferred to the uterus 2-5 days after fertilization of the egg. The procedure does not require anesthesia (pain relief) and is performed on a gynecological chair within a few minutes. The embryo is transferred to the uterus by passing a special elastic catheter through the cervix. According to Order No. 67 of the Ministry of Health of the Russian Federation, it is not recommended to transfer more than 4 embryos into the uterine cavity in order to avoid multiple pregnancies. Modern IVF practice in Russia is such that 2 embryos are usually transferred.

Estrogens stimulate the growth of the oviduct, uterus, vagina, proliferation of the inner layer of the uterus - the endometrium, promote the development of secondary female sexual characteristics and the manifestation of sexual reflexes. In addition, estrogens accelerate and enhance contraction of the uterine muscles and increase the sensitivity of the uterus to the neurohypophysis hormone oxytocin. They stimulate the development and growth of the mammary glands.

Under its influence, the mucous membrane (endometrium) of the uterus grows, which promotes the implantation of a fertilized egg in the uterus. Progesterone creates favorable conditions for the development of decidual tissue around the implanted egg, maintains the normal course of pregnancy by inhibiting muscle contractions of the pregnant uterus and reduces the sensitivity of the uterus to oxytocin. In addition, progesterone inhibits the maturation and ovulation of follicles due to inhibition of the creation of the hormone lutropin by the adenohypophysis.

The extragenital effects of sex hormones include, for example, the anabolic effect of androgens, i.e. increased protein synthesis, the catabolic effect of progesterone, the effect of androgens and gestagens on bone growth, increased basal body temperature, etc.

Cells of the corpus luteum of the ovaries, in addition to producing steroid hormones, synthesize the protein hormone relaxin. Increased secretion of relaxin begins in the later stages of pregnancy. The significance of this peptide hormone is the weakening (relaxation) of the ligament of the pubic symphysis with other pelvic bones, the mechanism of which is associated with an increase in the level of cAMP in chondrocytes. This causes the molecular components of their bond to disintegrate. In addition, under the influence of relaxin, the tone of the uterus and its contractility, especially the cervix, decrease. Thus, this hormone prepares the mother’s body for the upcoming birth.

Regulation of the secretion of female sex hormones(progesterone and estradiol) is achieved with the help of two gonadotropic hormones - follicle-stimulating(FSH) and luteinizing(LG). Under the influence of FSH, ovarian follicles develop and the concentration of estradiol increases, and when the ruptured follicle is converted (under the influence of PG) into the corpus luteum - progesterone. Sex hormones accumulated in the blood act on the hypothalamus or directly on the pituitary gland according to the principle of positive or negative feedback. An increased concentration of estradiol leads to an increase in LH levels (positive feedback), and progesterone in large quantities inhibits the release of FSH and LH (negative feedback, prevents the maturation of the next follicle).

Placental hormones

The placenta communicates between the mother’s body and the fetus and is at the same time the lungs, intestines, liver, kidneys and endocrine gland for the fetus. It has three main structures: chorionic, basement membrane and the parenchymal part located between them consists of chorionic villi, stem part and microvillous space.

The placenta performs many different functions, including metabolic (formation of enzymes, participation in the breakdown of proteins, fats and carbohydrates) and hormonal (forms two groups of hormones - protein and steroid). Protein hormones are human chorionic gonadotropin, placental lactogenic hormone (somatomotropin) and relaxin. Steroid hormones of the placenta include progesterone and estrogens (estriol). Hypothalamic releasing hormones were also detected in the placenta.

FSH- Binds to receptors on the membranes of its target cells in the ovaries and testes, resulting in activation of the adenylate cyclase system. The resulting cAMP activates protein kinase, which phosphorylates proteins that mediate the effects of FSH. FSH accelerates the development of follicles in the ovaries and the formation of estrogens

LH In both men and women, LH is essential for reproduction. In women during the menstrual cycle, FSH stimulates the growth of follicles and causes differentiation and proliferation of cells of the granular layer.

Under the influence of FSH, maturing follicles secrete ever-increasing amounts of estrogens, among which estradiol is the most important, and LH receptors are also expressed on their cells. As a result, by the time the follicle matures, the increase in estradiol levels becomes so high that it leads to activation of the hypothalamus according to the principle of positive feedback and intense release of LH and FSH by the pituitary gland. This surge in LH levels triggers ovulation, which not only releases the egg, but also initiates the process of luteinization - the transformation of the residual follicle into the corpus luteum, which in turn begins to produce progesterone to prepare the endometrium for possible implantation. LH is necessary to maintain the existence of the corpus luteum for approximately 14 days. In the event of pregnancy, luteal function will be supported by the action of the trophoblast hormone - human chorionic gonadotropin. LH also stimulates theca cells in the ovaries, which produce androgens and estradiol precursors.

Gonadotropin-releasing hormone, or gonadorelin, GnRH, gonadotropin releasing factor, abbreviated as GnRH, is one of the representatives of the class of releasing hormones of the hypothalamus. There is also a similar pineal gland hormone.

GnRH causes increased secretion of the anterior pituitary gland of gonadotropic hormones - luteinizing hormone and follicle-stimulating hormone. At the same time, GnRH has a greater effect on the secretion of luteinizing hormone than follicle-stimulating hormone, for which it is often also called luliberin or luteline.

Gonadotropin-releasing hormone is a polypeptide hormone in structure. Produced in the hypothalamus.

GnRH secretion does not occur constantly, but in the form of short peaks following each other at strictly defined time intervals. Moreover, these intervals are different in men and women: normally in women, GnRH emissions occur every 15 minutes in the follicular phase of the cycle and every 45 minutes in the luteal phase and during pregnancy, and in men - every 90 minutes.

The administration of exogenous GnRH in a constant drip infusion mode or the introduction of long-acting synthetic analogues of GnRH causes a short-term increase in the secretion of gonadotropic hormones, quickly followed by a deep depression and even shutdown of the gonadotropic function of the pituitary gland and the function of the gonads due to desensitization of the GnRH receptors of the pituitary gland.

At the same time, the introduction of exogenous GnRH using a special pump that imitates the natural rhythm of the pulsation of GnRH secretion provides long-term and persistent stimulation of the gonadotropic function of the pituitary gland, and the correct pump mode ensures the correct ratio of LH and FSH according to the phases of the cycle in women and the correct, characteristic for men, the ratio of LH and FSH in men.

Chorionic gonadotropin n has the biological properties of both LH and FSH, and binds to both types of gonadotropin receptors, but the luteinizing activity of hCG significantly prevails over the follicle-stimulating one. HCG is significantly superior in luteinizing activity to “regular” LH, produced by the anterior lobe of the pituitary gland.

It is thanks to the secretion of significant amounts of hCG by the fetal placenta that the corpus luteum, which normally exists for about 2 weeks during each menstrual cycle, does not undergo resorption in pregnant women and remains functionally active throughout the entire pregnancy. Moreover, the corpus luteum in pregnant women, under the influence of hCG, produces very large amounts of progesterone, which are physiologically impossible normally in a non-pregnant body. HCG also stimulates the production of estrogens and weak androgens by the follicular apparatus of the ovaries.

To some extent, hCG also appears to have corticotropic properties, increasing steroidogenesis in the adrenal cortex and promoting functional hyperplasia of the adrenal cortex in a pregnant woman. An increase in the secretion of glucocorticoids under the influence of hCG can play a role in the mechanisms of adaptation of the pregnant woman’s body to stress, such as pregnancy, and also provides the physiological immunosuppression necessary for the development of a genetically half-alien organism inside the uterus. In this regard, it is worth noting that pituitary gonadotropins do not have corticotropic properties.

Chorionic gonadotropin also plays a role in the development and maintenance of the functional activity of the placenta itself, improves its trophism and helps increase the number of chorionic villi.

In a non-pregnant body, hCG is normally absent, but it is often produced by various malignant tumors (ectopic hCG production).

The introduction of exogenous hCG in women in the middle of the cycle causes, in addition to an increase in the production of estrogen and progesterone in the ovaries, ovulation, and then luteinization of the ruptured follicle and further supports the function of the corpus luteum.

Agonists (analogs) of gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus. It has a clearly defined specificity. GnRH creates fairly strong complexes, most often interacting only with the corresponding receptors, which are located in the anterior lobe of the pituitary gland, as well as some proteins. Once the first phase of pituitary activation has passed (usually 7-10 days), GnRH sensitivity to stimuli begins to decline.

Then the level of LH and FSH decreases, and ovarian stimulation stops. The amount of estrogen decreases, its level drops below 100 pmol/l. Similar characteristics are observed in postmenopausal women. The amount of totestosterone and progesterone produced by the ovaries also decreases.

Gonadotropin-releasing hormone agonists increase the likelihood of fertilization through IVF programs.

The use of gonadotropin agonists has side effects. As a rule, unpleasant symptoms appear due to a lack of estrogen, a hypoestrogenic state develops, accompanied by headache, sweating, hot flashes, a feeling of dryness in the vagina, mood swings, and depression.

The most dangerous effect of agonists is on bone tissue, the density of which may decrease due to long-term use of these drugs. There is evidence that some restoration of bone tissue is observed over a year after treatment with agonists is completed.
Side effects of Triptorelin

From the nervous system and sensory organs: headache, sleep disturbance, mood lability, irritability, depression, asthenia, feeling tired, paresthesia, blurred vision. From the gastrointestinal tract: nausea, constipation or diarrhea, anorexia, weight gain, increased activity of liver transaminases, hypercholesterolemia. From the genitourinary system: symptoms associated with a decrease in the level of sex hormones in the blood, incl. in men - flushing of the face, decreased libido, impotence, decreased testicular size, gynecomastia; in women - spotting or dryness of the vaginal mucosa, decreased libido, pain during sexual intercourse, flushing of the face with profuse sweating. From the musculoskeletal system: myalgia, back pain, demineralization of bone tissue. Allergic reactions: skin rash, hyperemia, itching at the injection site, anaphylactic shock, anaphylactoid reactions. Others: temporary increase in symptoms (including arthralgia, progression of hematuria or urinary disorders), transient hypertension, anemia, swelling of the legs. In case of overdose, treatment with triptorelin should be stopped immediately and appropriate symptomatic therapy should be carried out.

PC, 1 time per day. The initial dose is 0.5 mg/day (for 7 days), the maintenance dose is 0.1 mg/day (starting from the 8th day). In the in vitro fertilization program, one IM injection per stimulation cycle is sufficient. forms: IM, s/c, 3.75 mg every 28 days (in women - starting from the 3rd day of menstruation), for no more than 6 months.

The drug Zoladex ® 3.6 mg is used to desensitize the pituitary gland, which is determined by the concentration of estradiol in the blood serum. Typically, the required level of estradiol, which corresponds to that in the early follicular phase of the cycle (approximately 150 pmol/l), is achieved between the 7th and 21st days. When desensitization occurs, stimulation of superovulation (controlled ovarian stimulation) with gonadotropin begins. The resulting pituitary desensitization with depot GnRH agonist use may be more persistent, which may result in increased gonadotropin requirements. At the appropriate stage of follicle development, the administration of gonadotropin is stopped and then human hCG is administered to induce ovulation. Monitoring of treatment, oocyte retrieval and fertilization procedures

New Generation:

Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH) and LH, is a trophic peptide hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the adenohypophysis. GnRH is synthesized and released from GnRH neurons in the hypothalamus. The peptide belongs to the gonadotropin-releasing hormone family. It represents the initial stage of the hypothalamic-pituitary-adrenal axis system.

Structure

The identification characteristics of GnRH were refined in 1977 by Nobel laureates Roger Guillemin and Andrew W. Schally: pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2. As usual for representing peptides, the sequence is given from N-terminus to C-terminus; It is also standard to omit the chirality designation and assume that all amino acids are in their L form. The abbreviations refer to standard proteinogenic amino acids, with the exception of pyroGlu - pyroglutamic acid, a derivative of glutamic acid. The NH2 at the C-terminus indicates that instead of ending in a free carboxylate, the chain ends in a carboxamide.

Synthesis

The GnRH precursor gene GNRH1 is located on chromosome 8. In mammals, the normal terminal decapeptide is synthesized from the 92-amino acid pre-prohormone in the preoptic anterior hypothalamus. It is a target for various regulatory mechanisms of the hypothalamic-pituitary-adrenal axis, which are inhibited when estrogen levels in the body increase.

Functions

GnRH is secreted into the pituitary bloodstream of the portal vein at the median eminence. The portal vein blood carries GnRH to the pituitary gland, which contains gonadotropic cells, where GnRH activates its own receptors, the gonadotropin-releasing hormone receptors, seven transmembrane G protein-coupled receptors, which stimulate the beta isoform of phosphoinositide phospholipase C, which proceeds to mobilize calcium and protein kinase C. This leads to the activation of proteins involved in the synthesis and secretion of the gonadotropins LH and FSH. GnRH is broken down by proteolysis within a few minutes. GnRH activity is very low during childhood and increases during puberty or adolescence. During the reproductive period, pulsatile activity is critical for successful reproductive function under the control of a feedback loop. However, GnRH activity is not required during pregnancy. Pulsative activity can be impaired in diseases of the hypothalamus and pituitary gland, either due to their dysfunction (for example, suppression of hypothalamic function), or due to organic damage (trauma, tumor). Elevated prolactin levels reduce GnRH activity. Conversely, hyperinsulinemia increases pulsatile activity, leading to impaired LH and FSH activity, as seen in polycystic ovary syndrome. GnRH synthesis is congenitally absent in Kallmann syndrome.

Regulation of FSH and LH

In the pituitary gland, GnRH stimulates the synthesis and secretion of gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These processes are regulated by the size and frequency of GnRH release pulses, as well as by feedback from androgens and estrogens. Low frequency GnRH pulses lead to the release of FSH, whereas high frequency GnRH pulses stimulate the release of LH. There are differences in GnRH secretion between women and men. In men, GnRH is secreted in pulses at a constant frequency, but in women, the pulse frequency varies throughout the menstrual cycle, and there is a large pulsatility of GnRH just before ovulation. GnRH secretion is pulsatile in all vertebrates [currently there is no evidence for this statement - only empirical evidence for a small number of mammals] and is necessary to maintain normal reproductive function. Thus, the separate hormone GnRH1 regulates the complex process of follicular growth, ovulation and development of the corpus luteum in women, as well as spermatogenesis in men.

Neurohormones

GnRH refers to neurohormones, hormones produced in specific nerve cells and released from their neuronal ends. The key area of ​​GnRH production is the preoptic area of ​​the hypothalamus, which contains the majority of GnRH-secreting neurons. GnRH-secreting neurons originate in the nasal tissues and migrate to the brain, where they disperse to the medial septum and hypothalamus and are connected by very long (>1 millimeter long) dendrites. They bundle together to receive common synaptic input, which allows them to synchronize the release of GnRH. GnRH-secreting neurons are regulated by many different afferent neurons via several different transmitters (including norepinephrine, GABA, glutamate). For example, dopamine stimulates LH release (via GnRH) in women following estrogen-progesterone administration; dopamine may inhibit LH release in women after oophorectomy. Kiss-peptin is a critical regulator of GnRH release, which can also be regulated by estrogen. It has been noted that there are kiss-peptin-secreting neurons that also express estrogen receptor alpha.

Effect on other organs

GnRH has been found in organs other than the hypothalamus and pituitary gland, but its role in other life processes is poorly understood. For example, GnRH1 probably affects the placenta and gonads. GnRH and GnRH receptors have also been found in breast, ovarian, prostate, and endometrial cancer cells.

Influence on behavior

Production/release influences behavior. Cichlid fish that exhibit a social dominance mechanism in turn experience upregulation of GnRH secretion, whereas cichlids that are socially dependent have downregulation of GnRH secretion. In addition to secretion, the social environment, as well as behavior, influence the size of GnRH-secreting neurons. Specifically, males that are more solitary have larger GnRH-secreting neurons than males who are less solitary. Differences are also observed in females, with breeding females having smaller GnRH-secreting neurons than control females. These examples suggest that GnRH is a socially regulated hormone.

Medical use

Natural GnRH was previously prescribed as gonadorelin hydrochloride (Factrel) and gonadorelin diacetate tetrahydrate (Cystorelin) for the treatment of human diseases. Modifications to the structure of GnRH decapeptide to increase half-life have led to the creation of GnRH1 analogs that either stimulate (GnRH1 agonists) or suppress (GnRH antagonists) gonadotropins. These synthetic analogues have replaced the natural hormone for clinical use. The analogue leuprorelin is used as a continuous infusion in the treatment of breast carcinoma, endometriosis, prostate carcinoma and following studies in the 1980s. It has been used by a number of researchers, including Dr. Florence Comit of Yale University, to treat precocious puberty.

Sexual behavior of animals

GnRH activity influences differences in sexual behavior. Elevated GnRH levels enhance sexual display behavior in females. Administration of GnRH increases the requirement for copulation (a type of mating ceremony) in white-headed zonotrichia. In mammals, GnRH administration increases the sexual display behavior of females, as seen by the reduced latency of the long-tailed shrew (Giant shrew) in displaying its hindquarters to the male and moving its tail towards the male. Increased GnRH levels increase testosterone activity in males, exceeding the activity of natural testosterone levels. Administration of GnRH to male birds immediately after an aggressive territorial encounter results in an increase in testosterone levels above the observed natural levels during an aggressive territorial encounter. When the functioning of the GnRH system deteriorates, an aversive effect on reproductive physiology and maternal behavior is observed. Compared to female mice with a normal GnRH system, female mice with a 30% reduction in the number of GnRH-secreting neurons provide less care for their offspring. These mice are more likely to leave their young separately than together, and will take longer to find the young.

Application in veterinary medicine

The natural hormone is also used in veterinary medicine as a treatment for cystic ovarian disease in cattle. A synthetic analogue of deslorelin is used in veterinary reproductive control using a sustained-release implant.

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List of used literature:

Campbell RE, Gaidamaka G, Han SK, Herbison AE (Jun 2009). "Dendro-dendritic bundling and shared synapses between gonadotropin-releasing hormone neurons." Proceedings of the National Academy of Sciences of the United States of America 106 (26): 10835–40. doi:10.1073/pnas.0903463106. PMC 2705602. PMID 19541658.

Brown R. M. (1994). An introduction to Neuroendocrinology. Cambridge, UK: Cambridge University Press. ISBN 0-521-42665-0.

Ehlers K, Halvorson L (2013). "Gonadotropin-releasing Hormone (GnRH) and the GnRH Receptor (GnRHR)". The Global Library of Women's Medicine. doi:10.3843/GLOWM.10285. Retrieved November 5, 2014.

In recent years, the possibilities of hormonal therapy for cancer have expanded due to the clinical use of gonadotropin-releasing hormone analogues. In 1971, A. Schally was able to establish that stimulation of the production of gonadotropic hormones of the pituitary gland - luteinizing and follicle-stimulating hormone - is carried out by the hypothalamic neurotransmitter - decapeptide - gonadotropin-releasing hormone. Its rhythmic secretion, which ensures the synthesis and release of luteinizing and follicle-stimulating hormone, is a necessary condition for maintaining the hormonal activity of the testicles - testosterone production. The discovery of the structure of gonadotropin-releasing hormone led to the synthesis of its analogues (about 700) with agonist properties that significantly exceed the biological activity of the native hormone and are characterized by prolonged action. The biological potential of synthetic derivatives of gonadotropin-releasing hormone is determined by their pronounced enzymatic stability and increased affinity for the gonadotropin receptors of the adenohypophysis. Initially, synthetic analogs of gonadotropin-releasing hormone found use in cases of endogenous gonadotropin-releasing hormone deficiency in patients with hypogonadotropic hypogonadism, delayed sexual development, cryptorchidism, and oligoazoospermia. However, when using synthetic analogues of gonadotropin-releasing hormone in physiological doses, it was not possible to achieve a positive effect due to the short biological half-life of this hormone.

The effect of superphysiological doses of gonadotropin-releasing hormone analogues was completely unexpected - a paradoxical effect was noted: inhibition of gonadotropin secretion and suppression of testicular hormonal activity. The mechanism of action of superphysiological doses of gonadotropin-releasing hormone analogues includes: 1) primary short-term stimulation of luteinizing hormone secretion with the subsequent development of refractoriness of gonadotropin receptors to the influence of gonadotropin-releasing hormone (desensitization phenomenon), as a result of which the secreted pool of luteinizing hormone decreases; 2) the direct inhibitory effect of gonadotropin-releasing hormone agonists on the production of androgens by the testes by blocking specific gonadotropin-releasing hormone receptors on the membranes of Leydig cells; 3) depletion of prolactin receptors in the testicles and a decrease in the level of estrogen in the blood plasma. With long-term administration of superphysiological doses of gonadotropin-releasing hormone analogues, the concentration of testosterone in the blood steadily decreases to the values ​​observed after orchiectomy (0.2 -0.4 μg/l). The introduction of gonadotropin-releasing hormone analogues into the practice of treating prostate cancer was preceded by experimental studies on male Copenhagen F-1 rats. When rats were administered a superactive gonadotropin-releasing hormone agonist - DTrp6 - LH-RH (decapeptyl), regression of the primary focus of prostate cancer occurred - Dunning-R-3327H prostate adenocarcinoma transplanted into the animal's body, which is a convenient model of human prostate cancer due to with preservation of its androgen-dependence qualities and the histological structure of the tumor of a highly differentiated type. Due to the ability of gonadotropin-releasing hormone analogues to suppress testicular androgen secretion to castration levels and the lack of side effects of these drugs during long-term treatment, there has recently been a tendency to use them for the treatment of prostate cancer instead of estrogen therapy and orchiectomy. At the same time, the effectiveness of monotherapy with gonadotropin-releasing hormone analogues is reduced, since they block the secretion of testicular androgens without affecting the production of androgens by the adrenal cortex. In addition, during monotherapy with gonadotropin-releasing hormone analogues, testosterone levels in the blood briefly increase during the first 5-10 days, which increases the risk of exacerbation of the tumor process.

Currently, numerous drugs from the group of gonadotropin-releasing hormone analogs have been introduced into clinical practice for the treatment of patients with prostate cancer. The drugs differ in their mode of action, but they all have similar endocrine and clinical effects, which are largely determined by the dose of the drug and the route of administration. One of the most common gonadotropin-releasing hormone agonist drugs in the treatment of prostate cancer is buserelin (Hoe 766, Hoechst, Germany). The drug belongs to synthetic analogues of gonadotropin-releasing hormone with prolonged action and is a nonapeptide. The mechanism of its action is associated with the blockade of gonadotropin receptors at the level of the adenohypophysis. After a short-term initial stimulation of the secretion of luteinizing and follicle-stimulating hormone, their synthesis is inhibited and the hormonal activity of the testicles is suppressed with a decrease in the level of testosterone in the blood. The drug has no toxic effect. Its effectiveness in inhibiting testicular steroidogenesis is the same when administered subcutaneously, into a muscle, or into a vein. Buserelin is used at a dose of 2 mg/day subcutaneously for 3–6 days, and subsequently intranasally at 0.4–1.2 mg/day for 24 weeks. During the treatment of patients with disseminated prostate cancer according to this regimen, after an initial increase in the levels of luteinizing hormone and testosterone in the blood plasma (in the first 3 days of treatment), they decrease by the 6th day of drug administration; Low levels of these hormones persist for 24 weeks. Maintenance therapy with long-term administration of the drug intranasally provides effective and sustainable inhibition of testosterone secretion by the testes (up to 6 months), the level of which in the blood reaches the values ​​​​observed after orchiectomy (below 1 μg/l). Histological studies of prostate biopsies 3 to 6 months after the start of drug treatment reflect a significant regression of signs of malignancy in prostate cancer tissue. Buserelin can be used in the treatment of newly diagnosed metastatic prostate cancer. When administered intranasally, the greatest degree of inhibition of androgenic secretion of the testicles is achieved with a dose of 1 mg/day (0.2 mg 3-5 times a day). This is confirmed by the long period of preservation of objective signs of regression of prostate cancer (up to 16 months) according to CT, bone scintigraphy, and the activity of the prostatic fraction of acid phosphatase in the blood. It should be noted that with parenteral administration of the drug, a more pronounced decrease in testosterone levels in the blood is achieved than with intranasal application. The effectiveness of buserelin is determined by the dose and method of administration. In high doses when administered parenterally (1.5 mg/day), it leads to a pronounced and long-term decrease in testosterone levels in the blood to a level below 1 μg/l; a dose of 0.05 mg/day is less effective in achieving castration levels of testosterone in the blood. An intranasal dose of 1.2 mg/day is more effective than 0.4 mg/day. At the same time, intranasal application without previous parenteral administration of the drug is not the optimal way to achieve medical castration, which is due to the absorption of less than 10% of the drug. A persistent decrease in testosterone levels in the blood plasma to a level below 1 mcg/l is achieved by the initial administration of buserelin subcutaneously at a dose of 1.5 mg/day for 7 days, followed by maintenance therapy - intranasal application at a dose of 1.2 mg/day for 4 - 29 months With this treatment regimen, testosterone levels decrease to trace levels (0.5 mcg/l) by the end of the 1st month of treatment and remain within these limits for 12 weeks. Along with this, by the 14th day of treatment the level of luteinizing hormone in the blood plasma decreases. When treated with buserelin, a decrease in the size of the prostate gland according to digital rectal examination and echography can be observed for 24 months. Long-term use of the drug (for 24 months) in some cases gives a good result in disseminated prostate cancer with metastases to the lungs, which is confirmed by the disappearance of the metastatic tumor according to X-ray studies and CT. A positive therapeutic response of a metastatic tumor to a gonadotropin-releasing hormone analogue can be explained by the preservation of a hormonally sensitive cell subpopulation in its structure. The lack of therapeutic effect is associated with the loss of androgen dependence of prostate cancer and can serve as a test for the early detection of hormonal resistance of the tumor. With long-term treatment with buserelin, there were no signs of irritation of the gastrointestinal tract, gynecomastia, thromboembolic complications, changes in blood biochemistry, or blood pressure; its side effects (“hot flashes”, feeling of heat) are observed in 65 - 80% of patients. In recent years, Depo-buserelin has been synthesized, which makes it possible to eliminate repeated intranasal applications of the drug or its parenteral administration several times a day. Depobuserelin in the form of tablets with a diameter of 5 mm is introduced through a small incision into the anterior subcutaneous tissue; abdominal pain. The tablet contains 5 mg of the drug; Are implantations performed? at intervals of 1 month. Treatment is carried out for 1 to 8 months (on average 4 months) under the control of blood levels of testosterone, luteinizing hormone, follicle-stimulating hormone. Depobuserelin is effective as the primary treatment for newly diagnosed prostate cancer in elderly patients, and its advantage is a persistent and long-term decrease in plasma levels of testosterone, luteinizing hormone and follicle-stimulating hormone, which do not increase with repeated implantations.

Medical castration of prostate cancer patients can be achieved by combination therapy with two synthetic analogues of gonadotropin-releasing hormone - buserelin and decapeptyl (DTrp6-LH-RH). Decapeptyl is a decapeptide with gonadotropin-releasing hormone analogue properties that have been supported by numerous experimental studies. The drug has been proven to be highly effective in suppressing testosterone secretion in patients with prostate cancer, its low toxicity and absence of side effects. The combination of buserelin and decapeptyl is effective in the treatment of metastatic prostate cancer. As a result of combination therapy, low levels of testosterone are persistently maintained (for 6–48 weeks), the activity of the prostatic fraction of acid phosphatase in the blood is normalized and the activity of alkaline phosphatase is reduced, urine passage improves in patients with previous symptoms of lower urinary tract obstruction, and the size of the prostate gland decreases echography data; in patients with diffuse metastases in the bones, the intensity of the pain syndrome significantly decreases and regression of the foci of metastases is observed according to scintigraphy.

Treatment is carried out according to the following regimen: decapeptyl at a dose of 0.1 mg subcutaneously + buserelin at a dose of 0.05 mg/day subcutaneously or 0.5 mg 2 times a day intranasally. Decapeptyl monotherapy is used to treat patients with newly diagnosed prostate cancer stages T2NxM0, T3 -4Nx-1M0-1. The drug is administered intramuscularly monthly at a dose of 3 mg for up to 6 months. Treatment with decapeptyl, compared with orchiectomy, is more effective in terms of duration of remission and persistent decrease in testosterone levels in the blood.

A group of synthetic analogues of gonadotropin-releasing hormone used in the treatment of patients with prostate cancer includes ICI-118630 ​​(zoladex). The drug is a synthetic decapeptide analogue of natural LH-RH, administered daily subcutaneously at 0.25 ml 2 times a day during the 1st week of treatment, followed by a dose reduction to 0.25 mg/day for 12 weeks. By the end of the 2nd week of treatment, the content of luteinizing hormone, follicle-stimulating hormone and testosterone in the blood plasma decreases significantly. The drug is effective in the treatment of newly diagnosed disseminated prostate cancer and in patients with prostate cancer who received standard hormonal treatment with subsequent development of disease relapse. Clinical improvement is manifested by a decrease in the size of the primary focus of prostate cancer, a significant reduction in pain, regression of bone metastases or their stabilization. In recent years, the depot drug ICI-118630 ​​has become widespread in the treatment of patients with newly diagnosed metastatic prostate cancer. It is administered subcutaneously at a dose of 3.6 mg once a month; The duration of treatment is determined by objective and subjective signs of improvement and can range from 5 to 19 months. To eliminate a possible exacerbation of the disease in the initial period of treatment with this drug, it is recommended to conduct a short course of treatment with diethylstilbestrol 1 mg 3 times a day a week before the first injection and within a week after it. The drug is highly effective in the treatment of patients with disseminated prostate cancer. With its use, the general condition of patients improves, regression or stabilization of bone metastases occurs.

Leuprolid is a synthetic analogue of gonadotropin-releasing hormone with high biological activity. Its biological activity is 12 - 20 times higher than that of native gonadotropin-releasing hormone. The drug is highly effective in suppressing the secretion of testosterone, luteinizing hormone, reducing the concentration of luteinizing hormone receptors in the testicles, which is accompanied by a significant decrease in the weight of the prostate gland, seminal vesicles, and testicles. The results of experimental studies, which showed a dose-dependent effect of the drug and the absence of toxic properties, formed the basis for choosing the optimal dose for the treatment of patients with prostate cancer, which is 1 - 10 mg/day. This dose contrasts with lower doses of other synthetic gonadotropin-releasing hormone analogues used in the treatment of prostate cancer patients. Inhibition of the synthesis and release of luteinizing hormone is most pronounced during treatment with high doses of leuprolid (10 mg/day), which is administered subcutaneously. In addition, the drug at a dose of 20 mg/day shows high efficiency and minimal toxicity in the treatment of patients with prostate cancer stages T2N0M0, T3 - 4Nx - 1M0-1, who have not previously received endocrine therapy. In this case, during a 2-week treatment period, there is a significant decrease in the blood levels of testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone. By 3 weeks of treatment, testosterone levels in the blood are less than 1 mcg/l and remain at these values ​​for 48 weeks of treatment. The effectiveness of long-term use of leuprolid in previously untreated patients with prostate cancer, manifested by moderate or significant regression of the primary site of prostate cancer, metastases, reduction of pain, decrease in the activity of the prostatic fraction of acid phosphatase in the blood, corresponds to the therapeutic response to estrogen therapy or orchiectomy. It is extremely important to note that increases in blood levels of prolactin and dehydroepiandrosterone associated with relapse of prostate cancer are not observed in patients receiving leuprolid treatment. This gives grounds to recommend this drug as a primary treatment method for patients with prostate cancer with concomitant diseases of the cardiovascular system, in whom estrogen therapy increases the risk of thromboembolic complications. Unlike other synthetic analogues of GN-RH, leuprolid in high doses has the ability to more significantly suppress the production of luteinizing hormone and reduce its level in the blood to trace levels, and in urine to values ​​​​observed in the period preceding puberty. These observations are important in choosing a drug from the group of gonadotropin-releasing hormone analogues for the treatment of patients with prostate cancer, taking into account previous endocrine therapy.

When treating prostate cancer patients with gonadotropin-releasing hormone analogues who have not previously undergone orchiectomy, there is no need to completely turn off the production of luteinizing hormone to achieve medical castration; in these cases, buserelin and decapeptyl are effective, providing direct inhibition of steroidogenesis at the testicular level. In patients with prostate cancer who have previously undergone orchiectomy, the gonadotropic activity of the adenohypophysis is disinhibited, which affects the activation of tumor growth; in such cases, treatment with high doses of leuprolide is rational. Treatment with leuprolid is well tolerated by patients, the drug does not have the side effects of estrogens, and there is no pain at the sites of subcutaneous injections. The side effect of the drug is manifested by “hot flashes”, which are much less intense in intensity than after orchiectomy. During the first days of leuprolid treatment, due to a short-term increase in testosterone levels in the blood, a transient increase in pain is observed in patients with bone metastases. However, this is not accompanied by objective signs of worsening of the disease, and after a week of treatment there are signs of improvement. At the same time, transient stimulation of prostate cancer is undesirable in malnourished patients with cancer intoxication and severe neurological complications, and therefore leiprolid treatment is contraindicated for them. Of interest are comparative data on the effectiveness of treatment with leuprolid 1 mg/day (subcutaneous) and diethylstilbestrol at a dose of 3 mg/day in patients with stage D2 prostate cancer. Of 98 patients with metastatic prostate cancer who received leuprolid, objective signs of complete or partial regression of the disease were noted in 86% of cases compared to 85% in the group of patients receiving diethylstilbestrol. Survival at one year of treatment was 87% when receiving leuprolid and 78% in the group of patients receiving diethylstilbestrol. While the effectiveness of treatment over 12 weeks with leiprolid and diethylstilbestrol did not differ significantly, the degree of side effects of diethylstilbestrol was more pronounced. Gynecomastia was observed in 50% of patients receiving estrogen therapy; nausea, vomiting, and swelling of the lower extremities occurred in 16%. At the same time, during treatment with leuprolid, these symptoms occurred in 2 - 3% of cases. Thromboembolic complications during treatment with diethylstilbestrol developed in 7% of cases and were less than 1% during treatment with leuprolid. Vasomotor reactions in the form of "hot flashes" predominantly occurred when leuprolid was prescribed. Thus, a comparison of the results of treatment of disseminated prostate cancer with 3 mg diethylstilbestrol and 1 mg/day leuprolid showed their identical clinical effect, a decrease in testosterone in the blood to castration levels, a decrease in the activity of the prostatic fraction of acid phosphatase in the blood, a decrease in pain and an improvement in the general condition of patients. At the same time, there was a significant difference in the manifestation of side effects of the drugs. In this regard, leuprolide represents a valuable alternative in the treatment of prostate cancer patients at high risk of thromboembolic complications. With long-term treatment with this drug, androgen resistance of the tumor does not develop, which is its valuable advantage. Long-term treatment with it leads to pronounced morphological changes in the testicles, reminiscent of the histological picture observed after estrogen therapy. The histomorphological picture of the testicles after long-term treatment with leuprolid is characterized by a disruption of the process of spermatogenesis; only spermatogonia can be traced in the tubules. Along with this, the number of Leydig cells decreases and peritubular fibrosis and wrinkling of cell membranes develop.

In assessing the effectiveness of treatment of prostate cancer with gonadotropin-releasing hormone analogues, an important role is played by transrectal echography, which makes it possible to determine changes in the volume of the prostate gland over time and compare the data obtained with changes in testosterone levels in the blood plasma. The dynamics of changes in the volume of the prostate gland in patients with prostate cancer during treatment with gonadotropin-releasing hormone analogues is closely dependent on fluctuations in testosterone levels in the blood. After orchiectomy, the volume of the gland in patients with prostate cancer decreases much faster than during treatment with gonadotropin-releasing hormone analogs, which is determined by a sharp drop in testosterone levels in the blood during the first days after surgery. When treated with gonadotropin-releasing hormone analogues, a transient increase in testosterone levels in the blood during the first week of administration of these drugs is accompanied by an initial increase in gland volume and a subsequent decrease during the 4-month treatment period (type A). Along with this nature of the dynamics of changes in the volume of the gland, in some cases there is a slow decrease in the volume of the gland without its initial short-term increase (type B). Changes in the volume of the type A gland reflect the increased sensitivity of the tumor to testosterone and, therefore, suggest a better prognosis than with type B.

During long-term treatment of prostate cancer patients with gonadotropin-releasing hormone analogues, about 10% of circulating androgens secreted by the adrenal cortex remain in the blood. After testicular function is turned off in patients with prostate cancer, the production of adrenal androgens increases under the influence of various factors - stress, pain, concomitant diseases, metabolic changes. This provides androgenic stimuli for prostate cancer cell populations that have retained hormonal sensitivity. The biological significance of adrenal androgens in activating the growth of prostate cancer is associated with their possible transformation at the cellular level of the prostate gland into biologically active metabolites. This explains the positive therapeutic effect of estrogen therapy and orchiectomy only in 60-70% of cases. The desire to improve the results of hormonal treatment of patients with prostate cancer has led to the idea of ​​using combination therapy with gonadotropin-releasing hormone analogues and antiandrogens to suppress the production of testicular androgens and neutralize adrenal androgens. Pure antiandrogens (flutamide, anandrone) do not interfere with the inhibition of testicular androgens by gonadotropin-releasing hormone analogues. Pure antiandrogens do not inhibit gonadotropic and adrenal activity, which prevents the development of adrenal insufficiency, but at the same time actively prevent the uptake of testosterone and dihydrotestosterone by prostate cancer cells. An important argument for the advisability of using a gonadotropin-releasing hormone analogue in combination with an antiandrogen is the suppression of transient stimulation of testicular androgen biosynthesis, which
occurs during the first days of administration of gonadotropin-releasing hormone analogues, which helps prevent possible activation of the tumor process. Combination therapy uses one of the gonadotropin-releasing hormone analogues (buserelin at a dose of 0.5 mg/day subcutaneously or leuprolid at a dose of 10 mg/day subcutaneously) in combination with flutamide (250 mg orally 3 times a day) or anandrone (100 mg 3 times a day) once a day). Treatment is carried out for 17 - 20 months. Treatment with an antiandrogen begins the day before the first administration of a gonadotropin-releasing hormone analogue. Experience with combination therapy with gonadotropin-releasing hormone analogues and antiandrogens indicates its greater effectiveness in the primary treatment of patients with metastatic prostate cancer compared with those previously treated with estrogen therapy or after orchiectomy. The high frequency of objective signs of improvement (95.4%) when using combination therapy with gonadotropin-releasing hormone analogues and antiandrogens in previously untreated patients indicates that even at the stage of dissemination of prostate cancer, sensitivity to androgens remains. In contrast, with prior estrogen therapy or orchiectomy, exposure of prostate cancer to low levels of adrenal androgens while eliminating the influence of testicular androgens promotes the development of autonomous growth of tumor cells. This explains the unsatisfactory results of combination therapy with gonadotropin-releasing hormone analogues and antiandrogens, amounting to about 60% in patients with prostate cancer who have previously received estrogen therapy or have undergone orchiectomy. Hormonal resistance of prostate cancer to estrogen treatment develops over a fairly short period of time (from 2 weeks to 1 month). Pure antiandrogens prevent the loss of androgen sensitivity of prostate cancer in the presence of low androgen levels, which partly explains the positive results of primary combination therapy. Antiandrogens not only block the stimulating effect of adrenal androgens on the growth of prostate cancer, the metabolites of which remain in the tumor tissue after medical or surgical castration, but also inhibit the spontaneous action of free androgen receptors and thereby prevent or slow down the development of androgen resistance of the tumor. Most prostate cancers become autonomously growing or treatment resistant at the time of relapse after estrogen therapy or orchiectomy. In this regard, delayed combination therapy with RN-RH analogues and antiandrogens will be less effective in terms of survival and duration of remission compared with its implementation at the time of initial diagnosis. Combination therapy with gonadotropin-releasing hormone analogues and a pure antiandrogen is the best alternative treatment for recurrent prostate cancer after initial standard endocrine therapy. Combined treatment with an RN-RH analogue and an antiandrogen, based on the classical hypothesis of inhibition of androgen secretion, is a promising method that has undoubted advantages over estrogen therapy and orchiectomy in higher efficiency and the absence of side effects.