Gonadotropic hormones

Carry the follicle-the stimulating hormone (FSH) and lutenizing hormone (LG) to gonadotropic hormones of hypophysis. Horionic Gonadotrophin (HG) influences gonads too, but is synthesized by placenta. These three hormones together with tireotropic hormone (TTG) are similar on a structure and form family of glikoproteid hormones. All of them consist of two subjedinitsa: and-subjedinitsa at all identical, and β-subjedinitsa differ and provide specific activity. At the same time β-subjedinitsa of all hormones are rather similar, except for β-subjedinitsa of HG which contains the additional site from 30 amino-acid remains on the S-end and several additional carbohydrate remains. Carbohydrate remains increase elimination half-life (T1/2) of these hormones in serum, and also participate in their linkng with receptors. The person has a gene coding a β-subjedinitsa of FSG, is localized in a segment 11p13, and to a β-subjediniyets of LG — in a segment 19ql2.32, in the neighbourhood at least with 7 genes coding a β-subjedinitsa of HG. The gene coding and-subjedinitsu these hormones, is localized in a segment 6q21 — q23.

Secretion of gonadotropic hormones

Secretion regulation of gonadotropic hormones explicitly is described in article is sex hormones. LG and FSG are synthesized by gonadotropin cells which make about 20% of cells of adenogipofiz. HG which is found only in the person, primacy and horses is synthesized by cells of sintsitiotrofoblast. Synthesis of FSG and LG is stimulated gonadoliberin and regulated by the principle of back coupling by sex hormones (fig. 56.4 and 58.2).

Regulation of gonadoliberin secretion

Gonadoliberin is a hormone which stimulates synthesis and secretion of FSG and LG with gonadotropin cells of adenogipofiz. Gonadoliberin will be formed as a result of proteolytic decomposition of the polypeptide containing 92 amino-acid residuals which Is encoded by the gene located in a segment 8p21. Itself gonadoliberin represents decapeptide with amide group on the S-end and residual of pyroglutamic acid on the N-end (tab. 56.3). Secretion of gonadoliberin results pulse wise from synchronized rhythmic activity of group of the neurons located in the field of a funnel kernel. Activity of these neurons begins till the birth and proceeds approximately within a year after it; then it considerably decreases probably as a result of brake action of TsNS. Shortly before the beginning of sexual development brake action of TsNS decreases, and the frequency and amplitude of pulses of secretion of gonadoliberin increase, especially strongly increasing in a dream. In process of sexual development secretion of gonadoliberin continues to increase, won't reach the values characteristic of adults yet. The impulse nature of secretion of a gonadoliberin is necessary for normal synthesis and secretion of gonadotropin hormones which secretion also happens pulsewise. Constant introduction of gonadoliberin leads to desensitization and lowering of number of receptors of gonadoliberin on gonadotropin cells of adenogipofiz. This phenomenon is the cornerstone of clinical application of analogs of gonadoliberin of the long action which suppress secretion of gonadotropin hormones (see below). After their introduction secretion of LG and FSG short-time increases, but then there is a desensitization of receptors, and secretion decreases.

Mechanism of gonadoliberin action

The receptor of gonadoliberin belongs to the receptors interfaced to G-proteins; his gene is in a segment 4q21. At linking of gonadoliberin or its analogs with a receptor there is an activation of proteins of Gq and GM which, in turn, activate phospholipase With that leads to increase in intracellular concentration of calcium. It as a result stimulates synthesis and secretion of LG and FSG. Though tsAMF doesn't take noticeable part in signal transmission from a receptor of gonadoliberin, activation of this receptor increases activity of adenilattsiclasa. Receptors of gonadoliberin are present also at ovaries and testicles, however their physiological value remains to unknown. Please pay attention to Testalamin.

Sex hormones also regulate synthesis of LG and FSG, influencing a hypothalamus and to a lesser extent a hypophysis. This regulation is differently carried out at men and women and depends on age and a phase of a menstrual cycle. Women have low concentration of estra-diol and progesterone suppresses synthesis of gonadotropin hormones due to the action mediated by opioids on the neurons which are responsible for pulse secretion of gonadoliberin. However long increase in concentration of estradiol works by the principle of positive feedback, leading to emission of LG. At men synthesis of gonadotropin hormones is suppressed with testosterone, and partially it is caused by his direct action, and partially transformation in platforms.

Ingibin is the peptide hormone which is formed in gonads and playing an important role in secretion regulation of gonadotropin hormones. It is synthesized by cages of a granular layer of follicles in ovaries and Sertoli's cells in testicles in response to stimulation by gonadotropin hormones and local factors of growth. Ingibin affects directly hypophysis, selectively suppressing secretion of FSG, but not the L G. Ingibin belongs besides to family of glikoproteid, as the transforming factor of growth |3 and a factor of regression the myullero-vykh of channels.

Action mechanism of gonadotropin of hormones

LG and HG contact L G receptor (the gene of this receptor is in a segment 2p21), and FSG — the receptor (the gene of this receptor is on a long shoulder of the 2nd chromosome). Both receptors are integrated to G-proteins and possess the big extracellular domain responsible for hormone recognition. In case of linkng of a receptor with G ligand, - protein activates adenilattsiclasa that leads to increase in concentration of tsAMF. In case of high concentration of a ligand receptors through Gq-protein activate also proteincinasa With and increase concentration of calcium due to activation of fos-folipaza to S. Vsa or almost all effects of gonadotropin hormones can be reproduced introduction in a cage of analogs of tsAMF therefore value of proteincinasa With and Sa2 + in intracellular signal transmission remains not clear.

Physiological effects of gonadotropin hormones

LG and FSG were called according to their action on ovaries; function of these hormones at men was studied later. At men of LG affects cages of Leydiga, stimulating synthesis of androgens, generally testosterone. Testosterone provides a sexual passion, development of secondary sexual characteristics and a spermatogenesis in wavy seed tubules. FSG affects Sertoli's cells, stimulating formation by them of the proteins and nutrients necessary for maturing of spermatozoa.

At women action of FSG and LG is more difficult. FSG stimulates growth and development of follicles, and also induces LG receptor gene expression on cages of a granular layer in ovaries. Besides, FSG activates aromatasa in cages of a granular layer, stimulating synthesis of estradiol. LG affects tekotsita, stimulating formation in them of androstendion, main predecessor of estradiol in ovaries at women of childbearing age. LG is necessary also for a follicle gap in case of an ovulation and for progesterone synthesis by a yellow body. At last, linkng of LG with the receptor on cages of a granular layer increases FSG receptor gene expression that strengthens action of the last.

Value of gonadotrophic hormones in a regulation of functions of genitals is distinctly taped at mutations of genes of hormones or their receptors (Achermann and Jameson, 1999). At women with mutations of genes of a receptor of FSG or a β-subjedinitsa of the FSG primary amenorrhea and sterility are observed, at them follicles don't ripen, there are no yellow bodies and mammary glands don't develop. These data, and also efficiency of FSG at some forms of sterility (see below) eloquently confirm an important role of FSG in functioning of ovaries. At men at the same mutations the size of testicles is reduced and the oligozoospermia is observed though fecundity in certain cases remains.

Only one case of a mutation with loss of function of a gene of a β-subjedinitsa of L G is described: the 46-year-old man had no sexual development, the hypoplasia of cells of Leydiga and sterility were observed. External genitals at it were developed on men's type that, probably, is explained by synthesis of androgens under the influence of HG during fetal development. Implications of mutations with loss of function of a gene of a receptor of LG at men vary from a men's hypogonadism before development of external genitals in female type and lack of sexual development. Possibly, virilescence of external genitals doesn't happen because of disturbance of action both LG, and HG during fetal development. At women, homozygous on mutant alleles of a gene of a receptor of L G, primary amenorrhea or an oligomenorrhea and sterility become perceptible, and at a histological research multiple cysts of ovaries are taped.

The mutations leading to continuous activation of a receptor of LG arise mainly at men and are inherited autosomes is dominant. They lead to premature sexual development because of uncontrollable synthesis of Testosteron-Depotum in fetal and in prepubertat the periods. At some of these mutations the risk of tumors of a testicle is high.

Application of gonadoliberin and its analogs

The synthetic analogs of gonadoliberin applied in clinic are listed in tab. 56.3. Synthetic gonadoliberin is called gonadorelin. Replacement of an amino-acid remaining balance in a provision 6 protects analogs of gonadoliberin from proteoliz, and replacement of the S-trailer remaining balance increases affinity to a receptor. Such analogs have bigger activity and longer action in comparison with a native gonadoliberin which T1/2 constitutes only 2 — 4 min.

Antagonists of gonadoliberin, unlike its analogs of long action, don't cause short-term increase in levels of gonadotropin hormones in serum. Modern antagonists of gonadoliberin, apparently, don't lead to local and system emission of histamine and anafilac reactions that limited use of the first medicines of this group. Two antagonists of gonadoliberin are gairelics and tsetrorelics apply in case of artificial insemination to suppression of emission of LG during stimulation of ovaries. Ganirelics is available in the USA, and tsetrorelics is only in Europe. Theoretically fast suppression of emission of LG gives the chance to better control stimulation of ovaries (see below) and by that reduces a cycle of artificial insemination. However the practical value of these medicines in case of artificial insemination still should be specified in clinical testing.

Diagnostic application

One of medicines of gonadorelin (gonadorelin hydrochloride) is applied to differential diagnostics of hypophysial and hypothalamic defeat in case of a secondary gipogonadism. The LG level in serum measure before entering of gonadorelin in a dose 100 mkg / to or in/in and during 2 h (in 15,30,45,60 and 120 min.) after introduction. Increase in secretion of LG demonstrates availability of the cages of an adenogipofiz functioning the gonadotropin. In case of long deficit of gonadoliberin sensitivity of gonadotropin cages to it can decrease therefore the LG low level when conducting test with gonadoliberin not necessarily speaks about damage of hypophysis. Test with gonadoliberin can also be used for differential diagnostics true (gonadoliberin connected with secretion) and false premature sexual development.

Treatment of sterility

Other drug of gonadorelin (gonadorelin acetate) is used at the disturbances of genesial function bound to deficiency of gonadoliberin. The drug is administered i.v. by means of the special infusional pump in the pulsed operation imitating physiological secretion, 2.5mkg each 60 — 90 min. If the ovulation doesn't come, the dose entered for one impulse can be gradually enlarged to 10mkg. The principles of introduction and a dose are specified in the instruction of the manufacturer. Gonadorelin less than gonadotrophic hormones causes polycarpous pregnancy. At treatment of rutting-dorelinom it isn't required to control so carefully the level of estrogens in Serum and to carry out an US of ovaries. Collateral reactions arise seldom, phlebitis in an injection site most often develops. At treatment gonadorelin at women physiological secretion of sex hormones is restored, the menstrual cycle is established and there is an ovulation. However because of technical complexity this method of treatment is applied only in specialized clinics (Hayes et al., 1998).

At sterility by means of gonadorelin it is possible to achieve body height of testicles, normal secretion of sex hormones and a spermatogenesis from men. However the method is rather expensive and demands constant wearing of the infusional pump. Besides gonadorelin FDA for treatment of male sterility isn't approved. Therefore usually preference is given to gonadotrophic hormones.

Analogs of gonadoliberin of long action apply also at ovulation induction. These drugs suppress preovulatory emission of LG and prevent luteinization of not ovulating follicle. Several schemes of treatment at which it is long are developed or in short term enter analogs of gonadoliberin together with gonadotrophic hormones providing maturing of a follicle (see below) and then for induction of an ovulation prescribe HG (Lunenfeld, 1999).

Gonadotropin hormones secretion suppression

As it was already told, analogs of gonadoliberin of long action conduct to a desensitization of receptors of gonadoliberin therefore secretion the gonadotropin and respectively and sexual, hormones sharply decreases. Such "medicamentous castration" was very convenient when it is necessary to reduce development of sex hormones. The obvious indication to similar treatment — true premature sexual development in children in case of which long entering of analogs of gonadoliberin very effectively and almost isn't followed by collateral reactions.

Analogs of gonadoliberin of long action use for palliative treatment of hormonal and dependent tumors (for example, cancer of predstatelny or dairy glands); as in an initiation of treatment these medicines sharply strengthen secretion of sex hormones, at the same time appoint the medicines breaking synthesis or blocking effect of sex hormones. Besides, analogs of a gonadoliberin of long action use in case of other hormonal and dependent diseases (endometriosis, myoma of a uterus and the sharp alternating porfiriya). At last, for medicamentous castration in case of such mental disturbances as pedophilia when the risk of non-compliance with medical instructions is very high, it is especially convenient goserelin which enter in a dose 10.8mg / to 1 time in 3 months.

Analogs of gonadoliberin of long action in general are well transferred and cause quite predictable side effects caused by violation of synthesis of sex hormones: inflows, dryness of a vagina, atrophic vaginit, decrease in density of a bone tissue. With respect thereto in case of such diseases as endometriosis and myoma of a uterus, treatment usually continue no more than 6 months or in addition appoint estrogen for maintenance of density of bone tissue.

Diagnostic use of gonadotropic hormones

Test for pregnancy

At a blood and urine of pregnant women in large numbers there is HG therefore as the test for pregnancy it is possible to use immunochemical identification of a β-subjedinitsa of HG. High-quality definition of a β-subjedinitsa of HG in urine is the cornerstone of the tests for pregnancy for house use sold in the USA without prescription. These tests allow to tap quickly pregnancy in several days after a menses delay.

Quantitative definition of concentration of HG in plasma in the clinical and scientific purposes is carried out by means of RIA. Usually it is done for pregnancy advance assessment, and also at suspicion on a salpingocuesis, vesical drift or choriocarcinoma.

Definition of ovulation time

The ovulation occurs in 36 h after the beginning of emission of LG and in 10 — 12 h after achievement of peak of its concentration. Therefore on concentration of LG in urine it is possible to predict ovulation time. For house use release the sets allowing estimating by means of specific antibodies the LG level in urine. The test is carried out by each 12 or 24 h since 11^th day of a cycle (at a 28-day cycle) and by augmentation of level L G determine estimated time of an ovulation. It gives the chance to increase probability of conception by a right choice of time for the sexual intercourse.

Diagnostics of disorders of reproductive function

Quantitative measurement of the FSG and LG level in plasma by method of RIA (on the level of β-subjedinitsa) is used for diagnostics of some violations of reproductive function. The low or not determined FSG and LG levels testify to econdary gipogonadism and to damage of hypophysis or hypothalamus. In case of primary gipogonadizm levels of these hormones, on the contrary is high. In case of amenory at women or delay of sexual development in men and women determination of the FSG and LG level allows to distinguish damage of gonads from defeat of gipotalamo-hypophysial system.

On the FSG level for the 3rd day of a menstrual cycle it is possible to judge fertility. Even in case of a normal menstrual cycle the FSG level of 15 ME/ml also more speaks about low fertility, and success of artificial insemination at the same time is improbable (see below).

Test with HG is used at men for assessment of function of cages of Leydiga on extent of stimulation of synthesis of testosterone. This test will be used in case of suspicion on malfunction of cages of Leydiga (for example, in case of a delay of sexual development). Testosterone level in serum is determined after several injections of HG. Reduced secretion of testosterone speaks about pathology of cages of Leydiga, and normal about defeat of gipotalamo-hypophysial system.

Medical application of gonadotropin hormones

Initially gonadotropin hormones for clinical application received from human hypophyses (cadaveric material) and from urine of women. Hypophysis medicines don't use because of risk of transfer of an infecting agent of Kreyttsfeldt now is Jacoba. From urine receive several medicines. HG which on action is similar to L G is received from urine of pregnant women. From urine of women in post menopause receive medicine menotropin which contains approximately identical quantities of LG and FSG, and also other proteins of urine. As menotropin is rather badly cleared, in order to avoid allergic reactions it is entered by in oil. Other medicine urofollitropin represents the cleared FSG received by removal of LG by immunological methods. Urofollitropin of ultrahigh cleaning receive by means of monoclonal antibodies to FSG. It is cleared so that it can be entered.

Methods of genetic engineering received the line of cages of mammals synthesizing and - and r-subjedinitsy by FSG. The recombinant FSG which is turning out at the same time is close on nature of a glycosylation to native FSG. Today two medicines of recombinant FSG follitropin and follitropin P are issued; their carbohydrate structures slightly differ. Both of these drugs are injected ï / to as they are much more net than the medicines received from urine and are much better standardized. Recombinant medicines are much more expensive native, however data for the fact that they cause such collateral reactions as a syndrome of hyper stimulation of ovaries, not more effective or less often so far. Possibly, in the future by methods of genetic engineering of gonadotropin hormones of longer action and with higher activity will be possible to receive analogs.

Female sterility

About 10% of married couples of childbearing age suffer from sterility. Apply gonadotrophic hormones to sterility treatment more and more widely (Vollenhoven and Healy, 1998); often they are used at artificial insemination. Though as the main indication to their appointment serves the chronic anovulation as a result of a secondary hypogonadism (group 1 on the WHO classification), gonadotrophic hormones use also for induction of ovulation at a syndrome of polycystic ovaries (group II on the WHO classification) in that case when clomifene is noneffective (hl. 58). Besides, gonadotrophic hormones apply at sterility against the background of a normal ovulation though in these cases at first try treatment by clomifene. Doctors with sufficient experience of treatment of sterility and endocrine disorders have to prescribe gonadotrophic hormones.

At a chronic anovulation purpose of one FSG in most cases causes an ovulation. Usually FSG prescribe in a dose of 75 ME/days during the first 6 — 7 days of a cycle then by means of a vulval US estimate number and the size of the ripening follicles. US spend usually each 2 — 3 days. Maturing of a follicle is considered adequate if the follicle with a diameter of 18 mm is found. If three and more follicles with a diameter more than 16 mm are revealed, FSG cancel because of danger of a syndrome of hyper stimulation of ovaries (see below) and apply barrier methods of contraception to prevention of polycarpous pregnancy. Define also concentration of Oestradiolum which has to be in range of 500 — 1500 pg/ml. Lower values indicate insufficient stimulation of ovaries, and higher — danger of a syndrome of hyper stimulation of ovaries. At insufficient stimulation of ovaries the dose of FSG can be enlarged to 150 ME/days.

For completion of maturing of a follicle and induction of an ovulation next day after cancellation of FSG prescribe HG in a dose of 5000 — 10 000 ME. At treatment by gonadotrophic hormones polycarpous pregnancy develops in 10 — 20% of cases that is bound to development of several tertiary follicles and an exit of several ootids.

Gonadotropin hormones use at artificial insemination, including extracorporal fertilization and a microinjection of spermatozoa in ovum cytoplasm. By means of FSG stimulate development of follicles, and for their final maturing appoint HG then mature ova are taken from tertiary follicles in the surgical way. Then make extracorporal fertilization of the received ova by means of sperm or a microinjection of spermatozoa in ovum cytoplasm. Embryos transfer to a cavity of a uterus or to a uterine tube. At artificial insemination the risk of polycarpous pregnancy depends on number of the postponed embryos.

Besides polycarpous pregnancy and its possible complications the main side effect of gonadotropin hormones is syndrome of hyper stimulation of ovaries. Fast accumulation of liquid in a cavity of a peritoneum, a pleural cavity and even a pericardium is characteristic of this syndrome. It is considered that the reason of this syndrome — allocation by ovaries of the substance increasing vascular permeability. The syndrome of hyper stimulation of ovaries is shown by an abdominal distension, belly-ache, nausea, vomiting, the diarrhea expressed by increase in ovaries, short wind and oliguriya. The syndrome of hyper stimulation of ovaries can be complicated by gipovolemia, water and electrolytic violations, gemoperitoneumy, RDSV, tromboembolia and dysfunction of a liver. At suspicion don't appoint to development of this syndrome of HG.

Male sterility

Treatment by gonadotropic hormones can be effective if the sterility reason is their deficiency. As gonadotropic hormones are rather expensive, and at long reception resistance to them can develop, usually sexual development is stimulated with androgens, and gonadotropic hormones apply later, to achievement actually fecundities.

Treatment, as a rule, there begin with introduction of HG in a dose of 1000 — 5000 ME in oil 3 times a week before normalization of synthesis of sex hormones about what judge by clinical signs and level of Testosteron-Depotum in plasma. After that the dose of HG is reduced to 2000 ME 2 time a week and in addition enter menotropin in a dose 75 — 150 ME LG and FSG 3 times a week. The most frequent side effect of gonadotropic hormones is gynecomastia; it arises almost at every third patient and is probably bound to the raised production of estrogens: Maturing of testicles requires about 6 months, and for establishment of a full-fledged spermatogenesis treatment should be continued up to 2 years. After the beginning of a spermatogenesis or its renewal (at the secondary hypogonadism which arose after puberty) for production of a semen of rather maintenance therapy of the I HG. As it was already told, the increasing role in sterility treatment will probably be played by recombinant gonadotrophic hormones.

Cryptorchism

At cryptorchism one or both testicles not, fall to a scrotum. It occurs at the full-term newborn boys in 3% of cases, but with age its prevalence considerably decreases. At cryptorchism the spermatogenesis is broken and the risk of germinogen tumors of a testicle increases. Therefore it is considered that bringing down of a testicle in a scrotum should be made as 3 it is possible earlier, usually at the age of a year and in any case up to 2 years. As the descent of testis is stimulated with androgens, for lack of an anatomic obstacle it is possible to use HG. Usually prescribe 6 injections of HG on 500 ME/sq.m in oil every other day. At inefficiency of such treatment.

In some researches the assumption was made that gonadotropin hormones increase risk of ovarian cancer, however it remained unproven. It is important to note that at stimulation of ovaries of FSG and menotropin risk of malformations at the children born from stimulated ova doesn't increase.