[Molecular and genetic study of the role of hormones, receptors, and enzymes in regulation of reproduction, lipid metabolism, and other human physiological functions].

Prevalence of uterine progesterone receptors over estrogen ones, high uterine cAMP level, and low uterine prostaglandin level are necessary conditions of normal pregnancy. In cases of spontaneous and antiprogestin RU486-induced abortions, estrogen receptors prevail over progesterone ones, cAMP level decreases, and prostaglandin concentration in decidual tissue increases. Porcine and bovine beta-lipotropines were the first proteins, whose correct amino acid sequence was first determined in Russia. Several research centers carried out collaborative studies of the nucleotide sequences of human and animal proopiomelanocortin (lipotropin precursor) and prolactin cDNA. Researchers constructed genetic engineering producers of human pre-proinsulin and somatostatin, identified structural genes expressed in pancreatic beta-cells, studied antigenic properties of glutamic acid decarboxylase (GAD), which determine insulin-dependent diabetes, and identified the cholesterase determinant. They revealed mutations in the genes of proopiomelanocortin and melanocortin receptors (MC4-P), which inhibit leptin regulation of appetite and are associated with human obesity.

Antibodies to pituitary surface antigens during various pituitary disease states.

Autoantibodies to cell surface antigens of human somatotropinoma (ASAS), human prolactinoma (ASAP) and rat adenohypophysis (ASARA) were assayed in the serum of patients with pituitary diseases associated with GH deficiency (GHD), such as pituitary dwarfism and primary empty sella syndrome (ESS), and in the serum of patients with hyperprolactinaemia of different etiologies: idiopathic hyperprolactinaemia, prolactinoma and ESS. The investigation was carried out with a cellular variant of an ELISA. Among children with GHD, the highest percentage of antibody-positive patients was found in the group with idiopathic isolated GHD (89% of ASAS(+) patients and 30% of ASARA(+) patients vs 33.3% and 0% respectively in the group with idiopathic combined pituitary hormone deficiency, and 33.3% and 9% in patients with pituitary hypoplasia associated with isolated GHD or combined pituitary hormone deficiency). Among hyperprolactinaemic patients, the highest ASAP and ASARA frequency was observed in patients with idiopathic hyperprolactinaemia (67.7% and 41.9% respectively) where it was twice as high as in the group of patients with prolactinoma. The proportion of ASAS(+) and ASARA(+) did not differ significantly between the groups of patients with ess with or without GHD. Similarly, there was no significant difference between the number of ESS ASAP(+) and ASARA(+) patients with or without hyperprolactinaemia. The data obtained suggested that autoimmune disorders may be primary, and responsible, at least in part, for pituitary dysfunction in the cases of idiopathic isolated GHD and idiopathic hyperprolactinaemia. At the same time, the autoimmune disorders in the patients with prolactinoma or ESS are probably secondary to the organic pituitary lesion and their significance in the development of the pituitary dysfunction is obscure.

Evidence for the promoting role of the intra-uterine kinin release in the development of late hypertonic saline-induced abortion.

Blood plasma kininogen (K), kininases (KS), kallikrein (KK), prekallikrein (PKK), and PGF2a were estimated in the common circulation of pregnant women during late saline-induced abortion and also in retroplacental blood after foetus delivery. The results provide evidence for intra-uterine kinin release from circulating blood K by locally activated KK from the very beginning of abortion. The greatest kinin release coincided with the strongest KS activity decrease at the time of foetus delivery. The pre-abortive KS levels correlated directly with abortus duration. Uterine PG biosynthesis was activated, but appeared to be a secondary process.

PIP: Although human kininogen involvement in hormonal homeostasis during pregnancy and activation of full-term delivery has been documented, the role of intrauterine kinin release in saline-induced late abortion has not been explored. Thus, kinin-related components in the circulation of 53 women with second-trimester (16-27 weeks) hypertonic saline-induced abortions and 20 nonpregnant controls were investigated. Observed were increases in both inactive precursors such as kininogen (K) and prekallikrein (PKK) and the active enzymes kallikrein (KK) and kinases (KS). The prostaglandin (PG) F-2 alpha-KK level in abortion patients did not differ from that in controls. The period from saline instillation to delivery of the fetus (26.5 +or- 2.4 hours) was accompanied only by K and KS changes; these levels decreased simultaneously, reaching their lowest value at the time of fetal expulsion. A 6-fold increase of KK-like activity was detected at fetal expulsion. Thus, the greatest contractile activity of the uterus coincided with the highest concentrations of free kinins and their longest life-time in the systemic circulation. The duration of abortion was directly associated with KS activity level, suggesting that kinins can be used to estimate abortion duration. Tissue KK synthesized in human myometrium and endometrium is considered responsible for local intrauterine kinin release after saline instillation. Finally, a sharp PGF-2 alpha increase (3.6-fold in the systemic circulation and 33-fold in retroplacental blood) was observed at the time of fetal expulsion. The high myometrial contractile activity at the final stage of saline-induced abortion appears to be achieved through the combined effects of locally released kinins and kinin-stimulated prostaglandins.

[Sex hormone receptors, prostaglandins and cAMP, in functional activity of the uterus]. / Rol retseptorov polovykh gormonov, prostaglandinov i TsAMF v funktsionalnoi aktivnosti matki.

The levels of progesterone and estrogen receptors, cAMP and prostaglandins E2 and F2 alpha were studied in the decidua of pregnant women, which was obtained during surgical, spontaneous or prostaglandin-induced abortion or by pregnancy termination with vacuum aspiration after RU-486 treatment (before the onset of abortion). Our data have allowed the authors to suggest that (i) for the maintenance of normal activity of decidua during pregnancy, the following points are considerably important: the constant ratio of progesterone and estrogen receptors in favor of progesterone receptors, low PG levels and high cAMP levels; (ii) both spontaneous and induced abortion are characterized by decreases in the levels of progesterone receptor (which in turn changes the ratio of progesterone and estrogen receptors in favor of the latter), by increased PG levels and decreasing cAMP concentrations.

[Humoral autoimmunity markers in autoimmune endocrine diseases]. / Markery gumoralnogo autoimmuniteta pri autoimmunnykh éndokrinnykh zabolevaniiakh.

To clarify the value of autoantibodies as risk factors of complications in various endocrine abnormalities, the incidence of autoantibodies to thyroid microsomal antigen (ATMA), thyroglobulin, and the surface antigens of the rat islet, adrenal cortex, adenohypophyseal cells and human skin fibroblasts was studied in patients with insulin-dependent mellitus (IDDM), at the onset of the disease and during one-year insulin therapy, non-insulin-dependent diabetes mellitus (NIDDM), Hashimoto thyroiditis, Graves' disease, diabetes associated with thyroidal dysfunction, euthyroid polynodular goiter, Schmidt and polyglandular syndromes and in the population. The antibodies were determined by ELISA. Polyclonal activation of the immune system was found in all abnormalities, except in polyglandular in children. The proportion of patients with more than one type of antibodies was minimal (26.4%) in IDDM and maximal (62.0%) in Graves' disease. Among IDDM patients, polyclonal activation of the immune system was observed more often in women than in men (48.5 vs 8.5%). The persistence of antibodies to fibroblasts in IDDM patients was associated with the development of vascular complications. The latter were observed in 4 of 7 patients who had these antibodies during a year and in none of negative patients. Thus, fibroblast antibodies may have a predicative significance for the development of late diabetic complications. The highest prevalence of these antibodies was discovered in Graves' disease (37.9%) wherein the antibodies may be involved in the development of exophthalmus and pretibial mixedema. Thyroidal dysfunction developed in all IDDM patients with ATMA preserved during a year and in none ATMA-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[Prostaglandin content in decidual tissue of women in spontaneous abortion]. / Soderzhanie prostaglandinov v detsidual'noi tkani zhenshchin pri samoproizvol'nom aborte.

Prostaglandins E2 and F2 alpha were measured in decidual tissue of women after spontaneous abortions at pregnancy terms 8 to 10 weeks and after abortions induced by sulprostone, a synthetic prostaglandin E2 analog, at pregnancy term 4-5 weeks. Women in whom pregnancy was terminated surgically at relevant periods were controls. Prostaglandin E2 concentration was found to be 5 times higher and that of prostaglandin F2 alpha 40 times higher in women with spontaneous abortions than in surgical abortion. In sulprostone-induced abortion prostaglandin concentrations in decidual tissue were the same as in controls. These data indicate that a drastic increase of prostaglandin levels in spontaneous abortion is not only a result of myometrial contractions or decidual tissue rejection, but an important component in the chain of events leading to miscarriage.

The effect of RU486 on progesterone and oestrogen receptor concentration in human decidua on early pregnancy.

Concentrations of progesterone receptor (PR) and oestrogen receptor (ER) were measured by radioligand assay in decidual tissue of women undergoing termination of early pregnancy (amenorrhoea up to 49 days). Pregnancies were terminated by vacuum aspiration at 12 or 36 h after oral administration of placebo or antiprogestin RU486 in different doses. Treatment with RU486 decreased decidual PR content, the effect being observed at 12 h as well as at 36 h after 600 mg RU486 and at 36 h after 3 x 25 mg RU486 given at 12 h intervals. PR concentration 12 h after a single dose of 25 mg RU486 was not affected. ER content was unchanged at 12 h after RU486 but increased 36 h after 600 mg and 3 x 25 mg RU486. Our data suggest that apart from blocking progesterone action, RU486 may exert its abortifacient effect through decreasing the PR concentration. The simultaneous decrease of PR concentration and an increase of ER concentration changes the balance between them in favour of ER, which might also play a role in the abortifacient effect of RU486.

[Contents of prostaglandins E2 and F2alpha and cAMP in the endometrium of women with habitual abortion during late pregnancy terms]. / Soderzhanie prostaglandinov E2 i F2 alfa i tsAMF v éndometrii zhenshchin, stradaiushchikh privychnym nevynashivaniem beremenosti pozdnikh srokov.

Measurements of prostaglandins E2 and F2 alpha in the endometrium of 35 women of a reproductive age, suffering from habitual abortions in late pregnancy terms, have shown elevation of these prostaglandin levels in the secretory phase as against the reference group and their normal values during the proliferative phase. It is possible, that disordered prostaglandin synthesis in the endometrium, manifesting in pregnancy, is one of the causes of habitual abortions. cAMP levels were somewhat decreased in the secretory phase in this patient population; this permits a hypothesis on disorders in the adenylate cyclase system.

[Metabolism of linoleic acid given with the feed in the calf liver]. / Metabolizm linolevoï kysloty v pechintsi teliat pry ïï spozhyvanni z kormom.

Calves were fed with the whole milk substitute containing different amounts of linoleic acid--0.70, 1.44 and 3.65 per cent from the total energy content of the ratio--for the 1st, 2nd and 3rd groups, respectively, beginning from the 2nd to the 60th day of life. The feeding of different amounts of linoleic acid has no significant effect on the lipid content and the ratio of different type of lipids as well as on prostaglandins E2 and F 2 alpha contents. The increase of linoleic acid quantity in the liver lipids of calves occurs parallel to that of its uptake. During the liver homogenates incubation in the medium containing [1-14C] linoleic acid 0.15-0.22 per cent of the label are found in the composition of 14CO2, 85.7-85.9 per cent--in lipids, 13,9-14,6 per cent--in prostaglandins.

[The effect of the synthetic analog of prostaglandin E2 sulprostone on the adenylate cyclase system in decidual tissue of women]. / Vliianie sinteticheskogo analoga prostaglandina E2 sul'prostona na adenilattsiklaznuiu sistemu v detsidual'noi tkani zhenshchin.

Activities of adenylate cyclase and phosphodiesterase were studied in decidual tissue of women, pregnancy of which was interrupted within the first term by means of synthetic analogue of prostaglandin E2 sulprostone; decidual tissue obtained after surgical abortion served as a control. Content of cAMP in decidual tissue was decreased 4-fold after administration of sulprostone. At the same time, activity od adenylate cyclase was decreased 2-3-fold, while activity of phosphodiesterase was unaltered. These data suggest that the decrease in cAMP concentration occurred as a result of inhibition of its synthesis. After administration of sulprostone the adenylate cyclase activity was decreased 3- and 4.5-fold in response to specific stimulators NaF and forskolin, respectively, thus indicating that content and activity of G protein, and apparently of catalytic subunits, were decreased. Long-term effect of prostaglandins on decidual tissue appears to cause a heterologous desensitization of adenylate cyclase and this phenomenon is responsible for pharmacologic action of prostaglandins.

[Mechanism of abortifacient effect of prostaglandins: changes in the level of cyclic adenosine monophosphate in the decidual tissue of women during abortion induced with sulprostone]. / O mekhanizme abortnogo deistviia prostaglandinov: izmenenie urovnia tsiklicheskogo adenozinmonofosfata v detsidual'noi tkani zhenshchin pri aborte, vyzvannom sul'prostonom.

PIP: The role of cyclic AMP (cAMP) in the mechanism of abortifacient effect of sulprostone was studied in women with pregnancy of 2-3 weeks of gestation (group 1) or 4-5 weeks of gestation (group 2). Pregnancy was confirmed by determining the beta-subunit of chorionic gonadotropin. The patients received intramuscular injection of sulprostone at 0.5 mg, 2 times with an interval of 4 hours (group 1), or 3 times with an interval of 3 hours (group 2). The cAMP level was determined in the decidual tissue removed immediately after abortion. Sulprostone-induced abortion resulted in marked decrease in the cAMP levels in the decidual tissue (from 491.5+/-70.4 picamol per 1 mg of protein to 224+/55.6 in group 1 and from 377.7+/-55.9 to 95.7+/-18.4 in group 2). Decrease in cAMP level was also observed during spontaneous abortion (122.3+/-28.5, compared with 691.1+/-110.5 during surgical abortion). To determine whether the decrease in cAMP level was associated with direct action of sulprostone, the decidual tissue was incubated with PGE1 in vitro (10, 25 or 50 microg/ml for 15 min). In vitro addition of PGE1 resulted in marked increase in the cAMP level. These findings indicated that decrease in cAMP level during sulprostone-induced abortion was associated not with its direct action on the decidual tissue but rather with reduced blood supply of the decidual tissue caused by uterine contractions.^ieng

[Prostaglandin and cAMP levels in the endometrium of women with a normal menstrual cycle]. / Soderzhanie prostaglandinov i tsAMF v éndometrii zhenshchin v techenie normal'nogo menstrual'nogo tsikla.

The content of prostaglandins and cAMP was determined in the endometrium of healthy women with a regular menstrual cycle in its different phases. It was shown that the PGE2 level in the proliferative (the 7th-10th day of the cycle) and secretory (the 24th-26th day of the cycle) phases was the same. At the same time the level of PGE2 in the secretory phase of the cycle was 3 times higher than in the proliferative phase. The level of cAMP in the secretory phase of the cycle was 2 times higher than in the proliferative phase.

[Comparative effects of prostaglandins and ACTH on the production of corticosterone and cyclic AMP in isolated adrenal gland cells of rats]. / Sravnenie deistviia prostaglandinov i AKTG na obrazovanie kortikosterona i tsAMF v izolirovannykh kletkakh nadpochechnikov krys.

The authors compared the effect of prostaglandin PGE2 and ACTH on corticosterone and cAMP production in isolated adrenal cells of rats. PGE2 stimulated steroidogenesis in the concentrations of 0.01-1.10 micrograms/ml and the maximum stimulation (2.5-fold) was observed in the PGE2 concentration of 0.1 micrograms/ml. ACTH stimulated steroidogenesis 12-fold as compared to PGE2. In combined addition of different PGE2 doses and the physiological ACTH dose (5 pg/ml) their steroid effects were summated. The results obtained are indicative of the fact that PGE2 is no mediator of the ACTH effect but that it is capable of potentiating this effect. Like ACTH, PGE2 raised the cAMP level in the adrenal gland. In concentrations causing a similar to ACTH increase in the cAMP level, PGE2 stimulated steroidogenesis to a lesser degree than ACTH, and in this connection a possibility of the existence of two cAMP foci in the adrenal gland is discussed. It is assumed that one of the foci is related and the other is not related with steroidogenesis, and PGE2 stimulates mainly the second focus.

[Effect of 15-methyl-prostaglandin F2 alpha used for dilating the cervix uteri before abortion on endogenous prostaglandin F2 alpha synthesis]. / Vliianie 15-metil-prostaglandina F2 al'fa, primeniaemogo dlia rasshireniia sheiki matki pered abortom, na sintez éndogennogo prostaglandina F2 al'fa.

PIP: The effects of methyl ester of 15-methyl-prostaglandin F2alpha (15-Me-PGFalpha) on the content in plasma of female peripheral blood of 15-keto-13, 14-dihydro-PGF2alpha--the basic metabolite of PGF2alpha--was investigated. The studies were performed in 46 women who received vaginal suppositories of 1 mg 15-Me-PGF2alpha or suppositories with placebo in order to dilate the uterine cervix before abortion in the 1st trimester of pregnancy. It was found that 6-12 hours after administration of suppositories with 15-Me-PGF2alpha, the PGF2alpha metabolite level in the blood increases 1 1/2-2 fold. The concentration of PGF2alpha metabolite in the blood is neither altered in the earlier periods or after administration of suppositories with placebo. (author's)^ieng

[Effect of ACTH in the biosynthesis of prostaglandins, adenosine cyclic monophosphate and steroids in the adrenal cortex of rabbits in vivo]. / Vliianie AKTG na obrazovanie prostaglandinov, tsiklicheskogo 3', 5'-adenozinmonofosfata i steroidov v kore nadpochechnikov krolikov v usloviiakh in vivo.

The effect produced by intravenous injection of ACTH to rabbits on the content of prostaglandins E and F (PGE and PGF) in the adrenal glands was studied. At the same time a determination was made of the cAMP content in the adrenal glands and of the peripheral blood corticosterone concentration. PGE and PGF were revealed in the adrenal cortex in concentrations of 199--550 and 271--335 pg/g respectively. After a dose of 50 Units there was a 2--3-fold rise of PGE, and a 1 1/2-fold rise of the PGF content. PG synthesis was elevated maximally in the adrenal glands 15 minutes after the ACTH injection, remaining at this level for 60 minutes; similar dynamics was revealed for the cAMP and corticoterone formation. The results obtained indicated that, along with intensification of the steroids and cAMP formation, ACTH stimulated PG synthesis in the adrenal glands. These data permit a suggestion to be made that PG participated in the ACTH action on the adrenal glands.