Development of the hypothalamic-hypophysial-gonadotrophic activities in fetal rats

Summary Pituitary responsiveness to LHRH and anti-LHRH serum was investigated in fetal rats aged 18.5–22.5 days. Synthetic LHRH injection in utero into fetuses brought about a remarkable depletion of pituitary-LH with a corresponding increase of serum-LH on day 18.5. On the contrary, anti-LHRH serum administration to day-20.5 fetuses caused a significant augmentation of pituitary-LH 1 day later. These data indicate that LH-gonadotrophs respond to LHRH even on day 18.5, and that endogenous LHRH begins to affect LH-gonadotrophs on day 20.5.This work was supported by a grant from Ministry of Education, Science and Culture, Japan. The exert technical assistance of Mr Yoshihito Okamura is gratefully acknowledged.     

Luteolytic action of LHRH in women]

Several subcutaneous administrations of 250 microgram of LHRH (4 or 5 adminstrations at 4-hourly intervals per day) between the 2nd and 7th day post-ovulation in 4 normal women led to early luteolysis as demonstrated by a fall in serum progesterone concentration and early onset (2 to 3 days earlier) of menstruation.     

Inhibitory effects of LHRH on ovarian LH receptors in rats]

The administration of LHRH or of its analog [D-Ala6, des-Gly-NH10(2)] LHRH ethylamide to the female rat on day 10 of gestation resulted in termination of pregnancy and in a marked decrease in ovarian LH receptors and plasma progesterone level. Asingle injection of either compound during diestrus I also led to a decrease in LH receptors. These data demonstrate the high sensitivity of the control of ovarian LH receptors by circulating gonadotrophins and suggest that the contraceptive action of pre- and postcoitally administered LHRH is mediated by negative control of LH receptors.     

Plasma growth hormone in the rabbit fetus. Relation to maturation of the liver and lung]

Day 25 after insemination is a date of peculiar importance in the maturation of several organs in the Rabbit fetus. From day 25 onward the fetal liver stores increasing amounts of glycogen and the lung stores increasing amounts of lecithins, concomitant with sudden rise in the activity of lung phosphatidic-acid phosphohydrolase. Earlier studies on decapitated fetuses established that glycogen storage in the liver is dependent on a dual hormonal control, comprising a pituitary hormone like growth hormone or prolactin (some placental hormones share the same activity) and corticosteroids (Jost, 1961). Since the variations in endogenous corticosteroids do not seem to herald these liver or lung changes (Mulay et al., 1973), a study was made of growth hormone. Plasma immunoreactive growth hormone--determined with a heterologous Rat system (Kervran et al., 1976)--increases eightfold between days 23 and 25. During the same time plasma prolactin does not change according to McNeily and Friesen, 1978, and to unpublished data obtained with Dr McNeilly. In preliminary assays, Rat growth hormone was seen to increase phosphorylase "a" activity in the lung of 18.5 day-old Rat fetuses, thus anticipating normal development. We suggest that growth hormone plays a role in initiating liver and lung maturation.     

Serum prolactin levels and maintenance of progeny by prenatally-stressed female offspring.

Prenatal stress significantly reduced the number of progeny born to 47% of the female offspring and significantly increased the incidence of low birthweight young. None of these litters survived by the tenth postpartum day when serum prolactin levels were significantly reduced. Upon autopsy, these females had twice as many uterine implantation sites than the number of fetuses they bore, suggesting that a) the reduced postpartum serum prolactin most likely was the cause rather than the effect of the neonatal mortality and b) major hormonal deficiencies (possibly gonadotropic-related) were present even before giving birth.     

Serum prolactin levels and maintenance of progeny by prenatally-stressed female offspring

Summary Prenatal stress significantly reduced the number of progeny born to 47% of the female offspring and significantly increased the incidence of low birthweight young. None of these litters survived by the tenth postpartum day when serum prolactin levels were significantly reduced. Upon autopsy, these females had twice as many uterine implantation sites than the number of fetuses they bore, suggesting that a) the reduced postpartum serum prolactin most likely was the cause rather than the effect of the neonatal mortality and b) major hormonal deficiencies (possibly gonadotropic-related) were present even before giving birth.     

Decidua and the control of corpus luteum function, follicular development and pituitary LHRH-responsiveness in pseudopregnant and pregnant rats

The mid-pregnancy rescue of corpora lutea can be mimicked in the pseudopregnant rat by induction of decidual tissue in the uterus: in such rats, around day 10, there is neither luteolysis, nor resumption of follicle-development or increase of the pituitary responsiveness to LHRH. The results suggest that the mid-pregnancy rescue of corpora lutea is caused by a maternal factor.     

Effect of low dose of 70 kVp X-rays on the intrauterine development of mice

Pregnant Swiss albino mice were exposed to low doses of X-rays (approximately 9 mGy) in the range used for diagnostic exposure, on day 3.5 of gestation (preimplantation period), day 6.5 (early organogenesis period) or day 11.5 (late organogenesis period). The fetuses were examined on the 18th day of gestation. Exposure at 3.5 days post coitus (d.p.c.) resulted in a significant increase in prenatal mortality, and an increased incidence of retarded fetuses was observed after exposure at 3.5 and 6.5 d.p.c. The major effect of exposure at 11.5 d.p.c. was a significant decrease in the fetal head size and brain weight.     

Influence of N-methylformamide on the development, the NAD synthesis, and the activity of the ADPR transferase of rat embryos

When N-methylformamide is administered to rats on the 11th day of pregnancy approximately 50% of the fetuses are resorbed and a reduced weight of the developed animals is found in comparison to the controls on the 21th day (delivery by Caesarian section). The toxic effect is increased by using nicotinamide and methionine. If a combination of these substances is employed practically all fetuses are resorbed. Tryptophan, however, has a considerably protective influence. N-Methylformamide has no influence on the NAD-synthesis induced by nicotinamide or tryptophan. It does, however, inhibits the activity of the ADPR transferase.     

Interaction of glucocorticosteroids with glucagon in the control of argininosuccinase activity in the fetal rat liver]

Exogenous glucagon, but not glucocorticosteroids cause a rise in argininosuccinase activity in the liver of 21.5 day old fetuses. When fetuses are deprived of glucocorticosteroids, glucagon is unable to promote the enzymic activity. This study indicates that glucocorticosteroids are required for the induction of the argininosuccinase activity by glucagon.     

Decidua and the control of corpus luteum function,follicular development and pituitary LHRH-responsiveness in pseudopregnant and pregnant rats

Summary The mid-pregnancy rescue of corpora lutea can be mimicked in the pseudopregnant rat by induction of decidual tissue in the uterus: in such rats, around day 10, there is neither luteolysis, nor resumption of follicle-development or increase of the pituitary responsiveness to LHRH. The results suggest that the mid-pregnancy rescue of corpora lutea is caused by a maternal factor.12 February 1987     

Increased responsiveness of the hypothalamic-pituitary axis to steroid feedback effects in ovariectomized rats treated neonatally with monosodium L-glutamate

Summary Chronic ovariectomized rats treated neonatally with MSG showed reduced circulating concentrations of LH coupled with elevated hypothalamic LHRH stores. Despite the apparent loss of LHRH secretion, the small pituitary glands showed an increased density of LHRH receptors and normal responsiveness to the releasing hormone. The positive feedback effects of progesterone on LH release in oestrogen-primed animals was greatly exaggerated reflecting the build-up of hypothalamic LHRH stores without loss of pituitary responsiveness to LHRH.     

Increased responsiveness of the hypothalamic-pituitary axis to steroid feedback effects in ovariectomized rats treated neonatally with monosodium L-glutamate

Chronic ovariectomized rats treated neonatally with MSG showed reduced circulating concentrations of LH coupled with elevated hypothalamic LHRH stores. Despite the apparent loss of LHRH secretion, the small pituitary glands showed an increased density of LHRH receptors and normal responsiveness to the releasing hormone. The positive feedback effects of progesterone on LH release in oestrogen-primed animals was greatly exaggerated reflecting the build-up of hypothalamic LHRH stores without loss of pituitary responsiveness to LHRH.     

Effect of low dose of 70 kVp X-rays on the intrauterine development of mice

Summary Pregnant Swiss albino mice were exposed to low doses of X-rays (9 mGy) in the range used for diagnostic exposure, on day 3.5 of gestation (preimplantation period), day 6.5 (early organogenesis period) or day 11.5 (late organogenesis period). The fetuses were examined on the 18th day of gestation. Exposure at 3.5 days post coitus (d.p.c.) resulted in a significant increase in prenatal mortality, and an increased incidence of retarded fetuses was observed after exposure at 3.5 and 6.5 d.p.c. The major effect of exposure at 11.5 d.p.c. was a significant decrease in the fetal head size and brain weight.     

Opioids and cytosolic calcium in rat anterior pituitary: dynorphin preparation showed LHRH-like action due to contamination

The effect of dynorphin A-(1-13) (Dyn A-(1-13] and other opioids on the cytosolic free calcium concentration [(Ca2+]i) in rat anterior pituitary cells was examined using the fluorescent indicator fura-2. A commercial synthetic Dyn A-(1-13) preparation elevated [Ca2+]i. Results, which were obtained with receptor antagonists, and in LHRH receptor radioligand binding studies as well as by HPLC combined with LHRH radioimmunoassay, strongly suggest that this effect of the dynorphin preparation was due to contamination with a LHRH-like compound. Dyn A-(1-13), purified by HPLC, as well as Dyn A-(2-13), [Leu5]enkephalin, beta-endorphin, morphine, or U50,488H had no effect on [Ca2+]i. LHRH caused a rapid increase in [Ca2+]i by about 50 nM which was blocked by the LHRH antagonist, [D-pGlu1,D-Phe2,D-Trp3,6] LHRH.     

Inhibitory effects of LHRH on LH receptors in the rat testis]

A single injection of LHRH to the adult male rat, as of its analog [D-Ala6, des-Gly-NH102] LHRH ethylamide, resulted in a marked decrease in LH receptors in the tests. Plasma testosterone level and the weight of the seminal vesicles and prostate were also decreased after treatment. These data demonstrate that LHRH can decrease the sensitivity of LH receptors and testicular function in the rat.     

Induction of developmental anomalies in mice by maternal stress

The short-time restraint of pregnant mice on day 8 of gestation led to a significant increase of the anomaly rate in fetuses. This effect may be due to stress factors of endocrine origin.     

Suppression by LH-releasing hormone (LHRH) of the augmenting effect of estradiol on the secretion of LH and FSH by the rat pituitary gland

Summary Estradiol sensitizes the pituitary gland for the gonadotropin-releasing activity of LHRH. LHRH desensitizes the pituitary gland and does so in a dose-dependent manner. Moreover, LHRH dose-dependently suppresses the sensitizing effect of EB. In rats with an LHRH concentration in the plasma of about 90 pg/ml, the sensitizing effect of estradiol is absent.     

Bacterial endotoxin and impaired fetal development

Summary Small doses ofE. coli endotoxin given to pregnant mice on the 13th day of pregnancy caused only a mild maternal illness but induced resorption of approximately half the number of fetuses in each mouse. The remaining live fetuses developed normally and showed no evidence of retarded growth or malformations. The weights of their placentas and maternal spleens increased significantly. Endotoxin given on the 6th day of pregnancy caused a small reduction in fetal weights.Acknowledgments. I am indebted to Mrs.Heather Sandison for technical assistance and to Mr.M. J. R. Healy for statistical examination of the results. Dr.A. B. G. Lansdown kindly advized on the interpretation of histological findings.     

Morphological and biochemical effects of excessive amounts of biotin on embryonic development in mice

Pregnant mice received excessive amounts of biotin either subcutaneously (sc) or orally during gestation. There were no differences in the successful pregnancy rates and number of dead or resorbed fetuses between the control and biotin-treated groups. In biotin-treated groups no increased incidence of fetuses with external malformations was clearly demonstrable. However, biotin accumulated in maternal and embryonic organs; especially, the serum biotin level in the biotin-treated dam was 200-fold higher than that in the control dam. There was a difference in biotinidase activity in maternal serum and placenta between the control and biotin-treated groups. It was concluded that excessive amounts of biotin affected the specific activity of biotinidase in pregnant mice, but did not disturb normal reproductive functions and embryonic development.