Increased Plasma Oestradiol Concentrations Research Articles

Effect of paracetamol treatment on maternal care and reproductive outcomes in female rat offspring.

Paracetamol (PAR) is one of the most commonly used drugs by pregnant women because it is considered safe for the mother and fetus. However, PAR is transferred into breast milk and crosses the blood-placental barrier, being present in the progeny during important stages of development. Intrauterine exposure to PAR may decrease the anogenital distance and follicle reserve in female rodent offspring. Therefore, the aim of the present study was to evaluate whether maternal PAR treatment altered the reproductive behaviour of dams and the sexual development of female rat offspring. Pregnant Wistar rats were gavaged daily with 350mg kg-1 day-1 PAR or water during gestation (from Gestation Day (GD) 6 until delivery) or during gestation and lactation (from GD6 until weaning). Maternal PAR treatment had maternal effects (increased grooming behaviour), and resulted in impaired sexual behaviour, decreased follicle reserve and increased plasma oestradiol concentrations in female offspring.

Detrimental effect of maternal and post-weaning high-fat diet on the reproductive function in the adult female offspring rat: roles of insulin-like growth factor 2 and the ovarian circadian clock

PurposeWe evaluate the impact of maternal and post-weaning high-fat (HF) diet on ovarian follicular population, steroidogenesis, and gene expression with a focus on the circadian clock system and insulin-like growth factor 2 (Igf2) in adult offspring ovaries, and to elucidate whether a maternal and post-weaning diet confers similar risks.MethodsVirgin Sprague-Dawley rats were fed with normal chow (C) diet or HF diet for 5 weeks before mating, during gestation, and lactation. Female offspring were fed with the C or HF diet from weaning to 6 months of age, resulting in four study groups (n = 6 per group): C/C, C/HF, HF/C, and HF/HF.ResultsOvaries from offspring exposed to post-weaning HF diet (i.e., the C/HF and HF/HF groups) had a decrease in small follicle numbers, but with similar numbers of antral follicles and corpora lutea. Offspring from HF-fed dams (i.e., the HF/C and HF/HF groups) had increased plasma estradiol concentrations and decreased luteinizing hormone levels at 6 months of age. In addition, Igf2 and each of the circadian rhythm core genes Clock, Per1, Per2, and Per3 were increased in the ovaries of offspring exposed to maternal HF diet (both HF/C and HF/HF groups).ConclusionsMaternal and post-weaning HF diet programs the reproductive profile of the female offspring in adult life through different manners. Post-weaning HF intake resulted in the reduction of small follicles in adulthood, whereas maternal HF diet had long-term deleterious consequences on female offspring steroidogenesis and coincided with alteration of the upregulation of the imprinted gene Igf2 and changes in ovarian circadian rhythms.

Formation of Follicular Cysts in Cattle and Therapeutic Effects of Controlled Internal Drug Release

Follicular cysts in cattle result from excessive growth of the dominant follicle without ovulation and still constitute a major reproductive disorder in this species. One key hormonal characteristic of cows with follicular cysts is the lack of an LH surge, although they have increased plasma estradiol concentrations. Another is a relatively high level of pulsatile secretion of LH that promotes continued growth of the dominant follicle. These LH characteristics seem to result from a functional abnormality in the feedback regulation of LH secretion by estradiol. Treatment with controlled internal drug release devices that increase circulating progesterone levels is effective in resolving follicular cystic conditions by 1) lowering pulsatile LH secretion and 2) restoring the ability of the hypothalamo-pituitary axis to generate an LH surge in response to an increase in circulating estradiol.

Transfer of polychlorinated biphenyls and chlorinated pesticides from mother to pup in relation to cytochrome P450 enzyme activities in harp seals (Phoca groenlandica) from the Gulf of St. Lawrence, Canada

Congener-specific transfer of polychlorinated biphenyls (PCBs) and chlorinated pesticides from female to pup was studied in harp seals from eastern Canada. Possible effects on hepatic cytochrome P450 enzymes (CYP450) due to contaminant mobilization from blubber lipids in females and ingestion of contaminated milk in pups were studied. Contaminant transfer from blubber to milk in females favored the more polar compounds (lower chlorinated PCBs, toxaphenes, hexachlorocyclohexanes, and hexachlorobenzene) relative to more lipophilic compounds (higher chlorinated PCBs, dichlorodiphenyltrichloroethane [DDT], chlordane). In spite of substantial contaminant mobilization from blubber in females and ingestion of contaminated milk by pups, CYP450 activities were low in all animals. Possibly, increased plasma estradiol concentrations, involved in breeding after lactation, suppressed CYP450 directly. Although the pups were exposed to contaminants in milk, CYP450 activities were low, resulting in low contaminant metabolism. This was confirmed by similar contaminant patterns in milk and pups. A strong positive relation between CYP1A-like activities and body weight in the pups suggested not yet fully developed CYP1A enzymes. A negative association between CYP3A and pesticides in females and pups was hypothesized to be a result of metabolic inactivation of CYP450. The CYP450 enzyme activities were considered unsuitable indicators for contaminant mobilization and transfer in harp seals.

Follicular 3 beta-hydroxysteroid dehydrogenase and cytochromes P450 17 alpha-hydroxylase and aromatase messenger ribonucleic acids in cattle undergoing superovulation.

In this study, we tested the hypothesis that there is altered abundance of transcripts of genes coding for the enzymes cytochrome P450 17 alpha-hydroxylase (P450(17 alpha)), cytochrome P450 aromatase (P450arom), and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in follicles of cattle hyperstimulated with eCG compared to FSH. Treatments were initiated on Day 10 of the cycle, and all cows received prostaglandin (PG) on Day 12. In experiment 1, blood samples were taken to determine plasma progesterone and estradiol concentrations during ovarian stimulation. In experiment 2, both ovaries were removed from stimulated cows by colpotomy before (n = 4 cows/treatment) and at 12 (n = 3/treatment) and 24 h (n = 3/treatment) after PG injection, and from nonstimulated controls (n = 4) 72 h after PG. The preovulatory follicle from nonstimulated heifers, and all follicles greater than 3 mm in diameter from superovulated heifers, were isolated and classified as small (3-5 mm), medium (6-9 mm), or large (> 9 mm). Steady-state levels of RNA for 3 beta-HSD, P450(17 alpha), and P450arom genes were determined by Northern analysis in the individual follicles. In experiment 1, stimulation with eCG significantly (p < 0.01) increased plasma progesterone concentrations compared to FSH-stimulated and nonstimulated controls, and increased (p < 0.05) plasma estradiol concentrations compared to FSH-stimulated controls. Stimulation with FSH did not alter progesterone concentrations, but significantly increased plasma estradiol concentrations compared to those of controls. In experiment 2, the number of large follicles increased significantly with time (p < 0.01), but there were no differences between eCG and FSH treatments in size distribution of follicles (p > 0.05). Relative abundance of P450(17 alpha) message (per 20 micrograms RNA) was significantly higher in large and small follicles (p < 0.05) in eCG-treated compared to FSH-treated heifers after PG injection. Analysis within this period revealed significant treatment effects at 12 h but not 24 h after PG injection. The bovine P450arom cDNA hybridized to 3 transcripts: a 6.5-kilobase (kb) polyadenylated transcript, and non-polyadenylated messages of 3.4 and 1.8 kilobases (kb), all of which hybridized with an oligonucleotide probe specific for the heme-binding region. In medium and small follicles, the 6.5-kb and 3.4-kb transcripts were present in similar quantities, and the 1.8-kb transcript was 25% less abundant. In large follicles recovered after luteolysis, the 3.4 and 1.8-kb transcripts were 3- to 4-fold more abundant in eCG-treated compared with FSH-treated and nonstimulated animals (p < 0.05). There were no significant differences between eCG and FSH treatments on steady-state 3 beta-HSD mRNA levels. Levels of 3 beta-HSD and P450(17 alpha) mRNA in large follicles in hyperstimulated heifers were not different from those in preovulatory follicles in nonstimulated cows. We conclude that hyperstimulation with eCG results in greater stimulation of follicular P450(17 alpha) message abundance compared to hyperstimulation with FSH, and that this may contribute to increased follicular estradiol secretion.

Alterations in behavior, steroid hormones and natural killer cell activity in male transgenic TGFα mice

The expression of transforming growth factor α (TGFα) is widely distributed throughout many normal and neoplastic tissues, but its physiological significance remains unclear. We have utilized male transgenic mice overexpressing the gene encoding human TGFα in multiple tissues to further identify those functions which are influenced by this protein. Male TGFα mice develop hepatocellular carcinoma at the age of 10–15 months. At the age of 2–3 months these mice, compared to age matched CD-1 controls, spent significantly longer times immobile in Porsolt's swim test, a model of stress and depressive behavior, and exhibiting aggressive behavior in the resident-intruder test. In contrast, the transgenic TGFα mice did not differ from the controls in either the plusmaze test of anxiety, or in their voluntary alcohol intake. Significantly, the TGFα mice exhibited a 25% lower Natural Killer (NK) cell activity and a four-fold increase in the plasma levels of 17- β-estradiol(E 2) than the controls. No significant changes in plasma testosterone or corticosterone levels were noted. The results indicate that transgenic male mice overexpressing TGFα exhibit behaviors characteristic of both an impaired ability to cope with stress and an increased aggressivity. The TGFα mice also show reduced NK cell activity and increased plasma estradiol concentrations. The present data suggest that TGFα may be important in influencing behavioral, immunological and hormonal systems prior to the onset of tumors. It remains to be determined whether hepatocarcinoma is associated with the direct proliferative and transforming effects of TGFα and/or indirect effects mediated through immune, hormonal and behavioral mechanisms.

Effects of hemicastration at various ages and of oestradiol-17 beta on plasma concentrations of gonadotrophins and androgens, testicular growth and interstitial cell responses in prepubertal lambs.

The effect of the removal of one testis from cross-bred lambs at 1, 4, 8 or 12 weeks of age on plasma FSH, LH and testosterone was studied until 16 weeks of age. Hemicastration at all ages elicited a significant increase in plasma FSH compared to controls without a corresponding change in plasma LH or testosterone. The raised FSH after hemicastration at 1 or 4 weeks of age was suppressed to control levels between weeks 7 and 8; such a suppression was not observed in the 4 weeks following hemicastration at 8 or 12 weeks of age. The weight of the remaining testis had increased compared with the control by 12 weeks of age after hemicastration at 1 week (+ 69%), 4 weeks (+ 13%) and 8 weeks (+ 40%); hemicastration at 12 weeks of age also resulted in growth of the remaining testis at 16 weeks (+ 82%). The total androgen production of interstitial cells in response to ovine LH stimulation in vitro did not differ significantly between lambs of 1 and 12 weeks of age, or in animals of 4, 8 and 12 weeks of age after hemicastration at 1 week of age. Subdermal implantation of oestradiol-17 beta into 1-week hemicastrated lambs at the time of operation or at 6 weeks of age increased plasma oestradiol concentrations by approximately 2-4-fold, prevented the FSH and testicular growth responses to hemicastration and suppressed plasma LH and testosterone to levels lower than those in control lambs. The total androgen response of interstitial cells from the remaining testis of oestradiol-implanted lambs at 12 weeks of age was significantly reduced. We suggest that the pituitary-testis axis varies in sensitivity during the prepubertal period although the interstitial cellular response of the testis to LH stimulation remains constant.

Postabortal contraception with norethisterone enanthate injections

Intramuscular injection of 200 mg norethisterone enanthate (NET-EN) was given to five women on the day of first trimester abortion. The injection was repeated twice at eight-week intervals, and thereafter at twelve-week intervals for one year. Plasma samples were collected for FSH, LH/hCG, estradiol, progesterone and norethisterone (NET) determinations. NET-EN did not affect the elimination of hCG, estradiol or progesterone. Plasma NET concentrations reached a peak (5.5–11 ng/ml) in about ten days after the injection and declined constantly thereafter, to levels of 0.18–0.64 ng/ml at 8 weeks after the injection. NET-EN postponed the increase in FSH secretion until 17–20 days after the injection, i.e. until plasma NET concentrations fell below 3 ng/ml. In three out of five women some follicular activity was present 5 weeks after NET-EN injection as evidenced by increased plasma estradiol concentrations. No ovulation occurred within 8 weeks after NET-EN injection, as judged by low progesterone values. There was a definite accumulation of NET during the first six months, when NET-EN injections were given at eight-week intervals. Mean plasma NET concentrations increased from 0.34 ng/ml at eight weeks to 0.78 ng/ml at 24 weeks. When the injection interval was increased to twelve weeks, the plasma NET concentrations prior to the next injection started to decrease. This was accompanied by increased follicular activity, culminating with one ovulation observed. It is concluded that in this population of women, an injection interval of less than twelve weeks is needed for ovulation inhibition.

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Intramuscular injection of 200 mg norethisterone enanthate (NET-EN) was given to five women on the day of first trimester abortion. The injection was repeated twice at eight-week intervals, and thereafter at twelve-week intervals for one year. Plasma samples were collected for FSH, LH/hCG, estradiol, progesterone and norethisterone (NET) determinations. NET-EN did not affect the elimination of hCG, estradiol or progesterone. Plasma NET concentrations reached a peak (5.5–11 ng/ml) in about ten days after the injection and declined constantly thereafter, to levels of 0.18–0.64 ng/ml at 8 weeks after the injection. NET-EN postponed the increase in FSH secretion until 17–20 days after the injection, i.e. until plasma NET concentrations fell below 3 ng/ml. In three out of five women some follicular activity was present 5 weeks after NET-EN injection as evidenced by increased plasma estradiol concentrations. No ovulation occurred within 8 weeks after NET-EN injection, as judged by low progesterone values. There was a definite accumulation of NET during the first six months, when NET-EN injections were given at eight-week intervals. Mean plasma NET concentrations increased from 0.34 ng/ml at eight weeks to 0.78 ng/ml at 24 weeks. When the injection interval was increased to twelve weeks, the plasma NET concentrations prior to the next injection started to decrease. This was accompanied by increased follicular activity, culminating with one ovulation observed. It is concluded that in this population of women, an injection interval of less than twelve weeks is needed for ovulation inhibition.

OESTRADIOL-17α AND PITUITARY RESPONSIVENESS TO LUTEINIZING HORMONE RELEASING FACTOR IN THE RAT: A STUDY USING RECTANGULAR PULSES OF OESTRADIOL-17β MONITORED BY NON-CHROMATOGRAPHIC RADIOIMMUNOASSAY

Plasma concentrations of oestradiol-17beta were measured by a non-chromatographic radioimmunoassay during the oestrous cycle, after the s.c. injection of 2-5 or 10 microgram oestradiol benzoate (OB), or the s.c. implantation of Silastic capsules containing crystalline oestradiol-17beta. The profile of endogenous plasma oestradiol-17beta concentrations was similar to that reported by other workers, and lay between the concentrations produced by the low and high doses of OB. The rectangular pulses of increased plasma oestradiol concentrations, produced during the period of implantation of the Silastic capsules, were used to determine the time taken for oestradiol-17beta to exert its facilitatory effect on the gonadotrophin response to LH-releasing factor (RF). In animals ovariectomized at dioestrus, oestradiol, at concentrations similar to those reached during the peak of the spontaneous surge, first reduced the LH response. However, after 7 h, responsiveness increased significantly to reach a peak at 12 h. The FSH response was also greatest 12 h after ovariectomy. In animals ovariectomized at metoestrus the effect of oestradiol on the LH response was significantly less than in rats ovariectomized at dioestrus, and the FSH responses were lower than those in animals bearing empty capsules and examined at the same time after ovariectomy. These findings together with the effects of long-term exposure to sodium pentobarbitone are considered with respect to the possible mechanisms, including the priming effect of LH-RF, which may produce increased pituitary responsiveness after ovariectomy and exposure to oestrogen.