Biomedical subjects
Publications and source records attributed to J Drouin.
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Synthetic "progestins" currently used in the contraceptive pill inhibited the luteinizing hormone (LH) responsiveness to LH-releasing hormone in cells in culture in a way undistinguishable from that of androgens. Moreover, they competed for binding of the 3H-labeled androgen R 1881 to the rat prostate androgen receptor and stimulated seminal vesicle and prostate weight in castrated rats. R 5020, a pure progestin, was without effect on the above-mentioned parameters. However, a complete inhibition of the LH surge measured in the afternoon of expected proestrus was obtained at a dose of R 5020 similar to that of D-norgestrel. The synthetic progestin was also found to inhibit ovulation and to delay vaginal cornification. The present data show that the synthetic "progestins" commonly used in the pill possess intrinsic androgenic activity which could well be responsible, to an unknown extent, for their effectiveness as contraceptive agents. R 5020, a synthetic progestin devoid of androgenic activity, is at least as potent as the most potent 19-nortestosterone derivative, D-norgestrel, in inhibiting gonadotropin secretion and other parameters of the estrous cycle in the rat. The availability of a pure progestin devoid of androgenic activity but highly effective as an inhibitor of gonadotropin secretion could be of great interest for the development of an improved contraceptive.
The effect of estradiol and thyroid hormone treatment on pituitary TRH binding and TSH and PRL responses to the neurohormone was studied. A significant increase in the number of pituitary TRH binding sites was observed between 2 and 4 days after daily administration of estradiol benzoate with a plateau at 300% of control being reached at 7 days. Plasma PRL levels showed a similar early pattern of response. In animals rendered hypothyroid by a 2-month treatment with propylthiouracil or 1 month after surgical thyroidectomy, the level of pituitary TRH receptors was increased approximately 2-fold, this elevation being completely reversed by treatment with thyroid hormone. Estradiol-17beta administered with L-thyroxine partially reversed the inhibitory effect of thyroid hormone on TRH receptor levels in hypothyroid animals. The antagonism between estrogens and thyroid hormone is also apparent on the TSH response to TRH since estrogen administration can reverse the marked inhibition by thyroxine of the TSH response to TRH either partially or completely in intact and hypothyroid animals, respectively. The PRL response to TRH is 55 and 40% inhibited in hypothyroid and intact rats, respectively, by thyroid hormone when combined with estrogen treatment. The present data clearly show that estrogens and thyroid hormones can affect TSH and PRL secretion, the effect of estrogens being predominantly on PRL secretion while thyroid hormone affects mainly TSH. The close correlation observed between the level of TRH receptors and PRL and TSH responses to TRH suggests that estrogens and, to a lesser extent, thyroid hormones, exert their action by modulation of the level of receptors for the neurohormone in both thyrotrophs and mammotrophs.
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Specificity of the effect of prostaglandins (PGs) on hormone release by the anterior pituitary gland was studied using cells in primary culture. Growth hormone (GH) release is stimulated by all eight PGs studied, PGE1 and E2 being 1000-fold more potent than the corresponding PGFs. The release of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) remains unchanged upon addition of PGEs. While the basal release of thyrotropin (TSH) is only slightly stimulated by concentrations of PGEs above 10(-6)M, an important potentiation of the stimulatory effect of thyrotropin-releasing hormone on TSH release is observed. The release of GH, TSH and LH is stimulated equally well by PGAs and PGBs at concentrations higher than 10(-6)M, 3 X 10(-6)M, and 10(-5)M, respectively. PGFs do not affect the release of any of the measured pituitary hormones at concentrations below 10(-4)M. The stimulation of GH release by PGE2 can be inhibited by the PG antagonist 7-oxa-13-prostynoic acid, a half-maximal inhibition being found at a concentration of 4 X 10(-5)M of the antagonist in the presence of 10(-6)M PGE2. In the presence of somatostatin 10(-8)M, the inhibition of GH release cannot be reversed by PGE2 at concentrations up to 10(-4)M. 8-bromo-cyclic AMP-induced GH release is additive with that produced by PGE2. The present data show that 1) of the five pituitary hormones measured, only GH release is stimulated by prostaglandins at relatively low concentrations, 2) the PGE-induced GH release can be competitively inhibited by 7-oxa-13-prostynoic acid, 3) the inhibition of GH release by somatostatin cannot be reversed by PGE2 and 4) the PGEs increase the responsiveness of the thyrotrophs to TRH.
A possible direct effect of prostaglandins E1 and E2 (PGE1 and PGE2) on luteinizing hormone (LH) release at the pituitary level was studied in vitro using anterior pituitary cells in primary culture, a system approximately 10-fold more sensitive to stimulation of LH release than previously used hemipituitaries. No effect of PGE1 or PGE2 could be detected on the time course of basal or LH-RH-stimulated LH release or on the LH responsiveness to LH-RH. This absence of a direct effect of PGEs at the pituitary level on LH release was confirmed by in vivo experiments using female rats under Surital anesthesia in the afternoon of proestrus. After intravenous injection, under these conditions, 15(S)-15-methyl PGE2 was 3-5 times more potent than PGE2 to increase plasma LH levels while PGE1 had about 50% the potency of PGE2. Injection of sheep anti-LH-RH serum one hour before PGE1 or PGE2 injection not only lowered basal plasma LH levels but prevented the rise induced by PGEs. These data indicate clearly that the increased plasma LH levels observed after in vivo PGE injection are secondary to a stimulation of LH-RH release while PGEs do not appear to have a significant effect on LH release at the pituitary level.
Somatostatin, at concentrations up to 10(-7) M, does not inhibit the basal release of TSH from primary cultures of rat anterior pituitary cells. The TRH-induced TSH release is however 65% reduced by somatostatin, half-maximal inhibition being measured at 2.5 x 10(-10) M somatostatin. The concentration of TRH giving half-maximal stimulation (ED50) of TSH release is only slightly increased from 1 to 3 x 10(-9) M in the presence of 10(-8) M somatostatin. Somatostatin inhibits by 45-65% both the basal and TRH-induced PRL release of pituitary cells prepared from adult female rats, with half-maximal inhibition at approximately 5 x 10(-10) M somatostatin. The TRH ED50 for PRL release was not significantly affected by somatostatin. Somatostatin (200 mug) has no effect on the basal plasma levels of TSH or PRL in anesthetized male rats treated with estradiol benzoate (EB), hypothyroid rats, or hypothyroid animals treated with EB. The plasma TSH response to TRH is, however, reduced by approximately 75% by somatostatin while the plasma PRL response is not affected by injection of the peptide. The interaction between TRH and somatostatin for both TSH and PRL release is non-competitive and is thus likely to occur at a step subsequent to the binding of the peptides to their specific receptors in both thyrotrophs and mammotrophs.
A possible direct effect of androgens at the pituitary level on gonadotropin release was studied using rat anterior pituitary cells in primary culture. The preincubation of cells with 3 X 10(-9)M testosterone (T) for 40 h increased the concentration of luteinizing hormone-releasing hormone (LHRH) required for half-maximal stimulation (ED50) of LH release from 3 X 10(-10)M to 1 X 10(-9)M. In the same experiment, the LHRH ED50 for FSH release (3 X 10(-10)M) was not affected by preincubation with T, while a slight stimulatory effect of the androgen was observed on balal FSH release and on the maximal FSH response to LHRH. Time-course experiments showed that the inhibitory effect of T on the LH response to LHRH was maximal after about 48 h of incubation and that 54 h after the removal of T, only 50% of the inhibition was reversed. 5 alpha-Dihydrotestosterone (DHT) and T led to the same maximal inhibition (15-20% of control) of the LH response to 10(-10)M LHRH. DHT was, however, about 3 times more potent than T, their ED50 values being 1.6 X 10(-10)M and 5 X 10(-10)M, respectively. In contrast to the effect on LH, the FSH response to 10(-10)M LHRH was only slightly, but not significantly, inhibited by increasing concentrations of DHT or T. The finding that total LH (medium + cell content) remained constant after incubation with T or DHT clearly indicates that the inhibition of the LH response to LHRH is really due to changes in the sensitivity of the releasing mechanisms in the LH-secreting cells. Androgens did, however, lead to increased total FSH. The present data indicate an independent control of LH and FSH secretion by a direct action of androgens at the pituitary level.
The effect of 17 beta-estradiol (E2) on LH secretion was studied using rat adenohypophyseal cells in primary culture. Preincubation of cells with 1 X 10(-9) M E2 for 40 h decreased the concentration of LHRH required for half-maximal stimulation (ED50) of LH release from 3.0 +/- 0.3 to 1.6 +/- 0.2 X 10(-10)M (P less than 0.01). Basal LH release was increased from 84 +/- 4 to 182 +/- 8 ng LH-RP-1/ml/4h (P less than 0.01) by E2 pretreatment. Time-course experiments showed that the stimulatory effect of 10(-8)M E2 on the LH response to LHRH can be first measured after 10 h of incubation in the presence of E2 and that this effect is maximal after 24 h of incubation with the steroid. While E2 increases the LH responsiveness to LHRH, androgens decrease the sensitivity of LH-secreting cells to the neurohormone. The LHRH ED50 value of testosterone-treated cells is of 7.2 +/- 0.4 vs. 3.7 +/- 0.3 X 10(-10)M for control cells (P less than 0.01). E2 can only partially reverse this inhibitory effect of androgens on the LH response to LHRH. These data show clearly that E2 can have a direct stimulatory effect on LH-secreting cells to increase the sensitivity of their response to LHRH.
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A novel peptide hormone, atrial natriuretic factor (ANF), was recently isolated and characterized in mammalian atria. This hormone has potent natriuretic diuretic and vasorelaxant activities. Since ANF bioactivity was initially found in atria but not in ventricles, it was assumed that the ANF gene is specifically expressed in atria. We now report that ANF mRNA is present in ventricular tissue as well as in atria. This is clearly demonstrated by in situ hybridization and by Northern blot analysis. Rat ventricular ANF mRNA concentration is a hundred-fold lower than in atria. As in atria, the 126 amino acids precursor form of ANF is predominant in ventricles and it is present at a thousand-fold lower concentration. The ten-fold discrepancy in the ratio of ANF mRNA to immunoreactivity between atria and ventricles could reflect a higher rate of peptide release in the latter. Thus, ventricular ANF production may be physiologically significant in view of the much larger ventricular mass.
Atrial natriuretic factor (ANF) is a 28-amino acid peptide hormone of cardiac origin. It has natriuretic, diuretic and vasorelaxant properties and inhibits several cardiovascular modulators. Because of the possible effects of arginine vasopressin (AVP) on ANF secretion, we have investigated ANF gene expression in Brattleboro rats which are genetically deficient in AVP. Our results indicate that cardiac ANF mRNA and ANF content are higher in Brattleboro rats compared to Long-Evans controls, whereas the plasma levels are similar in both groups. Typical secretory granules containing immunoreactive ANF are present in ventricular cardiocytes of Brattleboro but not of Long-Evans rats. These data suggest that ANF release may be uncoupled from its synthesis in the absence of AVP.
Atrial cardiocytes contain granules typical of protein-secreting cells, and atrial extracts are known to contain a powerful natriuretic and diuretic activity and to possess smooth muscle relaxant activity. A variety of active atrial peptides have been isolated, including a family of related peptides showing natriuretic, diuretic and smooth muscle relaxant activities in rat and human atria; these peptides were named atrial natriuretic factor (ANF). Another unrelated peptide from pig atria, cardiodilatin, is thought to possess only smooth muscle relaxant activity. Its partial amino acid sequence shows no homology with ANF sequences. The sequence analysis of a large form (106 amino acids) of ANF and of ANF complementary DNA clones indicates that cardiodilatin and ANF peptides are synthesized from a common precursor. This precursor also contains a signal peptide sequence expected of a secretory protein. We now describe the complete structure and sequence of the human gene for this novel hormone precursor that we call pronatriodilatin.