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Biomedical subjects

F Labrie

Publications and source records attributed to F Labrie.

At least 487 records · Page 27Linked to original sources
PubMed1983

Multiple hormonal control of pars intermedia cell activity.

In rat pars intermedia cells, the rate of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion was so far known to result from a balance between the stimulatory effect of beta-adrenergic agonists and the inhibitory influence of dopaminergic substances. Recently, we have identified a second stimulatory substance, namely corticotropin-releasing factor (CRF). CRF is a potent stimulator of pars intermedia adenylate cyclase activity, cAMP accumulation and alpha-MSH release. A requirement for calcium ions was observed on basal as well as on CRF-induced alpha-MSH secretion. The beta-adrenergic and CRF effects on adenylate cyclase activity, as well as the dopamine inhibition of adenylate cyclase activity, are potentiated by guanine nucleotides (GTP). Stimulation of the beta-adrenergic receptor with isoproterenol causes a rapid loss in cAMP responsiveness, which can be completely blocked by beta-adrenergic antagonists and partially prevented by dopamine. These findings suggest that CRF should now be considered, in addition to beta-adrenergic agents, as a stimulator of the activity of pars intermedia cells and that cAMP is also involved as mediator of its action. Changes of receptor sensitivity, as well as interaction of the two stimulatory receptors with the inhibitory dopaminergic receptor, are involved in the fine control of pars intermedia cell activity. All three receptors appear to exert their action through a common pathway, namely changes of adenylate cyclase activity.

1-Methyl-3-isobutylxanthine↗
PubMed1983

New hormonal therapy in prostate cancer: combined use of a pure antiandrogen and an LHRH agonist.

Treatment with an LHRH agonist (HOE-766) alone causes an almost complete blockage of testicular testosterone formation in rat and man. In order to neutralize androgens of adrenal origin, a pure antiandrogen (RU-23908) was given in combination with the LHRH agonist in the rat. At doses where each drug has no or minimal effect alone, prostate and seminal vesicle weight were reduced to 9 and 15% of control after 5 months of combined treatment, respectively. Among the species studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis. Near castration levels of serum testosterone and 5 alpha-dihydrotestosterone are obtained within 1-2 weeks of daily subcutaneous administration of the LHRH agonist [D-Ser(tbu)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) in adult men with cancer of prostate. The decrease in serum androgen levels is accompanied by objective remission of the cancer in approximately 75% of cases. In a preliminary study where the LHRH agonist was administered in combination with the pure antiandrogen RU-23908, it was shown that the antiandrogen does not interfere with the LHRH-induced inhibition of serum androgen levels. The ease of application of this new form of hormonal therapy should permit its use at early stages of the disease and thus reduce the development of metastases and androgen-resistant cell clones.

Androgen Antagonists↗
PubMed1983

Possible role of somatostatin in the regulation of the sexually differentiated steroid metabolism and prolactin receptor in rat liver.

The regulation of the sexually differentiated metabolism of 4-[4-14C]androstene-3,17-dione and the presence of PRL receptors in rat liver were studied. Electrolytic lesions in male rats placed in a restricted area in the anterior hypothalamic periventricular area caused a feminization of hepatic steroid metabolism (i.e. increased the 5 alpha-reductase and decreased the 6 beta- and 16 alpha-hydroxylase activities) and of the levels of PRL receptors (increased binding of [125I]-labeled human PRL). After periventricular lesions, histochemical analysis revealed a decrease in somatostatin-like immunoreactive cell bodies in the periventricular area. Also the number of immunoreactive somatostatin fibers in the median eminence was dramatically reduced. Somatostatin levels in the median eminence, as measured by RIA, were reduced to approximately 2-10% of control values after periventricular lesions. Large lesions in the amygdaloid complex in male rats caused a partial feminization of hepatic steroid metabolism and PRL receptors. Passive immunization during 4 days by multiple injections of an antiserum generated against somatostatin resulted in a partial feminization of the male rat liver. When somatostatin was injected into female rats, the PRL receptors were reduced to approximately 60% of the control female receptor levels. The present study indicates that the anterior periventricular hypothalamic area is important in the control of the sexually differentiated steroid metabolism and PRL receptors in the liver and that the amygdaloid complex also may have regulatory influences on this system. A possible central neuro-endocrine mediator of these sex differences in the liver could be somatostatin or a related compound.

Androstenedione↗
PubMed1983

Stimulation of phosphatidic acid and phosphatidylinositol labeling in luteal cells by luteinizing hormone releasing hormone.

Luteinizing hormone-releasing hormone (LHRH) causes a rapid and marked increase of [32P]orthophosphate incorporation into phosphatidylinositol (PI) and phosphatidic acid (PA) in rat luteal cells in culture. The neurohormone exerts its stimulatory effect at an ED50 value of approximately 15 nM. Human chorionic gonadotropin (hCG) has no effect alone and does not interfere with the LHRH-induced PA-PI labeling. The rapidity and the specificity of the effect of LHRH suggest that the stimulation of the PA-PI cycle may well serve as a potent transducing mechanism responsible for the direct action of LHRH and its agonists at the ovarian level.

Animals↗
PubMed1983

[New approach in the treatment of prostatic cancer: combined use of a LHRH agonist and an androgen antagonist].

Following the studies of Huggins and colleagues in 1941, the hormonal treatment of prostatic cancer has been aimed at neutralizing the influence of testicular androgens through surgical castration or the administration of high doses of estrogens. These two approaches cause a temporary improvement in 60 to 70% of advanced prostatic cancer. However, castration is not always well accepted and high doses of estrogens are frequently accompanied by lethal cardiovascular side effects. Following our observation that treatment with LHRH agonists causes a blockage in the biosynthesis of testosterone by the testis accompanied by a marked reduction in prostatic weight in the rat, the possibility was opened for a new approach in the treatment of prostatic cancer. Fortunately, among all species studied, man is the most sensitive to the inhibitory effect of LHRH agonists on testicular androgen biosynthesis and near-medical castration can be easily achieved without secondary effects other than those related to low androgen levels. Following long-term studies in the rat which have shown that the inhibitory effect of LHRH agonists is markedly potentiated by simultaneous administration of a pure antiandrogen, a study using the LHRH agonist [D-Ser(TBU)6, des-Gly-NH2(10)] LHRH ethylamide (HOE-766) and the pure antiandrogen RU-23908 was performed in men with advanced prostatic cancer. The combined treatment with the LHRH agonist and the antiandrogen in 37 patients not previously treated caused a positive objective response in 97% of cases while, previously, partial hormonal treatment achieved through castration or high doses of estrogens caused a positive response in 60 to 70% of patients. The serum levels of prostatic acid phosphatase (PAP) were decreased to 40% of control as early as four days after starting combined hormonal therapy. By contrast, in patients previously treated with estrogens or castrated, complete neutralization of adrenal androgens by the antiandrogen led to a much lower rate of positive response ranging from 25 to 55%. In patients previously treated, there is thus a predominance of tumor cells insensitive to androgens. An additional important finding in this study is that the administration of the antiandrogen prevents the flare-up of the disease frequently observed when LHRH agonists are administered alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Acid Phosphatase↗
PubMed1982

Mechanism of action of TRH: involvement of the phosphatidylinositol (PI) response in the action of TRH in rat anterior pituitary cells.

In order to further investigate the molecular basis for the action of TRH, experiments were performed to examine the ability of rat anterior pituitary cells to incorporate [32P]orthophosphate into phospholipids in response to the neurohormone. Addition of 0.1 microM TRH rapidly stimulates the phosphatidylinositol (PI) response. The incorporation of radioactivity into PA and PI is increased as early as in 2 and 5 min after TRH addition, respectively, and reaches 40 and 140% above control, respectively, at 20 min. By contrast, 0.1 microM somatostatin is inactive. TRH exerts its stimulatory effect at an ED50 value of ca. 10 nM. The present results suggest that the PI response is an early event associated with the action of TRH in the anterior pituitary gland.

Animals↗
PubMed1982

Site of calcium requirement for stimulation of ACTH release in rat anterior pituitary cells in culture by synthetic ovine corticotropin-releasing factor.

Synthetic ovine corticotropin-releasing factor (CRF) causes a 6- to 8-fold stimulation of ACTH release and cAMP accumulation in rat anterior pituitary cells in culture at ED50 values of 1 and 4 nM, respectively. Removal of Ca2+ from the incubation medium reduces CRF-induced ACTH release by 70% but have no effect on cyclic AMP accumulation. ACTH release induced by 8-Br-cAMP is inhibited by 65% in the absence of Ca2+. The Ca2+ ionophore A23187 does not alter spontaneous ACTH release. Verapamil, a pharmacological agent that blocks Ca2+ entry into cells, has no influence on spontaneous or CRF-induced ACTH release. The present data clearly demonstrate a role of Ca2+ in CRF action at a step subsequent to cAMP formation and suggest that Ca2+ is mobilized from intracellular stores during CRF stimulation.

Absorption↗
PubMed1982

Corticotropin-releasing factor stimulants adenylate cyclase activity in the anterior pituitary gland.

Ovine corticotropin-releasing factor (CRF) stimulates adenylate cyclase activity in rat anterior pituitary homogenate at an ED50 value of 70 nM. GTP increases the stimulatory effect of CRF on ]32p] cyclic AMP formation in a rat adenohypophysial particulate fraction and in bovine anterior pituitary plasma membranes. The present data show that CRF stimulates adenylate cyclase activity in the anterior pituitary gland at least partly through a guanyl nucleotide-dependent mechanism.

Adenylyl Cyclases↗
PubMed1982

Specificity of the beta 2-adrenergic receptor stimulating cyclic AMP accumulation in the intermediate lobe of rat pituitary gland.

Changes of cyclic AMP levels were used to assess the specificity of the beta-adrenergic receptor in primary cultures of cells prepared from the intermediate lobe of rat pituitary gland. During a 4 min incubation, beta-adrenergic agonists led to a 4 to 6 fold stimulation of cyclic AMP concentration with the following order of potency (Kd values): zinterol (0.75 nM) greater than hydroxybenzylisoproterenol (1.0 nM) greater than (--)-isoproterenol (4.6 nM) greater than soterenol greater than (7.7 nM) greater than (--)-epinephrine (10 nM) greater than OPC 2009 (procaterol, 11 nM) much greater than (--)-norepinephrine (300 nM). The potent antagonists cyanopindolol, (--)-propranolol and hydroxybenzylpindolol reversed the stimulatory effect of (--)-isoproterenol at Kd values of 0.4-0.6 nM. Other beta-adrenergic antagonists had the following order of potency: pindolol = (--)-alprenolol = timolol (0.9-1.0 mM) much greater than metoprolol (100 nM) greater than dichloroisoproterenol (300 nM) greater than butoxamine (1100 nM). The beta 1-selective antagonist practolol had a low potency at 700 nM. The stereoselectivity of the receptor is indicated by the 400 to 70 fold higher potency of the (--)-isomers of isoproterenol, epinephrine and propranolol as compared to their (+)-stereoisomers. The data show that the beta-adrenergic receptor in the intermediate lobe of the rat pituitary gland is mainly of the bet 2-subtype. Study of this pure population of postsynaptic beta-adrenergic receptors where binding could be correlated with other parameters of cellular activity (cyclic AMP formation and alpha-MSH secretion) should yield useful information about the less accessible adrenergic systems of the brain.

Animals↗
PubMed1982

Corticotropin-releasing factor stimulates secretion of melanocyte-stimulating hormone from the rat pituitary.

Administration of synthetic ovine corticotropin-releasing factor led to rapid, parallel increases in adrenocorticotropin and alpha-melanocyte-stimulating hormone concentrations in rat plasma. Prior treatment with dexamethasone almost completely blocked the adrenocorticotropin response but not the increase in melanocyte-stimulating hormone. These data demonstrate that corticotropin-releasing factor is a potent stimulator not only of adrenocorticotropin secretion from the corticotrophs of the anterior pituitary gland but also of peptide secretion from the intermediate lobe. Such data suggest that melanocyte-stimulating hormone and beta-endorphin play a role in the physiological response to stress.

Adrenocorticotropic Hormone↗
PubMed1982

Corticotropin-releasing factor stimulates accumulation of adenosine 3', 5'-monophosphate in rat pituitary corticotrophs.

The presence of synthetic ovine corticotropin-releasing factor leads to a rapid and marked stimulation of adenosine 3', 5'-monophosphate accumulation in an enriched population of rat pituitary corticotrophs in primary culture. The increase, observed as early as 60 seconds after the addition of corticotropin-releasing factor, suggests that changes in the intracellular concentration of the cyclic nucleotide coincide with or precede the secretion of adrenocorticotropic hormone in response to corticotropin-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1982

The dopamine receptor in the intermediate lobe of the rat pituitary gland is negatively coupled to adenylate cyclase.

The potency of a series of drugs to inhibit cyclic AMP accumulation in cells of the intermediate lobe of the rat pituitary gland in culture is typically dopaminergic. Dopaminergic antagonists reverse the inhibition of cyclic AMP levels according to their known pharmacological activity. The present data show that activation of the dopamine receptor in pars intermedia cells leads to inhibition of basal cyclic AMP accumulation and thus suggest that this receptor is negatively coupled to adenylate cyclase.

Adenylyl Cyclases↗
PubMed1982

Combined long-term treatment with an LHRH agonist and a pure antiandrogen blocks androgenic influence in the rat.

Daily administration for 5 months of the potent LHRH agonist (D-Ser(TBU)6, des-Gly-NH2(10)) LHRH ethylamide (250 ng) in combination with the pure antiandrogen RU23908 (5 mg) to adult male rats causes a marked inhibition of ventral prostate and seminal vesicle weight to 9% and 15% of control, respectively. At the doses used, owing to readjustments of the pituitary-testicular axis, neither treatment alone has an effect on prostate weight and exerts only minimal inhibitory effects on seminal vesicle weight. Whereas treatment with the LHRH agonist alone markedly inhibits testicular LH and PRL receptor levels, the antiandrogen alone stimulates the concentration of the two receptors and reverses the inhibitory effect of the LHRH agonist treatment on LH receptors. Treatment with the LHRH agonist decreases plasma PRL levels, whereas the antiandrogen increases the concentration of circulating LH and FSH by 250%. Treatment with the LHRH agonist decreases the concentration of testosterone and its precursors of the delta 4-pathway while stimulating 5 alpha-reductase activity in both the absence and presence of simultaneous treatment with the antiandrogen. The present data show that blockage of the delta 4-steroidogenic pathway induced by treatment with an LHRH agonist prevents the escape phenomenon observed during long-term treatment with a pure antiandrogen, and permits maximal inhibitory effects of the two treatments on secondary sex organ weight. Such combined treatment with an LHRH agonist (to block androgen formation) and an antiandrogen (to neutralize remaining androgens of testicular and adrenal origin) should be the hormonal therapy of choice in prostatic carcinoma.

Androgen Antagonists↗