This study describes the recovery of various parameters of the pituitary-gonadal axis following five months of daily treatment of adult male rats with a potent LHRH (luteinizing hormone-releasing hormone) agonist. Two-month-old male rats were treated daily with either 250 ng or 1 microgram of [D-Ser(TBU)6, des-Gly-NH2(10)]LHRH ethylamide (LHRH-A) s.c. for five months. At the end of treatment, prostate weights were within normal limits and seminal vesicle weights were only slightly decreased. While normal values were found three months following cessation of treatment, it was observed, somewhat unexpectedly, that ventral prostate and seminal vesicle weights were increased by 66 and 54%, respectively, five months after cessation of treatment with the 1 microgram daily dose of LHRH-A. Immediately following the five-month treatment period with either dose of the LHRH agonist, basal testicular levels of pregnenolone, progesterone (P), 17-OH-progesterone (17-OH-P), androstenedione, testosterone, androstane-3 beta,17 beta-diol and androst-5-ene-3 beta, 17 beta-diol were decreased, while the concentrations of dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol (3 alpha-diol) and 17 beta-estradiol were increased. Three months following cessation of treatment, all basal testicular steroid levels had returned to normal except pregnenolone, P, 17-OH-P and androstenedione, which were still reduced by 40 to 60%. Five months following cessation of treatment, on the other hand, basal levels of all testicular steroids were 40 to 200% increased in the animals having received either dose of the LHRH agonist. The testicular steroidogenic responsiveness was measured 2 hours following the subcutaneous administration of 10 micrograms oLH. Following five months of daily treatment with the LHRH agonist, the main findings are a decreased response of pregnenolone, P, 17-OH-P and androst-5-ene-3 beta, 17 beta-diol, and an increased DHT, 3 alpha-diol and androstane-3 beta, 17 beta-diol responsiveness. Three months post-treatment, on the other hand, particularly at the higher dose of LHRH agonist, there was an increased responsiveness of androstenedione, T, DHT and 3 alpha-diol, a finding which was maintained after two additional months of recovery. Degenerative changes were observed in most tubules following five months of LHRH-A treatment. While most tubules returned to normal five months later, some tubules still showed degenerative changes. Plasma LH measured by radioimmunoassay (RIA) was elevated after five months of treatment with the daily 1 microgram dose, but all other values were within normal limits.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Radioautographic localization of beta-adrenergic receptors in the rat ventral prostate.

Previous studies performed with crude homogenates have demonstrated the presence of beta-adrenergic receptors in the rat ventral prostate. The precise localization of these receptors in prostatic tissue, however, has not been determined. The present study describes the localization of beta-adrenergic receptors using in vitro radioautography. beta-adrenergic receptors are present exclusively in the epithelial cells, while no receptors could be detected in the stromal cells. The silver grains mostly are associated with the apical pole of the glandular cells and are much less concentrated in the basal nuclear region of the epithelium. Very low concentrations of grains are found in the lumen of the acini. Castration caused a dramatic fall in the receptor concentration, while treatment with dihydrotestosterone reversed these effects. The specific presence of beta-adrenergic receptors in prostatic epithelial cells and their control by androgens suggest that they could play a physiologic role in androgen action in prostatic tissue. Moreover, the level and activity of beta-adrenergic receptors could be used as parameters of prostatic activity.

Animals↗

PubMedDate not supplied

Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells.

Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist [125I]cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. [125I]cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for [125I]cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing [125I]cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Normal gonadal functions and fertility after 23 months of treatment of prepubertal male and female dogs with the GnRh agonist [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide.

The GnRH agonist [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide was administered to prepubertal male and female dogs daily for 23 months by subcutaneous injection. During GnRH agonist treatment, plasma steroid levels, namely dehydroepiandrosterone, androst-5-ene-3 beta-17 beta-diol, androstenedione, testosterone, dihydrotestosterone, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane, 3 beta, 17 beta-diol were markedly inhibited in male animals, whereas in female animals, the plasma concentration of DHEA and delta 5-diol were decreased. Within 2 months following cessation of therapy, all steroids increased to normal adult levels. Morphological studies reveal that treatment of male animals with the GnRH agonist is accompanied by a small volume of seminiferous tubules, Leydig cells, and prostate gland, whereas in the ovaries of female animals, there is a large number of primordial follicles, a few primary follicles, but no secondary follicles. In the pituitary gland of animals of both sexes, LH-secreting cells have high levels of glycogen particles in their cytoplasm and tend to be either of normal appearance with dilated rough endoplasmic reticulum (RER) or strongly atrophied with a dark-stained cytoplasm, a contraction of RER, and a decrease in the number of secretory granules. Reticular cells of the connective tissue also show high levels of glycogen particles. After the 14 month recovery period, spermatogenesis has a normal adult appearance, the prostate gland shows a normal secretory epithelium, and secondary follicles are easily observed in the ovary. Gonadotrophs are free of glycogen accumulation, but reticular cells continue to show an accumulation of glycogen particles in their cytoplasm. Two male and two female animals were mated after the recovery period and produced normal offspring with normal fertility. The present results indicate that GnRH agonist treatment achieves a blockade of sexual maturation and that following cessation of treatment, normal pituitary-gonadal functions resume, with apparently normal fertility and normal offspring.

Animals↗

PubMedDate not supplied

Multiple actions of synthetic 'progestins' on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids.

This study was designed to assess the multiple steroid receptor mediated activities of a series of synthetic 'progestins' on breast cancer cell growth, using the human ZR-75-1 cell line which possesses functional estrogen (ER), androgen (AR), and glucocorticoid (GR) receptors as well as progesterone (PgR) receptors. Four 17-hydroxyprogesterone derivatives (chlormadinone acetate, CMA; cyproterone acetate, CPA; medroxyprogesterone acetate, MPA; and megestrol acetate, MGA) and two 19-nortestosterone derivatives (norethindrone, NRE, and norgestrel, NRG) were thus investigated. Based on the requirement of estrogens for PgR-mediated antiproliferative effects and the reversal of PgR-mediated action by insulin, it was found that although all 'progestins' could inhibit ZR-75-1 cell growth through the PgR at low concentrations, the relative contribution of this receptor in cell growth control is highly variable between compounds. The quantitative importance of PgR-mediated inhibition of cell proliferation was inversely related to the amplitude of the androgenic effects induced by the compounds, the AR-mediated effects increasing in the order CPA less than MGA less than CMA less than NRE less than NRG less than MPA. The specificity of these androgenic effects is further supported by their reversal upon addition of the antiandrogen hydroxyflutamide. In addition, the 17-hydroxyprogesterone derivatives, but not the 19-nortestosterone derivatives, had glucocorticoid activities at high (micromolar) concentrations, as shown by reversal of growth inhibition by the antagonist RU486 in the presence of saturating concentrations of 5 alpha-dihydro-testosterone. All 'progestins' tested, except MPA and NRE, also had some antiglucocorticoid activity, NRG being the most potent in this respect. Finally, NRE and NRG exerted a marked mitogenic effect in estrogen-free medium which was clearly mediated through the ER as shown by the competitive reversal of their action by the steroidal antiestrogen EM-139. The present results show that growth measurements of the human breast cancer cells ZR-75-1 permit, with the appropriate steroid additions, the assay of progestin, androgen, estrogen, and glucocorticoid agonistic as well as antagonistic activities of test compounds. The present study shows, somewhat surprisingly, that while the AR is almost completely responsible for the action of MPA at low concentrations, the majority of the action of NRE, NRG, and MGA is also exerted through AR, while the androgenic action of CPA plays a lower role in the growth inhibition induced by this compound.(ABSTRACT TRUNCATED AT 400 WORDS)

Binding, Competitive↗

PubMedDate not supplied

Sensitivity of luteinizing hormone and gonadal steroid responses to single intranasal administration of an LHRH agonist (Hoe-766) in young normal adult men.

Explore the source record for details and available documents.

17-alpha-Hydroxyprogesterone↗

PubMedDate not supplied

Radioautographic localization of radioactivity in rat brain after intracarotid injection of 125I-alpha-melanocyte-stimulating hormone.

125I-alpha-melanocyte-stimulating hormone (MSH) was injected into the carotid artery of the rat and the radioactivity localized by radioautography. Radioactivity in the areas surrounding the ventricles and blood vessels after administration of 125I-alpha-MSH but not 125I-luteinizing hormone indicated passage of labeled material through the blood brain barrier. A specific concentration of radioactivity was found in the striatum and reticular nucleus of the thalamus. This localization, particularly in the thalamus, could be correlated with the previously reported effects of MSH on the brain of animals and man.

Animals↗

PubMedDate not supplied

Radioautographic localization of radioactivity in rat brain after intraventricular or intracarotid injection of 3H-L-prolyl-L-leucyl glycinamide.

Tritiated L-prolyl-L-leucyl-glycinamide was injected into the carotid artery or lateral ventricle of rats and the radioactivity localized by radioautography. After intracarotid administration, the radioactivity labeled the meninges, ependymal cells bordering the ventricles, and cells of the choroid plexus, as well as the median eminence and subfornical organ and thus may have reached the cerebrospinal fluid. After intraventricular injection, globus pallidus, indusium griseum, hippocampus, corpus callosum, and meninges. The results after intracarotid injection suggest that L-prolyl-L-leucyl-glycinamide may cross the blood brain barrier and the results after intraventricular injection suggest sites of localization which might be correlated with the previously reported effects of the tripeptide on the brain.

Animals↗

PubMedDate not supplied

Somatostatin prevents the desensitizing action of growth hormone-releasing factor on growth hormone release.

We have investigated the effect of prior exposure to somatostatin (SRIF) alone or in combination with growth hormone-releasing factor (GRF) on the subsequent cyclic AMP and GH responses to GRF in rat anterior pituitary cells in primary culture. The maximal 4.5-fold stimulation of GH release induced by a 3-hr incubation with GRF is reduced by 60% following a prior 3-hr exposure to 30 nM GRF. A 3-hr preincubation with GRF in the presence of 30 nM SRIF doubles spontaneous GH release while the maximal amount of GH released during a subsequent 3-hr exposure to GRF is similar to that measured in cells pretreated with control medium, thus completely preventing the loss of GH responsiveness induced by prior exposure to GRF. The prevention by SRIF of the desensitizing action of GRF on GH release is not observed on the cyclic AMP response which remains almost completely inhibited in GRF-pretreated cells. Similar protective effects are obtained when SRIF is incubated with prostaglandin E2 (PGE2), thus completely preventing the desensitizing action of PGE2 on GH release. Prior treatment with pertussis toxin completely prevents the protective action of SRIF on GH responsiveness. Pretreatment with GRF + SRIF increases by 85 and 60% the maximal amount of GH release induced by cholera toxin and 8-bromoadenosine 3',5'-monophosphate, respectively. The post-SRIF rebound effect on GH release occurs mainly during the first 30 min following withdrawal of the tetradecapeptide. The present data demonstrate that simultaneous preincubation with SRIF and GRF prevents the marked inhibition of GH release during subsequent exposure to GRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

[Epidermal growth factor: structure, location, phosphorylation and regulation of its receptor].

Epidermal growth factor (EGF) is a Mr 6045 polypeptide first characterized for its ability to stimulate mitogenesis in epidermal and epithelial cells. The first step in the action of the growth factor is its binding to specific, high affinity membrane receptors. These receptors have been studied in a number of tissues and cell culture lines. The level of EGF receptors is modulated by many agents. EGF down-regulates its receptor. In addition, the number of EGF receptors is decreased by other growth factors (platelet-derived growth factor; transforming growth factor), by many tumor promoters and by viral transformation. Several hormones also can regulate EGF binding in its target tissues.

Animals↗

PubMedDate not supplied

Antagonistic activity of analogs of luteinizing hormone-releasing hormone (LH-RH) in vitro.

The ability of eighteen analogs of LH-RH to inhibit LH-RH-induced LH release was tested in primary cultures of rat anterior pituitary cells. [Des-His2]LH-RH, [Des-His2, D-Leu6]LH-RH and [Des-His2, D-Phe6]LH-RH inhibited 50% of LH-RH-induced LH release at molar ratios (MR50S) of 3000, 500 and 60, respectively, while [D-Phe2]LH-RH, [D-Phe2, D-Leu6]LH-RH and [D-Phe2, D-Phe6]LH-RH had similar effects at MR50S of 1000, 150 and 25, respectively. This indicates that substitution of D-phenylalanine for histidine at position 2 of LH-RH leads to compounds approximately 3-fold more potent than the corresponding [Des-His2]-analogs. [D-Phe2, D-Phe6]LH-RH, the most potent antagonist tested has however a slight agonistic activity (0.003% that of LH-RH itself). [D-Phe2, D-Phe6, Phe7]LH-RH, [D-Phe2, Phe3, D-Phe6]-LH-RH and [D-Phe2, Phe5, D-Phe6]LH-RH inhibit 50% of LH-RH action at MR50S of 400, 100 and 75, respectively. All of the analogs mentioned in the last group have LH-releasing activities below 1/100,000 that of LH-RH itself.

Animals↗

PubMedDate not supplied

DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging.

Human and some other primates are unique since their adrenals secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes responsible for the transformation of these inactive precursor steroids into androgens and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is thought to be associated with a long series of age-related decreases such as insulin resistance, obesity, osteoporosis, cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is also of potentially major interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.

Aging↗