Dual control by androgens and peptide growth factors of prostatic growth in human benign prostatic hyperplasia.
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5-alpha Reductase Inhibitors↗
Biomedical subjects
M Serio
Publications and source records attributed to M Serio.
Growth factors in the human prostate.
Recent studies have focused on the potential role of local polypeptide growth-regulating factors in the etiology of benign prostatic hyperplasia (BPH) and prostatic carcinoma. In our studies we confirmed the presence of specific receptors for epidermal growth factor (EGF) in prostatic tissues from patients affected by BPH. In addition, we demonstrated that specific receptors for insulin-like growth factor type I (IGF-I) are present in BPH tissues. In order to identify a possible interaction between androgens and these growth-regulating factors, we investigated the effect of testicular suppression-induced androgen withdrawal on both EGF and IGF-I receptor concentrations in prostatic tissue from patients affected by BPH treated with a long-acting luteinizing hormone-releasing hormone analog. Both EGF and IGF-I binding capacities were significantly increased after treatment. This finding suggests that in vivo IGF-I and EGF receptor levels may be under negative androgenic regulation, indicating a potential role for these growth-regulating factors in the mechanism of response to the castration-induced regression of androgen-dependent prostatic tissue. Moreover, preliminary studies indicate that in human BPH prostatic tissue multiple IGF-binding proteins (IGF-BP) are present. This finding suggests a possible role of IGF-BP in modulating IGFs biological activities at the prostate level.
Aged↗
Steroid modulation of oxytocin/vasopressin receptors in the uterus.
Oxytocin (OT) and V1 vasopressin (VP) receptors are present simultaneously in several tissues, including the uterus. In myometrium these receptors mediate contractility, while in endometrium they mediate the release of other uterotonic substances as endothelin (ET). In rabbit myometrium, estrogens increase, while progesterone blunts neurohypophysial hormone receptors. However, the action of sex steroids on OT and V1 VP receptors differs in terms of the ED50 and maximal effect. Therefore, at parturition, only OT receptors show a dramatic rise, while V1 VP receptors do not change, suggesting a major role for OT in labor. ET is a potent stimulator of uterine activity acting through specific receptors present on myometrial cells. These receptors as well as the endometrial localization of ET are modulated by sex steroids, indicating that ET might represent a paracrine regulator of uterine activity. In humans, OT but not V1 VP receptors increase as pregnancy progresses, confirming the primary relevance of OT in timing delivery.
Animals↗
LDH and LDH-X activity in sperm from normospermic and oligozoospermic men.
Total lactate dehydrogenase (LDH) activity was measured in washed sperm from 74 oligozoospermic patients and 148 normospermic men. In the same samples, an additional iso-enzyme specific for germ cells, LDH-X was also measured. Both enzymatic activities were significantly higher in sperm from oligozoospermic patients than in those from normospermic men (P less than 0.001). In oligozoospermic patients, sperm LDH and LDH-X activities were related inversely to sperm concentration (r = -0.61 and r = -0.53, respectively). In normospermic men, this inverse relationship was less evident (r = -0.28 and r = -0.25, respectively). After separation of sperm on a discontinuous gradient of Percoll, LDH and LDH-X activities were increased in the non-migrated-sperm fractions and reduced in the migrated-sperm fractions in both groups of subjects when compared to the initial semen specimens. In addition, migrated sperm from oligozoospermic and normospermic men did not differ in their LDH and LDH-X activities. Although the possible contribution of immature germ-cells to these findings remains to be defined, the data suggest clearly that high levels of intracellular LDH and LDH-X are a biochemical feature of sperm from oligozoospermic subjects.
Centrifugation, Density Gradient↗
Insulin-like growth factor-I receptors in human hyperplastic prostate tissue: characterization, tissue localization, and their modulation by chronic treatment with a gonadotropin-releasing hormone analog.
Insulin-like growth factor I (IGF-I) receptors were characterized in membranes obtained from prostate tissue of patients affected by benign prostatic hyperplasia (BPH) before and after treatment with a GnRH agonist analog. Binding of [125I]IGF-I to membranes obtained from untreated patients was specific and time and temperature dependent. Analysis of the binding data yielded two classes of binding sites, one of high affinity (Kd, 10(-11) mol/L) and one of lower affinity (Kd, 10(-9) mol/L). BPH membrane preparations were affinity-cross linked to labeled IGF-I, and then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Analysis by autoradiography revealed one labeled protein with an apparent Mr = 300K under nonreducing conditions and two labeled protein with Mr = 270K and Mr = 130K under reducing conditions. Excess unlabeled IGF-II reduce both of them, whereas the same excess of IGF-I completely abolished them. In membrane preparations of prostatic tissues from patients affected by BPH and treated for 2 months with a GnRH agonist analog, the binding capacities of both binding sites were significantly higher than those of BPH tissue from untreated patients, whereas binding affinities were unchanged. The IGF-I receptor in BPH prostate tissue of untreated patients was mainly localized in the basal layer of the epithelium, as demonstrated by immunohistochemical staining, whereas in the tissue from treated patients positive staining was found also in the glandular epithelium. These results demonstrate that: 1) specific binding sites for IGF-I are present in prostatic tissue from patients with BPH, 2) androgen deprivation increases their binding capacities and seems to modify their epithelial localization.
Aged↗
Oxytocin and V1 vasopressin receptors in rabbit endometrium during pregnancy.
Neurohypophysial hormone receptors were identified and characterized in rabbit endometrium and decidua by radioligand binding methods. The results strongly support the presence of a heterogeneity of sites in the decidua of parturient rabbits. The oxytocin site (R1) binds oxytocin and oxytocin analogues ([Thr4, Gly7]oxytocin and OTA) with high affinity, whereas the AVP site (R2) was selective for the V1 AVP analogues, [Phe2, Orn8]VT and d(CH2)5TyrMeAVP. The concentration of oxytocin receptors was low (50-100 fmol/mg protein) at oestrus (Day 0) and on Day 29 of pregnancy, but increased significantly (about 8-fold, P less than 0.05) during parturition. Conversely, V1 AVP receptors were more concentrated than the oxytocin sites at the end of pregnancy (150 fmol/mg protein) but did not change during parturition. These results indicate that neurohypophysial hormones have specific receptors not only in the myometrium but also in the uterine mucosa and we suggest that these receptors may participate in the regulation of uterine activity during pregnancy.
Animals↗
Multiple forms of synaptic coordinative interactions in the autonomic neurotransmission. Tensiometric evaluations in peripheral tissues.
The existence of co-transmitters interacting in the complex regulation of autonomic neurotransmission, has led to investigate the interactive effects between the conventional neurotransmitters and other drugs, such as histamine, serotonin, substance P, strictly related to inflammatory mediators, in both vas deferens and urinary bladder of guinea pig. The results suggest that synergistic interactions, involving post-synaptic sites, exist between co-transmitters; furthermore, inflammatory mediators are able to modify the responses to endogenous (via intramural nerves stimulation) and exogenous conventional neurotransmitters. It is conceivable that inflammatory mediators, released by activation of mast cells either within or delivered to the tissues by the vascular supply, may alter the physiological responses of several organ systems.
Acute-Phase Proteins↗
Plasminogen activator and inhibin in the human testis. An immunohistochemical investigation.
It is generally accepted that Sertoli cells are the main source of active proteins in the human testis, these proteins can act by autocrine and/or paracrine mechanism, modulating both the gametogenic and the endocrine function of the male gonad. As to the Plasminogen Activators (T-PA, U-PA) the immunocytochemical reactivity was detectable in the Sertoli cells and in some Leydig cells. A positivity in spermatocytes and early spermatides appeared to be in relation to the stage of the cycle of the seminiferous epithelium. Inhibin was studied in foetal as well in prepubertal and adult life. The positivity for alpha human and alpha porcine subunits was intense only in the interstitial cells at 12-15 weeks of foetal life. Afterwards the staining was detectable in the Sertoli cells while it decreased in the interstitial cells. In prepubertal life, only the Sertoli cells were stained. In adult life, at the light microscopic level the Sertoli and Leydig cells were positive as well as the spermatocytes. At the electron microscopic level, coated pits and vesicles containing labelled golden particles were shown in both Sertoli cells and spermatocytes, suggesting a paracrine activity of the substance.
Adult↗
Ovarian function in premenopausal women affected by breast cancer: the measurement of glucuronoconjugate metabolites of 17 beta-estradiol and progesterone throughout one entire menstrual cycle.
For many years, hypersecretion of estrogens has been suspected of being one of the major risk factors of breast cancer for premenopausal women. Seventeen premenopausal women, who had undergone lumpectomy because of breast cancer (T1a No Mo) 3 yr before entering the study, were compared to 9 normal women of similar age, parity and body weight. A chemiluminescent method was used for the determination of estrone-3-glucuronide (E1-3G) and pregnanediol-3-glucuronide (Pd-3G) in early morning urine samples collected for an entire menstrual cycle of each of the 26 subjects. During the follicular phase, no significant differences in E1-3G and/or Pd-3G excretion were found between the two groups. During the luteal phase the E1-3G/Pd-3G ratio in the early, middle and late luteal phase had significantly increased in the women with breast cancer, in spite of normal Pd-3G excretion. Therefore, the measurement of glucuronoconjugate metabolites of ovarian hormones in overnight urine might be conveniently applied to the study of ovarian function in subjects with breast cancer. Furthermore, the results of this study may indicate that an estrogen/progesterone imbalance is an additional risk factor for the premenopausal breast cancer patient.
Adult↗
Pulsatile secretion of luteinizing hormone in agonadal men before and during testosterone replacement therapy.
UNLABELLED: We have reevaluated the question regarding the pulsatile pattern of LH secretion in agonadal men before and following testosterone replacement therapy. Five normal males were used as a reference group and four agonadal men were studied before and during replacement therapy with testosterone enanthate. All the subjects were sampled every 5 min for 12 h (08:00 to 20:00). Data were analyzed using the statistically based and validated pulse detection program DETECT. The normal subjects showed an LH pulse frequency of 10.2 +/- 1.7 peaks/12 h (mean +/- SEM) and a mean duration of 48.8 +/- 14 min, while in agonadal patients without testosterone replacement the frequency of LH peaks (27.5 +/- 2 peaks/12h) was significantly higher than for normal subjects (p less than 0.05), and the mean duration of peaks was lower than in controls (17.2 +/- 1.2 min; p less than 0.01). Following chronic testosterone enanthate replacement therapy (200 mg im every two weeks) these patients showed an increase in the duration and a significant reduction in the frequency of LH peaks (from 27.5 +/- 2 to 18.2 +/- 2.1 peaks/12 h; p less than 0.01) but pulse frequency remained significantly higher than for normal subjects (p less than 0.01). This finding is independent of the choice of p values for false positive detection rate (p = 0.01 or p = 0.005), but it does depend on sampling frequency and is influenced by large (four-fold) changes in the thresholds for peak detection. Using a "discrete deconvolution" technique we estimated the instantaneous secretory rate (ISR) for the two groups of patients. The results using ISR corroborated the findings obtained using analysis of observed plasma LH measurements. ISR computation also showed that the duration of the secretory events of the gonadotropes is significantly shorter (p less than 0.01) than the one estimated on plasma concentration, both in normal subjects and in agonadal patients before and during testosterone administration. IN CONCLUSION: LH pulse frequency observed in basal conditions in agonadal men was much higher than previously reported in primary testicular failure; during conventional testosterone replacement therapy LH pulse frequency of agonadal men was significantly reduced but still higher (p less than 0.01) than in normal men. This finding is probably related to the subnormal plasma levels of testosterone found in agonadal men during the replacement therapy; the analysis of data using a sampling interval of 10 min gave results similar to previous reports, confirming that the choice of sampling interval can markedly affect the evaluation of frequent LH pulsatile secretion.
Adult↗
Dopamine modulation of pathological human chromaffin tissue.
To evaluate the presence of dopamine-2(DA2) binding sites in pheochromocytoma tissue, we performed binding studies and light microscopy autoradiography on sections of 7 different tumors. 3-H-Spiroperidol, a DA2 ligand, bound specifically to tumor sections with a (mean +/- SD) Kd value of 1.93 +/- 0.62 nmol/L. Binding site density (Bmax) was 29.16 +/- 2.33 fmol/mg tissue. Light microscopy autoradiography showed a nonhomogenous localization of silver grains within chromaffin cells. The specific binding was about 50% of total. To investigate whether DA2 binding sites found on pheochromocytoma cells might modulate catecholamine (CA) release, we studied the effects of oral bromocriptine (2.5 mg) on circulating CA of 5 patients with pheochromocytoma. In these patients bromocriptine caused a decrease in blood pressure (P less than .05) but no significant change in plasma CA. Our study shows the presence of DA2 binding sites on tumoral chromaffin tissue. As bromocriptine, a DA2 receptor agonist, was not able to modify tumor CA secretion, the functional role, if any, played by these binding sites on tumor secretion is still to be clarified.
Adrenal Gland Neoplasms↗
Dopaminergic modulation of human adrenal medulla: indirect evidence for the involvement of DA-2 receptors located on the chromaffin cells.
1. Pharmacological blockade of DA-2 receptors causes a significantly higher epinephrine (E) response to physical exercise in normal man. 2. The present study was undertaken to evaluate whether dopaminergic modulation of E secretion is present also for a stimulus such as glucagon which acts directly on chromaffin cells. 3. Seven normal males were studied in a single blind randomized manner on two separate occasions, after pre-treatment with placebo or domperidone (DMP; 20 mg orally). Plasma E and norepinephrine, plasma prolactin, heart rate and blood pressure were measured on two separate occasions (placebo vs DMP) before and after a glucagon (1 mg i.v.) stimulation test. 4. Glucagon caused an increase in plasma E either after placebo (P = 0.043) or after domperidone (P = 0.012). DMP administration caused a significant increase in plasma E (P = 0.0008). Absolute increase in plasma E after glucagon was significantly higher after DMP than after placebo (P = 0.030). 5. As the dopaminergic modulation of human adrenal medulla is confirmed also for a stimulus acting directly on chromaffin cells, the results of the present study suggest that the DA-2 receptors responsible for the modulation are located on medullary cells.
Adrenal Medulla↗
Measurement of steroids in human plasma and tissues by isotope dilution mass spectrometry.
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Chemical Phenomena↗
Catecholamines and blood pressure regulation.
Catecholamines (CAs) play a central role in the regulation of blood pressure. Sympathetic adrenal effects are ultimately elicited by the neurotransmitter norepinephrine and the hormone epinephrine. Their release is under the control of higher centers and is finely modulated by several factors such as presynaptic receptors. Recent evidences suggest that also the peripheral dopaminergic system can participate in blood pressure regulation intervening in the blood flow regulation of some regions, and in sodium-water balance. The measurement of CAs in biological fluids has greatly enhanced our knowledge on the mechanisms regulating blood pressure and is widely applied in cardiovascular research. Clinical applications of CA measurement are still limited to the diagnosis of pheochromocytoma and to the differential diagnosis of hypotensive syndromes.
Adrenal Gland Neoplasms↗
Zoladex vs. Zoladex plus cyproterone acetate in the treatment of advanced prostatic cancer: a multicenter Italian study.
A collaborative multicenter trial was conducted by 17 Italian groups to verify whether the so-called total androgen blockade obtained with luteinizing hormone releasing hormone (LHRH) analogs combined with antiandrogens is more effective than conventional monotherapy in the treatment of advanced prostatic cancer. A total of 328 previously untreated patients were evaluated: 163 patients received Zoladex depot alone, 3.6 mg subcutaneously every 28 days, and 165 patients received Zoladex depot plus cyproterone acetate (CPA), 200 mg/day orally. The follow-up period ranged from 41-251 weeks. Treatment was well tolerated, and side-effects in both groups mainly comprised loss of libido and erections, hot flashes and breast swelling and tenderness. There was no significant difference in objective response after 6, 12 and 24 months of treatment between the 2 groups. Median time to disease progression was comparable in both groups: 55 weeks in the Zoladex group and 54 weeks in the Zoladex plus CPA group. The time to disease progression and the survival distribution was comparable in both groups. Although there were no significant differences in the overall subjective response to both treatments, a faster improvement, with respect to pain and performance status was noted in the Zoladex plus CPA group (8 weeks) compared to Zoladex alone (12 weeks). The addition of antiandrogen, by inhibiting the initial elevation of plasma testosterone, may prevent the disease flare-up which occurs in a small number of patients during the first few days of treatment with LHRH analogs alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Acid Phosphatase↗
Neurohypophyseal hormone regulation of endothelin secretion from rabbit endometrial cells in primary culture.
Immunoreactive endothelin-1 (IR-ET-1) was detected in the cultured medium from endometrial but not myometrial cells of rabbits in primary culture using a specific radioimmuno assay (RIA). Similar results were obtained with a radioreceptor assay using myometrial membranes. In a reverse-phase HPLC synthetic ET-1 and IR-ET-1 of the extract medium from endometrial cells revealed essentially the same elution profiles, as determined by RIA. Two selective agonists of oxytocin (OT) or V1 vasopressin (VP) receptors produced, respectively, a 6- and 2-fold increase of IR-ET-1 release from endometrial cells. These effects were completely reversed by the addition of two specific antagonists of OT and V1 VP receptors. Our results indicate that ET-1 is produced and released in the culture medium of rabbit endometrial cells in primary culture. The release of ET-1 is under receptor-specific control by neurohypophyseal hormones.
Animals↗
Human myometrium during pregnancy contains and responds to V1 vasopressin receptors as well as oxytocin receptors.
We have recently demonstrated the presence of two classes of neurohypophysial hormone receptors in the vagina, myometrium, and oviduct of rabbit: an oxytocin (OT) site and a V1 arginine vasopressin (AVP) site. We now report binding and in vitro contractility studies on human myometrial specimens obtained at cesarean section from women at the end of pregnancy. The program Ligand was used to analyze self- and cross-displacement curves for labeled OT, AVP or its V1 antagonist d(CH2)5TyrMeAVP, the corresponding unlabeled peptides, and selective analogs. Our results clearly indicate the presence of heterogeneity of binding sites in human uterus. Blocking experiments were performed to evaluate the density of OT and V1 AVP receptors in individual uterine specimens. The contractile response of the same samples to OT, AVP, and analogs was also evaluated. Our results indicate that V1 AVP receptors are present in all of the uterine specimens investigated, with virtually equal density from 32 weeks to term. AVP and the V1-selective agonist [Phe2,Ile3,Orn8]VP stimulate contractility of uterine strips, an effect blocked by nanomolar concentration of the V1 antagonist d(CH2)5TyrMeAVP. Uterine OT receptors increase during late pregnancy, peaking in early labor. A significant correlation between the density of OT receptors and the frequency of uterine contractions (external tocography) was found in pregnant women before surgery. OT stimulated in vitro contractility of uterine strips only when the density of receptors was more than 150 fmol/mg protein. In conclusion, we identified biologically active V1 AVP receptors in human uterus at the end of gestation and confirmed the primary relevance of OT receptors in human parturition.
Adult↗
Insulin-like growth factor-I receptors in nonfunctioning thyroid nodules.
We have recently demonstrated the production of insulin-like growth factor-I (IGF-I) as well as the presence of type I IGF receptors in human thyroid cells in primary culture. The role of IGF-I in the control of thyroid cell growth has been well established. In order to investigate the involvement of IGF-I in abnormal thyroid growth, the density of IGF-I receptors in solitary, cold, micro- and macro-follicular thyroid adenomas, and in extranodular histological normal tissue was studied. Forty-three euthyroid patients with isolated cold nodules were selected for the study. In 30 patients the presence of IGF-I receptors was evaluated by using quantitative immunohistochemistry; in 10 patients by using radioligand binding studies, and in 3 patients by using affinity labeling. Cross-linking and binding studies clearly demonstrated the presence of a homogeneous class of binding sites for type I IGF receptors. Furthermore, radioligand studies did not show any significant differences in receptor density between the 2 types of thyroidal tissues. Conversely, the computerized analysis of 900 fields of nodular and normal thyroid tissues immunostained with the monoclonal antibody alpha-IR3, strongly indicated that higher concentrations of IGF-I receptors were present in the epithelial cells of non-functioning thyroid nodules than in the adjacent extranodular thyroid tissues. These studies strongly suggest that the same type I IGF receptor is present in thyroid follicular adenomas as in histological normal thyroid tissue removed from the same patient. The higher concentration of IGF-I receptors as documented by immunostaining in the adenomas suggests that IGF-I may contribute to the abnormal growth of the neoplasms.
Adenoma↗