Pathophysiology of male hypogonadism associated with endogenous hyperestrogenism. Evidence for dual defects in the gonadal axis.
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17-alpha-Hydroxyprogesterone↗
Biomedical subjects
A D Rogol
Publications and source records attributed to A D Rogol.
Phorbol esters affect pituitary growth hormone (GH) and prolactin release: the interaction with GH releasing factor, somatostatin and bromocriptine.
Phorbol esters are tumor promotors that directly stimulate protein kinase C activity. We asked whether these agents affect basal or receptor initiated alterations in growth hormone (GH) and prolactin release. In 4 h incubations of anterior pituitary cells, phorbol esters enhanced basal and GH releasing factor (GRF)-induced GH release. Somatostatin reduced by 38% the 4-fold stimulation of GH release induced by phorbol ester. These tumor promoters also reversed the ability of bromocriptine, a dopamine agonist, to inhibit prolactin release, with no apparent effect on basal prolactin secretion. When these agents were applied for 24 h, an increase in the basal release of both GH and prolactin was apparent. These data lead us to suggest that an intact protein kinase C system may be necessary for the full expression of GRF-stimulated GH release and dopaminergic inhibition of prolactin release.
Animals↗
Development of antibody to growth hormone-releasing factor.
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Antibodies↗
Agents that increase cellular cyclic AMP or calcium stimulate prolactin release from the 235-1 pituitary cell line.
The 235-1 pituitary tumor clone was utilized to study prolactin secretion after perturbing cyclic AMP and calcium metabolism. Cellular cyclic AMP levels were elevated after treatment with PGE1, cholera toxin, forskolin, isobutylmethylxanthine as well as dibutryl cyclic AMP; these cyclic AMP responses were associated with increased prolactin release. Ionophore A23187 and maitotoxin, which enhance calcium uptake into cells, also amplified prolactin secretion. In contrast, the calmodulin antagonists penfluridol and W7 reduced basal prolactin release. These data support the hypothesis that cyclic AMP, calcium and calmodulin can participate in prolactin release from 235-1 cells.
Animals↗
Acceleration of growth in two children treated with human growth hormone-releasing factor.
Two growth hormone-deficient children were treated with growth hormone-releasing factor for six months. The pattern of administration--1 to 3 micrograms per kilogram of body weight, given subcutaneously over one minute every three hours by infusion pump--was chosen to simulate growth hormone secretion in normal children. During the first week of therapy, both children had evidence of the metabolic effects of increased growth hormone secretion--i.e., nitrogen retention, demonstrated by decreased nitrogen excretion (P less than 0.05), and increased urinary calcium excretion (P less than 0.01). Growth hormone secretion was increased after pulses of growth hormone-releasing factor during the entire six-month period, and growth was accelerated. One child grew at a rate of 7.1 cm per year, as compared with 4.6 cm per year before therapy; the other grew at a rate of 13.7 cm per year, as compared with 2.1 cm per year before therapy, and had increased serum levels of somatomedin C. Growth hormone--releasing factor can restore growth hormone secretion and its biologic effects, including an increase in nitrogen retention, an increase in serum somatomedin C, and acceleration of linear growth in children with growth hormone deficiency. It is premature to speculate how useful this agent will prove to be in the treatment of children with growth hormone deficiency.
Calcium↗
Human pancreatic tumor GH-releasing factor.
Within the past year, three similar peptides with specific growth hormone (GH) releasing effects have been extracted from human tissue, identified, and synthesized. Human pancreatic tumor GH releasing factor (I-40)-OH (hpGRF-40) was the sole hpGRF isolated from the pancreatic tumor of a patient in Charlottesville and was the predominant peptide isolated from the pancreatic tumor of a patient in Lyon. The Lyon tumor also contained hpGRF(1-37)-OH and hpGRF(1-44)-NH2. Both immunological and biochemical data suggest that hpGRF-40 and hpGRF-44 are present in the human hypothalamus and may be the human GH releasing hormone(s) (GHRH). In cultures of rat pituitary cells, hpGRF stimulates GH but affects neither basal and dopamine-inhibited prolactin release nor basal and gonadotropin releasing hormone (GnRH)-stimulated luteinizing hormone (LH) release. hpGRF stimulates cyclic AMP production within seconds, an effect which is blocked by somatostatin. In contrast, while hpGRF stimulates phosphatidylinositol turnover in the pituitary, the effect is not inhibited by somatostatin. In the human, hpGRF-40 (1 microgram/kg) given intravenously (i.v.) stimulates GH release within 5 minutes. hpGRF-40 does not elevate serum prolactin levels, thyrotropin (TSH), LH, or corticotropin (measured indirectly through plasma cortisol), or blood glucose or plasma concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, or somatostatin. When graded doses of hpGRF (0.1-10 micrograms/kg) are given i.v., no differences are noted in the maximal levels of serum GH achieved.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗
Minimizing false-positive errors in hormonal pulse detection.
To explore the problem of type I (false-positive) statistical errors associated with enumerating endocrine pulses, we used the analysis of immunoactive luteinizing hormone (LH) pulses as a paradigm. In this system, the distribution of measurement error was found to approximate a Gaussian pattern. Moreover, the choice of a fixed threshold criterion to identify a hormone pulse (as generally undertaken to date) was shown to yield significantly different false-positive error rates under different experimental conditions. Therefore, we developed a technique to minimize the detection of false-positive signals and to maintain an essentially uniform error rate among different experimental groups. This simple technique requires that the pulse-detection threshold be adjusted in relation to the degree of intra-assay measurement error present. Our method should facilitate the valid comparison of endocrine pulse frequencies in normal physiological states vs. those associated with hormonal deficiency when measurement error is typically greater. In addition, this approach will aid in a more meaningful assessment of pulse concordance between two or more different hormonal species (i.e., in different assays) and will assist in comparisons of pulse properties quantitated in different laboratories. In summary, rates of false-positive pulse detection using conventional fixed-threshold criteria are materially influenced by even small differences in within-assay variance. We present a technique to minimize this type I statistical error and to maintain an essentially uniform error rate among different experimental groups.
False Positive Reactions↗
Calcium channel agonist BAY k8644 enhances anterior pituitary secretion in rat and monkey.
A calcium channel agonist BAY k8644 was applied to anterior pituitary (AP) cells in vitro. BAY k8644 (0.1-10 microM) stimulated prolactin and growth hormone (GH) release from monolayer AP cultures; the calcium channel antagonist D-600 (1-10 microM) completely blocked this effect. By utilizing a perifusion system, we observed an immediate and sustained amplification of prolactin (2.9-fold), growth hormone (2.3-fold), and luteinizing hormone (LH, 1.6-fold) release during the 1-h application of BAY k8644 (3 microM). A hypophysiotrophic peptide pulse 4 h after the BAY k8644 was removed confirmed that the cells remained responsive to their natural secretagogues. In another perifusion study 10-3,000 nM BAY k8644 produced a graded increase in prolactin release that was maintained over the 30-min exposure period. Finally, individual primate mammotrophs and somatotrophs showed a marked enlargement of hemolytic plaque area, an index of hormone release, 1 h after BAY k8644 (1 microM). We conclude that this synthetic dihydropyridine enhances the rate of prolactin, GH, and LH release from AP cells of two species. Because this is the first synthetic calcium channel agonist, structure-function studies characterizing calcium channel activation and exocytosis are now feasible.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Differential effects of forskolin on LH and GH release.
The effects of forskolin, an agent which increases intracellular levels of cAMP, on basal luteinizing hormone (LH) and growth hormone (GH) release and on gonadotropin-releasing hormone (GnRH)-stimulated LH release were documented. Continuously perifused dispersed anterior pituitary cells from female rats at random stages of the estrous cycle were used. Secretory rates of both LH and GH increased in a concentration-dependent manner in response to a 1-h challenge with 0.03, 0.1, 0.3, 1, or 3 microM forskolin. In response to 0.3 microM forskolin, maximum GH release was achieved within 15-20 min, after which secretion decreased. In contrast, LH release increased gradually, became maximal at 1.5-2 h, and remained constant until the forskolin was withdrawn. Cells exposed to 10 nM GnRH for 4 h exhibited a biphasic release of LH with the interphase nadir occurring at 30 min. The second phase of LH release was enhanced by simultaneous addition of forskolin with the GnRH. Whereas second phase release did not increase further, exposure of the cells to forskolin for 60 or 120 min before GnRH resulted in increased first-phase LH release. We suggest that, whereas our data are consistent with a role for cAMP in mediating the acute release of GH, cAMP may be involved in the process through which nonimmediately releasable LH becomes available for release.
Animals↗
Growth hormone releasing hormone and growth hormone: genetic studies in familial growth hormone deficiency.
Four families with growth hormone (GH) deficiency, either isolated or with other pituitary hormonal deficits are described. Members of each underwent pharmacological testing for GH secretion and infusions of GH releasing hormone (GHRH) to determine the locus of the defect in GH secretion. In addition, we have extracted DNA from white blood cells to characterize the GHRH and GH genes. All members tested had the normal complement of GH and GHRH genes. Four generations of one family with isolated GH deficiency, autosomal dominant were studied. The younger members showed minimal GH responsiveness to a single infusion of GHRH. However, the older members did not respond even after 30 doses of GHRH given intravenously every 3 h. Two members of a family with the autosomal recessive type of isolated GH deficiency had large GH increases after GHRH infusion. Thus in these families the GH secretory defect lies within the hypothalamus. Members of two families with pituitary deficiency (GH and other tropic hormones) of the autosomal recessive type had variable responses to GHRH and varying amounts of pituitary tissue seen on high resolution CT scans. Although it is not possible to delineate the precise location of the secretory defects in these latter two families, a hypothalamic defect is probable based on the responses to multiple trophic stimuli. Heterogeneity of structure and function exists within and between families with isolated GH deficiency and within and among families with pituitary deficiency. It is from the study of such families in which all members presumably have the same underlying defect that one can more readily decide on a pathogenetic mechanism.
Adolescent↗
Pulsatile release of growth hormone and prolactin from the primate pituitary in vitro.
Perifused anterior hemipituitaries from one male and 4 female monkeys released GH and PRL in a pulsatile pattern, with mean +/- SE interpulse intervals of 8.2 +/- 0.4 and 8.5 +/- 0.3 min, as determined by a cycle detection computer algorithm. Mean hormone concentrations in the perifusate fractions collected at 2-min intervals were 435 +/- 89 (GH) and 515 +/- 262 (PRL) ng/ml. Pulse amplitudes averaged 74 +/- 16 ng/ml for GH and 189 +/- 89 ng/ml for PRL. These findings suggest the presence of a high frequency pulsatile secretory mechanism within the primate pituitary.
Animals↗
Divergent influences of the structurally dissimilar calcium entry blockers, diltiazem and verapamil, on thyrotropin- and gonadotropin-releasing hormone-stimulated anterior pituitary hormone secretion in man.
We have tested the influence of a new calcium ion channel antagonist, diltiazem, on hypothalamic releasing hormone-stimulated secretion of LH and other anterior pituitary hormones in man. To this end, six normal men received a continuous infusion of GnRH (1 microgram/min) and TRH (2 micrograms/min) for 3 h under three different experimental conditions: 1) saline (control) infusion; 2) iv diltiazem (0.3 mg/kg bolus dose, and 0.002 mg/kg . min) infusion for 4 h beginning 1 h before releasing hormone injection; and 3) oral diltiazem (60 mg, every 6 h) administration for 1 week before pituitary stimulation. Blood was sampled at 10-min intervals for the subsequent immunoassay of LH, FSH, TSH, PRL, and GH concentrations and at hourly intervals for the assay of plasma diltiazem concentrations by high performance liquid chromatography. Despite sustained plasma diltiazem concentrations of 80-120 ng/ml during either iv or oral drug administration, the GnRH/TRH-stimulated release of LH, FSH, TSH, and PRL or the basal secretion of GH did not differ significantly from that during saline infusion. In contrast, when these subjects underwent the same infusion schedule using a structurally dissimilar calcium influx blocker, verapamil (5-mg bolus dose and 15 mg/h, continuous infusion), there was significant suppression of the delayed component of GnRH/TRH-stimulated LH release, with simultaneous enhancement of PRL secretion. We conclude that exogenously stimulated anterior pituitary hormone secretion in man exhibits differential susceptibility to the structurally discrete calcium entry blockers diltiazem and verapamil. Moreover, the differential influence of these two calcium ion channel antagonists on gonadotropes is distinct from that described in cardiac and smooth muscle cells.
Administration, Oral↗
Altered neuroendocrine regulation of gonadotropin secretion in women distance runners.
We tested the hypothesis that the neuroendocrine control of gonadotropin secretion is altered in certain women distance runners with secondary amenorrhea. To this end, we quantitated the frequency and amplitude of spontaneous pulsatile LH secretion during a 24-h interval in nine such women. The ability of the pituitary gland to release LH normally was assessed by administration of graded bolus doses of GnRH during the subsequent 8 h. Compared to normally menstruating women, six of nine amenorrheic distance runners had a distinct reduction in spontaneous LH pulse frequency, with one, three, six, five, four, or two pulses per 24 h (normal, 8-15 pulses/24 h). This reduction in LH pulse frequency occurred without any significant alterations in plasma concentrations of estradiol and free testosterone or 24-h integrated serum concentrations of LH, FSH, or PRL. Moreover, in long-distance runners, the capacity of the pituitary gland to release LH was normal or accentuated in response to exogenous pulses of GnRH. In the six women athletes with diminished spontaneous LH pulsatility, acute ovarian responsiveness also was normal, since serum estradiol concentrations increased normally in response to the GnRH-induced LH pulses. Although long-distance runners had significantly lower estimated percent body fat compared to control women, specific changes in pulsatile gonadotropin release did not correlate with degree of body leanness. In summary, certain long-distance runners with secondary amenorrhea or severe oligomenorrhea have unambiguously decreased spontaneous LH pulse frequency with intact pituitary responsiveness to GnRH. This neuroendocrine disturbance may be relevant to exercise-associated amenorrhea, since pulsatile LH release is a prerequisite for cyclic ovarian function. We speculate that such alterations in pulsatile LH release in exercising women reflect an adaptive response of the hypothalamic pulse generator controlling the intermittent GnRH signal to the pituitary gland. The basis for amenorrhea in the remaining runners who have normal pulsatile properties of LH release is not known.
Adolescent↗
Endogenous opiates participate in the regulation of pulsatile luteinizing hormone release in an unopposed estrogen milieu: studies in estrogen-replaced, gonadectomized patients with testicular feminization.
Administration of opiate receptor antagonists augmented pulsatile LH release in six estrogen-treated, orchidectomized individuals with testicular feminization. In response to an opiate antagonist, LH pulse frequency increased from 3.0 +/- 0.55 (+/- SE) to 5.0 +/- 0.45 pulses/8 h (P = 0.034). Since these patients have inborn target tissue resistance to androgens, we infer that sustained androgen action is not obligatory to the emergence of endogenous inhibitory opiate tone in man. Rather, these observations document that the suppressive effects of opiates on gonadotropin secretion can be unmasked in the presence of an unopposed estrogen milieu.
Adolescent↗
Drugs to enhance athletic performance in the adolescent.
Why would any athlete expose himself to these pharmacologic agents? The most obvious answer is to improve performance. Since athletic performance is composed of so many variables, for example, attitude, diligence in training, strength, agility, and the competitive spirit, it is difficult to ascribe improvement in performance to any particular agent. It may be due to the placebo effect or to better or more efficient training, to say nothing about the effects of the normal maturational process. Certainly the peer pressure of others using these agents weighs heavily upon the adolescent's mind. Might peers have a competitive advantage? All of these points would be moot if it were not for the ready availability of many of these compounds. All are within reach of the athlete with a little knowledge of this subculture, and all are relatively inexpensive (with the exception of GH). They can be as tempting to adolescents as are brightly colored packages of household cleaners, vitamins, or flavored children's aspirin tablets to toddlers. Continuing with this analogy, one notes that most of the time children easily recover from accidental ingestions, but these instances, just as with drugs of adolescent and adult abuse, can be deadly.
Adolescent↗
Mammosomatotroph hyperplasia associated with acromegaly and hyperprolactinemia in a patient with the McCune-Albright syndrome. A histologic, immunocytologic and ultrastructural study of the surgically-removed adenohypophysis.
An 11-year-old girl, with the McCune-Albright syndrome, exhibited fibrous dysplasia of several bones, skin pigmentation, precocious puberty, growth hormone hypersecretion, acromegaly and hyper-prolactinemia. Histologic, immunocytologic and ultrastructural investigation of the surgically-removed pituitary showed massive mammosomatotroph hyperplasia. Since no adenoma was found, the abundance of these bihormonal cells, capable of producing both growth hormone and prolactin, was implicated in the causation of growth hormone and prolactin excess. Somatoliberin overproduction and/or somatostatin and dopamine deficiency could not account for the hypophysial abnormality, since changes in secretory rates of these hypothalamic hormones would lead to proliferation of mature somatotrophs and lactotrophs, rather than mammosomatotrophs. In our patient, a congenital hypothalamic malfunction might have been accompanied by hypersecretion of an unidentified releasing factor, resulting in pathologic differentiation of the pituitary and mammosomatotroph hyperplasia. Alternatively, mammosomatotroph hyperplasia may have been due to an inherent genetic or embryonic defect affecting primarily the pituitary. According to this interpretation, the pituitary lesion represented yet another developmental error in the setting of the McCune-Albright syndrome.
Acromegaly↗
Reversible growth hormone deficiency and delayed puberty triggered by a stressful experience in a young adult.
Growth retardation and delayed puberty developed in a young man after emotional trauma at age 12 years, three months. He had an eating disorder, was profoundly malnourished for several months, and then resumed eating spontaneously. Deficient secretion of growth hormone was documented during multiple arginine-insulin tolerance tests, and gonadotropin levels were low. These hormonal deficits persisted for many years in spite of good nutrition and lack of abuse, a course inconsistent with psychosocial dwarfism or effects of malnutrition per se. Later the patient spontaneously achieved normal height and secondary sexual characteristics. Apparently, psychic trauma induced a deranged hormonal state that persisted for several years.
Child↗
Anti-insulin-like (diabetogenic) peptides in pituitary extracts: role of oxytocin.
A peptide has been extracted and characterized from whole bovine pituitaries that has anti-insulin-like activities when assayed in rat adipocytes. This peptide has been purified approximately 100,000-fold, is homogeneous by thin-layer chromatography in three separate solvent systems, and shows a single peak by reverse-phase high-performance liquid chromatography. By these chemical criteria, as well as biological activity criteria (14CO2 production from D-[U-14C]glucose and D-[U-14C]glucose incorporation into glycogen in rat adipocytes], the peptide is indistinguishable from oxytocin. It reacts with anti-oxytocin antibody, and has an amino acid composition indistinguishable from purified oxytocin. The relationship between this material and other previously described anti-insulin or diabetogenic peptides is discussed, but it was not possible to conclude that this peptide, which has been purified to homogeneity and constant specific activity, is related to these previously described factors.
Adipose Tissue↗