Biomedical subjects

M O Thorner

Publications and source records attributed to M O Thorner.

At least 181 records · Page 10Linked to original sources

PubMed1985

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↗

PubMed1985

Follicle-stimulating hormone- and alpha-subunit-secreting pituitary tumor treated with bromocriptine.

Glycoprotein-secreting pituitary tumors are uncommon. With increased awareness that pituitary tumors may secrete FSH, LH, TSH, and the alpha-subunit, either as a sole product or in any combination, these tumors are more likely to be recognized. The standard therapy is surgical resection and, possibly, postoperative radiotherapy for residual tumor mass or persistent hormonal secretion. We report a patient with a FSH- and alpha-subunit-secreting tumor who refused surgery and was treated with the dopamine agonist bromocriptine as primary therapy. Bromocriptine treatment resulted in reduction of serum FSH and alpha-subunit levels to normal, improvement of visual field defects, and improvement in hypogonadism despite lack of demonstrable change in tumor size, as assessed by computed tomographic scan. Chromatographic analysis of the serum revealed distinct peaks corresponding to those of labeled FSH and alpha-subunit. The clinical and biochemical responses in this patient suggest that some glycoprotein-secreting tumors may be responsive to dopamine agonist therapy.

Adenoma↗

PubMed1985

Effects of intravenous, subcutaneous, and intranasal administration of growth hormone (GH)-releasing hormone-40 on serum GH concentrations in normal men.

In addition to stimulating GH release in normal subjects, GH-releasing hormone-40 (GHRH-40) stimulates GH secretion in some adults and children with GH deficiency. Recognizing that GHRH-40 may have potential as a therapeutic agent for the treatment of GH deficiency, we examined the effects of iv, sc, and intranasal (in) GHRH-40 administration on GH secretion and measured the plasma levels of immunoreactive GHRH achieved after the administration of the peptide via these different routes. Normal men were given vehicle or GHRH-40 iv (0.003, 0.01, 0.03, and 0.1 micrograms/kg; n = 10), sc (1, 3.3, and 10 micrograms/kg; n = 8), or in (3, 10, 30, and 100 micrograms/kg; n = 5). No subject had any symptoms after administration of vehicle or GHRH-40. During the 2-h period after iv administration of GHRH-40, the maximal increment in serum GH levels above basal (nanograms per ml; mean +/- SD) after the 0.1 micrograms/kg dose was 15.5 +/- 10.4 compared to 2.4 +/- 4.1 after vehicle (P = 0.0017). During the 3-h period after sc administration, when compared to the maximal increment in serum GH above basal after vehicle alone (10.2 +/- 12.9), the maximal increments above basal in serum GH were increased after both the 3.3 micrograms/kg (26.2 +/- 23.1; P = 0.022) and 10 micrograms/kg (63.6 +/- 53.5; P = 0.0003) doses. During the 3-h period after in administration, when compared to the maximal increment in serum GH above basal after vehicle alone (2.8 +/- 6.4), the maximal increments above basal in GH were higher after both the 30 micrograms/kg (18.5 +/- 10.4; P = 0.0053) and 100 micrograms/kg (21.7 +/- 8.1; P = 0.0028) doses. In addition, significant dose-response relationships were documented between the maximal increments above basal in serum GH and GHRH-40 administered by all routes. The mean (+/- SEM) peak plasma level of IR-GHRH (nanograms per ml) achieved after administration of 10 micrograms/kg GHRH-40, iv, as reported previously (66.6 +/- 17.6), was approximately 60- and 500-fold higher than the mean levels in the current study after administration of the same dose sc (1.11 +/- 0.39) or in (0.14 +/- 0.02), respectively. In summary, although GHRH-40 stimulates GH release when administered iv, sc, or in, significantly higher doses were required using the sc and in routes to achieve responses comparable to those obtained with iv administration.

Administration, Intranasal↗

PubMed1984

Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction.

To investigate whether the impaired growth hormone secretion associated with obesity is a result of a hypothalamic or a pituitary disorder and whether it is a cause or a consequence of obesity, we studied plasma growth hormone responses to growth hormone-releasing factor in morbidly obese patients before gastrointestinal surgical therapy, in formerly obese subjects who had lost considerable weight postoperatively, and in non-obese controls. Growth hormone secretion was also assessed in response to insulin-induced hypoglycemia (in seven patients preoperatively and four postoperatively). In patients studied preoperatively, growth hormone responses to growth hormone-releasing factor were markedly impaired (P less than 0.001 as compared with controls), whereas in patients studied postoperatively they were partially restored to normal (P less than 0.05 as compared with those studied preoperatively). Growth hormone responses to insulin-induced hypoglycemia were similarly diminished in obese patients studied before operation (P less than 0.02). The growth hormone response to growth hormone-releasing factor was inversely correlated with the percentage of ideal body weight (P less than 0.01) and directly correlated with the growth hormone response to insulin (P less than 0.01). The impaired responsiveness to growth hormone-releasing factor suggests that the diminished response to insulin hypoglycemia is mediated by an impaired pituitary response to endogenous growth hormone-releasing factor. The reversibility of the defect after weight reduction suggests that it is a consequence rather than a cause of obesity.

Adolescent↗

PubMed1984

Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study.

Corticotropin-releasing factor, a hypophyseo-tropic hormone that stimulates adrenocorticotropic hormone (ACTH) secretion, has recently been isolated, characterized, and synthesized in the sheep and rat. We report on a patient with metastatic carcinoma of the prostate presenting with anterior and posterior pituitary hormone deficiency together with ACTH-dependent Cushing's syndrome. At postmortem examination, large areas of the median eminence and pituitary stalk were replaced by tumor, but the corticotrophs were markedly hyperplastic. Immunostaining of tumor cells was positive for corticotropin-releasing factor and was negative for ACTH and a wide range of other hormones. Radioimmunoassay and bioassays showed that tumor extracts and further purified fractions were active in corticotropin-releasing factor, and the tumor material coeluted with corticotropin-releasing factor on high-pressure liquid chromatography. These studies demonstrate that ectopic secretion of corticotropin-releasing factor is a cause of Cushing's syndrome in human beings. The features of this syndrome include hypercortisolism, pituitary corticotroph hyperplasia, elevation of circulating ACTH levels, and failure to suppress the pituitary-adrenal axis with exogenous glucocorticoids.

ACTH Syndrome, Ectopic↗

PubMed1984

One minute of bromocriptine irreversibly inhibits prolactin release for hours.

The ability of the dopamine receptor antagonist spiperone to block dopamine- or bromocriptine-inhibited prolactin release from dispersed rat anterior pituitary cells was tested in vitro. In a continuously perfused cell column apparatus, spiperone rapidly counteracted the inhibitory effect of dopamine but was unable to reverse the inhibitory effect of the potent dopamine agonist bromocriptine when added 30 min after bromocriptine. However, spiperone completely blocked the bromocriptine action if added simultaneously with bromocriptine. These basic data were confirmed, and the time relationships more accurately defined, in static incubations of monolayer cultures. Spiperone blocked the typical inhibition of prolactin release by bromocriptine only if the cells were pre- or coincubated with the antagonist. If spiperone was added as soon as 1 min after bromocriptine, the antagonist was unable to block the complete expression of the bromocriptine inhibition. These results suggest that bromocriptine is a functionally irreversible dopamine agonist for at least the 4 h of these studies.

Animals↗

PubMed1984

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↗

PubMed1984

The effect of bromocriptine on the mammary glands of hyperprolactinemic rats. A histologic, ultrastructural and morphometric study.

Old female Long-Evans rats with elevated serum prolactin levels were used to study the effect of bromocriptine on the stimulated mammary glands by histology, electron microscopy, and morphometry. Untreated rats were divided into normoprolactinemic (below 30 ng prolactin/ml serum) and hyperprolactinemic control groups (above 30 ng/ml). Treated groups were injected subcutaneously with 1 mg/kg of bromocriptine once daily for 1 day, 30 days and 44 days. One group was treated with bromocriptine for 30 days, and then the drug was withdrawn for an additional 14 days. The light and electron microscopic features of breasts of hyperprolactinemic control, 1 day treatment and withdrawal groups resembled those of postpartum lactating breasts. A unique feature was the presence of large membrane-bound bodies, possibly lysosomes. The breasts of normoprolactinemic control, 30 and 44-day treatment groups were similar by histology and ultrastructure to involuted breasts after cessation of lactation. However, many large lysosome-like bodies and microvilli were found in the alveolar cells which remained tightly apposed. Hyperprolactinemic control rats showed breast stimulation which could be correlated with serum prolactin levels. Serum prolactin concentrations fell within 1 day of bromocriptine treatment, whereas breast tissue responded only after a longer interval. Pituitary weights could be correlated with serum prolactin levels. Withdrawal of bromocriptine resulted in an elevation of serum prolactin levels and breasts returned to the stimulated stage. It can be concluded that bromocriptine reversibly suppresses the stimulation of mammary glands in hyperprolactinemic rats.

Animals↗

PubMed1984

Mesulergine, a new dopamine agonist: effects on anterior pituitary function and kinetics.

We investigated the effects of single doses of mesulergine on basal and thyrotropin-releasing hormone (TRH)-stimulated serum levels of several anterior pituitary hormones in healthy men and defined its kinetics. We also compared the effects on serum prolactin (PRL) levels of three doses (0.1, 0.35, and 0.5 mg) of mesulergine to those in response to 2.5 mg bromocriptine. Secretory rates of PRL before the first dose of TRH were not affected by any dose of mesulergine or bromocriptine. TRH-stimulated PRL secretion was not altered by 0.1 mg mesulergine but was blunted by both the 0.35- and 0.5-mg doses at 10 A.M. and 1 P.M. Bromocriptine inhibited TRH-stimulated PRL secretion at 10 A.M. and 8 P.M. When analyzed as the 8 A.M. to 8 P.M. and the 8 P.M. to 9 A.M. (day 2) intervals, PRL secretion was not changed by 0.1 or 0.35 mg mesulergine but was suppressed during both periods by the 0.5-mg dose. A dose-response relationship was evident, however, between mesulergine and PRL secretion during both the 8 A.M. to 8 P.M. (R2 = 0.27) and the 8 P.M. to 9 A.M. (day 2; R2 = 0.18) intervals. Bromocriptine lowered PRL secretion during both intervals. Secretory rates of growth hormone during these intervals were not affected by 0.1 mg or 0.35 mg mesulergine but were increased during both intervals by the 0.5-mg dose. Neither the secretory rates of thyrotropin in response to TRH nor those of cortisol, luteinizing hormone, or follicle-stimulating hormone were changed by 0.1 or 0.35 mg mesulergine.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗

PubMed1984

LH release is facilitated by agents that alter cyclic AMP-generating system.

The issue of whether the adenosine 3',5'-monophosphate (cAMP)-generating system contributes to luteinizing hormone (LH) release was addressed by using several complementary probes in vitro. Pertussis toxin is considered to modify covalently an inhibitory adenylate cyclase regulatory protein. Treatment of gonadotrophs with this toxin increased both basal LH release and the efficacy of gonadotropin-releasing hormone (GnRH)-stimulated LH release with no apparent effect on GnRH potency. Cholera toxin, which probably activates adenylate cyclase by covalently altering another regulatory protein, forskolin, which directly stimulates the catalytic subunit of adenylate cyclase, and the cAMP analogue 8-Br-cAMP amplified both basal LH release (in a dose-dependent manner) and GnRH-stimulated LH release after a lag of 1 (cholera toxin and 8-Br-cAmP) and 4 (forskolin) h. It is noteworthy that these belated effects occurred in spite of the fact that cellular cAMP accumulation was markedly increased within 30 min after cholera toxin and at 1 min after forskolin addition. There was no change in total radioimmunoassayable LH (cellular + released) in either the basal or GnRH-treated cells after cholera toxin and forskolin for up to 24 h. Finally, the forskolin-amplified LH release was reversible and calcium dependent because D-600, EDTA, and calcium-free medium inhibited this effect. These results, generated with three complementary probes that affect integral proteins of the adenylate cyclase complex, suggest a function for cAMP in modulating LH release.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1984

Performance of LH pulse-detection algorithms at rapid rates of venous sampling in humans.

To assess the influence of the sampling rate on the quantitative characterization of pulsatile luteinizing hormone (LH) release, we withdrew blood at 4-min intervals for 8 h in five men and at 1-min intervals for 2 h in six other men. For comparative purposes, significant LH pulses were enumerated by three independent, computerized pulse-detection algorithms currently available. Our results indicate that, although the absolute number of LH pulses detected was influenced by the particular algorithm used and the estimate of intra-assay variance, all three analyses yielded increased pulse-frequency estimates at more intensive rates of venous sampling. Moreover, using a fourth, modified pulse-detection algorithm intended to maximize recognition of true-positive LH pulses while minimizing both false-positive and false-negative pulses, we observed that venous sampling at 4- and 1-min intervals exposed 4- and 12-fold more LH pulses, respectively, than could be discerned at conventional sampling rates. At rapid rates of venous sampling, the pattern of LH pulses comprised high-frequency, low-amplitude LH pulsations superimposed on lower-frequency LH peaks. This pattern suggests that the pituitary gland is responsive to high rates of intermittent neural stimulation. Moreover, these observed profiles are consistent with rapid initial rates of LH disappearance and/or distribution that we could demonstrate after intravenous bolus injections of purified LH in hypogonadotropic volunteers. In conclusion, we have compared results from three different pulse-detection algorithms at various rates of venous sampling and demonstrated a critical influence of sampling rate on apparent LH pulse frequency in humans.

Adult↗

PubMed1984

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.

The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) of human pancreatic tumor growth hormone releasing factor [hpGRF(1-40)] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 micrograms/kg hpGRF(1-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed. Graded, dose-constant infusions of hpGRF(1-40) at rates of 1, 3.3, 10, and 33 ng/kg per min were administered and the MCR was calculated from measurement of steady state plasma IR-GRF levels at each infusion rate. The postinfusion disappearance rate was determined by linear regression analysis of plasma IR-GRF levels during the 120-min period after cessation of the infusion. The calculated MCR during the single injection study was 194 +/- 17.5 liters/m2 per d and was not significantly different from the calculated value during the constant infusion study (202 +/- 16 liters/m2 per d). The disappearance rate during the single injection study was subdivided into two linear phases: an initial equilibration phase (7.6 +/- 1.2 min) and a subsequent elimination phase (51.8 +/- 5.4 min). The latter was similar to the linear disappearance rate observed (41.3 +/- 3.0 min) after cessation of the constant infusion. The chromatographic and biologic characteristics of plasma IR-GRF, 30 min after injection, were similar to those of synthetic hpGRF(1-40). The results have been discussed in relation to the MCR of other hypothalamic hormones and have been used to extrapolate secretion rates of GRF in patients with ectopic GRF production.

Adult↗

PubMed1984

Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

Administration of human pancreatic tumor growth hormone (GH) releasing factor (hpGRF[1-40]) as a single injection to normal human subjects stimulates the secretion of GH in a dose-responsive manner. In the present studies, hpGRF(1-40) was infused in a graded stepwise manner over a 6-h period in order to determine whether the GH secretory response would be sustained. Normal adult males received four consecutive 90-min infusions of hpGRF(1-40) at doses of 1, 3.3, 10, and 33 ng/kg per min, preceded and followed by a 90-min saline infusion; and the plasma GH responses were compared with those during a separate control infusion. Plasma GH levels were significantly elevated by each hpGRF(1-40) infusion; and dose responsiveness was evident for the lowest three doses. Mean integrated GH secretory rates for the four doses were 1.95, 3.29, 4.29, and 3.65 times those of the respective control study. Plasma GH responses exhibited considerable variability, frequently decreasing during the latter part of each infusion; and at the highest dose, they decreased continuously beginning shortly after the onset of infusion. Episodic GH secretion occurred in individual subjects during each of the infusion periods. The possible contribution of hypothalamic somatostatin secretion to the diminished GH responsiveness was evaluated by determining plasma thyroid stimulating hormone (TSH) levels during the infusions and the TSH responses to thyrotropin-releasing hormone (500 micrograms i.v.) during a separate hpGRF(1-40) infusion of 2 ng/kg per min. Neither basal nor stimulated TSH levels differed between GRF-infused and control groups. The results indicate that GH secretion is dose responsive to hpGRF(1-40) infusions, though the response to hpGRF(1-40) infusions, though the response is complex. The absence of impaired TSH secretion provides evidence against a mediating role of somatostatin. The explanation for the loss of GH responsiveness remains undetermined but could include GRF-induced receptor down-regulation, a postreceptor effect, or, in spite of our negative results, a somatostatin-mediated inhibition.

Adult↗

PubMed1984

The self-priming effect of gonadotropin-releasing hormone on luteinizing hormone release: observations using rat anterior pituitary fragments and dispersed cells continuously perifused in parallel.

To study in vitro the self-priming effect of GnRH on LH release, rat anterior pituitaries were prepared either as fragments or dispersed cells and continuously perifused in parallel chambers. The experimental groups consisted of rats killed at 0800 h on diestrus day 1, diestrus day 2, proestrus or estrus, or at 1400 h on proestrus. To insure truly independent observations, each experimental preparation was tested on three occasions. After basal LH release had stabilized, the tissue preparations were exposed to 10 nM GnRH as two 30-min challenges separated by 1 h. LH secretory rates (nanograms per min/pituitary for fragments; nanograms per min/10(7) cells for dispersed cells) were calculated 1) for basal release (during the 20-min period immediately preceding each GnRH challenge), 2) in response to GnRH, and 3) as the sum of basal and GnRH-stimulated release. Comparison of the two preparations revealed that basal and GnRH-stimulated LH release by pituitary fragments was more variable than LH release by dispersed cells. In addition, while dispersed cells responded promptly to the addition/withdrawal of stimuli, fragments did so more gradually. With respect to GnRH self-priming, the second mean secretory rate for basal LH release by fragments (range, 28.8-46.5) was significantly (0.1 greater than P greater than 0.01) higher than the first rate (range, 14.4-22.0) on diestrus day 1, diestrus day 2, proestrus at 0800 h, and estrus. With dispersed cells, the first and second basal rates were similar to each other on diestrus day 1 and estrus, but on diestrus day 2 and on proestrus at 0800 and 1400 h, the second basal rate (range, 36.8-93) was significantly (P less than 0.001) higher than the first range (range, 17.7-31.7). When fragments received GnRH, the second mean secretory rate (range, 35.2-64.2) was significantly (0.1 greater than P greater than 0.03) higher than the first rate (range, 13.4-34.1) on diestrus day 2 and proestrus at 0800 h. With dispersed cells, the mean secretory rate in response to the second GnRH challenge was higher only on diestrus day 2 (37.0 +/- 4.1 vs. 60.3 +/- 3.8; P less than 0.05). When considered as the total of basal plus GnRH-stimulated LH release, the second secretory rate by fragments (range, 54.5 - 110.8) was significantly (0.1 greater than P greater than 0.02) higher than the first rate (range, 27.9 - 51.4) on diestrus day 1, diestrus day 2, and proestrus at 0800 h.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Human pancreatic tumor growth hormone (GH) - releasing factor and cyclic adenosine 3',5'- monophosphate evoke GH release from anterior pituitary cells: the effects of pertussis toxin, cholera toxin, forskolin, and cycloheximide.

Both synthetic human pancreatic tumor GH-releasing factor (hpGRF) and prostaglandin E2 (PGE2) rapidly stimulate cellular cAMP accumulation in and GH release from primary cultures of rat anterior pituitary cells. SRIF inhibits both of these actins. A 1-h treatment with the protein synthesis inhibitor cycloheximide potentiates hpGRF-induced cAMP accumulation for hours and GH release for the first hour. This indicates that a rapidly turning over protein tonically mutes the degree of hpGRF-stimulated cAMP accumulation. Pretreatment of the cells with pertussis toxin amplifies hpGRF- and PGE2-stimulated cAMP levels and GH release; pertussis toxin also attenuates the ability of SRIF to affect these variables. This suggests that an inhibitory coupling protein contributes to these events. Finally, cholera toxin and forskolin are also potent stimulators of cAMP accumulation and GH release. We conclude that hpGRF-evoked GH release and the inhibitory action of SRIF are closely correlated with the cAMP-generating system.

Animals↗

PubMed1984

Human pancreatic tumor growth hormone-releasing factor stimulates anterior pituitary adenylate cyclase activity, adenosine 3',5'-monophosphate accumulation, and growth hormone release in a calmodulin-dependent manner.

Pituitary GH secretion is regulated by Ca+2 and cAMP. We show that human pancreatic tumor GRF (hpGRF) stimulates anterior pituitary adenylate cyclase activity, cAMP accumulation, and GH release. The relationship between Ca+2 and the stimulating effects of the Ca+2 ionophore A23187 on cAMP accumulation and GH release in vitro was studied. To evaluate the role of the Ca+2-binding protein calmodulin in this system, we used the calmodulin antagonist W7, a naphthalene-sulfonamide derivative, and its less active analog W5. W7 inhibited hpGRF-stimulated adenylate cyclase activity, cAMP accumulation, and GH release, whereas W5 was either poorly effective or ineffective. Somatostatin (SRIF) also attenuated hpGRF stimulation of adenylate cyclase. These results suggest that the actions of Ca+2-calmodulin and cAMP are interrelated in modulating GH release. Calmodulin participates in hpGRF stimulation of adenylate cyclase, cAMP formation, and GH release. The attenuation of hpGRF-stimulated adenylate cyclase activity by SRIF may be one of the mechanisms for its GH inhibitory action.

Adenylyl Cyclases↗

PubMed1984

Follicle-stimulating hormone-secreting pituitary tumor with concomitant elevation of serum alpha-subunit levels.

Hypersecretion of FSH and alpha-subunit was documented in a man with a pituitary adenoma that was previously diagnosed on clinical grounds as nonfunctioning who had been treated by transsphenoidal surgery and postoperative irradiation. Postoperatively, the patient had high serum FSH levels and normal serum, LH levels. Ten years after the surgery, immunostaining of the tumor revealed the presence of beta FSH, beta LH, and beta TSH in the cytoplasm of scattered adenoma cells, although not always in the same cells. LH levels were elevated during the middle portion of the 12 yr that this patient was followed. However, as LH immunoreactivity was shown (in specimens recently drawn) to be largely due to cross-reactivity in the alpha-subunit RIA, the high LH values may represent high alpha-subunit levels. The elevated FSH levels and alpha-subunit concentrations did not rise after GnRH administration. Thus, during the course of 12 yr, this patient's tumor hypersecreted FSH and alpha-subunit and possibly LH. The evolution of these events may represent the natural history of the tumor or the effects of the therapeutic modalities used. We conclude that adult men with pituitary tumors and complaints of hypogonadism should be evaluated for a FSH-secreting tumor.

Adenoma↗

PubMed1984

Stimulation of growth hormone (GH) and somatomedin C in idiopathic GH-deficient subjects by intermittent pulsatile administration of synthetic human pancreatic tumor GH-releasing factor.

After initial challenges with vehicle alone and then 10 micrograms/kg human pancreatic tumor GH-releasing factor (hpGRF)-40, six adult subjects who had presented in childhood with idiopathic GH deficiency were given 0.33 micrograms/kg hpGRF-40, iv, every 3 h for 5 days. Serum GH levels were monitored daily for 90 min after the 0800 h doses of 0.33 micrograms/kg hpGRF-40, and serum somatomedin C was measured at 0800 and 2000 h. In addition, plasma levels of cholesterol, high density lipoprotein cholesterol, and triglycerides were measured daily at 0800 h. Three hours after the last 0.33 micrograms/kg dose, all subjects were rechallenged with 10 micrograms/kg hpGRF-40. In response to the initial 10 micrograms/kg challenge with hpGRF-40, and although serum GH levels rose in two of six subjects, the mean maximum GH level achieved was no different from that after treatment with vehicle alone. Within 12 h after initiation of the intermittent administration of hpGRF-40, mean +/- SEM serum somatomedin C had risen by 0.1 +/- 0.05 U/ml, and at the end of the 5-day period, had increased from 0.24 +/- 0.07 to 0.78 +/- 0.32 U/ml. In response to the second challenge with 10 micrograms/kg hpGRF-40, serum GH levels rose in three of the four subjects who initially failed to respond or had a less than 1 ng/ml GH response. The increase in serum GH was greater in one of the two subjects who had responded to the first dose. In addition, unlike the first dose, the mean maximal serum GH level achieved in response to the second 10 micrograms/kg dose of hpGRF-40 was higher than that in response to vehicle (P = 0.031). Although there was no statistically significant change during the 5-day period, in plasma cholesterol, high density lipoprotein cholesterol, or triglycerides, the latter exhibited a trend toward increased levels. Our preliminary data show that 5 days of intermittent hpGRF-40 administration augment GH secretion in some adults with GH deficiency, suggesting that somatotropes are present in idiopathic GH deficiency and may be primed by hpGRF-40. The rise in serum somatomedin C to normal levels after multiple injections of hpGRF-40 is encouraging, since circulating levels of somatomedin C may be more important than the increase in immunoreactive GH levels as an index of response for induction of linear growth. The demonstration of biological effects of hpGRF-40 in all six subjects without any serious adverse effects suggests that hpGRF-40 has promise in the treatment of GH deficiency.

Adult↗