Chronic somatostatin analog administration in patients with alpha-subunit-secreting pituitary tumors.

Glycoprotein hormone-producing (GPH) pituitary adenomas represent approximately 25% of all pituitary tumors. Elevated serum levels of intact GPHs or their free alpha- and beta-subunits have been demonstrated in patients with such tumors, and isolated hypersecretion of alpha-subunit has been reported to occur in 7% of patients. Somatostatin has been shown to decrease GPH subunit levels in cultured adenoma cells in vitro, and somatostatin receptors have been identified on the cell membranes of these tumors. We, therefore, investigated the effect of chronic somatostatin analog administration on hormone production and tumor size in six patients with GPH-producing macroadenomas and elevated serum alpha-subunit levels. Patients initially received native somatostatin as an iv 250-micrograms bolus at 0800 h, followed by a constant infusion of 2 mg over 4 h, and serum alpha-subunit concentrations were measured at 30-min intervals after baseline sampling for a total of 9 h. Patients then received a somatostatin analog, octreotide (100 micrograms, twice daily, sc) for 8 weeks. Serum alpha-subunit levels were determined weekly at 30-min intervals before and for 4 h after the 0800 h octreotide dose. Pituitary magnetic resonance imaging scans and visual field testing were assessed before and after the study. During the 4-h somatostatin infusion, four patients had a significant decrease in alpha-subunit levels (P < 0.05). During the 8-week chronic octreotide administration period, two patients had significant decreases in alpha-subunit levels of 34.6% and 26.7% (P = 0.03 and 0.01, respectively). One of these two patients had a small reduction in tumor size. Two patients whose serum alpha-subunit level did not significantly change while receiving octreotide had a reduction in tumor size or definite improvement in visual field abnormalities. Three patients received a maximum octreotide dose of 250 micrograms, three times daily. In one patient, there was a significant decrease in alpha-subunit levels by 45% (P = 0.0001) in association with a marked improvement in visual field abnormalities. In another such patient, continued administration of octreotide to a maximum dose of 250 micrograms, three times daily, was associated with a marked reduction in tumor size. Of the four patients who demonstrated significant decreases in alpha-subunit concentrations during the initial somatostatin infusion, three patients had a significant reduction in alpha-subunit levels while receiving octreotide. One patient who did not have a decrease in alpha-subunit levels during the somatostatin infusion demonstrated a small decrease in tumor size during higher dose octreotide treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Dopaminergic regulation of alpha-subunit secretion and messenger ribonucleic acid levels in alpha-secreting pituitary tumors.

Glycoprotein hormone and/or subunit secretion has been increasingly recognized in patients with pituitary nonsecretory adenomas and alpha-subunit secretion has been reported to occur in 5-10% of all pituitary tumors. We investigated the dopaminergic regulation of alpha-subunit secretion in four patients with alpha-subunit secreting pituitary adenomas documented by serum and immunocytochemical studies. In three of the four patients there was a significant decrease in serum alpha-subunit concentrations during 6 weeks of bromocriptine administration. Tumor size decreased in two patients. In pituitary tumor cells from one patient cultured in vitro, dopamine caused a highly significant decrease in media alpha-subunit concentrations. To investigate whether dopaminergic regulation of alpha-subunit secretion occurs at a pre- or posttranslational level, messenger RNA (mRNA) from cultured tumor cells from one patient was analyzed by Northern blot techniques. A decrease in alpha-subunit mRNA occurred in cells incubated with 10(-10), 10(-8), and 10(-6) M dopamine. We conclude that dopamine suppressed pituitary tumor alpha-subunit secretion and mRNA levels. Dopamine agonists may be of benefit in the therapy of patients with such tumors.

Addison's disease secondary to lymphomatous infiltration of the adrenal glands. Recovery of adrenocortical function after chemotherapy.

This case represents the first known instance of reversal of Addison's disease after antineoplastic therapy. Malignant infiltration of the adrenal glands was demonstrated by cytologic findings of needle biopsy in a 57-year-old man suffering from disseminated large cell lymphoma and Addison's disease. He was treated with combination chemotherapy and adrenal hormone replacement. Improvement shown in his computed tomography (CT) scan and clinical status led to the successful discontinuance of cortisone and 9-alpha fluorohydrocortisone. Basal adrenal function and response to ACTH stimulation recovered.

Hormone production in clinically nonfunctioning pituitary adenomas.

Pituitary tumors in which no excess hormone secretion can be identified clinically have been considered as nonfunctioning or null-cell adenomas. Immunocytochemical data presented here suggest that many of these tumors contain subunits of the glycoprotein hormones. Of 160 patients referred for pituitary surgery, 37 (23%) had no evidence of excess hormone secretion on preoperative endocrine evaluation. Immunocytochemical staining of these tumors was carried out using antibodies specific for prolactin, growth hormone, adrenocorticotropic hormone, the beta subunits of luteinizing hormone (beta-LH), follicle-stimulating hormone (beta-FSH), and thyroid-stimulating hormone (beta-TSH), and the alpha subunit. One or more of these pituitary hormones were detected in 73% of cases. The alpha and beta subunits were detected most frequently, being found in 68% of cases; 27% had staining for one or more beta subunits and 37.9% had staining for both alpha and beta subunits. The incidence was: beta-FSH in 58%, beta-LH in 47%, beta-TSH in 33%, and the alpha subunit in 42%. Staining for multiple glycoprotein hormones was common (52%), and mixed glycoprotein hormones and prolactin cell types were found in 16% of cases. These data suggest that most apparently nonfunctioning pituitary tumors contain immunoreactive hormones and the majority of these are subunits of the glycoprotein hormones. Since the glycoprotein hormone beta subunits must combine with the alpha subunit to produce biologically active hormones, the production of the subunits alone may not have endocrine manifestations.

The dexamethasone suppression test in normal control subjects: comparison of two assays and effect of age.

he authors used competitive protein binding assay and radioimmunoassay to measure cortisol levels in 38 normal control subjects three times before and three times after administration of 1 mg of dexamethasone. They found significant interassay differences at 11:00 p.m. before dexamethasone and at all three postdexamethasone times. Analysis of variance revealed significant overall positive relationships between age and cortisol levels measured by both techniques. Age correlated significantly with postdexamethasone cortisol levels measured by radioimmunoassay but not when measured by competitive protein binding assay. Clinicians should obtain data from their laboratories as to appropriate cutoffs for cortisol suppression on the specific assay used.

Dynamics of cortisol and endorphin responses to graded doses of synthetic ovine CRF in sheep.

Corticotropin-releasing factor (CRF), recently isolated from sheep hypothalami, has been shown to stimulate secretion of ACTH and beta-endorphin in vitro, and in vivo in rat and man. In previous reports, responses to ovine CRF were studied in heterologous bioassay systems where the ovine sequence was likely to act as a CRF analogue. We administered synthetic ovine CRF to sheep to assess the dynamics of endorphin and cortisol responses. Graded doses of CRF caused a rapid increase in immunoreactive beta-endorphin (iB-E) within 2 min of iv administration, followed by a cortisol response which was maximal 15 min after the iB-E peak. Doses of CRF in excess of 10 micrograms did not increase the magnitude of the peak iB-E response but did prolong the duration of the plasma beta-endorphin rise. Ovine CRF is an extremely potent and rapidly-acting hypothalamic peptide in vivo when assayed in a homologous system.

Hyperprolactinemia is associated with increased immunoreactive somatomedin C in hypopituitarism.

Serum concentrations of immunoreactive somatomedin C were determined in 78 patients with pituitary tumors or craniopharyngiomas. Patients with large tumors, GH deficiency, and normal PRL levels (group 1) had low somatomedin C concentrations (mean, 0.23 U/ml; n = 23). Group 2 included patients with large PRL-secreting pituitary tumors and GH deficiency. This group had serum somatomedin C concentrations in the normal adult range (mean, 1.01 U/ml; n = 20). Patients with hyperprolactinemia and normal pituitary GH secretion (group 3) also had somatomedin C concentrations which were normal (mean, 1.47 U/ml; n = 17). As a group, these values were slightly greater than those of the GH-deficient patients with hyperprolactinemia (P less than 0.05), but not significantly different from a fourth group of patients with tumors, normal pituitary function, and normal PRL levels (mean somatomedin C, 1.40 U/ml; n = 18). It is concluded that significantly increased concentrations of human PRL have the capacity to raise serum somatomedin C concentrations into the normal range in individuals with GH deficiency. In patients with normal pituitary function, however, this weak stimulator of somatomedin C has no detectable effect.

Estradiol treatment of acromegaly. Reduction of immunoreactive somatomedin-C and improvement in metabolic status.

Administration of estrogens to acromegalic patients has been shown to reduce the serum concentrations of bioassayable somatomedin and to cause improvement in clinical status. These effects appear not to result from an effect on the secretion of growth hormone since growth hormone concentrations are not consistently reduced. Using a sensitive radioimmunoassay for somatomedin-C, we have assessed the relationship between the estrogen-induced reduction of somatomedin-C and changes in several indices of disease activity in five acromegalic patients. Statistically significant reductions in serum somatomedin-C (p < 0.02), urinary hydroxyproline (p < 0.05) and the phosphate clearance ratio (p < 0.01) occurred within three days of the institution of treatment with 1 mg ethynyl estradiol daily. Unlike the consistent reduction in serum somatomedin-C erratic changes in growth hormone were observed. The decline in serum somatomedin-C was not due to an estrogen-induced increase in somatomedin-binding proteins since total serum somatomedin-C concentrations measured after treatment of serum with acid also were reduced by estrogen therapy, and the magnitude of this reduction was equivalent to that observed in untreated serum. The study indicates that the reduction of immunoreactive somatomedin-C correlates with estrogen-induced improvement in the metabolic activity of acromegalic patients and suggests that measurement of somatomedin-C may be useful in monitoring the effects of other drugs on this disease.

The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men.

We studied the biologic activity of a long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH (LHRHa), in five normal men and four hypogonadotropic men previously unresponsive to natural LHRH. All subjects responded to LHRAa, but there were quantitative and qualitative differences between the normal and hypogonadotropic men. Normal men showed a linear dose-response relation, endogenous gonadal steroid secretion, and an adult pattern of gonadotropin secretion characterized by a high ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH). Hypogonadotropic men had improving pituitary responses to each dose of LHRHa (priming response), no demonstrable gonadal steroid secretion, and a prepubertal pattern of gonadotropin release characterized by reversal of the normal ratio of LH to FSH. When compared with native LHRH, LHRHa had an augmented ability to discharge gonadotropins acutely and to sustain their release in normal and hypogonadotropic men.

Metabolic clearance and production rates of prolactin in man.

Metabolic clearance rates (MCR) and production rates (PR) of prolactin (PRL) have been determined by the constant infusion to equilibrium technique in 11 normal subjects, 6 patients with hyperthyroidism, 4 patients with hypothyroidism, and 9 patients with hyperprolactinemia. PRL MCR was also determined tin four patients during dopamine infusion. Mean PRL MCR was 46 +/- 1 ml/min per m2 in women and 44 +/- 3 ml/min per m2 in men, and was significantly correlated with body mass (r = 0.84, P less than 0.001). In contrast with controls, PRL MCR was higher in hyperthyroidism (MCR = 52 +/- 8 ml/min per m2, P less than 0.05), was slightly lower in hypothyroidism (MCR = 38 +/- 10 ml/min per m2, P = NS), and was significantly correlated with serum thyroxine (r = 0.46, P less than 0.02). PRL MCR was lower than controls in hyperprolactinemia (MCR = 40 +/- 5 ml/min per m2, P less than 0.01) and was inversely correlated with serum PRL (r = -0.72, P less than 0.001). PRL MCR was not significantly changed by dopamine infusion. Mean PRL PR for women and men was 211 +/- 74 and 187 +/- 44 micrograms/d per m2, respectively (P = NS). In hyperthyroidism the PRL PR was elevated (PR = 335 +/- 68 micrograms/d per m2, P less than 0.02), but in hypothyroidism the increase (PR = 233 +/- 159 micrograms/d per m2) was not significant. In hyperprolactinemia the PRL PR was extremely high (PR = 31,000 +/- 29,000 micrograms/d per m2). Dopamine infusion decreased RPL PR from 270 to 66 micrograms/d per m2 indicating that its effect was on pituitary PRL secretion and not PRL metabolism. To evaluate possible circulating PRL heterogeneity that might arise during infusion, gel filtration of infusate and serum obtained during the MCR procedure was performed. Labeled monomeric PRL (peak III, Kav (partition coefficient) = 0.4) was partially converted to two larger forms (peaks I and II) in vivo. Peak I (Kav = 0) was 30--40% immunoprecipitable, although peak II (Kav = 0.2) was not immunoprecipitable. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of peak I resulted in greater than or equal to 90% conversion to peak III and restoration of full immunoactivity. Thus, peak I is a noncovalently linked aggregate that is partially immunoactive, and therefore able to alter MCR determinations. These studies demonstrate the impact of hormone heterogeneity on MCR estimations and suggest that gel filtration of immunoprecipitable material be an integral part of future MCR measurements.

Evaluation of acromegaly by radioimmunoassay of somatomedin-C.

We measured serum concentrations of somatomedin-C by radioimmunoassay in 57 acromegalic patients and compared them with various indicators of disease activity. The mean fasting somatomedin-C concentration was 6.8 U per milliliter (range, 2.6 to 21.7) for the acromegalics and 0.67 U per milliliter (range, 0.31 to 1.4) for 48 normal, fasting adults. The somatomedin-C concentration correlated significantly with: heel-pad thickness (r = 0.73), fasting glucose (r = 0.74), and one-hour postprandial glucose (r = 0.77). In contrast, "glucose-suppressed" growth hormone correlated weakly (r = 0.34, 0.36, 0.34) with these clinical indexes of severity. Fasting growth hormone levels showed no correlation (r = 0.14). Five active acromegalics had "normal" growth hormone levels after glucose suppression, but they had elevated somatomedin-C. In 15 patients studied one year after treatment, changes in somatomedin-C concentrations paralleled the degree of clinical improvement. Measurement of somatomedin-C appears to provide a reliable means for confirming the diagnosis of acromegaly and of clinical disease activity than measurement of growth hormone concentrations.

Tissue culture studies on human pituitary tumours: long term release of anterior pituitary hormones into the culture medium.

A study was undertaken to determine the length of time that human pituitary tumours are capable of releasing anterior pituitary polypeptide hormones in vitro under basal conditions and to study the spectrum of hormone release by functioning and "non-functioning" pituitary neoplasms. Fragments from the pituitary tumours of 10 patients in the following categories: 1 Cushing's disease, 2 with amenorrhoea-galactorrhoea, 3 with acromegaly, and 4 with "non-functioning" pituitary tumours and from 2 normal human anterior pituitary glands were placed in primary culture immediately after surgery. The in vitro release of human growth hormone (hGH), prolactin (Prl), thyrotrophin (TSH), adrenocorticotrophin (ACTH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) was measured by specific radioimmunoassays at the end of each week in culture. Hormone release was surveyed from 6 weeks to 6 months depending upon the survival of the culture. Hormone release patterns were compared with clinical and pathological data. In the initial week of the study, all 6 anterior pituitary polypeptides were detected in the media from the 2 control pituitaries and from 4 of the tumours (1 amenorrhoea-galactorrhoea and 3 acromegaly) in concentrations up to 100 ng/ml of medium while 5 of the 6 hormones were readily detectable in the media from 2 additional tumour samples (Cushing's disease and 1 "non-functioning" pituitary tumour). The media of the remaining 4 tumours contained at least 3 of the 6 hormones (1 amenorrhoea-galactorrhoea and 3 "non-functioning" pituitary tumours). After 6 months in culture, the 6 hormones were readily detectable in at least 1 of the 5 surviving cultures and hGH (up to 800 ng/ml) and LH were each detectable in the media from 2 cultures. Although most of the hormone concentrations in the media decreased with length of time in culture, there were 2 exceptions. First in the media from 5 of the 12 cultures from both controls and tumours, Prl concentrations increased after 50 to 80 days culture. This increase usually lasted for several weeks before Prl levels again began to decline. The second unusual finding occurred in a tumour from a patient with acromegaly in the media of which hGH levels rose from 60 ng/ml to 800 ng/ml between days 125 and 174. These findings of prolonged hormone release in vitro give promise of future usefulness of tissue culture methods for study of polypeptide hormone releasing mechanisms and long-term production of human anterior pituitary hormones for use in research and possible therapy.

Altered androgen metabolism in metastatic prostate cancer.

Admixture of androgen-sensitive elements from normal or hyperplastic prostatic tissue interferes with biochemical studies of prostate cancer in its primary site. Heterogeneity of cancer tissues, varying in stromal and epithelial elements, also complicates interpretation of data relating to androgen metabolism. Accordingly, we have compared metastatic deposits composed of epithelial cancer cells to the primary biopsies of 4 patients in respect to uptake of 3H-testosterone and its conversion to 5-alpha-dihydrotestosterone during in vitro incubation. 3H-testosterone uptake was similar for both tissue sites but 3H-dihydrotestosterone formation was reduced by 76% in the metastases compared to primary tissues. This group was not large enough to show statistical significance, whereas a total of 11 such primary studies compared to 6 metastatic specimens was significant. When either primary or secondary tissue results were compared to 12 cases of benign prostatic hyperplasia similarly studied the differences were highly significant. These results demonstrate a major impairment in the formation of dihydrotestosterone by metastatic prostatic cancer and a similar but less evident alteration in the primary site. This abnormality in testosterone metabolism is of major importance in the attempt to obtain effective hormonal control of human prostatic cancer.

Sex cord-stromal (gonadal stromal) tumors of the testis: a report of 5 cases.

Sex cord-stromal (gonadal stromal) tumors of the testis account for less than 4 per cent of the testicular tumors. The Leydig cell tumor in a child may produce isosexual virilization (case 3). In the adult it may have no endocrine manifestation (case 1) or gynecomastia and decrease in libidio may result from production of estrogens (case 2). Sertoli cell tumors (case 4) and granulosa cell tumors (case5) are rare.

In vitro uptake of 3H testosterone and its conversion to dihydrotestosterone by prostatic carcinoma and other tissues.

Needle biopsies of normal, benign hyperplastic, neoplastic and metastatic prostatic tissues were used to study the uptake of 3H testosterone by these tissues and their ability to convert testosterone to dihydrotestosterone. Histological quantification is important because stroma is active in both of these areas of biochemical activity. The 3H testosterone uptake by the tissues is relatively similar but benign prostatic hyperplasia and normal tissue consistently convert more testosterone to dihydrotestosterone than do neoplastic tissues. The least active in this regard are pure biopsies of neoplastic cells obtained from nodal metastases, suggesting extensive loss or repression of 5-alpha-reductase activity. Further, this defect is present in neoplastic tissues even if the patient has had an orchiectomy and/or received hormonal therapy. It is not known whether testosterone may substitute for dihydrotestosterone in the neoplastic nucleus. Our studies indicate that animal models that yield data on suppresion of 5-alpha-reductase activity by certain agents may have limited relevance to the tissues of human prostatic carcinoma.