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Biomedical subjects

A Klibanski

Publications and source records attributed to A Klibanski.

At least 91 records · Page 5Linked to original sources
PubMed1995

Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study.

One hundred and three acromegalic patients from 14 medical centers were enrolled in this study to determine the efficacy and safety of the somatostatin analog, octreotide acetate, during long term treatment. Seventy percent of the patients had undergone previous surgery or radiation treatment. Octreotide was initiated at a dose of 100 micrograms, sc, every 8 h and gradually increased to a maximum of 1500 micrograms daily depending upon the individual patient's clinical and biochemical response [GH and insulin-like growth factor I (IGF-I) reduction]. The mean duration of treatment was 24 months (range, 3-30 months). However, most patients were treated for a mean of 30 months, because this study took place after an initial 6-month study previously reported. Mean serum GH fell from 30.9 micrograms/L (range, 2.7-350) to 5.7 micrograms/L (range, 0.6-59) at the 3 months visit and remained suppressed (P < 0.001). Plasma IGF-I concentrations were also significantly reduced and remained in the normal range for at least half of the treatment visits in 56 of 87 patients (64%) treated for 12-30 months. Patients with higher initial GH concentrations were less likely to normalize IGF-I concentrations during treatment (P < 0.001). There was no evidence of drug tachyphylaxis in those patients who continued taking stable doses of medication. With some exceptions, dose increments above 800 micrograms daily in 31 patients did not provide additional benefit in terms of GH and IGF-I reduction. Headache, excessive perspiration, fatigue, and joint pain were ameliorated in 83-95% of patients. Mean finger circumference was decreased significantly at the 12 month visit (P < 0.05). The most common adverse events reported were diarrhea, abdominal discomfort, loose stools, and nausea; these symptoms usually disappeared within 3 months of treatment. Five patients discontinued octreotide because of adverse events. Of 102 patients with normal baseline ultrasound examinations of the gallbladder, 24 patients (23.5%) developed gallstones (usually during the first year of treatment), and 21 patients developed sludge alone. Gallstone formation was not related to the dose of octreotide. Most patients with cholelithiasis were asymptomatic, and none developed cholecystitis. These observations suggest that octreotide is a valuable long term medical treatment for acromegaly.

Acromegaly↗
PubMed1994

Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency.

BACKGROUND: Analogues of gonadotropin-releasing hormone (GnRH) are often given to induce hypogonadism in women who have estrogen-dependent disorders such as endometriosis and uterine leiomyomas. Because estrogen deficiency causes bone loss, concern about premature osteoporosis has prevented long-term therapy with GnRH analogues. We conducted a study to determine whether parathyroid hormone could prevent bone loss in women receiving therapy with GnRH analogues. METHODS: We administered human parathyroid hormone (40 micrograms subcutaneously daily) to 20 of 40 women with endometriosis who were being treated with nafarelin (200 micrograms intranasally twice daily) for six months; the remaining 20 women received only nafarelin. Cortical and trabecular bone density and biochemical markers of bone turnover were measured every three months during the six-month study period. RESULTS: Serum estradiol concentrations fell to postmenopausal values in 36 of the 40 women. In the women who received nafarelin alone, the mean (+/- SE) bone density in the lumbar spine decreased by 2.8 +/- 0.5 percent (P < 0.001) when measured in the anteroposterior projection and by 3.5 +/- 0.8 percent (P < 0.001) when measured in the lateral projection. In contrast, bone density in the lumbar spine did not change when measured in the anteroposterior projection and increased by 3.4 +/- 1.2 percent when measured in the lateral projection (P = 0.01) in the women who also received parathyroid hormone. Bone density at the femoral neck decreased slightly and similarly in both groups. Radial bone density did not change in either group. Serum alkaline phosphatase and osteocalcin concentrations and urinary hydroxyproline and pyridinoline excretion increased (P < 0.001) in the women who received nafarelin plus parathyroid hormone. CONCLUSIONS: Parathyroid hormone can prevent bone loss in the lumbar spine in young women with estrogen deficiency caused by treatment with GnRH analogues.

Adult↗
PubMed1994

Gonadotropin-releasing hormone receptor mRNA expression by human pituitary tumors in vitro.

An important question in the pathogenesis and regulation of human gonadotroph adenomas is whether heterogeneous gonadotropin responses to gonadotropin-releasing hormone (GnRH) are due to dysregulation of GnRH receptor biosynthesis and/or cell-signaling pathways. We investigated gonadotropin responsiveness to pulsatile GnRH in 13 gonadotroph adenomas. All tumors had evidence of follicle-stimulating hormone (FSH) beta and alpha subunit biosynthesis using reverse transcriptase/polymerase chain reaction (RTPCR) techniques. Four tumors significantly increased gonadotropin and/or free subunit secretion during pulsatile 10(-8) M GnRH administration. The GnRH antagonist Antide (10(-6) to 10(-8) M) blocked secretory increases in all GnRH-responsive tumors. Gonadotropin and/or free subunit secretion increased after 60 mM KCl, confirming that GnRH nonresponsiveness was not due to intracellular gonadotropin depletion. We hypothesized that GnRH nonresponsiveness in these tumors may be due to GnRH receptor (GnRH-Rc) biosynthetic defects. RTPCR analyses detected GnRH-Rc transcripts only in responsive tumors and normal human pituitary. This is the first demonstration of a cell-surface receptor biosynthetic defect in human pituitary tumors. We conclude (a) one third of gonadotroph tumors respond to pulsatile GnRH in vitro, (b) GnRH-Rc mRNA is detected in human gonadotroph adenomas and predicts GnRH responsiveness, and (c) GnRH-Rc biosynthetic defects may underlie GnRH nonresponsiveness in gonadotroph tumors.

Aged↗
PubMed1994

ras mutations in human prolactinomas and pituitary carcinomas.

Pituitary adenomas have been shown to be clonal in origin, indicating that one or more somatic mutations underlie tumor pathogenesis. Mutated oncogenic forms of ras protein have been identified in a number of human neoplasms, including thyroid adenomas and carcinomas. However, the potential role of activated ras in the development of specific human pituitary tumor phenotypes has not been determined. Although ras mutations were not found in glycoprotein hormone-secreting or somatotroph adenomas, we recently identified a mutation in the H-ras gene (Gly-Val) at codon 12 in a highly invasive prolactinoma. These data raise the possibility that ras mutations might play a role in the pathogenesis of PRL-secreting pituitary tumors and/or may be a marker for tumor invasiveness and malignant transformation. Therefore, we investigated 78 pituitary tumors (59 prolactinomas, 13 invasive prolactinomas, and 6 pituitary carcinomas) for activating point mutation in the three ras genes using oligonucleotide-specific hybridization. In contrast to the relatively high frequency of ras mutations in many different tumor types, no ras mutations were identified in either prolactinomas or pituitary carcinomas. Our data indicate that ras mutations are rare in prolactinomas and pituitary carcinomas.

Adolescent↗
PubMed1993

The retinoblastoma gene in human pituitary tumors.

Functional inactivation of the retinoblastoma (RB) tumor suppressor gene is important in the pathogenesis of many human tumors. Recently, the frequent occurrence of pituitary tumors was reported in mice genetically engineered to have one defective RB allele, a genetic background analogous to that of patients with familial retinoblastoma. The molecular pathogenesis of human pituitary tumors is largely unknown, and the potential role of RB gene inactivation in these neoplasms has not been examined. Consequently, we studied 20 human pituitary tumors (12 clinically nonfunctioning tumors, 4 somatotroph adenomas, 2 prolactinomas, and 2 corticotroph adenomas) for tumor-specific allelic loss of the RB gene using a highly informative polymorphic locus within the gene. Control leukocyte DNA samples from 18 of these 20 patients were heterozygous at this locus, permitting genetic evaluation of their paired tumor specimens. In contrast to the pituitary tumors in the mouse model, none of these 18 human tumors exhibited RB allelic loss. These findings indicate that RB gene inactivation probably does not play an important role in the pathogenesis of common types of human pituitary tumors.

Adenoma↗
PubMed1993

Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence.

The recurrence rate of pituitary adenomas has been reported to be as high as 10% to 35% despite their generally benign nature. A monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) was used to investigate whether the proliferative index might help to predict adenoma recurrence. This antigen is a nuclear protein identified as the auxiliary protein of deoxyribonucleic acid polymerase delta, and its gene expression correlates with cell proliferation. The authors studied 30 patients with recurrent pituitary adenomas, 32 with nonrecurrent adenomas, and seven normal pituitary tissue samples. The mean interval to recurrence ( +/- standard error of the mean) was 5.3 +/- 0.7 years. The age- and sex-matched nonrecurrent group had a mean follow-up period of 6.6 +/- 0.3 years without clinical recurrence. Mean percentages of PCNA-positive tumor nuclei in both the initial and the second surgical specimens of the recurrent adenomas (13.45% +/- 3.02% and 19.56% +/- 3.66%, respectively) were significantly higher than that of the nonrecurrent group (2.49% +/- 1.21%). In addition, recurrent tumors had a higher PCNA index than the initial tumors in the same patients. Normal anterior pituitary gland tissue had a significantly lower mean PCNA index (0.12% +/- 0.11%) than either patient group. Stepwise multivariate regression analysis indicated that factors which collectively correlated significantly with recurrence were: high PCNA index, large tumor size, extrasellar extension, and incomplete surgical excision. The PCNA nuclear count was not associated with age, sex, or hormone hypersecretion, but was higher in macro- than in microadenomas, in tumors with extrasellar extension, and in those incompletely excised. A higher PCNA index also correlated with a shorter disease-free interval. The authors conclude that evaluation of the PCNA index assists in predicting the likelihood of pituitary adenoma recurrence.

Adenoma↗
PubMed1992

Octreotide treatment of acromegaly. A randomized, multicenter study.

OBJECTIVE: To determine the effects of the somatostatin analog, octreotide acetate, in patients with acromegaly. DESIGN: Double-blind, randomized trial. SETTING: Fourteen university-affiliated medical centers. PATIENTS: One hundred fifteen acromegalic patients, 70% of whom had persistent disease after pituitary surgery or radiotherapy. INTERVENTION: Subcutaneous octreotide, 100 micrograms, or placebo every 8 hours for 4 weeks. Four weeks after the end of treatment, patients were randomized to receive 100 or 250 micrograms octreotide subcutaneously every 8 hours for 6 months. RESULTS: After 2 weeks of treatment, a single 100-micrograms injection reduced mean serum growth hormone (GH) to 30% of the pretreatment concentration within 2 hours. The integrated mean GH level was reduced over 8 hours from 39 +/- 11 micrograms/L to 9 +/- 2 micrograms/L (P less than 0.001). Mean plasma insulin-like growth factor-1 (IGF-1) was reduced from 5100 +/- 400 U/L to 2400 +/- 400 U/L (P less than 0.001). After 6 months, the mean GH was reduced from 39 +/- 13 to 15 +/- 4 micrograms/L by 300 micrograms of octreotide and from 29 +/- 5 micrograms/L to 9 +/- 2 micrograms/L by 750 micrograms of octreotide daily. The mean IGF-1 concentration was suppressed to 2100 +/- 300 and 2500 +/- 400 U/L after 300 and 750 micrograms octreotide, respectively. Integrated mean GH levels were reduced to < 5 micrograms/L in 53% (95% CI, 39% to 67%) and 49% (CI, 35% to 63%), and IGF-1 levels were normal in 68% (CI, 54% to 82%) and 55% (CI, 40% to 70%) of patients receiving low- and high-dose octreotide, respectively. A substantial decrease in headache, amount of perspiration, joint pain, and finger circumference occurred in two thirds of the patients. The pituitary size was reduced in 19% (CI, 5% to 33%) and 37% (CI, 22% to 52%) of patients receiving 6 months of low- and high-dose octreotide, respectively. Ten percent and 13% of patients in each treatment group developed transient diarrhea; 10% and 14%, biliary sludge; and 6% and 18%, cholelithiasis, respectively. CONCLUSION: Octreotide effectively decreased GH and IGF-1 concentrations in 53% and 68% of patients, respectively. The higher dose resulted in increased frequency of tumor shrinkage but added no biochemical or clinical benefit.

Acromegaly↗
PubMed1992

Osteopenia in men with a history of delayed puberty.

BACKGROUND AND METHODS: The effect of delayed puberty on peak bone mineral density in men is unknown. To determine whether such a delay reduces normal peak bone density and leads to osteopenia during adulthood, we measured radial bone mineral density by single-photon absorptiometry and spinal bone mineral density by dual-energy x-ray absorptiometry in 23 men who had a history of constitutionally delayed puberty and 21 men who underwent normal puberty. Their mean ages were 26 and 24 years, respectively. The groups were matched for other factors known to affect bone mass. RESULTS: The mean (+/- SD) radial bone mineral density was significantly lower in the men with a history of delayed puberty than in the normal men (0.73 +/- 0.07 vs. 0.80 +/- 0.05 g per square centimeter; P less than 0.0002). Spinal bone mineral density was also significantly lower in the men with delayed puberty than in the normal men (1.03 +/- 0.10 vs. 1.13 +/- 0.11 g per square centimeter; P less than 0.003). Radial bone density was at least 1 SD below the mean value for the normal men in 15 of the 23 men with a history of delayed puberty, and spinal bone density was similarly decreased in 10 of the 23. CONCLUSIONS: Adult men with a history of constitutionally delayed puberty have decreased radial and spinal bone mineral density. These findings suggest that the timing of puberty is an important determinant of peak bone density in men. Because the peak bone mineral density achieved during young adulthood is a major determinant of bone density in later life, men in whom puberty was delayed may be at increased risk for osteoporotic fractures when they are older.

Absorptiometry, Photon↗
PubMed1992

Ricin and lentil lectin-affinity chromatography reveals oligosaccharide heterogeneity of thyrotropin secreted by 12 human pituitary tumors.

Some patients with thyrotropin (TSH)-producing pituitary tumors are more hyperthyroid than others despite similar TSH levels in serum, suggesting that qualitatively different TSH molecules with differing bioactivities may be secreted by different tumors. We used ricin and lentil lectin-affinity chromatography to test whether the TSH oligosaccharides varied among 12 patients with TSH-producing tumors. We found that each tumor secreted heterogeneous isoforms of TSH that differed in their extents of exposed galactose (Gal) residues, and their degrees of sialylation and core fucosylation. These biochemical parameters also varied markedly for TSH secreted by different tumors. Isoforms appeared to reflect poor sialyltransferase activity in two tumors and efficient sialyltransferase in the remainder. TSH secreted by tumors was more fucosylated than TSH secreted by control euthyroid persons. There was an inverse relationship between the sialylation and fucosylation of tumor TSH. No simple relationship between TSH oligosaccharide structures and bioactivity was evident, although mixtures of isoforms having the least and most sialylated TSH seemed to be the most bioactive clinically. In three patients from whom serum and medium TSH were both available, TSH in serum was more sialylated than TSH secreted by the tumor in vitro, perhaps reflecting slow clearance of sialylated isoforms from the circulation. Core fucosylation of serum TSH was less than that of medium TSH. These data prove that human tumors secrete TSH with heterogeneous oligosaccharide structures.

Adult↗
PubMed1992

Effects of chronic GnRH analogue administration on gonadotrophin and alpha-subunit secretion in post-menopausal women.

OBJECTIVE: To investigate in detail the regulation of LH, FSH, and alpha-subunit secretion by a GnRH agonist analogue under physiological conditions of gonadotrophin elevation. SUBJECTS: Six normal healthy post-menopausal women. DESIGN: Subjects were given D-Trp6-Pro9-Net-GnRH (GnRHa), 32 micrograms/kg, subcutaneously, daily for 24 days. On days 1, 2, 3, 4, 7, 11, 14, 17, 21, and 24, blood samples before and after GnRHa injection were taken. Sampling was continued off GnRHa twice a week for 4 weeks and then on days 66, 76, and 98. GnRH tests (100 micrograms i.v.) were performed on days 0, 24, and 98. MEASUREMENTS: All serum samples were analysed for LH, FSH, and alpha-subunit levels. RESULTS: LH and FSH levels reached a maximum on day 2 after which there was a steady decline to day 24. LH did not begin to rise again until day 44 (20 days off GnRHa), then rose steadily. FSH began to rise earlier, on day 34 (10 days off GnRHa). alpha-Subunit levels also showed maximum elevation on day 2 but remained equally elevated throughout the period of GnRHa administration and then fell rapidly to baseline by day 34. LH, FSH, and alpha-subunit responses to i.v. GnRH were absent on day 24 and were equivalent to baseline on day 98. CONCLUSIONS: We conclude that there is a striking dissociation in the regulation of gonadotrophin and alpha-subunit secretion in response to GnRHa in normal post-menopausal women. Gonadotrophin secretion is profoundly suppressed during GnRHa administration and recovers only after a long delay post-treatment, while alpha-subunit is markedly stimulated and recovers rapidly. The difference between this pattern and that seen in patients with pituitary tumours could be useful for diagnosis.

Aged↗
PubMed1992

Ras mutations in human pituitary tumors.

The cellular basis for pituitary neoplasia is poorly understood. Mutations that activate the ras protooncogenes have been identified in a number of different types of human cancers and potentially represent one of the genetic alterations that occur in pituitary tumors. In this study we examined 19 pituitary tumors for the occurrence of ras mutations. The tumor types included 11 nonfunctioning adenomas, 6 somatotroph adenomas, and 2 prolactinomas. Each of the three ras genes (K-ras, N-ras, and H-ras) was amplified from pituitary tumor DNA using the polymerase chain reaction. Oligonucleotide-specific hybridization was used to screen for mutations that inhibit GTPase activity and cause activation of the ras oncogene. No ras mutations were observed in 18 of the pituitary adenomas. However, a mutation was identified in codon 12 of the H-ras gene (Gly to Val) in a recurrent prolactinoma that was highly invasive and ultimately proved to be fatal. We conclude that ras mutations are uncommon in pituitary adenomas, but may provide a marker for highly invasive tumors.

Adenoma↗
PubMed1992

Imbalanced follicle-stimulating hormone beta-subunit hormone biosynthesis in human pituitary adenomas.

Clinically nonfunctioning pituitary adenomas represent approximately 25% of all pituitary tumors. Recent studies using a number of in vitro techniques show that the majority of such tumors produce gonadotropins. Hypersecretion of uncombined gonadotropin subunits by these tumors has also been identified raising the possibility that gonadotropin biosynthetic alterations may occur in neoplastic pituitary tissue. To determine whether underlying intracellular biosynthetic alterations lead to imbalanced secretion of the gonadotropin subunits by such tumors, we investigated 1) steady state gonadotropin-subunit messenger ribonucleic acid (mRNA) levels in tumor tissue from 49 patients with clinically nonfunctioning adenomas, 2) secretion of gonadotropins in dispersed pituitary tumor cultures, and 3) serum concentrations of gonadotropins and free subunits. Northern blots of RNA extracted from surgically obtained pituitary tumor tissue were hybridized with complementary DNA probes for FSH beta, LH beta, and alpha-subunit, and quantitative analysis was done to compare alpha- and beta-subunit biosynthesis in individual tumors. Of these tumors, 47 contained sufficient RNA for Northern analysis and 77% of these tumors contained one or more of the gonadotropin-subunit mRNAs. Steady state alpha-subunit mRNA was detected in 57% of tumors, FSH beta mRNA in 49%, and LH beta in 1 (2%). We found FSH beta mRNA in excess of alpha-subunit mRNA in one-third of tumors, including 9 tumors where alpha-subunit mRNA was undetectable. In cultured cells, FSH beta was secreted in excess of alpha-subunit in 41% of tumors. For those tumors in which both mRNA and culture data were available, FSH beta mRNA and secreted subunit levels were in excess of alpha-subunit in 64% of tumors. We conclude that clinically nonfunctioning pituitary adenomas frequently synthesize excess FSH beta subunit relative to alpha-subunit. This finding is in contrast to previous data in normal pituitary or placental tissue where alpha-subunit is present in excess of beta-subunits at both the mRNA and protein levels. The free-beta-subunit hypersecretion identified in pituitary adenomas may be due to biosynthetic abnormalities intrinsic to neoplastic gonadotrophs.

Adenoma↗
PubMed1992

Progressive trabecular osteopenia in women with hyperprolactinemic amenorrhea.

Reductions in cortical and trabecular bone mass have been documented in young women with hyperprolactinemic amenorrhea. It is unknown whether trabecular osteopenia is progressive or reversible with treatment of hyperprolactinemia. In addition, it is not known whether clinical or hormonal variables can predict trabecular bone density (BD) changes. Therefore, we investigated prospectively trabecular BD by computed tomography in 52 hyperprolactinemic women and 41 controls. The mean follow-up interval was 1.8 +/- 0.1 (SEM) yr. Patient groups were defined as follows: group 1, amenorrhea during the entire study; group 2, restoration of menses during the study by treatment of hyperprolactinemia; group 3, regular menses despite hyperprolactinemia, with no history of prior amenorrhea; group 4, history of prior amenorrhea, but menses restored with treatment of hyperprolactinemia before study entry; and group 5, oligomenorrhea. Groups 1, 2, and 4 had significant (P = 0.0006) initial spinal osteopenia [mean BD 141 +/- 7 (SEM), 144 +/- 9, and 151 +/- 5 mg/cc K2HPO4, respectively] compared with controls or with group 3 (170 +/- 4 and 173 +/- 8 mg/cc K2HPO4, respectively). Group 5 had an initial mean BD which was midway between that of the amenorrheic and eumenorrheic women (156 +/- 13 mg/cc K2HPO4). Group 1 had a significant (P = 0.04) decrease in mean BD to 132 +/- 8 mg/cc K2HPO4 over 1.7 +/- 0.2 yr, with BD in 42% of the group more than 2 SD below the control mean at the final study point. The mean BD in group 2 increased to 155 +/- 9 mg/cc K2HPO4, approaching significance (P = 0.07) when compared with the initial BD. Five of the nine patients in this group (56%) had an increase in BD greater than the variation expected for the computed tomography technique. However, 44% of the group 2 patients had a spinal BD which remained more than 1 SD below the normal mean. There was no change in BD in the other groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Glycoprotein hormone alpha-subunit production in somatotroph adenomas with and without Gs alpha mutations.

Activating mutations of the Gs alpha subunit have been identified in a subset of somatotroph adenomas. The mutant form of the Gs alpha subunit causes persistent activation of adenylyl cyclase and consequently results in high intracellular levels of cAMP. Because cAMP is known to stimulate the synthesis of the glycoprotein hormone (GPH) alpha-subunit as well as GH, we examined somatotroph tumors with and without Gs alpha mutations for GPH alpha-subunit production. GPH alpha-subunit production was assessed in vivo by measuring serum hormone levels and in vitro by analyzing hormone secretion by cultured pituitary tumor cells. DNA was extracted from the pituitary tumors of 26 acromegalic patients. The Gs alpha gene was amplified by the polymerase chain reaction and screened for mutations at codons 201 and 227 using oligonucleotide specific hybridization. Nine of the 26 tumors (35%) had point mutations at Arg 201. Seven of these tumors contained a CGT to TGT mutation (Arg to Cys) and 2 contained a CGT to CAT mutation (Arg to His). No mutations were detected at codon 227. There were no significant differences in age, sex distribution, tumor size, or serum levels of GH or insulin-like growth factor-1 between the groups of patients with or was Gs alpha mutations. The mean serum level of the free GPH alpha-subunit was 1.9-fold higher in the group with Gs alpha mutations (0.48 +/- 0.37 micrograms/L) than in patients without mutations (0.25 +/- 0.17) (P less than 0.05). In pituitary tumor cell culture, 75% of somatotroph tumors with Gs alpha mutations secreted free GPH alpha-subunit into the media compared with 45% of tumors without Gs alpha mutations. The amount of GPH alpha-subunit secretion was 12-fold greater in the group of tumors containing the Gs alpha mutation (P less than 0.05). Immunocytochemical detection of the free GPH alpha-subunit was similar in the two groups of patients with 75% positive for the GPH alpha-subunit in tumors with Gs alpha mutations and 67% positive in tumors without mutations (P = 0.69). We conclude that GPH alpha-subunit production occurs in somatotroph tumors with and without Gs alpha mutations. The increased levels of GPH alpha-subunit secretion in vivo and in vitro suggest that the Gs alpha mutation may increase the amount of preexisting GPH alpha-subunit biosynthesis in the tumors, perhaps via activation of the cAMP pathway.

Adenoma↗
PubMed1992

Clonal origins of adrenocorticotropin-secreting pituitary tissue in Cushing's disease.

It is unclear whether Cushing's disease results from a primary pituitary disorder or arises in response to abnormal hypothalamic control of the pituitary gland. Clonal analysis can provide information as to whether neoplastic tissue is derived from a monoclonal proliferation of a genetically altered cell or from a polyclonal expansion of a group of cells affected by a common stimulus. We used X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase, hypoxanthine phosphoribosyltransferase, and DXS255 loci in 11 women with biochemically and pathologically confirmed Cushing's disease to determine the clonal origins of corticotroph adenomas and corticotroph hyperplasia. Tumor tissue from all 10 women with morphologically and immunohistochemically confirmed ACTH-secreting pituitary microadenomas demonstrated a monoclonal pattern. Pathologically confirmed corticotroph hyperplasia in a patient with a CRH-secreting bronchial carcinoid was found to be polyclonal. We conclude that corticotroph microadenomas in Cushing's disease are monoclonal, supporting the theory that a spontaneous somatic mutation is the primary pathogenetic mechanism in this disorder. In addition, the demonstration of polyclonality in corticotroph hyperplasia implies that excess of hypothalamic hormones is an etiologic mechanism in cases of Cushing's syndrome associated with ectopic CRH-secreting tumors.

Adrenocorticotropic Hormone↗
PubMed1992

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)

Adenoma↗