Diagnosis and management of hormone-secreting pituitary adenomas.
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Acromegaly↗
Biomedical subjects
A Klibanski
Publications and source records attributed to A Klibanski.
Age-related alterations in pulsatile secretion of TSH: role of dopaminergic regulation.
To investigate the influence of aging on dopaminergic modulation of pulsatile thyrotropin (TSH) secretion, we examined changes in circulating TSH levels during the day and night, with and without a dopamine antagonist metoclopramide, in healthy young (20-35 yr old) and old (69-83 yr old) subjects, with the use of cluster analysis. Baseline thyroid function tests including serum thyroxine, 3,5,3'-triiodothyronine (T3), T3 resin uptake, and TSH and the response of TSH to thyrotropin-releasing hormone were within normal limits in young and old subjects, and antimicrosomal and anti-thyroglobulin antibodies were absent in all participants. Pulsatile TSH secretion was identified in all subjects, and as a group there were significant increases in nocturnal peak height (P less than 0.01), amplitude (P less than 0.01), and mean TSH (P less than 0.001). TSH pulse amplitude increased 160% (P less than 0.05) at night compared with day in the young but was unchanged at night in the old. After the administration of metoclopramide there was a significant increase in peak height (P less than 0.01), amplitude (P less than 0.01), and mean TSH (P less than 0.01). However, the effect of metoclopramide was different in young and old subjects. In the young, daytime administration of metoclopramide increased TSH pulse height (P less than 0.02) and mean TSH (P less than 0.05); pulse parameters remained unchanged at night. In comparison, in old subjects after metoclopramide, pulse parameters were unchanged during the day but pulse amplitude significantly (P less than 0.01) increased at night. TSH pulse frequency remained stable with age and was unaltered after metoclopramide.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
The effects of activin on follicle-stimulating hormone secretion and biosynthesis in human glycoprotein hormone-producing pituitary adenomas.
The effects of activin on pituitary FSH biosynthesis have been previously characterized using primary rat pituitary cultures; however, little is known of the effects of activin on FSH biosynthesis and secretion in human pituitary tissue. Production of intact glycoprotein hormones and free subunits is increasingly recognized in pituitary tumors; however, the regulation of gonadotropins in such tumors has not been addressed. We have investigated the effects of human recombinant activin on glycoprotein hormone biosynthesis and secretion in primary cultures of 12 human glycoprotein hormone-producing pituitary adenomas and compared this with the effects of activin in normal rat anterior pituitary cells. In 33% of the human pituitary tumors studied, significant (P less than 0.05) increases in FSH beta secretion occurred in response to incubation with 20 ng/mL activin for 24 h (19-287% stimulation), without changes in the production of intact FSH. A Northern analysis performed on cells derived from one tumor indicated that FSH beta mRNA levels increased 350% after activin treatments; however, FSH secretion did not parallel the mRNA changes. None of the human glycoprotein hormone-producing tumors significantly increased FSH secretion in response to activin. To validate the biological activity of recombinant human activin-A and to confirm time and dose conditions for the human tumor cultures, we also examined its ability to stimulate FSH production in rat pituitary cultures. Activin (20 ng/mL) added to the culture medium significantly increased FSH secretion and steady state levels of FSH beta mRNA after 24 h. These data indicate that some glycoprotein hormone-producing pituitary tumors treated with purified activin have discordant responses of intact gonadotropins and free subunit responses. In contrast to responses in normal rat gonadotrophs, FSH beta biosynthetic pathways may be uncoupled from intact FSH secretion in a subset of glycoprotein hormone-producing pituitary adenomas.
Activins↗
Somatostatin regulation of glycoprotein hormone and free subunit secretion in clinically nonfunctioning and somatotroph adenomas in vitro.
There is increasing evidence that clinically nonfunctioning pituitary tumors produce and secrete glycoprotein hormone and/or free alpha- and beta-subunits. In addition, hypersecretion of free alpha-subunit occurs in up to 37% of patients with somatotroph adenomas. An understanding of glycoprotein hormone regulation is important in developing effective therapeutic strategies for patients with tumors associated with intact glycoprotein hormone and free subunit hypersecretion. We investigated glycoprotein hormone and free subunit secretion by somatostatin in primary dispersed cultures of pituitary tumor cells from 23 patients with pituitary adenomas. Fifteen tumors from patients with clinically nonfunctioning adenomas (group 1) and 8 tumors from patients with somatotroph adenomas and cosecretion of alpha-subunit (group 2) were studied. Cultures were incubated with control or somatostatin-supplemented media for 24 h. Media samples from group 1 tumors were assayed for intact glycoprotein hormones and free alpha- and beta-subunits secretion levels, while media samples from group 2 cultures were assayed for alpha-subunit and GH secretion levels. Significant (P less than 0.05-0.001) inhibition of secretion of 1 or more intact hormones and/or free subunits was found in 10 of the 15 group 1 tumors. SRIF[10(-7) M] suppressed intact gonadotropin secretion in 60% of FSH-producing tumors and 30% of LH-producing tumors. Media concentrations of FSH beta and LH beta were decreased in 31% and 50% of group 1 tumors, respectively, following somatostatin treatment in those tumors which secreted free beta-subunits. alpha-Subunit was secreted by 12 of the 15 tumors, but significant (P less than 0.02-0.01) inhibition by somatostatin was observed in only 2 tumors. In contrast, significant (P less than 0.05-0.001) inhibition of alpha-subunit in the somatotroph adenomas was found in 6 of the 8 tumors. Significant decreases in alpha-subunit were observed only in those tumors where GH was also significantly inhibited by somatostatin. We conclude that 1) somatostatin inhibits intact glycoprotein or free subunit secretion in the majority of clinically nonfunctioning pituitary tumors in vitro and 2) alpha-subunit secretion is suppressed in 17% and 69% of clinically nonfunctioning and somatotroph adenomas, respectively, consistent with a differential regulation of alpha-subunit by somatostatin in these two tumor types.
Adenoma↗
Osteopenia in women with hypothalamic amenorrhea: a prospective study.
Hypothalamic amenorrhea, a common disorder associated with abnormalities in gonadotropin pulsatility and subsequent estrogen deficiency, is usually transient, and treatment indications are unclear unless fertility is desired. To determine whether this disorder is associated with progressive bone loss, we studied 24 women with primary or secondary amenorrhea related to stress or simple weight loss, compared with 31 normal women of the same age. Amenorrheic women had significantly lower (P = .01) body fat (26.4 +/- 7.3 versus 30.6 +/- 4.7%) and higher (P = .0001) urine free cortisol levels (250 +/- 100 versus 140 +/- 50 nmol/day) than normals. Trabecular bone density in women with hypothalamic amenorrhea as assessed by spinal computed tomography was significantly (P = .001) lower than in normals (140.2 +/- 27.3 versus 175.1 +/- 24.6 mg K2HPO4/mL, respectively). Twenty of the 24 amenorrheic women had initial spinal bone density below the mean in normals, and in eight it was 2 standard deviations or more below the normal mean. Initial bone density correlated negatively with duration of amenorrhea (r = -0.489, P = .02) and positively with serum free testosterone levels (r = 0.517, P = .02). Prospective evaluation showed a decline in spinal bone density in those who were amenorrheic for fewer than 5 years. The slope of change in bone density correlated with initial weight, percent ideal body weight, and percent body fat (R2 = 0.597, P = .0003; R2 = 0.549, P = .0007; and R2 = 0.618, P = .0002, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Treatment of prolactin-secreting pituitary macroadenomas with the long-acting non-ergot dopamine agonist CV 205-502.
STUDY OBJECTIVE: Evaluation of the effects of an experimental long-acting non-ergot dopamine agonist, CV 205-502, on serum prolactin, tumor size, gonadal function, visual abnormalities, and tolerability in patients with macroprolactinomas. DESIGN: Prospective, unblinded, dose escalation as needed. SETTING: Four university medical centers; patients referred for treatment. PATIENTS: Twenty-six hyperprolactinemic patients (prolactin greater than 150 micrograms/L) with a pituitary macroadenoma were treated for 24 weeks with CV 205-502 given once daily. MEASUREMENTS AND MAIN RESULTS: Serum prolactin was measured at regular intervals. Prolactin levels decreased in all patients during treatment (mean pretreatment level, 2051.7 +/- 1077 micrograms/L [+/- SE]; 24 weeks, 39.0 +/- 11.3 micrograms/L; P = 0.0001); normal prolactin levels were achieved in 15 (58%). Tumor size decreased in 21 of 26 patients and ranged from 6% to 67% (mean, 19.2% +/- 3.4%). Onset or return of regular menses occurred in 11 of 15 premenopausal women, accompanied by an increase in estradiol concentrations (pretreatment, 186.5 +/- 25.0 pmol/L; on treatment, 690.9 +/- 104.3 pmol/L; P = 0.0003). Serum testosterone increased in 6 of 8 men; sexual function improved in 5 of 7 with pretreatment abnormalities. Two patients with reversible visual abnormalities improved within 2 weeks of starting treatment. Side effects occurred in 11 patients and abated over 1 to 2 weeks or after the dose was reduced. There was no evidence of toxicity as indicated by serial serum chemistries, liver function tests, hematologic profiles, thyroxine levels, and electrocardiogram studies. CONCLUSIONS: CV 205-502 reverses hyperprolactinemia and promotes reduction in tumor size with reversal of visual abnormalities and restoration of gonadal function in most patients. This compound will probably be useful in treating prolactinomas.
Adenoma↗
Serum prolactin concentrations in patients with the acquired immunodeficiency syndrome.
Experimental evidence suggests that prolactin is an important immunomodulator hormone. Because this endocrine-immune link may represent a potential new therapeutic avenue, we considered its application in states of immunodeficiency. We hypothesized that serum prolactin concentrations might be abnormal in AIDS. To test this hypothesis, we measured serum prolactin concentrations in blood samples obtained from patients who had either AIDS (n = 15) or AIDS-related complex (n = 12), asymptomatic subjects who were antibody-positive for human immunodeficiency virus (HIV) (n = 10), HIV antibody-negative homosexual subjects (n = 10), and heterosexual HIV antibody-negative controls (n = 21). We found no difference in the serum prolactin concentrations between the five subject groups. We conclude that circulating prolactin values are not altered by HIV infection; however, the possibility that prolactin administration may modulate immune function remains to be tested.
AIDS-Related Complex↗
Age alters pulsatile prolactin release: influence of dopaminergic inhibition.
To determine the effect of age on pulsatile prolactin secretion, we examined prolactin pulse characteristics by cluster analysis in healthy young and old male subjects during the day and night. Pulsatile prolactin secretion was identified in all subjects during the day and night, and prolactin pulse frequency remains stable with age. Younger subjects had a significantly higher prolactin pulse amplitude, area, and peak interval during the night compared with older subjects. In contrast, daytime prolactin pulse characteristics were similar in young and old subjects. Because the major neuroregulator of prolactin is dopamine and because normal aging has been reported to be associated with reductions in hypothalamic dopamine content and effect, we determined whether the mechanism of altered day-night prolactin pulsatile secretion was due to changes in dopaminergic tone. We examined endogenous prolactin secretion after administration of the dopamine antagonist metoclopramide. Metoclopramide significantly increased mean serum prolactin concentration and prolactin pulse height and amplitude in all subjects during the day and night. However, net prolactin pulse amplitude after metoclopramide stimulation at night was significantly higher in older subjects compared with younger subjects. We conclude that prolactin pulse amplitude is blunted in elderly men at night and that daytime pulsatile prolactin secretion is unaltered by age in normal men. The mechanism for this alteration of nighttime prolactin pulsatile secretion in elderly men may be due to age-associated changes in dopaminergic regulation.
Adult↗
Clinically nonfunctioning pituitary tumors are monoclonal in origin.
Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.
Adenoma↗
Abnormal cortisol secretion and responses to corticotropin-releasing hormone in women with hypothalamic amenorrhea.
Hypothalamic amenorrhea (HA) is a common disorder associated with hypoestrogenemia and has adverse effects. The mechanism of GnRH deficiency in these women is not yet known. To investigate the role of the hypothalamic-pituitary-adrenal axis in HA, we studied 10 women [mean age, 29 +/- 7 (+/- SD) yr] with 0.5-13 yr of amenorrhea (mean, 4.3 +/- 3.7 yr) related to simple weight loss or psychological stress. We investigated cortisol and ACTH responses to a bolus of ovine CRH, 24-h plasma cortisol levels obtained every 10 min, and urinary free cortisol levels in these patients. Results were compared with those obtained in normal women during all phases of the menstrual cycle. We found that mean basal concentrations of cortisol were significantly higher (P = 0.03) in the HA patients (mean, 210 +/- 130 nmol/L) than in the normal women (100 +/- 30 nmol/L). The delta (peak - basal) cortisol was significantly lower (P = 0.004) in the HA patients than in the normal women (320 +/- 100 vs. 440 +/- 90 nmol/L, respectively). ACTH responses to CRH did not differ between HA patients and normal women. The 24-h mean cortisol was significantly higher (P = 0.006) in the HA patients than in the normal controls (280 +/- 50 and 220 +/- 50 nmol/L, respectively), due to higher cortisol levels at night. The urinary free cortisol level was significantly higher (P = 0.005) in the HA patients (230 +/- 70 nmol/day) than in normal women (150 +/- 40 nmol/day). We conclude that women with HA have a blunted cortisol response to CRH administration. In addition, they have hypercortisolism, as demonstrated by elevated 24-h mean serum cortisol levels and urinary free cortisol values. This hypothalamic-pituitary-adrenal axis activation in patients with stress or weight loss may be a mechanism in the development of amenorrhea and may relate to other potential adverse effects of HA.
Adrenocorticotropic Hormone↗
Prevalence of alpha-subunit hypersecretion in patients with pituitary tumors: clinically nonfunctioning and somatotroph adenomas.
Hypersecretion of the pituitary glycoprotein hormone alpha-subunit has been reported in pituitary adenomas, particularly in clinically nonfunctioning tumors and somatotroph adenomas. However, the prevalence of such hypersecretion has not been precisely defined. Using both a new highly sensitive and specific monoclonal antibody assay and a polyclonal antibody assay, serum levels of free alpha-subunit were compared in 63 unselected patients with these tumors, 19 patients with acromegaly, and 95 normal controls. In all patients the monoclonal assay detected a significantly greater number of subjects with elevated alpha-subunit levels than did the polyclonal assay (21 vs. 14; P less than 0.01). Fourteen of the 63 patients with clinically nonfunctioning tumors (22%) had elevated serum alpha-subunit levels in the monoclonal assay vs. 11 (17%) in the polyclonal assay. Among the 19 patients with acromegaly, the prevalence was 7 (37%) and 3 (16%) using the monoclonal and polyclonal assays, respectively. Twenty-eight (44%) of the patients with clinically nonfunctioning pituitary adenomas were female. Eleven (39%) of the women were under 45 yr old, as were 10 (29%) of the men. We conclude that the prevalence of free alpha-subunit hypersecretion in patients with clinically nonfunctioning and somatotroph adenomas may be higher than previously recognized, and that a sensitive and specific monoclonal antibody free alpha-subunit assay may provide a useful tumor marker in these patients. The prevalence of clinically nonfunctioning pituitary tumors among younger men and women may also have been previously under-estimated.
Acromegaly↗
Further evidence for a somatic mutation theory in the pathogenesis of human pituitary tumors.
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GTP-Binding Proteins↗
The importance of dopamine in the pathogenesis of experimental prolactinomas.
The factors responsible for the production of prolactin-secreting tumors are obscure. One hypothesis, that chronic loss of dopamine control from the hypothalamus may be associated with prolactinoma formation, was tested. Female adult Fischer 344 rats were subjected to ovariectomy and were then given subcutaneous implants of diethylstilbestrol (DES) Silastic capsules to produce lactotrophic hyperplasia. Sequential studies assessed the neuronal activity of the tuberoinfundibular dopaminergic neurons of the arcuate nucleus of the hypothalamus (A12) during and after this estrogen-induced pituitary growth. Immunocytochemical staining for tyrosine hydroxylase was used as a marker for dopamine synthesis, plasma radioimmunoassay provided plasma prolactin levels, and magnetic resonance imaging and histological studies were performed to examine the structural changes occurring in the pituitary gland. Animals were sacrificed from 3 to 67 days after DES implantation. To determine the reversibility of the estrogen-induced changes, rats were also sacrificed at different time intervals after the removal of 30-, 40-, or 60-day DES implants. After 30 days of DES treatment, plasma prolactin levels increased 40-fold and pituitary weight increased more than threefold. Tyrosine hydroxylase immunoreactivity diminished gradually and was almost completely depleted at 30 days. Pituitary histology revealed marked prolactin cell hyperplasia. These changes were completely reversible; removal of the capsule after 30 days resulted in eventual normalization of plasma prolactin levels and pituitary size and in restoration of tyrosine hydroxylase immunoreactivity in the A12 region. Sixty days of DES treatment produced large hemorrhagic tumors with sustained high plasma prolactin levels and an irreversibly distorted A12 area. These observations suggest that in these animals loss of dopamine regulation secondary to estrogen stimulation initially produces prolactin hyperplasia but that prolonged loss leads to adenoma formation.
Animals↗
Elevated serum lipids in hypogonadal men with and without hyperprolactinemia.
STUDY OBJECTIVE: To determine whether men with hypogonadism are at risk for hyperlipidemia. DESIGN: Case-control study. SETTING: Neuroendocrine clinical center of a referral-based university medical center. PATIENTS: Consecutive sample of 18 men with testosterone deficiency who had prolactin-secreting pituitary adenomas, 15 men with acquired secondary hypogonadism and normal prolactin levels, and 33 normal male controls. MEASUREMENTS AND MAIN RESULTS: We found a significant elevation in fasting cholesterol (6.23 +/- 0.28 mmol/L [mean +/- SE] compared with 5.17 +/- 0.13 mmol/L [241 +/- 11 mg/dL compared with 200 +/- 5 mg/dL], P less than 0.01), low density lipoprotein (LDL) cholesterol (4.11 +/- 0.23 mmol/L compared with 3.34 +/- 0.13 mmol/L [159 +/- 9 mg/dL compared with 129 +/- 5 mg/dL], P less than 0.05), and triglycerides (1.85 +/- 0.26 mmol/L compared with 1.11 +/- 0.07 mmol/L [164 +/- 23 mg/dL compared with 98 +/- 6 mg/dL], P less than 0.001) in men with hyperprolactinemia compared with controls. In the normoprolactinemic hypogonadal men, cholesterol (6.28 +/- 0.34 mmol/L [243 +/- 13 mg/dL], P less than 0.01), LDL cholesterol (4.34 +/- 0.34 mmol/L [168 +/- 13 mg/dL], P less than 0.01), and triglycerides (1.61 +/- 0.18 mmol/L [143 +/- 16 mg/dL], P less than 0.05) were also significantly higher than in the controls, and were the same as in the hyperprolactinemic men. High density lipoprotein (HDL) cholesterol did not differ among the three groups. CONCLUSIONS: Hypogonadism in men, with or without hyperprolactinemia, may be associated with elevation of fasting serum cholesterol, LDL cholesterol, and triglycerides compared with normal men. These data suggest that serum lipid levels should be evaluated in hypogonadal men. The presence of lipid abnormalities may affect the decision to treat testosterone deficiency in these patients.
Adolescent↗
Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism.
STUDY OBJECTIVE: To determine the effects of alteration of gonadal steroids on bone mass in men with hyperprolactinemic hypogonadism. DESIGN: Prospective survey of patients for a median period of 33 months. SETTING: Neuroendocrine clinical center of a referral-based university medical center. INTERVENTIONS: Reversal of hyperprolactinemia by bromocriptine therapy, transsphenoidal surgery, or radiation therapy, alone or in combination. PATIENTS: Consecutive sample of 20 male patients with prolactin-secreting pituitary tumors. MEASUREMENTS AND MAIN RESULTS: In patients who had a reversal of hyperprolactinemia and a restoration of gonadal function, a significant increase in bone density of the radial shaft was noted (mean +/- SE, 0.77 +/- 0.03 to 0.84 +/- 0.03 g/cm2; P less than or equal to 0.05). These patients also had a minimal change in the density of vertebral bone (109 +/- 9 to 115 +/- 10 mg of potassium phosphate, dibasic/cm3). Patients who remained hypogonadal despite the reversal of hyperprolactinemia had no change in radial (0.76 +/- 0.03 to 0.76 +/- 0.04 g/cm2) or vertebral bone density (105 +/- 10 to 103 +/- 9 mg of potassium phosphate, dibasic/cm3). There was a positive correlation between the change in testosterone level and the change in radial (r = 0.67, P less than or equal to 0.003) or vertebral bone density (r = 0.70, P less than or equal to 0.003). CONCLUSIONS: The reversal of hypogonadism, independent of the prolactin concentration, is associated with an improvement in bone mass. Our findings emphasize the importance of gonadal steroids in maintaining skeletal integrity in men.
Adult↗
Age and bone mass in premenopausal women.
It is important to determine the bone mass in normal premenopausal women because increasing numbers of conditions have been identified that result in premenopausal osteoporosis. The relationship between age and bone density was evaluated in 57 carefully characterized normal, premenopausal women using both single energy quantitative computed tomography (SEQCT) and dual energy (DEQCT). The mean bone density measurements were 172 mg/ml K2HPO4 SEQCT and 185 DEQCT. Bone density showed no statistically significant decline between age 18 and age 44. Single- and dual-energy data were highly correlated with each other (r = 0.89), and dual energy appeared to confer no advantage. There was an inverse relation between density and age of menarche. Bone density did not correlate with ideal body weight, percentage fat, or subcutaneous fat area.
Adolescent↗
Body fat distribution measured with CT: correlations in healthy subjects, patients with anorexia nervosa, and patients with Cushing syndrome.
Computed tomography (CT) was used to study fat distribution in three groups of women of comparable age: 39 healthy volunteers, 15 patients with anorexia nervosa, and seven with Cushing syndrome. Patients with anorexia nervosa had a fivefold decrease in subcutaneous fat and only a twofold decrease in intraabdominal fat compared with the values for the volunteers. Patients with Cushing syndrome had less than a twofold increase in subcutaneous fat and greater than a fivefold increase in intraabdominal fat compared with values for the healthy subjects. These findings suggest that fat in different body compartments responds differently to disease processes and that CT can be used to measure these changes.
Adipose Tissue↗
Intravertebral fat measurement with quantitative CT in patients with Cushing disease and anorexia nervosa.
Dual-energy quantitative computed tomography can be used to calculate the intravertebral fat content as well as to correct the effect of intravertebral fat on bone density measurements. The authors studied seven female patients with Cushing syndrome and 15 female patients with anorexia nervosa--conditions known to result in abnormalities of somatic fat distribution--to determine whether the intravertebral fat content was normal and whether it reflected somatic fat quantities. Intravertebral fat content could not be predicted on the basis of somatic fat, weight, or bone mineral content. Intravertebral fat content was elevated in patients with anorexia nervosa (compared with normal values in young female volunteers). In patients with anorexia, the amount of fat increase was disproportionately large for the severity of osteopenia. In patients with Cushing syndrome, the intravertebral fat content did not differ from that in the volunteers. Intravertebral fat does not correlate well with bone mineral content within any group and appears to be related to other factors.
Adolescent↗