Search PubMed⌕ Search

Biomedical subjects

A Klibanski

Publications and source records attributed to A Klibanski.

At least 73 records · Page 4Linked to original sources
PubMed1996

Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency. A randomized, placebo-controlled trial.

BACKGROUND: Patients with adult-onset growth hormone deficiency have reduced bone density and increased fat mass. Growth hormone at high doses may decrease body fat in these patients, but the effects of growth hormone at more physiologic doses on bone density and body composition have not been convincingly shown. OBJECTIVE: To determine whether long-term growth hormone therapy at a dose adjusted to maintain normal insulin-like growth factor 1 (IGF-1) levels has clinical effects in patients with adult-onset growth hormone deficiency. DESIGN: Randomized, placebo-controlled study. SETTING: Tertiary referral center. PATIENTS: 32 men with adult-onset growth hormone deficiency. INTERVENTION: Growth hormone (initial daily dose, 10 micrograms/kg of body weight) or placebo for 18 months. The growth hormone dose was reduced by 25% if IGF-1 levels were elevated. MEASUREMENTS: Body composition and bone mineral density of the lumbar spine, femoral neck, and proximal radius were measured by dual energy x-ray absorptiometry at 6-month intervals. Markers of bone turnover were also measured during the first 12 months of the study. RESULTS: Growth hormone therapy increased bone mineral density in the lumbar spine by a mean (+/- SD) of 5.1% +/- 4.1% and bone mineral density in the femoral neck by 2.4% +/- 3.5%. In the growth hormone group, significant increases were seen in the following markers of bone turnover: osteocalcin (4.4 +/- 3.6 mg/L to 7.2 +/- 4.6 mg/L) and urinary pyridinoline (39.0 +/- 19.8 nmol/mmol of creatinine to 55.7 +/- 25.5 nmol/mmol of creatinine) and deoxypyridinoline (8.4 +/- 7.1 nmol/mmol of creatinine to 14.9 +/- 9.4 nmol/mmol of creatinine). Percentage of body fat in the growth hormone group decreased (from 31.9% +/- 6.5% to 28.3% +/- 7.0%), and lean body mass increased (from 59.0 +/- 8.5 kg to 61.5 +/- 6.9 kg). These changes were significant compared with corresponding changes in the placebo group (P < 0.01 for all comparisons). CONCLUSIONS: Growth hormone administered to men with adult-onset growth hormone deficiency at a dose adjusted according to serum IGF-1 levels increases bone density and stimulates bone turnover, decreases body fat and increases lean mass, and is associated with a low incidence of side effects.

Adult↗
PubMed1996

Gonadotropin-releasing hormone messenger RNA expression in gonadotroph tumors and normal human pituitary.

Gonadotroph tumors predominantly secrete FSH or free gonadotropin hormone subunits and rarely LH. In contrast to normal gonadotrophs, a subset of tumors synthesize FSH beta-subunit (SU) in excess of alpha-SU, and the cause of gonadotropin hormone-SU biosynthetic defects in these tumors is unknown. Gonadotropin-releasing hormone (GnRH) is known to modify gonadotropin hormone-SU biosynthesis and secretion and may be an important determinant of gonadotroph tumor hormone regulation. Data in experimental animals have demonstrated that endogenous expression of GnRH may occur in the pituitary. We therefore determined whether 1) the GnRH gene is expressed in gonadotroph tumors and normal pituitaries using reverse transcriptase (RT)-PCR; 2) the GnRH receptor gene is co-expressed in gonadotroph tumors; 3) an alternative upstream transcriptional start site on the GnRH gene is utilized; and 4) media from primary cultures of gonadotroph tumors have detectable GnRH immunoreactivity by RIA. GnRH messenger RNA (mRNA) was detected in 10/10 gonadotroph tumors, eight of which expressed GnRH-Receptor mRNA. Both mRNAs were detected in all normal pituitaries studied (n = 6). Six of 10 gonadotroph tumors and 3/6 normal pituitaries had GnRH transcripts derived from the upstream transcriptional start site (5'GnRH). GnRH immunoreactivity was detected in overnight media from 3/3 primary gonadotroph tumor cultures (range: 1.89-5.86pg/mL; limit of detection (LD) = < 1.58pg/mL) but was not detectable in control media. This is the first study to demonstrate endogenous GnRH gene expression in human pituitary adenomas and normal human pituitary tissue. The presence of both GnRH and GnRH-Rc suggest that GnRH may be a paracrine/autocrine regulator of cell function in the pituitary and may affect gonadotroph tumor hormone phenotype.

Adenoma↗
PubMed1996

Assessment of growth hormone (GH) secretion in men with adult-onset GH deficiency compared with that in normal men--a clinical research center study.

It is not known how patients who acquire GH deficiency (GHD) in adulthood differ in measures of GH secretion from normal adults. To characterize measures of GH secretion in such patients compared to those in normal subjects, we studied 23 men (median age, 51 yr; range, 32-62 yr) with adult-onset pituitary disease, defined as GH-deficient based on having no detectable GH response to two pharmacological agents, and 17 normal men. Patients less than 50 yr old received insulin (0.1 U/kg, i.v.) and clonidine (0.15 mg, orally), whereas those 50 yr of age or older as well as normal controls received arginine (30 g, i.v.) and clonidine. Patients were compared to normal men by investigating GH sampling every 10 min for 24 h and serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein 2 (IGFBP-2), IGFBP-3, and GH-binding protein. Frequent venous sampling of GH was analyzed in terms of mean 24-h levels, pooled 24-h GH, mean levels over the 12 h between 2000-0800 h (mean overnight GH level), and pulse analysis (pulses per 24 h and pulse amplitude) by the Pulsar computer program. Although there were significant differences between the two groups for almost all measures of GH secretion, overlap between the groups was always present. GH levels measured using a highly sensitive chemiluminescence assay on 24-h pools derived from frequent sampling displayed the least overlap between the two groups, as only 2 of 17 normal controls overlapped with the GHD patients. The pooled 24-h GH level using this technique was significantly lower in patients with GHD than in controls (0.117 +/- 0.021 vs. 0.861 +/- 0.098 micrograms/L; P < 0.0001). In the analysis of frequent GH sampling using a standard immunoradiometric assay, mean overnight GH levels provided the best separation between the two groups, as all 23 patients had values of 0.6 microgram/L or less, and 13 of 17 normal controls had values greater than 0.6 microgram/L. The mean overnight GH level in patients was 0.6 +/- 0.0 microgram/L compared to 1.0 +/- 0.1 microgram/L in controls (P < 0.0001). The mean 24-h GH level in patients was 0.5 +/- 0.0 microgram/L compared to 0.8 +/- 0.1 microgram/L in normal controls (P < 0.0001). GH pulse frequency and pulse amplitude were also reduced in patients with GHD compared to those in normal controls [1.7 +/- 0.5 vs. 5.1 +/- 0.5 pulses/24 h (P < 0.0001) and 0.6 +/- 0.1 vs. 2.8 +/- 0.4 microgram/L (P < 0.0001), respectively]. The mean serum IGF-I level was significantly lower in patients with GHD than in normal controls (106.7 +/- 8.0 vs. 218.7 +/- 16.7 microgram/L; P < 0.0001). Three of 23 patients overlapped with control values. Mean serum levels of IGFBP-3 and the serum IGF-I/IGFBP-2 ratio were also significantly lower in patients than in controls, but values overlapped substantially. We conclude that overlap occurs on measures of GH secretion between normal men and men identified as GH deficient despite a stringent definition of GHD. The best separation was obtained using pooled 24-h GH levels determined by a highly sensitive chemiluminescence assay.

Adult↗
PubMed1996

Serum leptin levels in women with anorexia nervosa.

Leptin is a protein encoded by the ob gene that is expressed in adipocytes and regulates eating behavior via central neuroendocrine mechanisms. Serum leptin levels have been shown to correlate with weight and percent body fat in normal and obese individuals; however, it is not known whether the regulation of leptin is normal below a critical threshold of body fat in chronic undernutrition. We investigated serum leptin levels in 22 women, aged 23 +/- 4 yr, with anorexia nervosa. Duration of disease, weight, BMI, percent body fat, and serum leptin levels were determined for each patient. Nutritional status was assessed further by caloric intake and measurement of insulin and insulin-like growth factor I (IGF-I) levels. Twenty-three healthy women, aged 23 +/- 4 yr, taking no medications, with normal menstrual function and body mass index (BMI) between 20-26 kg/m2 (mean, 23.7 +/- 1.7 kg/m2), served as a control population for comparison of leptin levels. Subjects with anorexia nervosa were low weight (BMI, 16.3 +/- 1.6 kg/m2; normal, 20-26 kg/m2) and exhibited a striking reduction in percent body fat (7 +/- 2%; normal, 20-30%). The mean serum leptin level was significantly decreased in subjects with anorexia nervosa compared with that in age- and sex-matched controls of normal body weight (5.6 +/- 3.7 vs. 19.1 +/- 8.1 ng/mL; P < 0.0001). Serum leptin levels were correlated highly with weight, as expressed either BMI (r = 0.66; P = 0.002) or percent ideal body weight (r = 0.68; P = 0.0005), body fat (r = 0.70; P = 0.0003), and IGF-I (r = 0.64; P = 0.001), but not with caloric intake or serum levels of estradiol or insulin in subjects with anorexia nervosa. The correlation between leptin and body fat was linear, with progressively lower, but detectable, leptin levels measured even in patients with less than 5% body fat, but was not significant when the effects of weight were taken into account. In contrast, the correlation between leptin and IGF-I remained significant when the effects of weight, body fat, and caloric intake were taken into account. In normal controls, leptin correlated with BMI (r = 0.55; P = 0.007) and IGF-I (r = 0.44; P < 0.05), but not with fat mass. These data demonstrate that serum leptin levels are reduced in association with low weight and percent body fat in subjects with anorexia nervosa compared to normal controls. Leptin levels correlate highly with weight, percent body fat, and IGF-I in subjects with anorexia nervosa, suggesting that the physiological regulation of leptin is maintained in relation to nutritional status even at an extreme of low weight and body fat.

Adipose Tissue↗
PubMed1996

Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa.

Significant osteoporosis affects over half of all women with anorexia nervosa (AN). The mechanisms of bone loss in this condition are not known, and estrogen administration alone has not been shown to prevent bone loss. Insulin-like growth factor I (IGF-I), a nutritionally dependent bone trophic hormone, is know to stimulate osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that short term administration of recombinant human IGF-I (rhIGF-I) would increase bone turnover in young women with AN. We studied 23 women, aged 18-29 yr (mean +/- SD, 23 +/- 4 yr) with AN. Spinal bone density was significantly reduced compared to that in age-matched controls (0.85 +/- 0.11 vs. 1.19 +/- 0.12 g/cm2 by dual energy x-ray absorptiometry; P < 0.001) and was below the normal mean in 54% of the women. Patients were randomized to receive rhIGF-I (100 or 30 micrograms/kg) or placebo sc twice a day for 6 days. Bone turnover was assessed at baseline and after 3 and 6 days of treatment using two markers of bone formation [osteocalcin (OC) and type I procollagen carboxyl-terminal propeptide (PICP)] and three specific markers of bone resorption [pyridinoline (PYRX), deoxypyridinoline (DPYRX), and N-telopeptide (NTX)]. Serum OC was reduced significantly (P < 0.001) in women with AN compared to normal premenopausal women (5.4 +/- 3.8 vs. 8.6 +/- 4.5 ng/mL) and correlated with percent fat mass (r = 0.60;P < 0.01) and body mass index (r = 0.50;P < 0.05). Markers of bone resorption were elevated significantly compared to normal levels [DPYRX, 18.2 +/- 7.0 vs. 11.4 +/- 5.2 nmol/mmol creatinine, (P < 0.001); NTX, 53.5 +/- 22.5 vs. 36.5 +/- 14.6 nmol BCE/mmol creatinine (P < 0.01)]. IGF-I levels were relatively low at baseline compared to those in age-matched controls (203 +/- 93 vs. 262 +/- 84 ng/mL;P < 0.01) and increased to 673 +/- 268 ng/mL [P < 0.05; 100 micrograms/kg twice daily (BID)] and 545 +/- 255 ng/mL (P < 0.05; 30 micrograms/kg BID). During short term administration of rhIGF-I at a dose of 100 micrograms/kg BID, there was a significant (P < 0.05) increase in markers of bone formation, as assessed by both PICP (147 +/- 33 to 303 +/- 187 ng/mL) and OC (5.3 +/- 3.8 to 10.9 +/- 7.4 ng/mL). There was also a significant (P < 0.05) increase in markers of bone resorption as assessed by PYRX (51.0 +/- 16.6 to 87.1 +/- 8.2 nmol/mmol creatinine) and DPYRX (17.3 +/- 4.5 to 26.3 +/- 3.7 nmol/mmol creatinine). The group randomized to receive short term administration of rhIGF-I at a dose of 30 micrograms/kg BID demonstrated a significant (P < 0.05) increase in PICP (110.9 +/- 47.0 to 134.8 +/- 43.2 ng/mL) and an insignificant increase in OC levels (4.5 +/- 3.2 to 6.8 +/- 5.9 ng/mL). However, markers of bone resorption were unchanged during rhIGF-I administration at this dose. Serum PTH and serum and urinary calcium were unchanged in both treatment groups compared to placebo levels. These data demonstrate that young women with anorexia nervosa have decreased markers of bone formation and increased bone resorption. This is the first demonstration that short term rhIGF-I administration increases markers of bone turnover in severely osteopenic women with AN. The effects of short term rhIGF-I on bone turnover are dose dependent. At a dose of 100 micrograms BID, rhIGF-I administration significantly stimulated both markers of bone formation and bone resorption. At a dose of rhIGF-I of 30 micrograms BID, there was an increase in one marker of bone formation, PICP, without a change in markers of bone resorption. Further studies are required to determine whether chronic administration of rhIGF-I can affect bone mass in young women with profound osteopenia due to anorexia nervosa.

Adolescent↗
PubMed1996

Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting.

The acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS) is a devastating complication of human immunodeficiency virus infection characterized by a disproportionate decrease in lean body mass. The pathogenesis of the AWS is unknown, but recent data suggest that endogenous secretion of the potent anabolic hormone, testosterone; is decreased in 30-50% of men with AIDS. However, it is unknown whether decreased androgen levels are associated with decreased lean body mass and/or functional decreases in muscle strength and aerobic capacity in hypogonadal men with the AWS. In addition, testosterone is known to have stimulatory effects on GH secretion, and the loss of these effects on the GH-insulin-like growth factor I (IGF-I) axis may be an additional mechanism of decreased lean body mass in this population. Twenty hypogonadal subjects (free-testosterone < 12 pg/mL) with weight loss > 10% of preillness weight or absolute weight < 90% ideal body weight (IBW) were enrolled in the study. None of the subjects were receiving Megace. Lean body mass and fat-free mass were determined by potassium-40 isotope analysis (40K) and dual-energy x-ray absorptiometry, respectively, and analyzed with respect to gonadal function by linear regression analysis. Muscle mass was determined by urinary creatinine excretion, and exercise functional capacity was assessed by a 6-min walk test, a sit-to-stand test, and a timed get-up-and-go test. Results also were compared with gonadal function by regression analysis. IGF-I and mean overnight GH levels, determined from frequent sampling (q20 min from 2000-0800 h), were compared with results obtained from age- and sex-matched normal controls. Subjects were 26-58 yr of age (39 +/- 7 yr, mean +/- SD) with a CD4 cell count of 150 +/- 186 cells/mm3. Serum levels of FSH were elevated in 30% of the subjects. Muscle mass was significantly reduced, compared with expected mass for height (23.3 +/- 5.5 vs. 29.3 +/- 1.7 kg, P = 0.0001) and was decreased disproportionately to weight (77% of expected value for muscle mass vs. 93% of expected value for weight). Free-testosterone levels were correlated with total body potassium (R = 0.45, P < 0.05) and muscle mass (R = 0.45, P < 0.05). Total-testosterone levels were correlated with exercise functional capacity (R = 0.64, P = 0.01 for the sit-to-stand test and R = 0.53, P < 0.05 for the 6-min walk test). Mean GH levels were significantly increased (3.03 +/- 1.76 vs. 0.90 +/- 0.37 ng/mL, P < 0.001) and IGF-I levels decreased (167 +/- 66 vs. 225 +/- 69 ng/mL, P < 0.01), compared with age- and sex-matched eugonadal controls. GH levels were inversely correlated with caloric intake (R = -0.60, P = 0.02) and percent fat mass by dual-energy x-ray absorptiometry (R = 0.58, P = 0.02). Six additional hypogonadal subjects receiving Megace for AIDS wasting were analyzed separately. Nutritional status and parameters of body composition were compared in the Megace and non-Megace-treated subjects. No significant differences in caloric intake, lean body mass, fat mass, or muscle mass were demonstrated. These data demonstrate that changes in body composition, including loss of lean body and muscle mass, and deterioration in exercise functional capacity are highly correlated with androgen levels in hypogonadal men with the AWS. Furthermore, our data demonstrate significantly increased GH levels and decreased IGF-I in association with low weight in this population. These data suggest that androgen deficiency combined with classical GH resistance may contribute to the critical loss of lean body and muscle mass in hypogonadal men with the AWS. These data are the first to link muscle and lean body wasting with progressive gonadal dysfunction among the large percentage of men with AIDS wasting who are hypogonadal. This demonstrates the need for additional studies to determine the efficacy of gonadal steroid replacement to increase lean body mass in this population.

Adult↗
PubMed1996

Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism.

Acquired hypogonadism is being increasingly recognized in adult men. However, the effects of long term testosterone replacement on bone density and body composition are largely unknown. We investigated 36 adult men with acquired hypogonadism (age, 22-69 yr; median, 58 yr), including 29 men with central hypogonadism and 7 men with primary hypogonadism, and 44 age-matched eugonadal controls. Baseline evaluation included body composition analysis by bioimpedance, determination of site-specific adipose area by dual energy quantitative computed tomography scan (QCT) of the lumbar spine, and measurements of spinal bone mineral density (BMD) using dual energy x-ray absortiometry, spinal trabecular BMD with QCT, and radial BMD with single photon absorptiometry. Percent body fat was significantly greater in the hypogonadal men compared to eugonadal men (mean +/- SEM, 26.4 +/- 1.1% vs. 19.2 +/- 0.8%; P < 0.01). The mean trabecular BMD determined by QCT for the hypogonadal men was 115 +/- 6 mg K2HPO4/cc. Spinal BMD was significantly lower than that in eugonadal controls (1.006 +/- 0.024 vs. 1.109 +/- 0.028 g/cm2; P = 0.02, respectively). Radial BMD was similar in both groups. Testosterone enanthate therapy was initiated in 29 hypogonadal men at a dose of 100 mg/week, and the subjects were evaluated at 6-month intervals for 18 months. During testosterone therapy, the percent body fat decreased 14 +/- 4% (P < 0.001). There was a 13 +/- 4% decrease in subcutaneous fat (P < 0.01) and a 7 +/- 2% increase in lean muscle mass (P = 0.01) during testosterone therapy. Spinal BMD and trabecular BMD increased by 5 +/- 1% (P < 0.001) and 14 +/- 3% (P < 0.001), respectively. Radial BMD did not change. Serum bone-specific alkaline phosphatase and urinary deoxypyridinoline excretion, markers of bone formation and resorption, respectively, decreased significantly over the 18 months (P = 0.003 and P = 0.04, respectively). We conclude that testosterone therapy given to adult men with acquired hypogonadism decreases sc fat and increases lean muscle mass. In addition, testosterone therapy reduces bone remodeling and increases trabecular bone density. The beneficial effects of androgen administration on body composition and bone density may provide additional indications for testosterone therapy in hypogonadal men.

Adult↗
PubMed1996

Tumor-specific expression and alternate splicing of messenger ribonucleic acid encoding activin/transforming growth factor-beta receptors in human pituitary adenomas.

Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.

Activin Receptors↗
PubMed1996

A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty.

We have previously demonstrated that men with histories of constitutionally delayed puberty have significantly lower spinal and radial bone mineral density than normal men. Because these men were in their mid-twenties, it is possible that bone density was decreased because bone development was still incomplete. In addition, there is no information on the bone density of the proximal femur, the most important clinical site for osteoporotic fractures, in men with histories of delayed puberty. To address these issues, we performed repeat measurements of radial and spinal bone mineral density 2 yr after the initial evaluations in 18 men with histories of delayed puberty. Bone mineral density of the femoral neck was also measured at the time of follow-up evaluations. The mean radial bone mineral density at the time of the repeat evaluations was similar to the mean value from the initial evaluations (0.74 +/- 0.08 vs. 0.74 +/- 0.07 g/em2) and the mean change was 0.00 +/- 0.04 g/cm2. Similarly, the mean spinal bone mineral density at the time of the repeat evaluations was similar to the mean value from the initial evaluations (1.02 +/- 0.10 vs. 1.01 +/- 0.10 g/cm2) and the mean change was -0.01 +/- 0.04 g/cm2. Bone mineral density of the femoral neck was significantly lower in the men with histories of delayed puberty than in normal men (0.88 +/- 0.11 vs. 0.98 +/- 0.14 g/cm2 P < 0.02). These data indicate that bone accretion is complete by the mid-twenties in men with histories of constitutionally delayed puberty and that their bone mineral density does not improve with time. In addition, these men have decreased bone density of the femoral neck, which might increase their risk for hip fractures when they are older.

Adult↗
PubMed1996

Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline.

Dopamine agonist administration is the primary therapy for macroprolactinomas, but bromocriptine is the only agent approved in the United States. Its use is limited by a high incidence of side effects, a short duration of action, and a lack of effectiveness in some patients. Cabergoline is a long-acting dopamine agonist specific for the D2 receptor that is more effective and better tolerated than bromocriptine in women with microadenomas or idiopathic hyperprolactinemia. However, experience with cabergoline in the treatment of patients with macroadenomas is limited. We report the first study of chronic administration of cabergoline conducted exclusively in patients with macroprolactinomas. Fifteen patients (8 women, 7 men) ages 18-76 yr were studied in an open-label 48-week dose escalation trial of cabergoline administered once per week. Eleven patients had received prior therapy with other dopamine agonists. Mean prolactin (PRL) levels decreased by 93.6%, and normal levels were attained in 73% of patients at doses of 0.5-3.0 mg per week. Three of five patients who had failed to normalize PRL on prior dopamine agonists achieved normal levels. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea. Tumor size decreased in 11 of the 15 patients. Side effects were minimal. Of the 5 patients who had experienced side effects in prior dopamine agonists, 4 had none on cabergoline, and the fifth had milder symptoms. During two further years of follow up, the improvement in PRL levels, gonadal function, and tumor size has persisted during cabergoline administration, and three patients have experienced a further decline in PRL and/or tumor size. This study demonstrates the effectiveness and minimal side effects of once-weekly cabergoline for treatment of macroprolactinomas.

Adenoma↗
PubMed1995

Symptomatic salivary-rest cyst of the sella turcica.

Although ectopic salivary tissue in the posterior pituitary is frequently observed in microscopic examination at autopsy, this tissue is considered clinically insignificant. The authors report a case of sella turcica mass causing progressive menstrual irregularities and mild hyperprolactinemia in a 22-year-old woman. Magnetic resonance imaging revealed a 1.2 x 0.9 cm non-enhancing mass of the postero-inferior sella turcica. The lesion was isointense to brain on T1-weighted images and hypo- to iso-intense on T2-weighted images. Transsphenoidal exploration revealed that the cyst wall consisted entirely of normal appearing salivary gland. The clinical, radiographic, and pathologic features of this unique entity are discussed.

Adult↗
PubMed1995

Effects of rhIGF-I administration on bone turnover during short-term fasting.

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.

Adult↗
PubMed1995

Human pituitary adenomas express endogenous inhibin subunit and follistatin messenger ribonucleic acids.

Specific factors involved in the pathogenesis of tumors that stimulate clonal human pituitary adenoma cell proliferation remain unknown. An important question regarding the pathogenesis of human pituitary tumors is whether they synthesize autocrine regulatory factors that regulate both hormone biosynthesis and neoplastic growth. Activin and inhibin are both comprised of inhibin subunits and have diverse regulatory roles as growth and differentiation factors in normal and neoplastic tissue. Activin stimulates FSH beta messenger ribonucleic acid (mRNA) biosynthesis and FSH secretion, and these effects are down-regulated in normal gonadotrophs by the endogenous glycoprotein follistatin. In addition to its effects on gonadotrophs, activin modulates hormone secretion by somatotroph and corticotroph cell lines. It is not known whether human neoplastic pituitary tissue synthesizes inhibin subunits or follistatin or whether their expression is cell type specific. We investigated whether alpha-, beta A-, and beta B-inhibin subunit and follistatin mRNAs could be detected in 27 human pituitary adenomas [clinically nonfunctioning (n = 11), somatotroph (n = 5), corticotroph (n = 5), and lactotroph (n = 6)] using reverse transcriptase-polymerase chain reaction techniques. Twenty-six of the tumors contained mRNAs encoding one or more inhibin subunits. beta B-Inhibin mRNA was the most prevalent (81% of tumors), followed by beta A-inhibin (59% of tumors) and alpha-inhibin (52% of tumors). Endogenous alpha-, beta A-, and beta B-inhibin subunit mRNA synthesis was also examined in normal human pituitary and testicular complementary DNA libraries, and all subunit mRNAs were detected. In contrast to the widespread expression of inhibin subunits in pituitary tumors, follistatin mRNA was detected in a subset of nonfunctioning tumors (54%) as well as in control normal human pituitary and testicular complementary DNA libraries. Tumor-specific follistatin biosynthesis was not observed in other pituitary tumor subtypes. These data are the first to demonstrate that 1) endogenous inhibin subunits are synthesized in human pituitary adenomas of all known secretory phenotypes as well as normal pituitary tissue; and 2) follistatin gene expression in pituitary adenomas is specific to clinically nonfunctioning or gonadotropin subunit-producing tumors. The characterization of inhibin subunit and follistatin biosynthesis by human pituitary tumors will be important in investigating their potential roles in regulating both tumor phenotype and cell proliferation.

Adenoma↗
PubMed1995

Decreased bone formation and increased mineral dissolution during acute fasting in young women.

Severe chronic undernutrition is associated with decreased bone turnover and significant bone loss. However, little is known about the short-term effects of nutritional deprivation on bone turnover. To investigate the effects of short-term fasting on bone metabolism and the contribution of acidosis to these changes, 14 healthy women ages 18-26 (mean, 21 +/- 2 (SD years) were randomized to potassium bicarbonate (KHCO3, 2 meq/kg/day in divided doses) to prevent acidosis or control (potassium chloride, 25 meq/day) during a complete 4-day fast. Bone turnover was assessed using specific markers of formation [osteocalcin (OC) and Type I procollagen carboxyl-terminal propeptide (PICP)] and resorption [pyridinoline (PYRX) and deoxypyridinoline (DPYRX)]. Serum bicarbonate levels fell significantly from 27.0 +/- 3.2 to 17.3 +/- 2.6 mmol/L (P < 0.01) in the control group and were decreased compared to patients receiving KHCO3 [17.3 +/- 2.6 vs. 23.4 +/- 2.4 mmol/L, (P < 0.001)]. Serum total and ionized calcium increased significantly in the control group [9.1 +/- 0.1 to 9.4 +/- 0.2 mg/dL (P < 0.01) and 1.20 +/- 0.03 to 1.23 +/- 0.03 mmol/L (P < 0.05), respectively], but not in patients receiving KHCO3. In addition, serum parathyroid hormone (PTH) levels decreased from 32 +/- 17 to 16 +/- 10 pg/mL (P < 0.05) and urinary calcium excretion increased [86 +/- 51 to 182 +/- 103 mg/day (P = 0.01)] in the control group, but not in patients receiving KHCO3. Serum osteocalcin (OC) and procollagen carboxyl-terminal propeptide (PICP) levels decreased significantly after 4 days of fasting from 9.1 +/- 3.4 to 5.5 +/- 4.2 ng/mL (P < 0.01) and 121 +/- 21 to 46 +/- 13 ng/mL (P = 0.0001) respectively in the patients receiving bicarbonate, and from 10.1 +/- 3.3 to 4.0 +/- 2.9 ng/mL (P < 0.01) and from 133 +/- 22 to 47 +/- 19 ng/mL (P < 0.001) respectively in the control group. The decrease in osteocalcin and PICP during fasting was comparable in both treatment groups. By contrast, urinary excretion of PYRX and DPYRX did not change significantly in either group with 4 days of fasting. These data are the first to demonstrate that markers of bone formation decline significantly with short-term fasting, independent of changes in acid-base status. By contrast, these data demonstrate a direct effect of acidosis in stimulating calcium release from bone during short-term fasting and suggest that acidosis may increase mineral dissolution independent of osteoclast activation and PTH in this experimental model of acute starvation.

Acid-Base Equilibrium↗
PubMed1995

Serum insulin-like growth factor-binding protein-3 levels in the diagnosis of acromegaly.

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a GH-dependent protein that binds insulin-like growth factor-I (IGF-I) in the circulation and modulates its action at the tissue level. Because IGFBP-3 is a stable and specific marker of somatotroph function, we hypothesized that it would be a useful biochemical marker in the diagnosis of patients with acromegaly and the assessment of surgical cure. We, therefore, investigated the sensitivity of serum IGFBP-3 levels to detect GH excess in 44 patients with clinical acromegaly and pathologically confirmed somatotroph adenomas, including a cohort of 18 patients with untreated disease evaluated before transsphenoidal surgery and medical therapy. IGFBP-3 levels were compared to IGF-I and random GH levels before and after transsphenoidal surgery. Concordance among IGFBP-3, IGF-I, and GH suppressibility by glucose was also determined. In addition, the response of IGFBP-3 to glucose suppression was investigated. All 18 patients with untreated acromegaly had elevated serum IGFBP-3 levels, ranging from 4,186-10,026 micrograms/L (mean +/- SD, 6566 [plusm] 1800 micrograms/L). There was no overlap with the age-adjusted normative ranges (P = 0.0001 in patients 18-55 yr old and P = 0.0176 in patients > 55 yr old) or with the levels obtained in age-comparable controls (P = 0.0001). In 11% of untreated patients with clinical findings of acromegaly and a pathologically confirmed adenoma, IG-FBP-3 levels were elevated, although GH was suppressed to less than 2 micrograms/L with glucose. In these patients, IGF-I levels were either normal or minimally elevated and considered nondiagnostic. IGFBP-3 and IGF-I levels were correlated in patients with untreated acromegaly (r = 0.650; P = 0.0162) and after transsphenoidal surgery (r = 0.644; P = 0.0001). Neither IGF-I nor IGFBP-3 correlated with random GH levels before surgery. However, both IGF-I (r = 0.471; P = 0.0001) and IGFBP-3 (r = 0.259; P = 0.041) correlated with random GH levels in patients studied more than 1 month after transsphenoidal surgery. IGFBP-3 and IGF-I levels were concordant with GH suppressibility by glucose (P = 0.0039) and IGFBP-3 decreased with glucose suppression in 7 of 10 patients. These data indicate that IGFBP-3 is a sensitive physiological marker of somatotroph function and is concordant with glucose suppression and IGF-I levels before and after transsphenoidal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗
PubMed1995

The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa.

To study the effects of prolonged anorexia nervosa on bone density (BD) and to determine whether estrogen administration prevents bone loss in women with this disorder, 48 amenorrheic women with anorexia nervosa (mean age, 23.7 yr) were randomized to receive estrogen and progestin replacement (n = 22) or no replacement (n = 26). Clinical variables, biochemical indices, and spinal trabecular BD were measured every 6 months for a mean of 1.5 yr. Initial mean BD (130 +/- 27 mg K2HPO4/cm3, +/- 1 SD) was significantly (P < 0.001) less than normal (176 +/- 26 mg K2HPO4/cm3) and less than 2 SD below normal in 21 of the 48 women. Forty-four women completed the study (19 in the estrogen group and 25 in the control group). The mean duration of follow-up was comparable in the estrogen-treated (1.57 +/- 0.89 yr) vs. the control group (1.41 +/- 0.69 yr). The estrogen-treated group had no significant change in BD compared with the control group; however, there was a 4.0% increase in mean BD in patients with an initial ideal body weight of less than 70% who were treated with estrogen. In contrast, control patients with comparably low initial weight had a 20.1 % decrease in BD. Women in the control group with spontaneous resumption of menses, all of whom had an initial percent ideal body weight of greater than 70%, had a 19.3% increase in bone mass. It is concluded that: 1) estrogen replacement cannot prevent progressive osteopenia in young women with anorexia nervosa; 2) a subset of patients may have improved BD with estrogen and progestin administration depending on initial body weight; and 3) recovery from anorexia nervosa is associated with significantly improved BD.

Adolescent↗
PubMed1995

Somatostatin receptor subtype gene expression in pituitary adenomas.

Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors. In addition to inhibiting GH secretion, SRIF has antiproliferative effects and has been used clinically in the treatment of pituitary tumors. SRIF receptor (SSTR) expression has recently been identified in pituitary adenomas, and it is unknown whether differential expression of SSTR subtypes predicts clinical responses to SRIF analogs. We therefore determined which SSTR subtype messenger RNAs (mRNAs) are expressed in pituitary adenoma phenotypes and in normal human pituitary tissue using reverse transcriptase-polymerase chain reaction and tested whether expression of specific SSTR subtype mRNA is necessary for SRIF inhibition of GH secretion in human somatotroph adenomas in vitro. Expression of SSTR subtypes 1, 2, and 5 mRNA was identified in all pituitary adenoma types and normal pituitary tissue. In contrast, SSTR3 mRNA was detected in only one somatotroph adenoma as well as in control insulinoma tissue, a tissue known to express SSTR3 mRNA, and was not detected in normal pituitary tissue. SSTR4 mRNA was not detected in any human pituitary tissue. To determine whether specific SSTR subtype mRNA expression is required for SRIF inhibition of GH secretion, five somatotroph adenomas were treated with 10(-7) mol/L SRIF in vitro, and significant inhibition of GH release occurred in all adenomas. All five tumors expressed SSTR2 mRNA and SSTR5 mRNA, and three expressed SSTR1 mRNA. The absence of SSTR1 mRNA expression did not affect the ability of SRIF to suppress GH secretion. We conclude that: 1) human pituitary adenomas and normal pituitary express multiple SSTR gene transcripts; 2) SSTR5 mRNA, which has not been reported in other human endocrine tumor types, is expressed in neoplastic and normal pituitary tissue; and 3) SSTR2 mRNA, SSTR5 mRNA, and variable SSTR1 mRNA are expressed in GH-secreting tumors, which are responsive to SRIF in vitro. Further understanding of SSTR gene expression in pituitary adenomas will facilitate our understanding of the pathogenetic mechanisms of tumorigenesis and may provide a rationale for the use of specific SRIF analogs for clinical application.

Adenoma↗