Acromegaly: an endocrine society clinical practice guideline

OBJECTIVE: The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS: The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS: Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.(AU)

Treatments, complications, and healthcare utilization associated with acromegaly: a study in two large United States databases.

The economic burden of acromegaly in the US has been largely unknown. We describe the prevalence of treatment patterns, complication rates, and associated healthcare utilization and costs of acromegaly in the US. Patients were identified between 1/1/2002 and 12/31/2009 in claims databases. During 1-year after each continuously-enrolled patient's first acromegaly claim, pharmacy and medical claims were used to estimate outcomes. Regression models were used to adjust outcomes. There were 2,171 acromegaly patients (mean age: 45.3 years; 49.7% female); 77.8% received the majority of their care from non-endocrinologists. Pharmacologic treatment was used by 30.8% of patients: octreotide-LAR in 18.6%, dopamine agonists in 9.8%, short-acting octreotide in 4.7%, pegvisomant in 4.1%, and lanreotide in 1.2%; 56% had biochemical monitoring. Comorbidities were common, ranging from 6.6% (colon neoplasms) to 25.6% (musculoskeletal abnormalities). Mean healthcare costs were $24,900. Adjusted analyses indicated comorbidities increased the odds of hospitalization: by 76% for musculoskeletal abnormalities; 193% for cardiovascular abnormalities; and 56% for sleep apnea (p < 0.05). Odds of emergency department visits increased by 87% (musculoskeletal) and 132% (cardiovascular abnormalities) (p < 0.01). After adjustments, colon neoplasms were associated with $8,401 mean increase in costs; musculoskeletal abnormalities with $7,502, cardiovascular abnormalities with $13,331, sleep apnea with $10,453, and hypopituitarism with $6,742 (p < 0.01). Complications are common and increase utilization and cost in acromegaly patients. Cardiovascular complications nearly tripled the odds of hospitalization (OR 2.93) and increased annual mean cost by $13,331. Adequate management of this disease may be able to reduce health care utilization and cost associated with these complications and with acromegaly in general.

Retrosellar intracranial extracerebral glioneuronal heterotopion: case report.

We report the case of an 18-year-old woman with an intradural retroclival retrosellar glioneuronal heterotopion. At the time of surgery, a well circumscribed pale-tan mass was identified posterior to and distinct from the posterior pituitary. Pathologic examination showed disorganized, non-neoplastic glial tissue characteristic of glioneuronal heterotopia. To our knowledge, this is the first report of such a lesion in this location.

Effects of a growth hormone receptor antagonist on bone markers in acromegaly.

OBJECTIVE: Excess GH secretion, as occurs in acromegaly, is associated with abnormalities in bone turnover markers and bone mineral density (BMD). GH administration in GH deficient patients causes an increase in bone turnover. IGF-I mediates many of the metabolic actions of GH, although GH may have direct effects upon bone. In patients with acromegaly who are treated with a GH receptor antagonist, selective blockade of the GH receptor results in a decrease in circulating IGF-I levels in the majority of cases. We hypothesized that, in acromegaly, antagonism of GH receptors would result in a decrease in serum markers of bone turnover, including serum procollagen I carboxy-terminal propeptide (PICP), osteocalcin and N-telopeptide (NTx). DESIGN AND SUBJECTS: Twenty-seven patients with acromegaly were enrolled as part of a multicentre 12-week trial of a GH receptor antagonist and were randomized to placebo (n = 7) or 10, 15 or 20 mg of pegvisomant (n = 20). MEASUREMENTS: Serum markers of bone turnover were determined at baseline and 12 weeks. RESULTS: Baseline bone turnover markers were above the upper limit of normal in 23%, 19% and 32% of subjects for osteocalcin, PICP and NTx, respectively. During the 12-week placebo-controlled period, there were significant decreases in serum markers of bone formation, osteocalcin (-2.2 +/- 0.44 vs. placebo +0.01 +/- 0.39 nmol/l, P = 0.009) and PICP (-23.6 +/- 9.6 vs. placebo +18.1 +/- 12.8 micro g/l, P = 0.022) and a serum marker of bone resorption, NTx (-4.4 +/- 1.4, placebo +1.0 +/- 0.3 nm, P = 0.024). CONCLUSIONS: Using a specific GH receptor antagonist, we found that normalization of IGF-I is associated with rapid reductions in markers of both bone formation and resorption, and that these processes remain coupled. These data confirm the highly significant effects of GH and IGF-I in modulating bone turnover. The independent contributions of GH and IGF-I to these effects and the long-term effects on BMD in this population remain to be determined.

Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.

BACKGROUND: Pegvisomant is a new growth hormone receptor antagonist that improves symptoms and normalises insulin-like growth factor-1 (IGF-1) in a high proportion of patients with acromegaly treated for up to 12 weeks. We assessed the effects of pegvisomant in 160 patients with acromegaly treated for an average of 425 days. METHODS: Treatment efficacy was assessed by measuring changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 patients who received pegvisomant by daily subcutaneous injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and are excluded from the efficacy analysis. FINDINGS: Mean serum IGF-1 concentrations fell by at least 50%: 467 mg/L (SE 24), 526 mg/L (29), and 523 mg/L (40) in patients treated for 6, 12 and 18 months, respectively (p<0.001), whereas growth hormone increased by 12.5 mg/L (2.1), 12.5 mg/L (3.0), and 14.2 mg/L (5.7) (p<0.001). Of the patients treated for 12 months or more, 87 of 90 (97%) achieved a normal serum IGF-1 concentration. In patients withdrawn from pegvisomant (n=45), serum growth hormone concentrations were 8.0 mg/L (2.5) at baseline, rose to 15.2 mg/L (2.4) on drug, and fell back within 30 days of withdrawal to 8.3 mg/L (2.7). Antibodies to growth hormone were detected in 27 (16.9%) of patients, but no tachyphylaxis was seen. Serum insulin and glucose concentrations were significantly decreased (p<0.05). Two patients experienced progressive growth of their pituitary tumours, and two other patients had increased alanine and asparate aminotransferase concentrations requiring withdrawal from treatment. Mean pituitary tumour volume in 131 patients followed for a mean of 11.46 months (0.70) decreased by 0.033 cm(3) (0.057; p=0.353). INTERPRETATION: Pegvisomant is an effective medical treatment for acromegaly.

Somatostatin receptor-specific analogs: effects on cell proliferation and growth hormone secretion in human somatotroph tumors.

Somatostatin (SST) acts through a family of seven transmembrane domain G protein-coupled receptors to inhibit hormone secretion and cell proliferation in a variety of neuroendocrine tissues. In normal and neoplastic human pituitary somatotroph cells, SST-specific receptor types (SSTR) 1, 2, 3, and 5 are prevalently expressed, and SST and its analogs have been shown to inhibit GH secretion. However, in somatotroph adenomas, little is known regarding: 1) effects of SST and its analogs on pituitary tumor proliferation; 2) the relationship between the effects of SST analogs on GH secretion and tumor cell proliferation; and 3) whether SSTR expression predicts the antiproliferative effects of SST analogs in human somatotroph tumors. We investigated the effects of SST-14, lanreotide, and SSTR 2 (BIM-23190) and SSTR 5 (BIM-23268) specific analogs in 18 somatotroph pituitary adenomas in primary culture. Our results showed that cell proliferation was significantly inhibited by SST-14, lanreotide, BIM-23190, and BIM-23268 in 4, 7, 3, and 4 tumors, respectively (range of proliferation suppression 5-60%; median, 16%). Tumors that were responsive to SSTR 2- and 5-specific analogs were also responsive to lanreotide. SST-14 inhibited GH secretion in 8 of 13 tumors; lanreotide, BIM-23190, and BIM-23268 inhibited GH secretion in six tumors each (range of GH secretion inhibition 23-43%; median 33%). SSTR 2 and 5 messenger RNA was expressed in all tumors investigated, whereas SSTR 1 and 3 messenger RNA was expressed in 11 and 12 tumors, respectively. We observed a dissociation between the in vitro effects of SST-14 or lanreotide on tumor cell proliferation and the effects on GH secretion in human somatotroph tumors. Although differences in receptor concentration and the presence of other SST receptor subtypes may play a role, the presence of SSTR 2 and/or 5 did not have a predictive value. These data suggest that inhibition of cell proliferation occurs independently of effects on GH secretory pathways. Further studies are needed to clarify the mechanism of SST induced antiproliferative effects.

Hypothalamic/pituitary function following high-dose conformal radiotherapy to the base of skull: demonstration of a dose-effect relationship using dose-volume histogram analysis.

PURPOSE: To evaluate the incidence and pattern of hypopituitarism from hypothalamic (HT) and pituitary gland (PG) damage following high-dose conformal fractionated proton-photon beam radiotherapy (PPRT) to the base of skull (BOS) region in adults. The relationship between dose, volume, and PG function is explored. METHODS AND MATERIALS: Between May 1982 to October 1997, 107 adults with non-PG and non-HT neoplasms (predominantly chordoma and chondrosarcomas) of the BOS were treated with PPRT after subtotal resection(s). The median age was 41.2 years (range, 17-75) with 58 males and 49 females. Median prescribed target dose was 68.4 cobalt gray equivalent (CGE) (range, 55.8-79 CGE) at 1.80-1.92 CGE per fraction per day (where CGE = proton Gy x 1.1). The HT and PG were outlined on planning CT scans to allow dose-volume histograms (DVH) analysis. All patients had baseline and follow-up clinical testing of anterior and posterior pituitary function including biochemical assessment of thyroid, adrenal, and gonadal function, and prolactin secretion. RESULTS: The 10-year actuarial overall survival rate was 87%, with median endocrine follow-up time of 5.5 years, thus the majority of patients were available for long-term follow-up. Five-year actuarial rates of endocrinopathy were as follows: 72% for hyperprolactinemia, 30% for hypothyroidism, 29% for hypogonadism, and 19% for hypoadrenalism. The respective 10-year endocrinopathy rates were 84%, 63%, 36%, and 28%. No patient developed diabetes insipidus (vasopressin deficiency). Growth hormone deficiency was not routinely followed in this study. Minimum target dose (Dmin) to the PG was found to be predictive of endocrinopathy: patients receiving 50 CGE or greater at Dmin to the PG experiencing a higher incidence and severity (defined as the number of endocrinopathies occurring per patient) of endocrine dysfunction. Dmax of 70 CGE or greater to the PG and Dmax of 50 CGE or greater to the HT were also predictive of higher rates of endocrine dysfunction. CONCLUSION: Radiation-induced damage to the HT & PG occurs frequently after high-dose PPRT to the BOS and is manifested by anterior pituitary gland dysfunction. Hyperprolactinemia was detected in the majority of patients. Posterior pituitary dysfunction, represented by vasopressin activity with diabetes insipidus, was not observed in this dose range. Limiting the dose to the HT and PG when feasible should reduce the risk of developing clinical hypopituitarism.

Hypogonadism in patients with acromegaly: data from the multi-centre acromegaly registry pilot study.

OBJECTIVE: Because acromegaly is an uncommon disorder, epidemiological data regarding the demographics of the disease such as the prevalence of hypogonadism have been limited. In order to derive clinical and epidemiological information, including underlying hormonal factors, regarding hypogonadism in patients with acromegaly, we performed a pilot study designed to develop a multi-centre acromegaly patient registry. DESIGN AND MEASUREMENTS: Medical records of patients with acromegaly seen between 1976 and 1996 at three Institutions were reviewed, and data were entered into a database using a secure internet website. Hypogonadism was defined as amenorrhoea in women and testosterone deficiency in men. Subanalysis was performed in patients with microadenomas and women less than 50 years of age, to include women of reproductive age. RESULTS: Information was available on 363 patients, of whom 54% were women. The mean age at diagnosis was 41 +/- 13 years. In subjects less than 50 years of age, hypogonadism was present in 59%. Hyperprolactinaemia was present in 45% and 21% of hypogonadal and eugonadal patients of reproductive age, respectively (P = 0.0003). GH levels were higher in patients with hypogonadism (P = 0.03). In patients < 50 years of age with microadenomas, hypogonadism was present in nine of the 22 (41%) patients, including 55% of the women and 27% of the men (P = ns). Hyperprolactinaemia was present in three of the 10 and four of the 14 of microadenoma patients with hypogonadism and eugonadism, respectively. CONCLUSION: We developed a web-based acromegaly patient registry and used it to show that hypogonadism is a frequent consequence of acromegaly, even in patients with microadenomas, who are not at risk from hypopituitarism due to local mass effects. We also demonstrated that prolactin and GH hypersecretion contribute to the pathogenesis of hypogonadism in acromegaly, and that hypogonadism may occur in microadenoma patients even in the absence of hyperprolactinaemia.

Primary medical therapy of micro- and macroprolactinomas in men.

The presentation and long-term therapeutic responses of PRL-secreting pituitary tumors in men have been only partially studied. Gender-specific differences in tumor size at clinical presentation and possible differences in tumor biology in men compared to women make it important to determine treatment outcomes of male patients with prolactinomas. We performed a retrospective review of men with prolactinomas medically managed at Massachusetts General Hospital between 1980 and 1997. We identified 46 male patients with prolactinomas managed with medical therapy alone. Twelve patients had microadenomas, defined as a serum PRL level greater than 15 ng/mL and a normal pituitary scan or a tumor smaller than 1 cm. Thirty-four patients had macroprolactinomas, defined by a serum PRL greater than 200 ng/mL and pituitary adenoma larger than 1 cm. Bromocriptine, quinagolide, and/or cabergoline were administered as medical therapy. All patients had at least one follow-up visit, and the most recent serum PRL measurement after initiating dopamine agonist therapy was reported. Baseline clinical characteristics for patients with macroprolactinomas and microprolactinomas showed a larger proportion of patients with macroprolactinomas reporting a history of headache (74% vs. 0%), whereas the prevalence of sexual dysfunction and testosterone deficiency was similar between the two groups. Median serum PRL at presentation was 99 ng/mL (range, 16-385 ng/mL) vs. 1,415 ng/mL (range, 387-67,900 ng/mL), in the microprolactinoma and macroprolactinoma groups, respectively. A normal PRL level was achieved in a similar percentage of men with microprolactinomas vs. macroprolactinomas (83% vs. 79%, respectively). Although the majority of patients in both groups were treated with bromocriptine, a comparable number of patients with microprolactinomas vs. macroprolactinomas achieved a normal PRL level with cabergoline therapy. The response rates for bromocriptine and cabergoline were similar in both groups. No patient with a microprolactinoma required hormone replacement therapy, in contrast to patients with macroprolactinomas, who required thyroid, testosterone, and/or glucocorticoid replacement therapy. No patient had evidence of an increase in tumor size during therapy. In summary, we investigated the clinical presentation and treatment outcome in men with prolactinomas. We found that normalization of serum PRL levels occurs in approximately 80% of men with prolactinomas. Of importance, dopamine agonist administration yielded similar biochemical remission rates in men with microprolactinomas and macroprolactinomas.

Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

The reliability and validity of the impact on lifestyle questionnaire in patients with acromegaly.

OBJECTIVES: Treatments for acromegaly, a growth hormone disorder, can be burdensome to patients, often requiring multiple self-administered injections daily. We developed the Impact on Lifestyle Questionnaire (ILQ) to measure the impact on patient's lifestyle imposed by the burden of injectable treatments for acromegaly. The primary objective of this study was to establish the reliability and validity of the ILQ. METHODS: The ILQ consists of the SF-12 and 30 additional questions. Thirty-four patients, from two sites, completed the ILQ and scales measuring related concepts. Fourteen patients also completed a retest survey 4 weeks later. Survey sample data were combined with ILQ data from another 56 patients with acromegaly for a factor analysis. Reliability was assessed with Cronbach's alpha and test-retest. Zero-order correlations were examined between ILQ subscales and symptoms, depression, SF-12 mental and physical components, a measure of self-care burden, appraisal of illness, and single-item measures of quality of life and satisfaction. RESULTS: The preconceived subscale structure was supported by factor analysis. These factors were internally consistent and stable over time. Good convergent validity was demonstrated between the Burden and Disruption scales with other measures of the burden of treatment. Patients indicated that they were generally compliant with therapy, and that treatment was not particularly burdensome or disruptive. Results based on the ILQ were consistent with other scales and qualitative responses. CONCLUSIONS: The ILQ has three subscales, Burden, Lifestyle Disruption, and Compliance, that are reliable and demonstrate preliminary evidence of construct validity.

Long-term mortality after transsphenoidal surgery for Cushing disease.

BACKGROUND: Untreated Cushing disease historically has a high mortality rate, but the long-term survival of patients with Cushing disease after transsphenoidal surgery has not been reported. OBJECTIVE: To determine long-term mortality rate in patients who are treated for Cushing disease with current management techniques. DESIGN: Retrospective case series. SETTING: Tertiary care center. PATIENTS: 161 patients (32 men and 129 women; mean age, 38 years) who were treated for Cushing disease between 1978 and 1996. INTERVENTION: Transsphenoidal adenomectomy and as-needed adjunctive therapy. MEASUREMENT: Record review with follow-up interview. RESULTS: The cure rate for patients with microadenomas who had no previous therapy was 90% (123 of 137). No perioperative deaths occurred (0 of 193 procedures [95% CI, 0.0% to 1.9%]). Follow-up data (mean, 8.7 years) were obtained for 99% of patients (159 of 161). Six patients died. The 5- and 10-year survival rates were 99% (CI, 97% to 100%) and 93% (CI, 88% to 99%), respectively. Survival was similar to that seen in an age- and sex-matched sample that was based on U.S. population data (standardized mortality ratio, 0.98 [CI, 0.44 to 2.2]; P > 0.2). CONCLUSION: Survival of patients treated for Cushing disease with current management techniques between 1978 and 1996 was better than the poor survival historically associated with this disorder.

Medical therapy for gonadotroph and thyrotroph tumors.

Gonadotroph adenomas, a common type of pituitary tumor, are not associated with syndromes of hormonal hypersecretion and thus present as pituitary macroadenomas with mass effects, or as incidentally discovered pituitary masses. When indicated, primary therapy is neurosurgery, but there may be a limited role for medical therapy in patients with residual disease. Thyrotroph adenomas are rare neoplasms that present with hyperthyroidism and local mass effects. Medical therapy may be effective in controlling tumor growth and in achieving euthyroidism, when surgery or radiation, or both, do not control the tumor.

Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting.

It is unknown whether hypogonadism contributes to decreased insulin-like growth factor I (IGF-I) production and/or how testosterone administration may effect the GH-IGF-I axis in human immunodeficiency virus (HIV)-infected men with the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). In this study, we investigate the GH-IGF-I axis in men with the AWS and determine the effects of testosterone on GH secretory dynamics, pulse characteristics determined from overnight frequent sampling, arginine stimulation, and total and free IGF-I levels. Baseline GH-IGF-I parameters in hypogonadal men with AWS (n=51) were compared before testosterone administration (300 mg, im, every 3 weeks vs. placebo for 6 months) with cross-sectional data obtained in two age-matched control groups: eugonadal men with AIDS wasting (n=10) and healthy age-matched normal men (n=15). The changes in GH-IGF-I parameters were then compared prospectively in testosterone- and placebo-treated patients. Mean overnight GH levels [1.8+/-0.3 and 2.4+/-0.3 vs. 0.90+/-0.1 microg/L (P=0.04 and P=0.003 vs. healthy controls)] and pulse frequency [0.35+/-0.06 and 0.37+/-0.02 vs. 0.22+/-0.03 pulses/h (P=0.06 and P=0.002 vs. healthy controls)] were comparably elevated in the eugonadal and hypogonadal HIV-positive groups, respectively, compared to those in the healthy control group. No significant differences in pulse amplitude, interpulse interval, or maximal GH stimulation to arginine administration (0.5 g/kg, i.v.) were seen between either the eugonadal and hypogonadal HIV-positive or healthy control patients. In contrast, IGF-I levels were comparably decreased in both HIV-positive groups compared to the healthy control group [143+/-16 and 165+/-14 vs. 216+/-14 microg/L (P=0.004 and P=0.02 vs. healthy controls)]. At baseline, before treatment with testosterone, overnight GH levels were inversely correlated with IGF-I (r=-0.42; P=0.003), percent ideal body weight (r=-0.36; P=0.012), albumin (r=-0.37; P=0.012), and fat mass (r=-0.52; P=0.0002), whereas IGF-I levels correlated with free testosterone (r=0.35; P=0.011) and caloric intake (r=0.32; P= 0.023) in the hypogonadal HIV-positive men. In a stepwise regression model, albumin (P=0.003) and testosterone (P=0.011) were the only significant predictors of GH [mean GH (microg/L)=-1.82 x albumin (g/dL) + 0.003 x total testosterone (microg/L) + 6.5], accounting for 49% of the variation in GH. Mean overnight GH levels decreased significantly in the testosterone-treated patients compared to those in the placebo-treated hypogonadal patients (0.9+/-0.3 vs. 0.2+/-0.4 microg/L; P=0.020). In contrast, no differences in IGF-I or free IGF-I were observed in response to testosterone administration. The decrement in mean overnight GH in response to testosterone treatment was inversely associated with increased fat-free mass (r=-0.49; P= 0.024), which was the only significant variable in a stepwise regression model for change in GH [change in mean GH (microg/L)=-0.197 x kg fat-free mass - 0.53] and accounted for 27% of the variation in the change in GH. In this study, we demonstrate increased basal GH secretion and pulse frequency in association with reduced IGF-I concentrations, consistent with GH resistance, among both hypogonadal and eugonadal men with AIDS wasting. Testosterone administration decreases GH in hypogonadal men with AIDS wasting. The change in GH is best predicted by and is inversely related to the magnitude of the change in lean body mass in response to testosterone administration. These data demonstrate that among hypogonadal men with the AWS, testosterone administration has a significant effect on the GH axis.

Long-term mortality after transsphenoidal surgery and adjunctive therapy for acromegaly.

To analyze the long term outcome after multimodality therapy for acromegaly, a retrospective review was performed on 162 patients who underwent transsphenoidal surgery at Massachusetts General Hospital between 1978 and 1996. The surgical cure rate for microadenomas was 91%, that for macroadenomas was 48%, and it was 57% overall. The surgical cure rate was significantly dependent on tumor size, but was not dependent on age or sex. An improvement in the surgical cure rate was noted over the course of the review, from 45% before 1987 to 73% since 1991. Long term follow-up was obtained in 99% of U.S. residents (149 of 151), with a mean follow-up period of 7.8 yr. Adjuvant radiation and/or pharmacological therapy was given to 61 patients. Of the entire group, 83% (124 of 149) were in biochemical remission as determined by normalization of serum insulin-like growth factor I levels or by GH suppression after oral glucose tolerance testing at last contact or at death. The recurrence rate was 6% at 10 yr and 10% at 15 yr after surgery in those patients who initially met the criteria for surgical cure. The 10-yr survival rate was 88%, and there were 12 deaths at postoperative intervals of 2-12 yr, with the most common cause of death being cardiovascular disease. A Cox proportional hazards model showed that patient-years with persistent disease carried a 3.5-fold [95% confidence interval (CI), 1.0-12; P = 0.02] relative mortality risk compared to those patient-years in remission. A Poisson person-years regression analysis showed no significant difference in survival between those 86 patients cured at operation and an age- and sex-matched sample from the U.S. population [standardized mortality ratio (SMR), 0.84; 95% CI, 0.3-2.2; P = 0.35]. A similar analysis on the entire group of 149 patients showed no significant difference in survival from that in a control sample (SMR, 1.16; 95% CI, 0.66-2.0; P = 0.3). Mortality risk for patient-years with persistent active disease after unsuccessful treatment vs. that in the U.S. population sample remained increased (SMR, 1.8; 95% CI, 0.9-3.6; P = .05). This analysis suggests that the decreased survival previously reported to be associated with acromegaly can be normalized by successful surgical and adjunctive therapy.

Effects of physiological growth hormone (GH) therapy on cognition and quality of life in patients with adult-onset GH deficiency.

GH replacement of adults with acquired GH deficiency (GHD) results in body composition changes including increases in lean mass and bone mineral density. However, the effects of long-term GH therapy on cognitive function are largely unknown, and there are conflicting data regarding quality of life. We performed a randomized, double-blind, placebo-controlled study of GH replacement in adults with GHD and measured cognition and sense of well-being using standardized psychometric tests before and after therapy. Forty men (median age 51 yr, range 24-64 yr) with a history of pituitary disease were randomized to GH therapy (starting dose, 10 +/- 0.3 micrograms/kg per day: mean treatment dose, 4 +/- 2 micrograms/kg per day) vs. placebo for 18 months, and GH doses were adjusted according to serum insulin growth factor-I levels. At baseline, the patients displayed a full-scale intelligence quotient (IQ) score nearly 1 SD above the normal mean. Mean scores on all cognitive tests fell within normal limits, and on many tests, fell above the mean. On tests of verbal learning and delayed visual memory, mean test scores fell below the mean (although within normal limits), suggestive of a relative compromise in the area of memory performance. Following 18 months of GH replacement therapy, there were no significant changes in cognitive function or quality of life. We conclude that acquired GHD in adult men is not associated with significant alterations in cognitive function as assessed by standardized tests, and chronic low-dose GH replacement therapy does not result in significant beneficial effects on cognitive function or quality of life. Although previous studies have suggested that GH replacement in adults with acquired GHD may improve quality of life, our data do not support the use of physiological GH replacement in GHD men for this indication.

Biochemical assessment of Cushing's disease in patients with corticotroph macroadenomas.

The majority of cases of Cushing's disease are due to an underlying pituitary corticotroph microadenoma (< or = 10 mm). Corticotroph macroadenomas (> 10 mm) are a less common cause of Cushing's disease, and little is known about specific clinical and biochemical findings in such patients. To define further the clinical characteristics of patients with corticotroph macroadenomas, we performed a retrospective review of Cushing's disease due to macroadenomas seen at Massachusetts General Hospital between 1979 and 1995. Of 531 patients identified with a diagnostic code of Cushing's syndrome, 20 were determined to have Cushing's disease due to a macroadenoma based on radiographic evidence of pituitary adenoma greater than 10 mm and pathological confirmation of a pituitary adenoma. A comparison review of charts of 24 patients with Cushing's disease due to corticotroph microadenomas identified on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/- SD) with macroadenomas and microadenomas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The baseline median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/day) for macroadenoma and microadenoma patients, respectively (P = 0.058). After the 48-h high dose dexamethasone suppression test, UFC decreased by 77 +/- 19% (mean +/- SD) and 91 +/- 7% in macroadenoma and microadenoma subjects, respectively (P = 0.04). Fifty-six percent of macroadenoma patients and 92% of microadenoma patients had greater than 80% suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHCS) excretion was 52 mumol/day (range, 25-786 mumol/day) and 44 mumol/day (range, 17-86 mumol/day) for macroadenoma and microadenoma subjects, respectively (P = 0.09). After the standard high dose dexamethasone suppression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/- 22% for macroadenoma and microadenoma subjects, respectively (P = 0.02). Fifty-three percent of patients with macroadenomas and 86% of patients with microadenomas had greater than 50% suppression of 17-OHCS after high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma patients and in 45% of microadenoma subjects (P = 0.05). Tumors were immunostained with the MIB-1 antibody for Ki-67 to investigate proliferation in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas vs. three (18%) microadenomas had labeling indexes greater than 3%, but this was not statistically significant. In summary, corticotroph macroadenomas are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of suppression of UFC or 17-OHCS after the administration of high dose dexamethasone in a patient with Cushing's disease does not necessarily imply the presence of ACTH-independent Cushing's syndrome and is more commonly seen in patients with corticotroph macroadenomas than in those with microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.

Prolactin pulsatile characteristics in postmenopausal women.

Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 +/- 4 yr) and in 2 control groups, 8 men (age, 25 +/- 8 yr) and 22 cycling women (age, 28 +/- 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 microg, i.v.) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.

Using quantitative CT to assess adipose distribution in adult men with acquired hypogonadism.

OBJECTIVE: Quantitative CT is a powerful tool that may be used to assess distribution of adipose and lean mass and bone mineral density in specific anatomic compartments. Testosterone deficiency (hypogonadism) is increasingly recognized in adult men and is associated with osteoporosis, diminished strength, and an increase in cardiovascular risk. We used quantitative CT to determine whether hypogonadism is associated with fat redistribution and altered bone density. SUBJECTS AND METHODS: Quantitative CT was performed at the level of the L4 vertebra in 26 men with adult onset testosterone deficiency and 17 eugonadal men of similar body mass index and age. Adipose area in the subcutaneous, visceral, and skeletal muscle areas was determined and trabecular bone density was measured. Values between the groups were compared using t tests. RESULTS: The ages of the hypogonadal and eugonadal men were 52 +/- 14 years and 51 +/- 8 years (p value not significant), respectively. Subcutaneous fat area was higher in the testosterone-deficient men than in the control subjects (270 +/- 101 cm2 versus 202 +/- 111 cm2; p = .046). Muscle fat area was higher in the hypogonadal men (6 +/- 3 cm2 versus 2 +/- 1 cm2; p = .001). Measurements of visceral fat were similar for both groups. Trabecular bone density was lower in the hypogonadal than in the eugonadal men (112 +/- 38 mg K2HPO4/dl versus 148 +/- 34 mg K2HPO4/dl, respectively; p = .003). CONCLUSION: Our findings indicate that testosterone deficiency is associated with a decrease in bone density and a redistribution of fat. Quantitative CT is a sensitive method that may be useful in determining alterations in regional adipose deposition in hypogonadal men and in evaluating the benefit of interventional therapy such as testosterone replacement.

Therapeutic role of androgens in the treatment of osteoporosis in men.

There has been much recent interest in the relationship between androgens and bone mineralization in men. Increases in serum androgens during puberty allow for skeletal maturation and the attainment of peak bone mass, and the persistence of normal testosterone secretion during adulthood is important for the maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. The administration of testosterone to androgen-deficient men leads to an increase in bone mass, particularly in the trabecular bone compartment, and a reduction in levels of surrogate markers of bone turnover, suggesting that androgens have a dampening effect on bone remodelling. In addition, the administration of androgens to eugonadal men with idiopathic osteoporosis, with resulting supraphysiological testosterone concentrations, may lead to increases in bone mineral density. The risk of osteopenia due to androgen deficiency and the benefits of testosterone substitution therapy or supraphysiological administration on bone will be reviewed.