Craig A. Jaffe

Regulatory mechanisms of growth hormone secretion are sexually dimorphic.

Sexually dimorphic growth hormone (GH) secretory pattern is important in the determination of gender-specific patterns of growth and metabolism in rats. Whether GH secretion in humans is also sexually dimorphic and the neuroendocrine mechanisms governing this potential difference are not fully established. We have compared pulsatile GH secretion profiles in young men and women in the baseline state and during a continuous intravenous infusion of recombinant human insulin-like growth factor I (rhIGF-I). During the baseline study, men had large nocturnal GH pulses and relatively small pulses during the rest of the day. In contrast, women had more continuous GH secretion and more frequent GH pulses that were of more uniform size. The infusion of rhIGF-I (10 microg/kg/h) potently suppressed both spontaneous and growth hormone-releasing hormone (GHRH)-induced GH secretion in men. In women, however, rhIGF-I had less effect on pulsatile GH secretion and did not suppress the GH response to GHRH. These data demonstrate the existence of sexual dimorphism in the regulatory mechanisms involved in GH secretion in humans. The persistence of GH responses to GHRH in women suggests that negative feedback by IGF-I might be expressed, in part, through suppression of hypothalamic GHRH.

Androgen deprivation therapy for prostate cancer results in significant loss of bone density

OBJECTIVES Advanced prostate cancer is a frequently diagnosed condition in the aging male population, and many men will ultimately be treated with androgen deprivation therapy (ADT). Long-term consequences of ADT on bone mineral density (BMD) have not been systematically studied. We performed a pilot study to test the hypothesis that ADT in patients with prostate cancer results in the measurable loss of BMD. METHODS A cross-sectional study of 32 men with prostate cancer who were about to begin ADT or who had been receiving ADT for more than 1 year was conducted. BMD was measured by single and dual energy x-ray absorptiometry in the lumbar spine, hip, and forearm. Linear regression analysis was used to estimate the time necessary to develop significant BMD loss in the spine, hip, and forearm regions. RESULTS Five (63%) of 8 men who had not received ADT and 21 (88%) of 24 men who had received ADT for more than 1 year fulfilled the BMD criteria for osteopenia or osteoporosis at one or more sites. When BMD was compared at each site, men who received ADT for more than 1 year had significantly lower BMD in the lumbar spine than men who had not started treatment (P<0.05). On the basis of regression analysis, an estimated 48 months of ADT would be necessary to develop BMD criteria for osteopenia in the lumbar spine for a man with average BMD at the initiation of therapy. CONCLUSIONS Pre-existing osteopenia and osteoporosis were common in men with prostate cancer before initiating ADT. Both ADT and the duration of ADT were significantly associated with the loss of BMD in men with prostate cancer.

Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin.

To investigate the mechanisms of the negative feedback inhibition of growth hormone (GH) secretion by IGF-I, we studied parameters of GH pulsatility in six normal, fed men before and during a 48-h infusion of recombinant human IGF-I (rhIGF-I) (10-15 micrograms/kg per h). Plasma levels of IGF-I increased from the baseline value of 163.5 +/- 9.3 micrograms/liter (mean +/- SE) to a new steady state of 452.0 +/- 20.9 micrograms/liter during the infusion. Plasma GH concentrations were measured every 10 min for 24 h during both saline and rhIGF-I infusions using a sensitive chemiluminescent assay. Overall, GH concentrations were suppressed during the rhIGF-I infusion by 85 +/- 3%, mainly by attenuating spontaneous GH pulse amplitude (77 +/- 4% suppression). The apparent GH pulse frequency was attenuated from 7.8 +/- 0.9 to 4.7 +/- 0.6 pulses/24 h (P = 0.006). Administration of rhIGF suppressed GH responses to exogenous GH-releasing hormone by 82 +/- 3%, and thyroid-stimulating hormone responses to thyrotropin-releasing hormone were also suppressed by 44 +/- 9%. This constellation of hormonal effects is most compatible with the rhIGF-I-induced stimulation of hypothalamic somatostatin secretion.

Suppression of growth hormone (GH) secretion by a selective GH-releasing hormone (GHRH) antagonist: Direct evidence for involvement of endogenous GHRH in the generation of GH pulses

To study the potential involvement of growth hormone-releasing hormone (GHRH) in the generation of growth hormone (GH) pulses in humans we have used a competitive antagonist to the GHRH receptor, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2(GHRH-Ant). Six healthy young men were given a bolus injection of GHRH-Ant 400 micrograms/kg body wt or vehicle at 2200 h and nocturnal GH concentrations were assessed by every 10-min blood sampling until 0800 h. Integrated total and pulsatile GH secretion were suppressed during GHRH-Ant treatment by 40 +/- 6 (SE) % and 75 +/- 5%, respectively. GHRH-Ant suppressed maximum (7.6 +/- 2.2 vs 1.8 +/- 0.5 micrograms/liter; P < 0.001) and mean (3.3 +/- 1.0 vs 1.1 +/- 0.2 micrograms/liter; P = 0.02) GH pulse amplitudes. There was no change in integrated nonpulsatile GH levels, pulse frequency, or interpulse GH concentration. GHRH-Ant 400 micrograms/kg also suppressed the GH responses to intravenous boluses of GHRH 0.33 micrograms/kg given 1, 6, 12, and 24 h later by 95, 81, 59, and 4%, respectively. In five healthy men, the responses to 10-fold larger GHRH boluses (3.3 micrograms/kg) were suppressed by 82 and 0%, 1 and 6 h after GHRH-Ant 400 micrograms/kg, respectively. These studies provide the first direct evidence that endogenous GHRH participates in the generation of spontaneous GH pulses in humans.

Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli.

The roles of hypothalamic growth hormone-releasing hormone (GHRH) and of somatostatin (SRIF) in pharmacologically stimulated growth hormone (GH) secretion in humans are unclear. GH responses could result either from GHRH release or from acute decline in SRIF secretion. To assess directly the role of endogenous GHRH in human GH secretion, we have used a competitive GHRH antagonist, (N-Ac-Tyr1,D-Arg2)GHRH(1-29)NH2 (GHRH-Ant), which we have previously shown is able to block the GH response to GHRH. We first tested whether an acute decline in SRIF, independent of GHRH action, would release GH. Pretreatment with GHRH-Ant abolished the GH response to exogenous GHRH (0.33 microgram/kg i.v.) but did not modify the GH rise after termination of an SRIF infusion. We then investigated the role of endogenous GHRH in the GH responses to pharmacologic stimuli of GH release. The GH responses to arginine (30 g i.v. over 30 min), L-dopa (0.5 g orally), insulin hypoglycemia (0.1 U/Kg i.v.), clonidine (0.25 mg orally), or pyridostigmine (60 mg orally) were measured in healthy young men after pretreatment with either saline of GHRH-Ant 400 microgram/kg i.v. In every case, GH release was significantly suppressed by GHRH-Ant. We conclude that endogenous GHRH is required for the GH response to each of these pharmacologic stimuli. Acute release of hypothalamic GHRH may be a common mechanism by which these compounds mediate GH secretion.

Insulin-like growth factor-1, insulin-like growth factor binding protein-3, and body mass index: clinical correlates of prostate volume among Black men

OBJECTIVES To examine the relationship between insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and body mass index and prostate volume, as a surrogate marker for benign prostatic hyperplasia, in a community-based sample of black men. Epidemiologic studies examining the role of IGF-1 and IGFBP-3 suggest that increased levels of serum IGF-1 and decreased levels of serum IGFBP-3 are associated with an increased risk of prostate cancer. Few studies have examined these factors with respect to benign prostatic hyperplasia, and these have been limited to white men. METHODS The study population consisted of a sample of 364 black men, 40 to 79 years of age, residing in Genesee County, Michigan. Men with prostate cancer or prior prostate surgery were excluded. All subjects completed a clinical examination, which included a complete urologic examination with transrectal ultrasonography, anthropometric measurements, and serum assays for IGF-1 and IGFBP-3. RESULTS Multivariable regression models demonstrated that prostate volume increased with increasing age (P <0.0001) and body mass index (P = 0.03). IGFBP-3 rather than IGF-1 was positively associated with increasing prostate volume (P = 0.003). CONCLUSIONS This is the largest study describing the relationships between IGF-1, IGFBP-3, and body mass index and prostate volume, and the only study in black men. Although earlier studies demonstrated an association between IGF-1 and prostate cancer risk, our findings indicate that IGFBP-3 is more relevant for prostate enlargement, suggesting that IGF-1 and IGFBP-3 may play different pathophysiologic roles in benign and malignant prostatic conditions.

Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism

Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.

Acromegaly. Recognition and treatment.

Acromegaly is a chronic debilitating disease caused by growth hormone (GH) hypersecretion, usually from a pituitary adenoma. It is frequently diagnosed after many years of active GH hypersecretion, and causes significant morbidity and mortality due to cardiac, pulmonary and musculoskeletal changes. Local complications resulting from the pituitary tumour can also occur. The most important feature that will enable a physician to diagnosis the disease is clinical vigilance. Measurement of elevated plasma mecasermin (insulin-like growth factor I, IGF-I) is the single best test to make the diagnosis. Once the diagnosis is confirmed, a GH-secreting tumour should be sought, by performing a careful magnetic resonance imaging or computed tomography scan of the pituitary gland and hypothalamus. Therapy is directed at both preventing local complications of the tumour mass as well as normalising GH secretion. Surgical resection of the tumour is almost always the first step in treatment. If GH secretion is not normalised, which is best assessed by determining whether plasma IGF-I returns to the normal range, further treatment with radiation and/or medical therapy is required. Bromocriptine normalises GH in approximately 10% of patients and causes pituitary shrinkage in a similar fraction of patients. Octreotide is considerably more expensive than bromocriptine and is given subcutaneously, but is more effective in both normalising GH secretion and in shrinking tumours. Octreotide treatment of the pituitary tumours prior to surgical resection may be of value, but requires further investigation.

Reevaluation of Conventional Pituitary Irradiation in the Therapy of Acromegaly

External beam pituitary irradiation has been frequently used in the treatment of growth hormone (GH) secreting pituitary adenomas. Many studies have demonstrated that serum GH declines rapidly and reliably following treatment and early “cure” rates, based on a basal serum GH below 10 µg/L were as high as 80%. The definition of “cure” has become more stringent over time and retrospective studies have indicated that GH must be below 2.5 µg/L for acromegalics to achieve mortality rates comparable to a normal population. Only 20% of irradiated patients will achieve this goal by 10 yr. Even fewer will achieve a normal serum insulin-like growth factor I (IGF-I) levels. Although pituitary irradiation still has a role in the control of tumor size, its importance as a treatment for normalizing serum GH is being reevaluated.

Cryptococcal Thyroiditis and Hyperthyroidism

We report a case of cryptococcal thyroiditis presenting with hyperthyroidism that evolved through a transient euthyroid phase to hypothyroidism and finally recovered to normal function. This four-phase clinical presentation is similar to that of subacute thyroiditis, and it is unusual in the setting of infectious nonviral thyroiditis. Cryptococcal thyroiditis is rare; only three cases have been reported. Our patient is the first who survived the disseminated cryptococcal infection with thyroid involvement, thus enabling longitudinal clinical and endocrinologic follow-up.