Growth hormone treatment in adults with growth hormone deficiency: the transition.

The approval of GH treatment of adults with GH deficiency (GHD) raises issues regarding continuation of GH treatment in the GH-deficient child following achievement of near adult height. The transition period begins in late puberty and ends with full adult maturation and includes hormonal and many lifestyle changes. Children treated with GH should be retested near the time of reaching adult height to determine if they have persistence of GHD. Although most children with organic causes of GHD will again be found to have GHD on retesting, most of those with idiopathic GHD will not. Retesting usually involves measurement of IGF-I and stimulation with insulin-induced hypoglycemia or arginine-GHRH, but important questions remain about adjustment of established cut-offs for age and body mass index. Most studies have shown the benefit of GH treatment in young adults with GHD in body composition, especially the achievement of peak bone mass. It is important for pediatric endocrinologists to discuss the potential need for continued treatment beyond achievement of adult height at the time of initiation of GH treatment, especially in those children with organic causes of GHD.

The cold thyroid nodule: an analysis of diagnostic and therapeutic options.

We applied decision analysis to the controversy over the management of the solitary nonfunctioning thyroid nodule. Three standard management plans were considered: immediate subtotal thyroidectomy; a six month trial of thyroid suppression with L-thyroxine, with non-suppressible lesions being removed surgically; and aspiration cytology followed by surgery or thyroid suppression based on the cytologic examination. The literature formed the basis for quantitative assumptions of the analysis, including the consequences of thyroidectomy, the probability of malignancy, the types and prognoses of cancers found at operation, the likelihood of successful suppression adn relapse, and the possible results of aspiration cytology. We used Bayes' rule to revise the probability of cancer on the basis of cytological results. The relative worths of the 59 possible diagnostic and therapeutic outcomes were expressed as quality-adjusted life expectancies. The expected utility of each management plan was determined by "folding back" the decision tree. Although we found that each possible approach yielded a quality-adjusted life expectancy very close to that of the healthy population, aspiration biopsy with cytologic examination appeared slightly superior. Extensive sensitivity analyses demonstrated that either aspiration biopsy or immediate thyroid suppression was the treatment of choice over a wide range of assumptions, although in no case did the benefit exceed 1 year of life. We conclude that all therapies for cold thyroid nodule are essentially equal, viewed in terms of mortality and morbidity. The decision to operate, suppress or aspirate is thus a " tossup ", dependent in the individual case upon such subjective factors as psychological disutility , relative cost, and attitudes toward operative risk and long-term medical therapy. The controversy concerning the "best" management of the cold thyroid nodule is an illusion: quantitative analysis shows the futility of pursuing the debate any further.

Low plasma growth hormone binding protein in IDDM.

Poorly controlled insulin-dependent diabetes mellitus (IDDM) is associated with elevated basal plasma growth hormone (GH), disproportionally low insulin-like growth factor I (IGF-I) levels, and impaired somatic growth. These derangements in the GH-IGF axis imply a state of GH resistance. The mechanism of GH resistance is unknown; it may involve a defect at the level of the GH receptor, unresponsiveness due to a postreceptor defect in GH action, or both. To investigate a potential receptor involvement, we measured plasma high-affinity GH-binding protein (GHBP), which represents a truncated GH receptor and may reflect GH receptor levels in tissues, in patients with IDDM, patients with non-insulin-dependent diabetes (NIDDM), and nondiabetic control subjects. Patients with IDDM had significantly lower plasma GHBP levels than either patients with NIDDM or nondiabetic control subjects (mean value 18.2 vs. 24.6 and 23.8% GH bound/ml plasma, respectively, P less than 0.001). This difference persisted when only lean patients (less than 115% ideal body wt) were included in the analysis. Basal plasma GH levels were significantly elevated in IDDM compared with either patients with NIDDM or nondiabetic control subjects (mean 6.9 vs. 2.1 and 2.0 micrograms/L, respectively, P less than 0.001), whereas IFG-I levels were not significantly different in IDDM and NIDDM. No correlations were found between levels of GHBP and HbA1, duration of diabetes, or plasma GH. GHBP and IGF-I levels were significantly correlated in NIDDM but not in IDDM. We conclude that IDDM is associated with low GHBP levels and that GH resistance found in this disorder may be mediated, at least in part, by a decrease in GH receptor levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone therapy for hypopituitary adults: time for re-appraisal.

The advent of the production of large quantities of recombinant growth hormone (GH) has made it possible to have sufficient material to assess its efficacy in adult growth hormone deficiency (GHD). Although some studies have shown that patients who are severely deficient benefit from GH therapy, the spectrum of GHD is broad, and the degree of deficiency at times is very difficult to define. In some cases, benefit is not easily quantified, and some studies have claimed benefits that, although statistically significant, are either not clinically important or are so marginal as to be questionable in terms of cost, difficulty of administration and potential risks. The purpose here is to identify the current problems in the diagnosis of GHD, to discuss the rationale for GH therapy and to assess the potential effects of GHD as well as the benefits of GH therapy in GHD adults. We will include a commentary as to which effects appear more robust than others and which are likely to result in the greatest patient benefit. Finally, some attention will be paid to long-term safety issues that should be monitored to ensure that this medication is safe even for the patients with the greatest need.

Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with "conventional" insulin therapy.

Low-dose insulin infusion has recently been used to treat ketoacidosis. We have prospectively compared patients with ketoacidosis either treated with insulin infusion at the rate of 6 units per hour or with high-dose, intermittent subcutaneously administered insulin, with emphasis placed on the hormonal responses. Basal glucagon, cortisol, and growth hormone levels were elevated in both groups. Cortisol and growth hormone levels did not fall with therapy in either group but glucagon levels fell in parallel with glucose levels in both groups. There was no difference in the time taken for glucose levels to fall below 250 mg/100 ml between groups. Whereas both methods of therapy appeared to be equally effective, low-dose infusion had the advantages of ease of administration, a predictable, relatively linear rate of fall of glucose levels, and ability to be stopped abruptly in the event of hypoglycemia.

Effect of pregnancy on renal function in patients with moderate-to-severe diabetic renal insufficiency.

OBJECTIVE: Previous studies of patients with diabetic nephropathy and mild renal impairment have suggested no determination in renal function as a result of pregnancy. The objective of this study was to determine whether pregnancy may permanently worsen renal function in women with diabetic nephropathy and moderate-to-severe renal insufficiency. RESEARCH DESIGN AND METHODS: Eleven patients were identified with diabetic nephropathy and moderate-to-severe renal dysfunction (creatinine [Cr] > or = 124 mumol/l [1.4 mg/dl]) at pregnancy onset by retrospective chart review. Alterations in glomerular filtration rate were estimated by using linear regression of the reciprocal of Cr over time. An equal number of nonpregnant premenopausal type 1 diabetic women with similar degrees of renal dysfunction served as a comparison group for nonpregnant rate of decline of renal function and potential contributing factors. RESULTS: Mean serum Cr rose from 159 mumol/l (1.8 mg/dl) prepregnancy to 221 mumol/l (2.5 mg/dl) in the third trimester. Renal function was stable in 27%, showed transient worsening in pregnancy in 27%, and demonstrated a permanent decline in 45%. Proteinuria increased in pregnancy in 79%. Exacerbation of hypertension or preeclampsia occurred in 73%. Seven patients progressed to dialysis 6-57 months postpartum, with 71% (five of seven) of these cases attributed to acceleration of disease during the pregnancy. Student's tests and repeated-measures analysis of variance support a pregnancy-induced acceleration in the rate of decline of renal function. CONCLUSIONS: In this series, patients with diabetic nephropathy and moderate-to-severe renal insufficiency were found to have a > 40% chance of accelerated progression of their disease as a result of pregnancy.

Relationship Between Hyperglycemia and Heart Transplant Rejection.

PURPOSE: Hyperglycemia increases risks of kidney and liver transplant rejection. To determine whether perioperative and subsequent glycemic control was associated with increased risk of heart transplant rejection over the year after transplantation, we performed a retrospective analysis of glycemic control and rejection rates in heart transplantation patients. METHODS: Perioperative glucose levels were analyzed in 157 patients undergoing transplantation at Northwestern Memorial Hospital from June 2005 to December 2012 and compared in patients with and without rejection found on routine follow-up biopsy specimens. RESULTS: Grade ≤1R rejection on biopsy was observed in 116 patients and grade ≥2R rejection (grade requiring increased anti-rejection treatment) in 41 patients. Although no significant differences in the preoperative fasting or inpatient mean glucose levels were found, the mean glucose levels from discharge to 1 year trended higher in those with grade ≥2R compared to grade ≤1R (128.8 ± 40.9 versus 142.2 ± 46.6 mg/dL, P = .084). In a multivariable logistic regression model, neither the lowest nor highest quartile of glucose levels had significantly different odds ratios (ORs) for the development of ≥2R compared to the middle 50% glucose levels. Older age (OR 0.96, P = .020) and higher body mass index levels (OR 0.86, P = .004) were significantly associated with lower odds of developing grade ≥2R. CONCLUSIONS: Although the glucose trend regarding rejection was not statistically significant, we cannot exclude the possibility that much higher glucose levels would influence rejection rates.

Distribution of immunoreactive human growth hormone-like material and thyrotropin-releasing hormone in the rat central nervous system: evidence for their coexistence in the same neurons.

The distribution of a substance with human GH (hCG)-like immunoreactivity was studied in the rat brain after rapid fixation with acrolein. Using this method of tissue preparation, the hGH-like material (hGH-LM) was found in several hypothalamic and extrahypothalamic regions of the brain and extended into the spinal cord and posterior pituitary. On serial sections, the distribution of the hGH-LM was observed to be identical to that of TRH throughout the neuraxis. Sequential immunostaining of the hGH-LM and TRH in the same tissue section revealed the coexistence of these two peptides in the same neuronal cell bodies in the hypothalamus and brain stem and in beaded processes in all regions of the central nervous system studied. These findings demonstrate the intimate association between the hGH-LM and TRH in the central nervous system and raise the possibility that the hGH-LM forms part of a precursor hormone from which TRH is derived.

Immunohistochemical identification of a novel substance with human growth hormone-like immunoreactivity in rat brain.

Through use of an antiserum directed against hGH, an immunoreactive hGH-like material has been identified in the rat brain by peroxidase immunohistochemistry. Peroxidase-positive material was found in beaded, neuronal fibers in the external zone of the median eminence, lateral septum, and organum vasculosum of the lamina terminalis and was unaffected by prior hypophysectomy. After pretreatment with intraventricular colchicine, numerous immunoreactive neuronal cell bodies were visualized within the parvocellular medial division of the paraventricular nucleus, periventricular nucleus, dorsomedial nucleus, lateral hypothalamus, and preoptic area. Immunohistochemical staining was completely abolished by preincubation of the antiserum with 10(-6) M hGH, the 20,000 mol wt variant of hGH. hGH dimer, core peptide 20-64/135-167, proteolytically derived hGH fragments 1-134 and 147-91, and human placental lactogen. There was no diminution in staining after preincubation with hGH N-terminal fragment 1-43, hGH C-terminal fragment 171-191, rat GH, rat or human PRL, and numerous other neuropeptides and anterior pituitary hormones. Bilateral electrolytic ablation of the paraventricular nucleus area caused a loss of immunostaining in the median eminence. These results indicate the presence of a hitherto undescribed intrinsic neuronal system in rat brain that contains a substance bearing immunological similarity to the midportion of the hGH molecule and to human placental lactogen. It is proposed that this substance is part of a tuberoinfundibular neuronal system deriving from the parvocellular medial division of the paraventricular nucleus-immunoreactive perikarya and may, therefore, be involved in hypophysial regulation. It may also act as a neuromodulator of limbic lobe structures and other hypothalamic regions.

Human growth hormone and somatomedin C suppress the spontaneous release of growth hormone in unanesthetized rats.

To investigate the feedback control of GH secretion, we examined the effects of human GH (hGH) and somatomedin C (SmC) on spontaneous GH secretory surges in unanesthetized, freely moving rats. Under pentobarbital anesthesia a right atrial catheter and an intracerebroventricular cannula were placed 7-10 days before the experimentation. For iv studies, hGH (0.3 U/ml.h) was infused for 6 h after an iv loading dose (0.3 U) at the beginning of the experiments. For intraventricular injections, hGH (0.1 U/10 microliter) or SmC (500 ng/10 microliter) were injected into the lateral ventricle 2 h before the experiments. The equivalent dose of crystalline BSA diluted in the same vehicle solutions was administered to the same rat as a control on a separate day. Venous blood samples were collected every 20 min for 6 h. Intravenous and intraventricular administration of crystalline BSA did not affect the typical rat GH (rGH) surges which appeared about every 3 h and reached peak values of more than 300 ng/ml. The iv infusion of hGH significantly inhibited the amplitude of rGH surges compared to controls (planimetric areas under the secretory profile 752 +/- 172 vs. 1921 +/- 183, P less than 0.01, n = 6). rGH secretion was similarly inhibited by intraventricular hGH (701 +/- 127 vs. 2208 + 225, P less than 0.01, n = 6) and by intraventricular SmC (537 +/- 70 vs. 1503 +/- 114, P less than 0.01, n = 6). These findings suggest that both GH and SmC are active in the feedback regulation of rGH secretion.

Vasoactive intestinal peptide is a physiological mediator of prolactin release in the rat.

To determine whether VIP functions as a physiological PRL-releasing factor, the effects of immunoneutralization of endogenous vasoactive intestinal peptide (VIP) on the PRL secretory response to suckling and ether stress were assessed. Using a porcine VIP-thyroglobulin conjugate as antigen, a peptide-specific antiserum was generated in a rabbit which bound porcine VIP with a Kd of 5.1 X 10(-11) M and a maximum binding capacity of 1830 ng/ml. In a RIA, this antiserum demonstrated immunoreactive VIP in tissue extracts of various regions of the brain and gastrointestinal tract. IR VIP in extracts of cerebral cortex and hypothalamus coeluted with synthetic porcine VIP on Bio-Gel P-30 column chromatography. Using chronically implanted right atrial catheters for blood sampling to avoid effects of stress and anesthesia, PRL blood levels in normal controls began to rise almost immediately after initiation of suckling from basal values of 3.0 +/- 0.9 ng/ml to reach a plateau of 158.1 +/- 33.5 ng/ml after 40 min. When the VIP antiserum was administered immediately before initiation of suckling, the onset of the PRL response was delayed by 40 min, but PRL levels then rose at a slower rate to reach the plateau level of normal animals approximately 80 min later. When VIP antiserum was administered to rats who had been suckling for at least 1 h, PRL levels fell from a mean basal elevated level of 152.7 +/- 16.0 ng/ml to a nadir of 50.4 +/- 9.1 ng/ml 80 min after injection and then gradually returned to basal levels. The effect of VIP antiserum was studied in rats in whom PRL secretion was increased by exposure to ether, a stimulus that acts on the release phase of PRL secretion. In rats in whom the depletion-transformation of PRL was induced by a prior brief period of suckling, subsequent exposure to ether caused a rise in serum PRL levels. The response was completely blocked in rats given VIP antiserum, whereas animals given nonimmune serum showed a significant increase in serum PRL to 38.6 +/- 17.3 ng/ml. We conclude from these studies that VIP mediates the acute PRL response to suckling and is required for maintenance of PRL levels in continuously suckling animals but is not the only factor causing PRL elevation. Complete abolition by the VIP antiserum of the PRL response to ether indicates that the effect of the anesthetic is mediated entirely by the release of VIP. These findings are consistent with the view that VIP is a physiological PRL-releasing factor in the rat.

Clinical review 65. Evaluation and treatment of the patient with a pituitary incidentaloma.

Incidental pituitary adenomas are being found commonly with our improved neuroradiological imaging procedures. Screening for hormone oversecretion by these tumors appears to be warranted. For patients with macroadenomas, patients should also be screened for hypopituitarism. In the absence of visual field abnormalities or hypothalamic/stalk compression, it may be appropriate to observe such patients carefully with repeated CT or MRI scans. A limited amount of data suggests that significant tumor enlargement will occur in less than 15% of patients with microadenomas (7). However, all macroadenomas must start out as microadenomas, so periodic follow-up is indicated to assess this possibility. Macroadenomas, by their very existence at the time of detection, have already indicated a propensity for growth. Over the limited period of follow-up in the two series reported, significant growth occurred in almost one third of patients with macroadenomas (7, 8). Hemorrhage into such tumors is uncommon, but anticoagulation may predispose to this complication. When there is no evidence of visual field deficits, an attempt at medical therapy with a dopamine agonist is reasonable, realizing that only about 10% of such patients will respond with a decrease in tumor size. Surgery is indicated if there is evidence of tumor enlargement, especially when such growth is accompanied by compression of the optic chiasm, cavernous sinus invasion, or the development of pituitary hormone deficiencies.

Lack of modulation of pituitary hormone stress response by neural pathways involving opiate receptors.

To evaluate the role of the opiate-like peptidergic pathways in modulating the pituitary hormone response to stress, we measured the GH, PRL, and cortisol responses to hypoglycemia and exercise in normal subjects with and without pretreatment with naloxone, given in the centrally active dose of 0.4 mg iv. Basal serum levels of GH, PRL, and cortisol were not changed significantly by prior naloxone administration. The maximum incremental response of GH to exercise was significantly blunted (13.1 +/- 1.6 vs. 6.0 +/- 1.4; P less than 0.001) by prior naloxone administration. Pretreatment with naloxone did not affect the responses of GH, PRL, or cortisol to hypoglycemia or the PRL response to L-dopa. On the basis of these studies we conclude that the opiate-like peptidergic pathways are not important in the regulation of basal levels of GH, PRL, and cortisol and have only a modest modulating influence on the stress-induced release of the hormones, which may be obscured in the face of severe stress.

Effect of angiotensin-converting enzyme inhibition on pituitary hormone responses to insulin-induced hypoglycemia in humans.

Renin, angiotensin-II, and angiotensin-converting enzyme (ACE) have been found in the hypothalamus and pituitary in rats, and renin, angiotensinogen, and ACE have been found in human pituitary lactotrophs. To determine the physiological relevance of the renin-angiotensin system in the pituitary hormone response to stress in humans, we created significant inhibition of ACE by administering a clinically used dose (10 mg) of enalapril (E) 4 h before measuring the stress hormone responses to insulin-induced hypoglycemia. Eight fasting lean healthy males (aged 20-35 yr) were given either placebo (P) or E (10 mg, orally) in two studies separated by at least 5 days in a blinded study design. Glucose, ACTH, cortisol, PRL, and GH levels were measured before E or P and at 20-min intervals beginning 20 min before insulin administration. ACE levels were similar at baseline (E, 21.6 +/- 2.7; P, 22.4 +/- 2.4 mU/mL/min), but were significantly lower at the time of insulin injection with E treatment (E, 2.9 +/- 0.5; P, 20.9 +/- 2.5 mU/mL/min; P less than 0.001). The mean of the total area under the curve of PRL secretion was significantly lower for the E group (E, 3767.2 +/- 710.7; P, 4554.9 +/- 650.1 micrograms/L.min; P less than 0.05). Although the mean peak PRL levels were lower for the E group, this did not reach statistical significance (E, 53.0 +/- 9.7; P, 64.4 +/- 9.4 micrograms/L; 0.05 less than P less than 0.10). These differences in PRL responses appeared to be due primarily to substantial decreases in PRL responses with E in three of the eight subjects. No significant differences were found with ACTH, cortisol, or GH for basal levels, peak levels, or areas under the curve.

Pharmacokinetic studies of highly purified human prolactin in normal human subjects.

Previous estimates of PRL pharmacokinetics have been made using radioiodinated human PRL (hPRL) infusions or by measuring serum PRL disappearance following prolactinoma resection. The recent purification of hPRL in significant quantities made it possible to measure the clearance and volume of distribution directly. Studies were also carried out to determine absorption and clearance after im injection. In five normal men whose endogenous PRL secretion was suppressed by dopamine, a loading dose of hPRL (70-90 micrograms) followed by a constant infusion (1.39-2.9 ng/min) produced steady state serum PRL levels of 15.2-25.4 ng/mL by 30-60 min. The calculated mean volume of distribution was 7.3 +/- 2.9 (+/- SD) L. The calculated MCR was 71 +/- 19 mL/min X m2, and the calculated production rate was 802 +/- 377 micrograms/24 h X m2. The plasma disappearance half-life following discontinuation of the infusion was 37 +/- 10 min. The PRL infusate consisted primarily (75.6%) of a 22.5 K dalton species, probably PRL monomer, a component eluting at 45K daltons (16.1% of the total radioimmunoreactivity), probably dimer, and a small amount of a larger mol wt species. Serum obtained during dopamine infusion but before hPRL infusion contained 68.1% of the 22.5K, 7.2% of the 45K, and 24.7% of the larger mol wt moieties. During hPRL infusion in two men there was a relative decrease in the proportion of PRL monomer to 55% and 69% and a relative increase in the PRL dimer to 33% and 18%, respectively. hPRL was injected im in doses of 1, 2, 4, and 8 micrograms/kg without prior dopamine infusion. No significant changes in serum PRL levels occurred after the 1 and 2 micrograms/kg doses (n = 5). After the 4 micrograms/kg dose (n = 8), mean serum PRL levels rose from 10.0 +/- 1.8 (+/- SEM) ng/mL to peak levels of 13.1 +/- 1.8 ng/mL (P less than 0.01). After the 8 micrograms/kg dose (n = 7), PRL levels rose from 9.3 +/- 1.6 to 16.5 +/- 1.8 ng/mL (P less than 0.01). The PRL rise began between 60 and 80 min after injection; peak levels occurred at 160-180 min. In two men given 8 micrograms/kg who were sampled for an additional 3 h, PRL levels peaked at 200-220 min and began to fall by 220-240 min, but had not returned to baseline by 6 h. There were no side-effects of PRL administration, although the 8 micrograms/kg dose caused transient local discomfort.(ABSTRACT TRUNCATED AT 400 WORDS)

New technique for quantitation of pituitary adenoma size: use in evaluating treatment of gonadotroph adenomas with a gonadotropin-releasing hormone antagonist.

Because administration for 1 week of the GnRH antagonist Nal-Glu GnRH had been shown to decrease FSH secretion from supranormal to normal in men with gonadotroph adenomas, we investigated the effect of prolonged administration of Nal-Glu on the size of gonadotroph adenomas. To quantitate the effect of Nal-Glu GnRH on gonadotroph adenoma size, we first developed a technique for calculating adenoma volume. The technique involved collecting magnetic resonance (MR) imaging data from each adenoma at 1-mm slice intervals in the coronal, axial, and sagittal views and using the Softvu computer program to calculate adenoma volume from the MR data. The precision of this technique, as judged by the coefficients of variation of the calculations of the same view of the same study three times, was 1.7%, 1.0%, and 1.0% for each of three studies. When Nal-Glu GnRH (5 mg, sc, every 12 h) was self-administered for 3-12 months to five men with gonadotroph adenomas and supra-normal serum FSH concentrations, the serum FSH concentrations decreased to normal or below normal for the entire treatment period. Adenoma size, however, did not change during treatment in any of the five men. We conclude that calculating pituitary adenoma volume from MR data using the Softvu computer program is a highly reproducible technique, but that Nal-Glu GnRH is not an effective treatment for reducing gonadotroph adenoma size. The failure of Nal-Glu to reduce adenoma size despite its success in reducing FSH secretion suggests that FSH secretion from gonadotroph adenomas is dependent on endogenous GnRH, but growth of gonadotroph adenomas is not.

CV 205-502 treatment of hyperprolactinemia.

CV 205-502 is a nonergot oral dopamine agonist with specific D2 activity, which has a prolonged suppressive effect on serum PRL and may have fewer side-effects than other dopamine agonists. We treated 26 hyperprolactinemic women with this compound given as a single bedtime (hs) dose for up to 12 weeks. All had gonadal dysfunction, either amenorrhea or oligomenorrhea, and 15 had galactorrhea. The initial and subsequent doses were administered in a randomized fashion; the initial dose ranged from 0.01-0.05 mg, and the dose at 12 weeks ranged from 0.03-0.09 mg. The women were evaluated every 2 weeks, and the dose was increased by 0.02 mg every 4 weeks if the serum PRL level was greater than 20 micrograms/L. Of the 26 women initially enrolled, 24 completed 12 weeks of therapy, and 2 discontinued therapy because of side-effects. Thirteen women (54%) had return of menses, and 12 (80%) had either a decrease in or disappearance of galactorrhea. Serum PRL concentrations decreased to a variable degree in all patients; 13 (54%) achieved a normal serum PRL level (less than or equal to 20 micrograms/L). The mean (+/- SE) pretreatment serum PRL concentration was 129 +/- 34, and it was 29.9 +/- 5.9 micrograms/L after 12 weeks of treatment (P = 0.005). The mean (+/- SE) percent reduction in serum PRL was 66.5 +/- 5.0% (median, 78.0%). A dose response was not demonstrated (r = -0.08; P = 0.70) among the 6 dose groups during the last 4 weeks of therapy. In 5 women, serum PRL levels, measured frequently for 24 h after treatment remained low. Side-effects after the initiation of therapy included nausea, headache, and morning fatigue in 10 women. These symptoms caused 2 women to discontinue therapy; they subsided in the other women. An optimal dose was not determined and will probably need to be determined by titration in each patient. CV 205-502, given once daily, appears to be a safe and effective alternative to other dopamine agonists in the treatment of hyperprolactinemia.

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.

Galactorrhea, oligo/amenorrhea, and hyperprolactinemia in patients with craniopharyngiomas.

We report three patients with craniopharyngiomas who had galactorrhea, oligo/amenorrhea, and abnormal sellar tomograms, clinically suggesting the presence of a prolactinoma. One patient had an intrasellar craniopharyngioma (Rathke's cleft cyst) diagosed during surgical exploration of the pituitary fossa for removal of a suspected prolactinoma, and two had suprasellar caraniopharyngiomas whose presence was suspected on the basis of computed tomography. This finding emphasizes the importance of computed tomography in the evaluation of patients with the clinical presentation of a prolactinoma. In two patients, PRL levels were elevated before surgery and remained elevated after removal of the craniopharyngioma. In the third case, an initially normal serum PRL level became elevated after removal of the tumor.

Surgical cure of prolactinoma reverses abnormal prolactin repsonse to carbidopa/L-dopa.

To determine whether the abnormalities in dopaminergic regulation of PRL secretion in patients with prolactinomas persist after resection of the adenoma, we evaluated PRL inhibitory responses to L-dopa alone and L-dopa given after pretreatment with the dopa decarboxylase inhibitor carbidopa before and after transsphenoidal selective resection of prolactinomas in 23 women. Eighteen women were cured by surgery (normal PRL, menses, no galactorrhea), while 5 women were not cured. Preoperatively, the PRL inhibitory responses to L-dopa cured, 4 .3 +/- 3.8%; uncured, 50.1 +/- 5.5% of baseline) was blunted by pretreatment with the decarboxylase inhibitor carbidopa (cured, 79.1 +/- 4.1%; uncured, 76.8 +/- 9.2%). Postoperatively, this blunting disappeared in the cured patients (L-dopa, 49.1 +/- 3.5%; carbidopa/L-dopa, 56.3 +/- 5.1%), but the blunting persisted in the uncured patients (L-dopa, 49.3 +/- 7.9%; carbidopa/L-dopa, 69.3 +/- 4.2%). The return to normal of the carbidopa/L-dopa test in cured prolactinoma patients after surgery is evidence that in these individuals, preoperative abnormalities of secretion are due to either intrinsic abnormalities of the tumor or alteration of hypothalamic function secondary to tumor secretion. In those patients not cured by surgery, dynamic tests of function remain abnormal, findings attributable to either incomplete tumor resection or the presence, in some patients, of underlying hypothalamic dysregulation.