Functional evaluation of prolactin secretion in patients with hypothalamic-pituitary disorders.

Prolactin secretion was assessed in 23 patients with hypothalamic-pituitary disorders using L-Dopa suppression, chlorpromazine (CPZ), and thyrotropin-releasing hormone (TRH) stimulation tests. Based on the responses to these tests, three groups of patients were identified: those with panhypopituitarism (group I) and those with partial hypopituitarism either with (group II) or without (group III) evidence of hypothalamic involvement. Panhypopituitary patients (group I) consistently had low serum prolactin values and failed to respond to all tests. Patients with hypothalamic involvement (group II) exhibited (a) elevated basal prolactin values. (b) an increase in serum prolactin after TRH stimulation. (c) blunted response to L-Dopa, and (d) lack of response to chlorpromazine stimulation. Patients with partial hypopituitarism but without hypothalamic involvement (group III) had normal serum prolactin levels and suppressed normally after L-Dopa; although the magnitude of response to both stimulatory agents was significantly lower than normally found the ratio of prolactin levels post-CPZ and TRH (Delta prolactin CPZ/Delta prolactin TRH) was similar to the ratio of normal individuals suggesting that these patients (group III) had a normal hypothalamic-pituitary prolactin axis. In the 23 patients studied, the most consistent disorder of pituitary function proved to be an abnormal response to one or other of the three tests employed for the evaluation of prolactin secretion. Hence these tests have considerable potential as a sensitive screening procedure in the evaluation of patients suspected of having hypothalamic-pituitary disease.

Somatostatin analogues suppress the inflammatory reaction in vivo.

Somatostatin (Sms) and its agonist analogues inhibit the secretory activities of endocrine and neural cells. Recent studies have suggested that Sms has significant immunomodulatory properties. In this study, we examine the effects of two Sms octapeptide analogues on the inflammatory reaction in vivo. BIM 23014 (Somatulin) and Sandostatin were administered to male Sprague-Dawley rats subject to carrageenin-induced aseptic inflammation, at doses of 2-10 micrograms/rat, given either systemically or locally. Animals were killed 7 h after the induction of the inflammation, and the inflammatory exudates were aspirated and quantitated in terms of volume and leukocyte concentration. Sms analogues, administered via either route, significantly reduced the volume and the leukocyte concentration of the exudate in a time- and dose-dependent fashion. In corroboration of these, immunohistochemical evaluation of the levels of local inflammatory mediators, such as immunoreactive (Ir) TNF-alpha, Irsubstance P, and Ircorticotropin-releasing hormone, was inhibited significantly by Sms analogue treatment. These findings suggest that Sms analogues have significant antiinflammatory effects in vivo, associated with suppression of proinflammatory cytokines and neuropeptides. Furthermore, these data suggest that Sms agonists may be useful in the control of inflammatory reaction.

Suppression of androgen production by D-tryptophan-6-luteinizing hormone-releasing hormone in man.

Four male transsexual subjects were given a superactive luteinizing hormone-releasing hormone (LHRH) analogue, D-tryptophan-6-LHRH at daily doses of 100 micrograms for 3--6 mo. A decrease in beard growth, acne, and erectile potency was noted; the latter was documented objectively with the recordings of nocturnal penile tumescence episodes. Plasma testosterone and dihydrotestosterone levels fell to castrate values; basal prolactin and luteinizing hormone levels showed a small decline, whereas the acutely releasable luteinizing hormone was significantly suppressed. A rise of plasma testosterone from castrate to normal levels was demonstrable with the use of human chorionic gonadotropin. Discontinuation of treatment led to a normalization of erectile potency and plasma testosterone. The suppression of Leydig cell function by D-tryptophan-6-LHRH might have wide application in reproductive biology and in endocrine-dependent neoplasia (where it could replace surgical castration).

Sporadic hypoparathyroidism treated with teriparatide: a case report and literature review.

Herein we describe the case of a 64-year-old woman with hypoparathyroidism diagnosed at the age of 40, after an acute episode of tetany and seizures due to severe hypocalcemia. She was treated for more than 20 years with calcitriol and calcium supplementation but she presented with marked hypercalciuria and recently nephrolithiasis, although serum calcium was maintained at levels below normal range. Provided that any attempt to increase the recommended dose of calcitriol was leading to an exacerbation of hypercalciuria, we decided to enroll an alternative tool in the treatment strategy. In order to avoid further deterioration of renal function she was administered once-daily a subcutaneous (sc) injection of synthetic human parathyroid hormone (PTH 1-34) while doses of calcium and calcitriol were gradually decreased depending on the response of calcium metabolism in serum and urine samples taken periodically. Within two months of administration, PTH (1-34) significantly reduced the level of urine calcium excretion compared with calcitriol therapy and maintained serum calcium in the normal range. The relevant literature is reviewed in light of this alternative therapeutic approach in long-standing hypoparathyroidism, illustrating the potential benefits and the unresolved issues in parathyroid hormone replacement.

Glucose metabolism, insulin secretion and insulin sensitivity in juvenile hemochromatosis. A case report and review of the literature.

Among specific diabetes subtypes secondary to pancreatopathies, hereditary hemochromatosis is an inherited disorder of iron metabolism resulting in excessive iron overload and tissue damage in various organs. We here report the case of a man with the young-onset form of the disease and describe his glycaemic status before and during venesection therapy. A 25-year old man visited our clinic in Athens, Greece, with hypogonadotropic hypogonadism due to hereditary hemochromatosis. Genetic analysis revealed that he was suffering from the juvenile aggressive form and treatment was initiated with frequent phlebotomies in conjunction with androgen substitution. Within 18 months of therapy ferritin level was normalized and hypogonadism was fully restored. Despite severe iron overload, glucose tolerance remained normal during the various stages of the disease, although alterations in both insulin secretion and sensitivity were detected. Present data indicate that in juvenile hemochromatosis, the efficacy of the chelation therapy and probably the chronic interval required to restore normal iron concentration both play important roles in the formation of glucose metabolism characteristics.

Coronary artery bypass grafting in severe left ventricular dysfunction: excellent survival with improved ejection fraction and functional state.

OBJECTIVES: The present study evaluated our experience with coronary artery bypass grafting in patients with severe left ventricular dysfunction. BACKGROUND: Despite the ominous prognosis of advanced ischemic cardiomyopathy, coronary artery bypass grafting in this setting remains controversial because of concerns over operative risk and lack of functional or survival benefit. METHODS: We analyzed the data of 83 consecutive patients (69 men, 14 women, aged 42 to 83 years [mean 66.8]) with a left ventricular ejection fraction < or = 30% who underwent isolated coronary artery bypass grafting (without aneurysmectomy, valve replacement or other open heart procedures) performed by one surgeon during a 6-year period. The ejection fraction ranged from 10% to 30% (mean 24.6%). Preoperatively, 49% of patients had angina, 52% had congestive heart failure (17% with pulmonary edema) and 30% manifested significant ventricular arrhythmia. The mean number of grafts was 2.7/patient. The internal mammary artery was used in 82% of grafts to the left anterior descending coronary artery. The intraaortic balloon pump was required therapeutically (for angina or pump failure) in 19% of patients and was prophylactically placed preoperatively in another 43% of patients. RESULTS: The hospital mortality rate was 8.4% (7 of 83). The mortality rate was 3.3% (2 of 61) in those patients who did not require admission to an intensive care unit immediately before operation. Canadian Cardiovascular Society angina class improved postoperatively by 1.9 categories and New York Heart Association congestive heart failure class by 1 category. Left ventricular ejection fraction (assessed postoperatively in 68 of 76 hospital survivors) improved from 24.6% preoperatively to 33.2% postoperatively (36% increase) (p < 0.001). At 1 and 3 years, respectively, all-cause survival was 87% and 80% and freedom from cardiac death was 89.8% and 84.5%. CONCLUSIONS: In patients with coronary artery disease and advanced ventricular dysfunction: 1) coronary artery bypass grafting can be performed relatively safely, 2) good medium-term survival is attained, 3) improvement in left ventricular function can be documented objectively after bypass grafting, 4) quality of life is improved (as reflected by improvement in anginal and congestive heart failure status), and 5) the internal mammary artery can safely be used as a conduit. The use of coronary artery bypass grafting is encouraged for this group of patients and may provide a viable alternative to transplantation in selected patients.

Effects of estrogen deprivation due to breast cancer treatment.

Breast cancer is one of the main life-threatening diseases that a woman may have to face during her lifetime. The increasing incidence of breast neoplasia reported over the last few decades has led to widespread screening of women resulting in early diagnosis. One common but challenging question for most doctors, after the surgical excision of the lesion, is determination of the ideal adjuvant therapy for their patients for the achievement of maximum life expectancy with the best quality of life. Since the beginning of the last century, the knowledge that breast cancer arises from hormone-responsive tissues has long made use of hormone-blocking agents in the beneficial treatment of breast neoplasia. The discovery of new molecules with endocrine actions has rendered the use of adjuvant therapy in a tailor-made pattern too complicated, as these agents have a different mode of action, different adverse effects and probably different indications. The aim of the present review is to clarify these issues, analyzing the mechanism of action of available drugs and their actions on specific areas of uncertainty: cognitive function, cardiovascular system, urogenital tract, bone metabolism, weight gain, hot flushes and premature menopause. Regarding the efficacy of adjuvant therapy, there has been particular focus on the multiple hormonal-induced consequences of each regimen in order to provide the clinician with the available data for choosing the ideal therapy for the patient.

Opiates, prolactin, and the dopamine receptor.

The administration of a dopamine antagonist, chlorpromazine, and two opiates, morphine and methadone, resulted in a significant rise in serum PRL within 90-150 min. Prior administration of dopamine receptor agonists (apomorphine, levodopa, aand bromocriptine) blocked this effect. In contrast, cyproheptadine, a serotonin antagonist, did not. We suggest that the opiates induce hyperprolactinemia in man via dopamine receptor blockade.

Effects of morphine on serum growth hormone, cortisol, prolactin and thyroid stimulating hormone in man.

Morphine administration in man results in a significant increase in serum prolactin without altering the levels of growth hormone, thyroid stimulating hormone and cortisol. Apomorphine prevented the morphine induced prolactin rise. It is suggested that the effect on prolactin is not mediated via non specific stress or changes in the thyroid stimulating hormone releasing factor, but via suppression prolactin inhibiting factor or activation of a specific prolactin releasing factor.

Ineffectiveness of pyridoxine (B6) to alter secretion of growth hormone and prolactin and absence of therapeutic effects on galactorrhea-amenorrhea syndromes.

The acute effect of pyridoxine (B6) on serum GH and PRL levels and its chronic effects on galactorrhea in nine subjects (group I, n=4, idiopathic galactorrhea with normal PRL levels and normal menses; Group II, n=5, galactorrhea-amenorrhea with increased PRL levels) have been studied. Pyridoxine did not acutely alter GH or PRL levels. There was no decrease in galactorrhea, no resumption of menses and no decrease in PRL following tow months of B6 therapy. In contrast, bromocriptine was effective in suppressing galactorrhea and restoring normal menses in group II subjects and remains the therapy of choice for this purpose.

The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies affecting women of reproductive age; it is associated with hyperandrogenism, hyperinsulinemia, and dyslipidemia. This study was designed to assess the long term effects of a pure androgen receptor blocker, flutamide, on the lipid profile in women with PCOS and to examine the possible mechanisms by which androgens may exert their influence. Seventeen women with PCOS (10 obese and 7 lean) were studied. All subjects received a 12-week course of oral flutamide (500 mg/day). The baseline and posttreatment evaluations included lipid profile, androgen levels, insulin sensitivity, and serum catecholamine determinations. The primary outcome was the change in the ratio of low density lipoproteins (LDL) to high density lipoproteins (HDL). Treatment with flutamide was associated with a significant decrease in the LDL/HDL ratio by 23% (P = 0.005), in total cholesterol by 18% (P < 0.0001), in LDL by 13% (P = 0.002), and in triglycerides by 23% (P = 0.002). Flutamide treatment was also associated with a trend toward an increase in HDL (by 14%; P = 0.14). The effects on lipid profile were found regardless of obesity and were not associated with a change in weight. Furthermore, actions of flutamide on lipid metabolism were not associated with significant changes in circulating adrenaline or noradrenaline, glucose metabolism, or insulin sensitivity. This report has demonstrated for the first time that treatment with the pure antiandrogen, flutamide, may improve the lipid profile and that this effect may be due to direct inhibition of androgenic actions.

Urinary and plasma cyclic adenosine 3',5'-monophosphate in patients with idiopathic edema.

Urinary excretion and plasma concentrations of adenosine 3',5'-monophosphate were determined in idiopathic edema patients both at rest and after assumption of the upright position. Patients and normal subjects responded similarly to upright posture with decreases in urinary volume and creatine excretion and their urinary excretion of cyclic AMP was not significantly different. The plasma concentration of cyclic AMP was high in patients, both in the recumbent and upright positions, and its renal clearance (unlike that of creatinine) was low. Plasma cyclic AMP increased in response to upright posture both in patients and normal subjects. Even if the significance of elevated plasma cyclic AMP is unknown, its presence without an increase in urinary cyclic AMP suggests that the renal handling of cyclic AMP is abnormal is idiopathic edema; this may be related to an excessive beta-adrenergic tone.

Effect of clonidine on growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone in the serum of normal men.

Clonidine (0.15 mg iv), a selective noradrenergic receptor agonist, increased serum growth hormone (GH) levels (greater than 6 ng/ml) on 8 out of 12 administrations to 6 normal men. This increase was independent of the hypotensive effects of the drug and unrelated to changes in serum cortisol. Clonidine induced a hyperglycemic effect in all subjects which was greatest 15 min after commencint the injection. No changes in blood sugar or GH occurred after placebo injection. Apomorphine, a selective dopamine receptor agonist, elevated GH in each of these 6 subjects (greater than 10 ng/ml). Clonidine had no effect on serum prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), or thyroid-stimulating hormone (TSH). These data are compatible with a dual dopaminergic and noradrenergic mechanism modulating GH secretion in normal men and with the absence of a noradrenergic mechanism in the regulation of PRL, LH, FSH, or TSH.

Response of several adrenal steroids to ACTH stimulation in essential hypertension.

Plasma concentrations of progesterone (P), deoxycorticosterone (DOC), 17-hydroxyprogesterone (17-OH P), corticosterone (B), deoxycortisol (S), cortisol (F), and aldosterone were measured in 8 control subjects and in 10 patients with low and normal renin essential hypertension (EH) before and 4 and 8 h after an iv infusion of 25 units of ACTH. Secretion rates of 18-hydroxy-11-deoxycorticosterone (18-OH DOC) were measured for the 24 h prior to and the day of the ACTH infusions. The hypertensive patients had significantly higher plasma levels of aldosterone, DOC and S after ACTH than the controls, whereas plasma B levels were significantly lower. The low renin subgroup considered separately had significantly higher plasma levels of aldosterone and DOC than controls, and higher levels of B and lower levels of F than the normal renin subgroup in response to ACTH. Although not significantly different, the plasma levels of P and the secretion rate of 18-OH DOC tended to be higher, and plasma 17-OH P and F levels lower after ACTH in patients with EH than in controls. The low renin subgroup tended to have the highest plasma S levels and 18-OH DOC secretory rates and lowest F levels. Estimations of adrenal 11beta-hydroxylating efficiency in response to ACTH in patients and controls by plasma steroid ratios revealed significantly lower B/DOC ratios in both low and normal renin patients compared to controls, supported by somewhat lower F/S ratios in these patients, especially those in the low renin subgroup. Altered 17-hydroxylating efficiency seen by significantly lower 17-OH P/P ratios were also found in those with EH, supported by somewhat lower F/B and S/DOC ratios in these patients, agian especially in the low renin subgroup. These data are compatible with a pattern of altered adrenocortical steroid biosynthesis in essential hypertension bearing features similar to adrenal 11beta and 17alpha-hydroxylation deficiencies.

Pituitary hyperthyroidism. Case report and review of the literature.

A 58 year old woman with an enlarged sella turcica was found to have hyperthyroidism with a supranormal concentration of serum thyrotropin. Transsphenoidal microsurgery resulted in the removal of a chromophobe adenoma comprised mainly of thyrotropes. Postoperatively, serum thyrotropin, thyroxine and triiodothyronine levels fell within normal limits, and the patient maintained normal thyroid and pituitary function.

Reversible symmetric polyneuropathy with paraplegia after heart transplantation.

BACKGROUND: Neurotoxicity is a well-recognized side effect of cyclosporine therapy in transplant recipients. Cyclosporine can cause a wide range of adverse effects on both the central and peripheral nervous systems. METHODS: We present a case history of symmetric polyneuropathy with flaccid paraplegia, a rare neurological complication of cyclosporine administration. RESULTS: Blood levels of the drug above the therapeutic range accompanied the neurological manifestations. The syndrome subsided fully with dose reduction. Patients' symptoms were attributed to axonal degeneration of the peripheral nerves, according to electromyography findings. CONCLUSIONS: Cyclosporine neurotoxicity should always be considered in patients with neurological complications following transplantation. The case presented in this article illustrates an additional potential mechanism of this adverse effect, namely, axonal degeneration of the peripheral nerves, causing symmetric polyneuropathy.

Pharmacology of bromocriptine in health and disease.

Bromocriptine, a lysergic acid derivative with a bromine atom at position 2, has been found to have unique effects on the dopamine receptors in the pituitary and central nervous system and peripherally. It is rapidly and completely absorbed from the gut and is mainly excreted in the bile and faeces. It seems to have a particular specificity for the pituitary prolactinotrophe although it does have other effects in different diseases states. In spite of the fact that it is an ergot derivative, it is remarkably free of ergot vascular side effects in the doses needed for therapeutic benefit. The most common adverse effect are nausea, vomiting and postural symptoms. These can be overcome by starting at low doses and increasing the therapeutic levels. Its major use is in the suppression of prolactin in states where this hormone is elevated irrespective of cause. It has also been used in the treatment of acromegaly and is under investigation for use in other disease states probably linked with prolactin system or dopaminergic receptors.

Lanreotide in the treatment of patients with thyroid eye disease.

Octreotide, a potent synthetic somatostatin (SM) analogue, was recently evaluated and found to have a beneficial effect in thyroid eye disease (TED), mostly in those patients with a positive Octreoscan-111. Lanreotide (LRT; Somatuline-Ipsen), a new SM long-acting analogue, is more active than natural SM and shows a much longer duration of action. The aim of the present preliminary study was to evaluate the therapeutic effect of LRT in the treatment of TED. Five patients, three males and two females, mean age 50.6 +/- 7.6 S.D. (45-64) years, all with severe symptoms of TED were studied. A similar number of patients, matched for age, sex and severity of ophthalmopathy served as controls. All the patients and controls were investigated with orbital scintigraphy using 111 In DTPA-D-Phe1-octreotide (Octreoscan-111) and selected on the basis of positive octreoscan. The NOSPECS system, as adapted by Donaldson et al. (Journal of Clinical Endocrinology and Metabolism 1973 37 276-285) and a disease activity score, as proposed recently by an International Workshop, have been followed in this study in order to evaluate the response to treatment. The five patients who comprised the treatment group received 0.04 g LRT i.m. once every 2 weeks over a period of 3 months, after which the Octreoscan-111 was repeated. The control patients were given an injection of water i.m., also once every 2 weeks for 3 months, after which they were evaluated clinically. No Octreoscan-111 was performed in the controls. All patients and controls were evaluated by the same physician, who was unaware of the type of treatment used. A decrease in the NOSPECS score and the clinical activity score was regarded as a positive response, while no change or an increase in the NOSPECS score along with no clinical improvement was regarded as a negative response. After 3 months of treatment with LRT, four patients showed a statistically significant improvement in ophthalmopathy in both eyes and one in one eye. Three of the control patients with TED did not show any change, one showed a minor improvement in one eye and no change in the other and one showed deterioration in both eyes. An interesting finding was that orbital Octreoscan-111 activity was absent in all the patients after LRT treatment. In conclusion, these preliminary results show that LRT has a beneficial effect on patients with TED, and that since it has to be given only once every 2 weeks, it is probably superior to any other form of SM treatment. However, as the number of patients was small, further studies are needed to confirm our results.

Amenorrhea in beta-homozygous thalassemia major.

Hemolytic anemias, and, in particular, beta-homozygous thalassemia, derange all vital organs. A shift of the survival curve to the right has been achieved, thanks to the intensive programs of blood transfusion; iron chelation; infectious control; and, most recently, bone marrow transplantation. Metabolic and endocrine abnormalities do occur, albeit in less severe forms in comparison to available data from 10 to 20 years ago, for example, osteopenia. The most commonly encountered hormonal disorder is the attenuation of gonadal function on a downstream basis, linked to iron deposition in the hypothalamic-pituitary gonadotropin axis. A transition, from low-amplitude endogenous GnRH pulses to apulsatility of LH patterns, precedes the inability of the pituitary gonadotrope to respond to the GnRH decapeptide administered either as an acute bolus injection or in a pulsatile manner for up to 7 days.

Therapeutic use of gonadotropin-releasing hormone agonists in polycystic ovarian syndrome.

Polycystic ovarian syndrome is a heterogeneous disorder characterized by abnormal function of the hypothalamic-pituitary-gonadal axis, excessive production of androgens, aberrant intermediary metabolism, and structural changes in ovarian morphology. Long-term administration of the GnRH agonistic analogues brings about pituitary gonadotroph down-regulation after an initial period of stimulation of FSH/LH release. The resulting decrease in LH output and ovarian androgen production exerts beneficial effects on the clinical and biochemical parameters of the PCO syndrome. Ovarian volume and stroma usually decrease, but the results of treatment are not permanent, since relapse of the syndrome is usually observed a few months after cessation of the agonist. There are no serious side effects, and a small decrease in bone mineral content is recovered after discontinuation of the treatment. Possible indications for this regime include patients with very large ovaries and resistant hyperandrogenemia. On the other hand, the use of GnRH agonists in the preparation of PCOS patients for ovulation induction is already established.