Influence of long term erythropoietin therapy on the hypothalamic-pituitary-thyroid axis in patients undergoing capd

OBJECTIVE: Treatment of anemia with recombinant human erythropoietin (rHuEpo) in hemodialysis patients has been associated with improvement of several abnormalities in hypothalamic-pituitary function. The aim of the present study is to investigate the effects of long term erythropoietin therapy on the hypothalamic-pituitary-thyroid hormone axis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Single center, prospective study. PATIENTS AND METHODS: Ten patients who were clinically stable and had been on CAPD were evaluated. Eleven age and sex matched healthy volunteers were chosen as controls. All of the patients were clinically euthyroid. All patients were on CAPD therapy and none of them had received rHuEpo treatment previously. In all patients after basal estimations of free T3, free T4, TSH, GH and prolactin levels, a bolus of 400 microg TRH was administered intravenously. Levels of TSH, GH and prolactin were measured in blood samples collected every 30 min of the 3 h test period. After the treatment with rHuEpo, TRH test with the same protocol was repeated. RESULTS: Before the improvement in serum hemoglobin levels with rHuEpo treatment, the patients on CAPD showed abnormal hypothalamic-pituitary-thyroidal functions, including delayed and prolonged TSH (NS), paradoxically elevated GH (p < 0.001) and increased and prolonged prolactin (p = 0.001) responses to TRH. After improvement of anemia with rHuEpo no significant difference was found between the patients and control groups for baseline TSH levels. In the patients peak TSH level and AUC of TSH secretion were significantly reduced after the treatment (p < 0.05 for both). Furthermore the improvement in anemia did not eliminate the paradoxic GH and prolonged prolactin responses to TRH administration. CONCLUSION: Some hypothalamic-pituitary-thyroid function abnormalities including delayed and blunted TSH, increased and prolonged prolactin and paradoxical GH responses to TRH administration were observed in uremic patients treated with CAPD and the improvement in anemia with rHuEpo seems to cause slight changes on the hypothalamic-pituitary-thyroid axis and peripheral thyroid hormones.     

Prolactin secretion in the human male is increased by endogenous oestrogens and decreased by exogenous/endogenous androgens

There is evidence that prolactin may be involved in testicular steroidogenesis, and we have therefore investigated whether there is feedback regulation of androgens/oestrogens on prolactin secretion in the human male. To assess this we have measured basal and TRH-stimulated prolactin levels in:
A) Six eugonadal men before and after 2 weeks' administration of the aromatase inhibitor Δ'-testolactone, which led to a fall in oestradiol levels with unchanged levels of testosterone. In these patients, prolactin levels decreased.
B) Six eugonadal subjects before and after 2 weeks' administration of dihydrotestosterone undecanoate. In these subjects, prolactin levels decreased.
C) Six agonadal subjects, tested after 12 weeks' treatment with dihydrotestosterone undecanoate and compared to
D) Six agonadal subjects who received no sex steroid treatment. Again, it was found that dihydrotestosterone treatment decreased prolactin levels in patients from Group C.
E) Six eugonadal subjects were also studied before and after 6 weeks' administration of the androgen receptor antagonist, spironolactone, and this treatment increased Prl secretion.
It is concluded that in the human male, endogenous oestrogens increase prolactin secretion whilst exogenous/endogenous androgens decrease prolactin secretion.     

Testicular Function and Prolactin Responsiveness to TRH and Cimetidine After Renal Transplantation

The hypothalamic-pituitary-testicular axis and the regulation of prolactin secretion were investigated in eleven male renal transplant recipients. Mean serum levels of testosterone and estrone were normal, whereas those of androstenedione and estradiol were low. Mean basal luteinizing hormone (LH) levels were slightly elevated, but the peak responses to 50 micrograms i.v. gonadotropin-releasing hormone (GnRH) were not dissimilar from controls. Both basal and GnRH-stimulated follicle-stimulating hormone (FSH) levels were elevated (p less than 0.02-0.05) and also positively correlated with the time spent on hemodialysis (p less than 0.005-0.002). Basal prolactin (PRL) levels were normal, in all subjects. Nine out of 11 patients had a normal PRL response to Thyrotropin-releasing Hormone (TRH). However only six out of 11 had a normal response to 200 mg i.v. Cimetidine (Cim). Three subjects normally responding to TRH failed to respond to Cim. Uremic primary hypogonadism is not fully reversed by renal transplantation: a slight defect in the pituitary LH release may persist and the impairment of the tubular testicular function is left unchanged. While uremic hyperprolactinemia is corrected, the responsiveness to PRL-stimulating agents, particularly Cim, is not restored to normal, reflecting a derangement at the pituitary as well as the hypothalamic level.     

TRH: Pathophysiologic and clinical implications

Summary Thyrotropin releasing hormone is thought to be a tonic stimulator of the pituitary TSH secretion regulating the setpoint of the thyrotrophs to the suppressive effect of thyroid hormones. The peptide stimulates the release of normal and elevated prolactin. ACTH and GH may increase in response to exogenous TRH in pituitary ACTH and GH hypersecretion syndromes and in some extrapituitary diseases.The pathophysiological implications of extrahypothalamic TRH in humans are essentially unknown.The TSH response to TRH is nowadays widely used as a diganostic amplifier in thyroid diseases being suppressed in borderline and overt hyperthyroid states and increased in primary thyroid failure. In hypothyroid states of hypothalamic origin, TSH increases in response to exogenous TRH often with a delayed and/or exaggerated time course.But in patients with pituitary tumors and suprasellar extension TSH may also respond to TRH despite secondary hypothyroidism. This TSH increase may indicate a suprasellar cause for the secondary hypothyroidism, probably due to portal vessel occlusion. The TSH released in these cases is shown to be biologically inactive.     

Absence of orgasm-induced prolactin secretion in a healthy multi-orgasmic male subject

In several studies we have recently demonstrated that orgasm induces prolactin secretion in healthy males and females. This suggests that prolactin may form a feedback regulator of the refractory period following orgasm. To examine this position we investigated the prolactin response of a healthy multi-orgasmic male subject. Blood was drawn continuously during masturbation-induced orgasm. The prolactin response of the case-subject was compared with that of nine healthy adult men with a normal refractory period. The case-subject showed no prolactin response to three orgasms. Data from this multi-orgasmic subject support the hypothesized role of plasma prolactin in contributing to sexual-satiation mechanisms.     

Thyrotropin-releasing hormone provocative release of prolactin and thyrotropin in acute head injury

The thyrotropin-releasing hormone (TRH) test was performed in 30 patients soon after trauma to evaluate the effects of acute head injury on hypothalamohypophyseal functions. Plasma prolactin (PRL) and thyrotropin (TSH) were measured before and after TRH loading. The basal level of the plasma PRL was elevated in patients with severe head injuries compared to those without. The patients with severe head injuries exhibited a lower PRL response to TRH. On the other hand, the basal level of plasma TSH and its response to TRH remained within the normal range. These findings suggest that the PRL data in the TRH test are significant in evaluating the severity of head injuries.     

Prolactin Secretion in Adolescent Boys with Hypogonadism

Basal and TRH stimulated plasma prolactin levels were determined in 24 pubertal boys with hypogonadism (Primary: n = 10; secondary: n = 4; tertiary (hypothalamic): n = 10) and controls matched for pubertal stage (n = 12). The differentiation between secondary and tertiary hypogonadism was made with the help of a prolonged LRH test. The TRH test was performed by injecting 200 mcg i.v. in one bolus and taking plasma samples at 0, 15, 30, 60 and 90 minutes. No statistically significant differences were found between any of the groups. It is concluded that determination of basal or TRH stimulated prolactin does not contribute to clarify the etiology of hypogonadism or to determine the grade of damage or dysfunction in the hypogonadic testes.     

Pituitary responsiveness to LHRH and TRH in men: effect of bromocriptine and clomiphene treatment

The effect of the concomitant use of bromocriptine and clomiphene on pituitary function was tested in 8 healthy men, who ingested either 100 mg of clomiphene, 5 mg of bromocriptine or 100 mg of clomiphene +5 mg of bromocriptine daily for 7 days. Plasma concentrations of FSH and LH increased similarly during clomiphene and clomiphene + bromocriptine intake. Bromocriptine decreased the plasma levels of prolactin (Prl) and this decrease was unaffected by clomiphene. The latter blunted the plasma LH response to LHRH whilst bromocriptine blunted the Prl response to TRH, but Clomiphene and bromocriptine together had no additive effects on gonadotrophin and Prl secretion. It thus seems likely that this combination offers no advantage over clomiphene alone in the treatment of normoprolactinaemic infertile men.     

Pancreatic exocrine and endocrine functions stimulated with secretin and thyrotropin-releasing hormone in patients with hyperparathyroidism]

This study was designed to investigate pancreatic exocrine and endocrine secretion stimulated with secretin and thyrotropin-releasing hormone (TRH) in hyperparathyroidism. Pancreatic exocrine secretion during 30 min stimulated by constant secretin infusion of 1U/kg/hour was significantly increased in patients with secondary hyperparathyroidism compared with controls and patients with primary hyperparathyroidism. Intravenous administration of TRH at a dose of 20 micrograms/kg/hour, superimposed on secretin, produced a significant decrease of pancreatic exocrine secretion in both primary and secondary hyperparathyroidism but not in control. Serum insulin, glucagon and secretin levels were significantly higher in the subjects of both primary and secondary hyperparathyroidism than those of controls. Serum glucagon and secretin levels were significantly higher in secondary hyperparathyroidism than primary hyperparathyroidism. The pancreatic endocrine secretion was not influenced by TRH administration. Pancreatic exocrine secretion was not changed by parathyroidectomy in patients with primary hyperparathyroidism. As for endocrine secretion, however, only serum secretin level decreased to the level before parathyroidectomy. In this study, it was speculated that the increase of pancreatic secretion in secondary hyperparathyroidism may be due to hypersecretinemia, and the decrease of exocrine secretion by TRH in primary and secondary hyperparathyroidism may be resulted from the direct effect of TRH on the pancreatic acinar cells.     

Effect of the nonsteroidal antiandrogen nilutamide on adrenal androgen secretion

The nonsteroidal androgen-receptor antagonist nilutamide has previously been shown to inhibit adrenal androgen steroidogenesis in patients with prostatic carcinoma treated in combination with an LHRH agonist. In order to understand better the mechanisms subserving this observation, we have studied the effects of nilutamide alone on the serum concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), and DHEA-sulphate (DHEA-S) in 12 patients with prostatic cancer and compared them with those achieved in 21 patients treated with the agonist D-Trp-6-LHRH. In addition, the adrenocorticotropic hormone (ACTH)-stimulated adrenal response and the thyrotropin releasing hormone (TRH)-stimulated prolactin (PRL) response observed in the patients treated with nilutamide were compared with a control group of healthy age-matched controls. No significant variation in the basal concentrations of adrenal androgens occurred either within or between both treatment groups. In response to ACTH, a decreased 17-α hydroxyprogesterone (17-OHP) accumulation and an augmented A/17-OHP ratio were observed in the antiandrogen group (P < 0.05 for both), suggesting the partial removal of the 17,20 lyase block which was distinctive of the untreated controls, while no significant difference was found for other steroids. Basal PRL levels were not affected by the antiandrogen, but the response to TRH was increased. We conclude that no significant inhibition of adrenal androgen secretion occurs after nilutamide or LHRH agonist treatment. Rather, administration of the antiandrogen alone may partially remove the physiologic decrease in adrenal androgen secretion observed in the elderly. © 1994 Wiley-Liss, Inc.     

Cervical sympathectomy affects adrenocorticotropic hormone and thyroid-stimulating hormone in rats

To examine the effects of bilateral cervical sympathectomy on the secretion of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), growth hormone (GH), and prolactin (PRL), 18 male rats were divided into three groups: control (Cont), sham operation (Sham), and bilateral cervical sympathectomy (Symp). All rats were kept under a normal circadian rhythm for 2 weeks. Subsequently, blood was collected and plasma ACTH as well as serum TSH, GH, and PRL levels were measured. The difference in ACTH levels between the Cont and Sham groups was not significant, but ACTH levels in the Symp group were significantly higher than those in the other groups. The difference in TSH levels between the Cont and Sham groups was also not significant, but TSH levels in the Symp group were significantly lower than those in the Cont group. There were no statistically significant differences in GH and PRL levels among these groups. The present results suggest that cervical sympathectomy in the rat increases ACTH secretion and decreases TSH secretion in the pituitary. These effects seem to be due to a mildly increased secretion of melatonin in the pineal body that probably in turn increases corticotropin-releasing factor (CRF) secretion and decreases thyrotropin-releasing hormone (TRH) secretion in the hypothalamus. Extrapolation of these findings to humans suggests that longterm and repeated stellate ganglion block would affect the pituitary secretions of ACTH and TSH.     

Physiology of the pituitary, thyroid and adrenal glands

The pituitary gland is made of clusters of cells producing specific hormones that control growth (growth hormones, GH), thyroid function (TH), adrenal function (ACTH), gonadal function (FSH and LH). In addition, the neurons that join the posterior pituitary (neurohypophysis) secrete vasopressin - the antidiuretic hormone involved in maintaining water balance.The negative feedback loop is the basic mechanism to control the regulation of all endocrine glands. Hypothalamic peptides - releasing hormones (e.g. TRH, CRH) reach the hypophysis via the portal venous system and induce the secretion of specific stimulating hormones (e.g. TSH, ACTH) that drive the end-target endocrine cells to secrete hormones (e.g. thyroid hormones - T3 and T4 or adrenal hormones - cortisol, DHEAS). The plasma levels of these circulating hormones inhibit the pituitary (short feedback) or the hypothalamus (long feedback) and limit the further release of releasing- and stimulating- hormones.The effects of circulating hormones on different tissues are mediated via specific receptors on the cell membrane (e.g. vasopressin receptors), in the cytoplasm (steroid receptor for cortisol) or in the nucleus (e.g. thyroid hormone receptors). Understanding the physiological effects of peripheral hormones helps understanding the mechanisms by which clinical signs and symptoms developed in diseases characterised by excessive hormone secretion (e.g. thyrotoxicosis, Cushing syndrome, phaeochromocytomas) or lack of hormone secretion (e.g. diabetes insipidus).     

Cyclosporine-induced alterations in the hypothalamic hypophyseal gonadal axis in transplant patients

We evaluated the response of 20 male patients, 13 cadaveric kidney and 7 heart transplant recipients, to the administration of 100 micrograms GnRH (gonadotropin-releasing hormone) and 500 micrograms TRH (thyrotropic-releasing hormone). All of the heart transplant recipients and 7 of the kidney transplant patients were receiving a combination of cyclosporine, azathioprine and prednisone; while the 6 remaining kidney transplant patients received azathioprine and prednisone. The patients receiving cyclosporine had decreased plasma levels of prolactin, and manifested a blunted response to TRH administration for prolactin and TSH. The heart transplant patients had a blunted response of LH and FSH to the administration of GnRH. The levels of testosterone were found to be low in all patients regardless of the immunosuppressant therapy. Despite the low testosterone levels, no increment in the concentration of LH or FSH was present. Intramuscular administration of HCG (human chorionic gonadotropin) (Ayerst Laboratories, New York, N.Y.) failed to increase the testosterone concentration in 5 of 6 patients with renal transplants, 3 taking cyclosporine and 3 taking azathioprine. This study suggests that cyclosporine has a selective effect on the hypothalamus and/or hypophysis, resulting in lower baseline levels of plasma prolactin and a pituitary insensitivity to TRH administration. In addition, FSH and LH were low or normal in the presence of low testosterone levels, suggesting that the hypothalamic pituitary gonadal axis is impaired. Furthermore, there may be a direct toxic effect of the immunosuppressant medications on the gonads, manifested as lower testosterone levels and inability to respond to the administration of HCG.     

Influence of naloxone on prolactin secretion in patients with acute and chronic renal failure

The influence of the opiate antagonist naloxone on chlorpromazine induced prolactin secretion was examined in 12 patients with acute renal failure (ARF), 12 patients with chronic renal failure (CRF) and in 12 healthy subjects. In all examined groups naloxone showed a suppressive effect on chlorpromazine induced prolactin secretion, which was more accentuated in normals and patients with ARF then with CRF. The results of these investigations suggest that endogenous opiates may be of importance in the regulation of prolactin secretion both in normals and uremic patients.     

Endocrine responses after thyrotrophin-releasing hormone stimulation and dexamethasone suppression tests in the major depressive syndrome

The effects of dexamethasone 1 mg on plasma cortisol levels and of thyrotrophin-releasing hormone (TRH) 200 micrograms on thyrotrophin (TSH), growth hormone and prolactin levels in 107 patients with a major depressive disorder (MDD) were compared with those in 87 healthy subjects. Individual hormonal responses and combinations of hormonal responses after administration of dexamethasone and TRH were evaluated as diagnostic aids for MDD by calculating sensitivity, specificity and efficiency for single and multiple hormonal abnormalities. In patients suffering from MDD, 65% of men, 74% of reproductive women and 71% of menopausal or hysterectomized (H/M) women had abnormal responses (sensitivity) to a dexamethasone suppression test (DST). When the DST and TSH responses to TRH were combined, 85% of men, 87% of reproductive women and 84% of H/M women had abnormal results. If the efficiency of the different combinations of hormone responses is calculated, a totally different picture emerges.     

Effects of Experimental Hyperprolactinemia and Clomiphene on Pituitary Responsiveness to LHRH and TRH in Men

The effect of clomiphene citrate during sulpiride-induced hyperprolactinemia on pituitary function was tested in 8 healthy men, who ingested 100 mg of clomiphene, 150 mg of sulpiride or 100 mg of clomiphene + 150 mg of sulpiride daily for 7 days. Clomiphene treatment increased FSH and LH plasma concentrations and this increase was unaffected by sulpiride-induced hyperprolactinemia. Sulpiride intake alone did not alter serum gonadotropin concentrations. A reduced LH response to LHRH during sulpiride intake was seen, whereas the FSH response was unchanged. The prolactin response to TRH was unaffected during the combined sulpiride + clomiphene ingestion. Sulpiride treatment did not change the basal and/or clomiphene-stimulated gonadotropin secretion in healthy men. Thus, oligozoospermic men using psychotropic drugs and/or with hyperprolactinemia may be suitable candidates for clomiphene treatment.     

Elevated Basal Levels and Exaggerated Responses to Thyrotrophin-Releasing Hormone of Prolactin and Thyrotrophin in Turner-Noonan-Syndrome

Basal levels of prolactin (Prl), FSH, LH, testosterone, estradiol, total thyroxine (T4), total triiodothyronine (T3) and thyrotrophin (TSH) were determined in four males with Turner-Noonan-Syndrome. The responsiveness of gonadotrophins to LH-RH (100 micrograms i.v.) and of Prl and TSH (200 micrograms i.v.) was studied. High basal levels and exaggerated responses to TRH of Prl were found in all patients. However no evidence of any of the well known causes of hyperprolactinaemia could be detected in them. The four men were with normal levels of T4 and T3 and showed exaggerated TSH responses to TRH. It is suggested that the alterations in Prl and TSH release are reflections of a congenital disorder in Turner-Noonan-Syndrome not yet well studied.     

Prolactin secretion in women after plastic breast augmentation and reduction

Prolactin secretion in women undergoing augmentation and reduction mammaplasties was studied by determining serum prolactin concentrations preoperatively, intraoperatively, and for one year postoperatively. Thyrotropin-releasing hormone tests for prolactin secretion were performed in a small subgroup of these patients. The subjects were 7 women undergoing reduction mammaplasty, 13 women undergoing augmentation mammaplasty, and 14 normal control women. Short-term (up to three days postoperatively) but not long-term changes in prolactin secretion were identified. Persistent hyperprolactinemia does not appear to be a common complication of plastic breast operations.     

Bromocriptine therapy in oligozoospermic infertile men

A prospective, randomized double-blind study with crossover using bromocriptine and placebo was performed on a group of 17 infertile males with idiopathic oligozoospermia. Twelve patients completed the duration of this study of eight months by receiving 5 mg of bromocriptine per day for four months followed by four months of placebo or vice versa. Prior to treatment, the sperm count was 8.76 +/- 1.32 (10(6)/ml). The hormonal profile was performed prior to treatment and included estimation of prolactin, T3, T4, thyroid stimulating hormone (TSH), testosterone, follicle stimulating hormone (FSH), and plasma LH. Stimulation studies using LHRH and TRH were also performed. All hormonal estimations were within normal limits. Compared to placebo, bromocriptine had no significant effect on sperm analysis, or basic hormonal profile. The stimulation test with luteinizing hormone releasing hormone (LHRH) was unchanged except for the basic plasma testosterone, which increased. The prolactin decreased following the thyrotropin releasing hormone (TRH) stimulation. Two pregnancies were noted four to six weeks following the end of treatment. Bromocriptine did not seem to be more effective than placebo in the treatment of idiopathic oligozoospermia.     

Gamma-aminobutyric acid and dysregulation of TSH secretion in uremic male rats

The role of gamma-aminobutyric acid (GABA) in the abnormal secretion of thyrotropic hormone (TSH) in uremia was studied in male Sprague-Dawley rats rendered renally insufficient by subtotal nephrectomy. Baseline TSH concentrations in normal control animals and in the uremic animals were similar. The peak TSH response to thyrotropin-releasing hormone (TRH; 5 micrograms i.v.) was significantly blunted in the uremic animals compared to the controls. Pretreatment of the uremic animals with the specific GABA antagonist, bicuculline (1.5 mumol i.v.) resulted in normalization of the peak TSH response to TRH. Bicuculline pretreatment, however, did not alter the basal secretion of TSH in either the normal or the uremic animals, and it also did not augment the TRH-stimulated TSH response in the normal animals. Sham-operated animals demonstrated basal and TRH-stimulated TSH responses comparable to the control group. In order to assess whether the weight loss associated with uremia could have accounted for the blunted TRH-stimulated TSH secretion in the uremic animals, a group of rats were starved so that their weights were comparable to those of the uremic animals. Basal and TRH-stimulated TSH responses in this group were not significantly different from the controls. Bicuculline pretreatment of the starved animals also failed to alter the basal and TRH-stimulated TSH responses. These data indicate that an increase in central gabaergic tone may be partly responsible for the blunted TSH response to TRH seen in uremia, but that GABA is not an important modulator of TSH secretion in the normal rat.