Prolactin in patients with major depressive disorder and in healthy subjects. II. Longitudinal study of basal prolactin and post-TRH-stimulated prolactin levels

Longitudinal investigations of basal prolactin (PRL) and prolactin concentrations following thyrotopin-releasing hormone (TRH) stimulation (delta PRL) were conducted in 17 patients with major depressive disorder and healthy subjects. The patients were being treated with either clomipramine or maprotiline. Both basal and delta PRL increased significantly after clinical response during treatment with both drugs. However, these increases in basal and delta PRL were independent of each other. Surprisingly, elevations of basal PRL were significantly greater in responders than in nonresponders, whereas those in delta PRL showed no corresponding significant difference. These results suggest that the two drugs stimulate basal and delta PRL by different mechanisms. The increases in basal prolactin levels found in responders may possibly be due to weaker inhibition of prolactin due to "down-regulated" beta adrenergic receptors and/or enhanced activity of supersensitive serotonergic receptors. Neither basal PRL nor delta PRL proved to be a predictor of therapy response. The intraindividual retest reliabilities of both basal and delta PRL in healthy subjects was so good that a single blood sample would seem to be sufficient for investigating most issues involving PRL in psychiatric patients.     

Peripheral white blood cells and HPA axis neurohormones in major depression

Alterations in peripheral blood leukocyte distribution in major depression, including leukocytosis, neurotrophilia and lymphopenia, have been described. To assess peripheral white blood cells and the hypothalamic-pituitary (HP) axis in drug-free patients with major depression, we measured the total white blood cell count (WBC), and percentage of lymphocytes, and the plasma levels of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH) and prolactin (PRL). Twenty male patients with major depression had relative lymphopenia and leukocytosis when compared with 20 age, sex and racematched control subjects. Elevated Beck and Hamilton depression scores correlated with a decreased percentage of lymphocytes, in a group of all subjects combined. There was a weak tendency for elevated growth hormone to correlate with relative lymphopenia in the control subjects only. Relative lymphopenia and leukocytosis may be a part of the psychobiology of major depression.     

Immune cells and the hypothalamic-pituitary axis in major depression

To explore changes in immune cell status with changes in the hypothalamic-pituitary (HP) axis in 20 patients with major depression as compared with 20 age-, sex-, and race-matched control subjects, we examined peripheral blood mononuclear cells (PBMC) for total T-cells (T3), total B-cells (B1), two T-cell subsets (T4 and T8), and natural killer cells (NKH1), and we measured the plasma level of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin (PRL). The ratio of T4/T8 was increased in the patients. Within the group of control subjects only, increasing age correlated significantly with decreasing plasma PRL. Within the group of patients only, GH positively correlated significantly with T8 and NKH1, as did PRL with NKH1. No between-groups difference was found for T3, B1, T4, T8, NKH1, cortisol, ACTH, GH, or PRL.     

Multiple hormonal responses to morphine: relationship to diagnosis and dexamethasone suppression

Plasma cortisol, prolactin (PRL), growth hormone (GH), and thyroid stimulating hormone (TSH) responses to intravenous morphine (0.1 mg/kg body weight) were investigated in five healthy women and 22 female psychiatric inpatients (eight with major depression, 12 with schizophrenia and two with personality disorders) during a 120 min period. The results were also related to a subsequent dexamethasone suppression test (DST). Morphine caused a strong and progressive decline in plasma cortisol which was uniform in controls, depressed, and nondepressed patients. DST nonsuppressors had significantly higher cortisol levels during the entire period, but the same response to morphine. Morphine strongly stimulated PRL secretion, which was found to be significantly smaller in patients than in controls, but no difference was seen between depressed and nondepressed subjects. GH and TSH showed only minor and variable changes after morphine, with no overall significant differences. The data in this study do not support the assumption of a major alteration in opiate receptor responsivity either in depression or in DST nonsuppressor patients insofar as the regulation of the adrenal, thyroid, GH and PRL hormone secretion is concerned.     

Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects

To ascertain the extent of dysregulation of prolactin (PRL) secretion in endogenous depression, we determined nocturnal serum PRL concentrations and PRL responses to thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria (RDC) primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared to their matched controls, the patients showed no difference in basal nocturnal PRL concentrations, a marginally significant 20%-25% increase in the PRL response to TRH, and no differences in post-LHRH or postdexamethasone PRL concentrations. In the patients, there was a weak, negative correlation between age and PRL (r = -0.30), but none of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the PRL measures. The PRL measures also were unrelated to pre- and postdexamethasone cortisol concentrations and to the thyrotropin (TSH) responses to TRH in both groups of subjects. In contrast to the previously reported hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities in these patients, our findings suggest that PRL secretion was relatively normal.     

Growth hormone (GH) and prolactin responses after GH-releasing hormone in major depressive disorder: relationship to somatomedin C levels and dexamethasone suppressibility of cortisol

To explore the growth hormone-releasing hormone (GHRH)-GH-somatomedin axis in major depressive disorder, 12 patients and 12 normal controls matched to the patients on age, sex, ovarian status and body weight received synthetic human GHRH-44 amide (1 microgram/kg) as an intravenous bolus. Compared to controls, the depressed patients showed a reduction in baseline plasma GH and a significant attenuation of net plasma GH responses to GHRH. The blunted GH responses occurred along with significantly increased somatomedin C (Sm-C) concentrations. The impairment of GH responses to GHRH and the increased Sm-C concentrations in patients with depression could have resulted from episodic hypersecretion of GH during the daytime, indicating integrity of the negative feedback circuitry. Normal feedback regulation suggests that diurnal episodic hypersecretion of GH reflects an abnormality at or above the level of the hypothalamus, so that the GHRH-GH-somatomedin axis hyperactivity observed in certain patients with major depressive disorder may be due, at least in part, to hypersecretion of hypothalamic GHRH. Our failure to demonstrate a difference in plasma prolactin (PRL) responses to GHRH between controls and depressed patients indicates that GHRH is not a PRL releaser in patients with major depression and that the altered GH secretory dynamics may not be directly related to the altered circadian PRL secretion linked to depression.     

Platelet serotonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women

Serotonin (5-hydroxytryptamine, 5-HT) is involved in the regulation of hypothalamic-pituitary-adrenal axis (HPA) activity and prolactin (PRL) secretion. The present study examined the relationship between platelet 5-HT and plasma cortisol and PRL concentrations in 20 schizophrenic, 25 depressed, and 25 healthy women. At the time of blood sampling, the schizophrenic and depressed patients had been drug-free for at least 7 days. Platelet 5-HT, plasma cortisol and PRL concentrations were determined by spectrofluorimetric, radioimmunoassay and immunoradiometric methods, respectively. Platelet 5-HT concentration was significantly higher in schizophrenic patients than in depressed patients or in healthy controls, while it was significantly lower in depressed patients than in healthy controls or in schizophrenic patients. Plasma cortisol levels were significantly increased both in schizophrenic and in depressed patients compared with values in healthy controls. Values of plasma PRL were similar across groups. A significant correlation was found between platelet 5-HT and plasma cortisol, and platelet 5-HT and plasma PRL concentrations in healthy controls, but not in schizophrenic or depressed patients. There was no significant relationship between plasma PRL and cortisol levels in any of the groups. Our data, although obtained on peripheral biochemical markers, indicate that depression and schizophrenia are characterized by disturbed 5-HT transmission and dysregulated HPA axis activity.     

Thyroid stimulating hormone and prolactin responses to thyrotropin releasing hormone in nondepressed alcoholic inpatients.

Thyroid stimulating hormone (TSH) and prolactin (PRL) responses to thyrotropin releasing hormone (TRH) stimulation are sometimes blunted in alcoholic subjects; however, the mechanisms involved in these phenomena have not been established. We hypothesized that elevations in free thyroid concentrations might be related to these abnormal responses and then tested that hypothesis in a sample of nondepressed alcoholic inpatients (n = 21). Four alcoholic patients had delta max TSH responses that were < 7 mIU/l; three had PRL responses at or below 8 micrograms/l. Baseline TSH was the only significant predictor of peak TSH; however, free thyroxine (FT4) and baseline TSH both were significant predictors of peak PRL. The average baseline FT4 concentration in alcoholic patients was significantly higher than that in healthy control subjects (n = 10). Our data, thus, suggest that small elevations of FT4 play a role in the inhibition of TSH and PRL responses to TRH among nondepressed, abstinent alcoholic patients.     

Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Relation to duration of illness and depressive symptoms

The responses of serum prolactin (PRL) and growth hormone (GH) to the dopamine agonist apomorphine hydrochloride (0.75 mg subcutaneously) were studied in a large group of unmedicated hospitalized patients with functional psychoses. There were no differences in the GH response in various diagnostic groups. The PRL response was greater in patients with affective disorders. The GH response was inversely related to total duration of illness in the entire sample of patients, but this correlation was independent of age effect only in the group of patients with major depression. In schizophrenics, the effect of the two factors, age and duration of the illness, could not be separated. The apomorphine-induced GH response was significantly correlated with psychosis ratings and negative symptom scale scores. The apomorphine-induced PRL suppression correlated significantly with various measures of depression across diagnostic groups.     

TRH stimulation test in obsessive-compulsive patients

Serum thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) levels were measured before and after stimulation with 200 micrograms of thyrotropin releasing hormone (TRH) in 10 patients with obsessive-compulsive disorder (OCD) and in 10 control subjects. There were significantly more blunted TSH responses among OCD patients than control subjects. PRL and GH responses to TRH challenge did not differ between OCD patients and controls. These results may indicate dysregulation of the hypothalamic-pituitary-thyroid axis in OCD.     

Effects of sertraline treatment on plasma cortisol, prolactin and thyroid hormones in female depressed patients

The aim of the study was to evaluate the effects of 4 and 24 weeks of sertraline treatment (average dose 42.5 mg/day) on plasma hormone levels in 15 female patients with major depression. Baseline levels of triiodothyronine (T(3)) were lower, while cortisol, prolactin (PRL), thyroid-stimulating hormone (TSH), and thyroxin (T(4)) levels did not differ from the values in 16 female controls. There was a positive correlation between the scores on the Montgomery-Asperg Depression Rating Scale and baseline cortisol levels. Treatment with sertraline for 4 weeks increased plasma cortisol levels, while 24 weeks of sertraline treatment increased plasma T(3) levels in depressed patients. Neither 4, nor 24 weeks of sertraline treatment affected PRL, T(4) and TSH levels in depressed patients. The data show different and time-dependent effects of sertraline treatment on plasma cortisol, PRL and thyroid hormones in female depressed patients.     

Gonadotropin releasing hormone elicits abnormal hormone responses in schizophrenia

We studied the non-specific responses of GH and PRL to gonadotropin releasing hormone (GnRH) in eleven male patients aged 18–30 in whom a diagnosis of acute schizophrenia was made according to Crow's criteria. GnRH administration was followed by a significant increase in plasma GH in five patients; plasma PRL increased in two patients. The two prolactin responders were also GH responders. Non-specific GH response was confirmed on repeated testing in two patients in whom GnRH stimulation was performed twice. During saline control, non-specific hormone responses were not observed. The abnormal hormone responses observed in acute schizophrenia are probably due to the disordered monoamine regulation characteristic of this condition.     

Effects of Carbamazepine Therapy on Serum Sex Hormone Levels in Male Patients with Epilepsy

The effects of carbamazepine (CBZ) therapy and epilepsy on sex hormone plasma levels in male patients with epilepsy were evaluated by measuring the levels of testosterone (T), free testosterone (FT), sex hormone binding globulin (SHBG), estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and dehydroepiandrosterone sulfate (DHEAS) and by calculating the free androgen index (FAI) in 23 male patients with epilepsy receiving CBZ medication, in 18 untreated male patients with epilepsy, and in 19 healthy age-matched control subjects. No significant differences in the mean T or FT levels were found between the three groups, but the CBZ-treated patients had significantly higher SHBG levels and their FAI values and DHEAS concentrations were lower. The LH, FSH, PRL, or E2 levels in CBZ-treated and untreated male patients with epilepsy did not differ from the controls. CBZ monotherapy does not significantly change the serum balance of sex hormones; however, CBZ clearly affects the serum levels of SHBG and DHEAS.     

Parental divorce and neuroendocrine changes in adolescents

Plasma noradrenaline (NE), adrenocorticotrophic hormone (ACTH), growth hormone (GH), prolactin (PRL) and luteinizing hormone (LH) concentrations were examined in basal conditions and after stimulation by the step test in two groups of psychophysically healthy adolescent girls, 18 from divorced families and 16 from non-divorced families. Basal NE, ACTH, GH, PRL values did not differ in the two groups, whereas those of LH were significantly lower in the adolescents from divorced parents than in those from non-divorced families. Responses of NE and ACTH to the stimulus were normal, of GH and PRL were weaker, and of LH slightly weaker in children of divorced parents. An impaired catecholaminergic and serotoninergic tonus in children of disrupted families might underly the hormonal alterations.     

Prolactin responses to thyrotropin-releasing hormone in multi-infarct dementia and senile dementia of the Alzheimer type

The serum prolactin (PRL) responses to stimulation with thyrotropin-releasing hormone (TRH) (500 micrograms Protirelin) were compared in 14 patients with multi-infarct dementia (MID) and 10 patients with senile dementia of the Alzheimer type (SDAT). Between the MID and the SDAT patients, there were no statistically significant differences in the median serum PRL concentrations, median changes in serum PRL concentrations or median proportional changes in serum PRL concentrations. Further, the serum PRL responses did not correlate with the GBS scale scores (degrees of dementia) or the GBS subscale scores (clinical profiles, including motor functioning, emotional functioning and intellectual functioning). In conclusion, the study does not support the hypothesis that serum PRL responses to TRH stimulation are of diagnostic value in differentiating between MID and SDAT.     

The influence of psychotropic drugs and releasing hormones on anterior pituitary hormone secretion in healthy subjects and depressed patients

Pharmacoendocrinological studies have shown that psychotropic drugs with different actions have different effects on anterior pituitary hormone secretion in man. Substances with different effects on the central nervous system are characterized by a different pharmacoendocrinological profile. Studies with various receptor blockers have shown varying influences on the DMI-induced growth hormone, prolactin, and ACTH/cortisol secretion. Growth hormone stimulation was shown to be mediated by alpha 2-receptors and inhibited by beta-receptors. Investigations in male and female endogenous depressive patients demonstrated a significantly blunted growth hormone response to DMI compared with age- and sex-matched healthy subjects. A comparative study in male endogenous depressive patients showed a significantly diminished growth hormone stimulation both after DMI and after growth hormone-releasing hormone compared to healthy male subjects. In further tests a simultaneous application of four releasing hormones (GHRH, CRH, GnRH, TRH) was used. These investigations showed a significantly lower GH stimulation in endogenous depressive patients compared with age- and sex-matched healthy subjects, but not in neurotic depressive or schizophrenic patients. Cortisol stimulation was similar in all groups of patients and healthy subjects. TSH stimulation was significantly lower in endogenous depressive and schizophrenic patients than in healthy subjects. Somatomedin-C concentrations were significantly elevated in endogenous depressed patients compared with healthy subjects. The blunted growth hormone response in endogenous depression could be explained by inhibitory influences such as increased somatomedin-C concentrations or a hyperactivity of central beta-adrenergic-receptors.     

Immunoendocrine aspects of major depression

Recently, a complete bidirectional circuit between the immune and neuroendocrine systems has been documented. Previous reports from this laboratory have shown that there are complex reciprocal relationships between immune and hypothalamic-pituitary-adrenal (HPA)-axis function in major depression. To further examine the immune-endocrine relationships, this study investigates plasma baseline cortisol and prolactin secretion in relation to plasma interleukin-6 (IL-6) and soluble IL-2 receptor (sIL-2R) levels in 34 healthy controls and 56 major depressed patients. There were significant positive correlations between IL-6 or sIL-2R and plasma cortisol in major depressed subjects and in the combined group of major depressed and healthy subjects. There were also significant positive correlations between plasma prolactin and sIL-2R concentrations in major depressed subjects and in the combined groups of normal and major depressed subjects.     

Neuroendocrine responses to intravenous tryptophan in major depression

The increases in plasma levels of prolactin (PRL) and growth hormone (GH) following intravenous administration of the 5-hydroxytryptamine precursor tryptophan (100 mg/kg) were assessed in 30 depressed patients and 30 control subjects. In depressed patients who lost less than 10 lb, PRL responses were significantly reduced compared with controls. In contrast, the PRL responses of patients with weight loss exceeding 10 lb were significantly greater than those of either controls or the other depressed patients. Growth hormone responses to tryptophan were significantly decreased in patients who lost less than 10 lb. Prolactin, but not GH, responses correlated significantly with the postdexamethasone plasma cortisol concentration; however, an apparent relationship between GH and PRL responses and suicidal behavior was probably due to the common factor of weight loss. The results suggest that depressed patients have different types of abnormal 5-hydroxytryptamine-mediated neuroendocrine responses that correlate with the presence or absence of severe weight loss and cortisol hypersecretion. Further investigations are needed to establish if these abnormalities are central to the depressive disorder or have implications for treatment response.     

Plasma cortisol, prolactin, growth hormone, and immunoreactive beta-endorphin response to fenfluramine challenge in depressed patients

The effect of a single dose (60 mg p.o.) of the serotonin agonistic agent fenfluramine (FNF) on plasma cortisol, prolactin (PRL), growth hormone (GH), and immunoreactive beta-endorphin (ir-beta-EP) levels was assessed in eight major depressed patients and eight controls. The hormones were monitored at basal level (0') and hourly during 5 h following FNF administration. The pharmacological challenge caused an elevation of 80% in PRL secretion in the healthy controls and only 42% in the depressed patients. However, the actual prolactin response (delta max) failed to discriminate depressed patients from controls. A blunted response followed by a decrease (33%) in serum cortisol levels was observed in depressed patients 5 h after drug administration while an increase of 94% was obtained in controls after 3 h. FNF provocation did not affect GH and ir-beta-EP plasma levels. The blunted cortisol responsiveness to FNF administration in depressed patients may reflect functional hypoactivity of central serotonergic system at least during the acute phase of major depression. It is not clear why the cortisol hyporesponsivity in depressed patients is not accompanied by a similar reduced PRL response to FNF challenge.     

Insulin-like growth factor I in depressed patients and controls

To explore the role of the somatomedin-mediated long-loop negative feed-back mechanism in altered growth hormone (GH) secretory dynamics associated with depression, plasma IGF-I concentrations were measured in 34 patients with a major depressive episode and matched healthy subjects. Compared with controls, depressed patients exhibited significantly increased plasma IGF-I concentrations. In the patient group plasma IGF-I concentrations were positively correlated with the maximum post-dexamethasone plasma cortisol concentrations. Our data suggest that increased plasma IGF-I concentration may reflect diurnal GH hypersecretion, contribute to deficient GH responses to dynamic challenges, and indicate an interrelationship between the hypothalamic-pituitary-somatotropic (HPS) and -adrenocortical (HPA) system regulation in depression.