THE EFFECTS OF CHOLINERGIC BLOCKADE ON THE GROWTH HORMONE AND PROLACTIN RESPONSE TO INSULIN HYPOGLYCAEMIA

The effect of cholinergic blockade on growth hormone (GH) and prolactin (PRL) secretion during insulin-induced hypoglycaemia was assessed in six normal male volunteers (mean age 23, age range 21-25). Each subject underwent two insulin tolerance tests with and without atropine. GH responses were significantly lower 45 min after insulin administration with atropine (17.5 +/- 2.5 mU/l (mean +/- SEM) than with placebo (37.6 +/- 3.6 mU/l, P less than 0.0006). In contrast PRL responses were higher (P less than 0.01) at 45 and 90 min after insulin during treatment with atropine. These data demonstrate that cholinergic mechanisms are involved in stimulatory and inhibitory pathways in the medication of the respective GH and PRL responses to insulin induced hypoglycaemia in man.     

EFFECT OF SUBACUTE CABERGOLINE TREATMENT ON PROLACTIN, THYROID STIMULATING HORMONE AND GROWTH HORMONE RESPONSE TO SIMULTANEOUS ADMINISTRATION OF THYROTROPHIN-RELEASING HORMONE AND GROWTH HORMONE-RELEASING HORMONE IN HYPERPROLACTINAEMIC WOMEN

It is known that dopaminergic neurotransmission is involved in the control of PRL, TSH and GH secretion. Cabergoline (CAB) is a new ergolinic derivative with a long-acting dopaminergic activity. We evaluated 11 women with pathological hyperprolactinaemia before and during sub-acute CAB treatment (0.8-1.2 mg/p.o.; 8 weeks). Simultaneous administration of TRH (200 micrograms i.v.) and GHRH 1-44 (50 micrograms i.v.) were carried out before and after 4, 8 and 10 week intervals from the beginning of CAB treatment. Basal PRL levels (2453.5 +/- S.E. 444.5 mU/l) were significantly reduced during CAB administration (week 4: 164.5 +/- 66.5 mU/l; week 8: 168.0 +/- 66.5 mU/l; P less than 0.01) and no variations were observed 2 weeks after drug discontinuation (week 10: 210.0 +/- 98.0 mU/l). PRL percentage change after TRH was increased by CAB (P less than 0.05). No variation in basal and TRH-stimulated TSH levels was found during CAB administration. A slight increase in GH basal levels (3.0 +/- 0.6 mU/l) was found after weeks 4 (6.4 +/- 2.0 mU/l) and 10 (5.8 +/- 1.6 mU/l) (P less than 0.05). GH response to GHRH was significantly enhanced (ANOVA: P less than 0.01) during sub-acute CAB treatment. A positive correlation was found between GH secretory area and weeks of CAB therapy (P less than 0.01). Our data show that CAB is very effective in lowering PRL secretion in hyperprolactinaemia, and is able to modify PRL and GH responses after TRH and GHRH. The increasing trend in GH basal and GHRH-stimulated GH levels seems to indicate that CAB can override the central dopaminergic tone which is operative in hyperprolactinaemia.     

THE EFFECT OF THYROTROPHIN-RELEASING HORMONE ON PLASMA PROLACTIN AND THYROTROPHIN LEVELS IN PRIMARY HYPOTHYROIDISM

Plasma prolactin and thyrotrophin (TSH) were measured by radioimmunoassay before, at 20 min and 60 min after the intravenous administration of 200 μg thyrotrophin-releasing hormone (TRH) in thirty-two patients with untreated primary hypothyroidism and in sixteen normal volunteers. Whereas basal plasma TSH was markedly elevated in all the patients with hypothyroidism, a slight, but significant increase (P<0.05) in basal plasma prolactin in primary hypothyroidism could only be demonstrated by matching for age, sex and circulating gonadotrophin levels, ten patients with hypothyroidism with ten normal volunteers. There was, however, no significant difference between the two groups, matched or unmatched, in the plasma prolactin levels, in contrast to the plasma TSH levels, following TRH administration. No apparent relationship was found between basal prolactin and follicle-stimulating hormone (FSH), luteinizing hormone (LH) or TSH. Assuming the release of prolactin by TRH to be of physiological significance, the results suggest that TRH secretion by the hypothalamus may be increased in untreated hypothyroidism and that low levels of circulating thyroid hormone increase the sensitivity of the pituitary thyrotrophs, but not the prolactin secreting cells, to TRH. Markedly elevated plasma prolactin levels associated with galactorrhoea were not seen in primary hypothyroidism in the absence of the puerperium or oestrogen therapy.     

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH-releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11.0-17.1 years were given oxandrolone 0.1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1-40, 1 microgram/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously-released neurohormone.     

THE PROLACTIN RESPONSE TO METOCLOPRAMIDE IN GROWTH HORMONE DEFICIENT ADOLESCENT MALES

The growth hormone (GH) and prolactin (PRL) responses following administration of 10 mg i.v. metoclopramide (MCP) (‘Maxolon’—Beecham Pharmaceuticals) have been examined in thirty adolescent males with short stature and delayed puberty, eight of whom have isolated growth hormone deficiency. The results demonstrate that peak GH and PRL levels following stimulation were highly significantly correlated when all subjects were analysed together (r=0·61, P < 0·001) but when the responses of the GH deficient and non-deficient groups of subjects were analysed separately no significant correlation was obtained (P > 0·1), this reflected the fact that the PRL response to MCP was significantly lower in the GH deficient group (P < 0·0002). In addition two boys who demonstrated biochemical GH deficiency prior to puberty only, showed PRL responses similar to boys with normal GH reserves. The results suggest that the PRL response to MCP may be of value in the assessment of stimulation tests of GH reserve, as well as in the selection of patients for treatment with G.H.     

THE EFFECT OF OESTROGEN PRETREATMENT ON SUBSEQUENT RESPONSE TO LUTEINIZING HORMONE RELEASING HORMONE IN NORMAL WOMEN

Twenty-two normal, regularly menstruating female subjects had an LHRH test performed before and after pretreatment with 0.5 mg, 1 mg or 2.5 mg of oestradiol benzoate during the follicular phase of their menstrual cycles (days 4–8). Two further women acted as controls and received no oestrogen; they showed identical responses for both LH and FSH release when LHRH tests were performed at intervals of 48 h. Oestrogen pretreatment induced a biphasic effect upon subsequent LHRH response. Four subjects retested 20 h after 0.5 mg oestradiol benzoate showed either no change or a slight suppression of LH and FSH release. Fifteen of the eighteen women pretreated with oestradiol benzoate and retested 44 h later showed significantly increased LH release and fourteen significantly increased FSH release when compared to their control responses. The responses appeared to be dose related with a positive correlation between sum of LH increments and basal oestradiol levels (r= 0.61; P<0.001) and a similar correlation (r= 0.67; P<0.001) between sum of FSH increments and basal oestradiol levels. The physiological significance of this biphasic action of oestrogen upon pituitary sensitivity is discussed in relation to the control of the menstrual cycle.     

THE EFFECT OF PHYSIOLOGICAL CHANGES IN OVARIAN STEROIDS ON THE PROLACTIN RESPONSE TO GONADOTROPHIN RELEASING FACTOR

This study was designed to assess the effect of an altered level of serum oestrogen and progesterone on the prolactin (PRL) response to gonadotrophin releasing hormone (GnRH). Six normal women were studied in the early follicular phase and the mid-luteal phase of one cycle and five menopausal women were studied before and after treatment with progesterone. Blood samples were collected at 15 min intervals for 6 h after a basal collection period of 30 min. Intravenous boluses of GnRH (1 microgram, 10 micrograms and 50 micrograms) were given at 0, 2 and 4 h. Basal samples were assayed for 17 beta-oestradiol (E2), oestrone (E1) and progesterone (P); LH, FSH and PRL were measured in all samples. Serum PRL was significantly elevated in all groups after 10 micrograms of GnRH with maximum increments (+/- SEM) ranging from 3.9 +/- 1.3 micrograms/l in early follicular phase women to 14.7 +/- 4.7 micrograms/l in progesterone-treated menopausal women. The PRL response to GnRH was significantly greater in the luteal phase and in menopausal women compared to early follicular phase women. There was a significant correlation between the maximum PRL response and the maximum LH response to GnRH in all the women studied (r = 0.7; P less than 0.01). A significant correlation was also found between the maximum PRL response and the basal serum oestrogen concentration in the normal cycling women (r = 0.8; P less than 0.01), but not when the menopausal women were included in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

IMMUNOCYTOCHEMICAL GROWTH HORMONE AND PROLACTIN IN PITUITARY ADENOMAS CAUSING ACROMEGALY AND THEIR RELATIONSHIP TO BASAL SERUM HORMONE LEVELS AND THE GROWTH RESPONSE TO THYROTROPHIN RELEASING HORMONE

Basal prolactin levels and the dynamics of growth hormone secretion in response to intravenous TRH in 34 untreated acromegalic patients were compared with immunocytochemical localization of growth hormone and prolactin in the adenoma cells. The serum prolactin level was elevated in 13 patients. All adenomas contained growth hormone detectable by immunocytochemistry. Twelve adenomas contained prolactin as well; of these only six were associated with hyperprolactinaemia. In six patients with a mixed adenoma the serum prolactin levels were in the normal range. In 17 patients the growth hormone value more than doubled after TRH. Eight of these patients had hyperprolactinaemia, and in only six did the adenomas contain immunoreactive prolactin; eight were associated neither with hyperprolactinaemia nor with positive immunostaining for prolactin. Eight adenomas had suprasellar extension, six of these were associated with hyperprolactinaemia. Of the seven adenomas with hyperprolactinaemia but no adenomatous prolactin immunoreactivity, four had supprasellar extension. In three patients hyperprolactinaemia was associated neither with prolactin immunoreactivity in the adenoma cells nor with suprasellar extension of the tumour. It is concluded that in acromegalics (1) there is no relation between hyperprolactinaemia, and the presence of prolactin in the adenoma cells; (2) the hyperprolactinaemia may be due either to adenomatous prolactin secretion or possibly suprasellar mass interference of hypothalamic control of normal prolactin cells; and (3) the presence of hyperprolactinaemia or immunocytochemically defined adenomatous prolactin does not correlate with the reactivity of the adenomatous growth hormone cells to TRH.     

THE HALF-LIFE OF EXOGENOUS GROWTH HORMONE AFTER SUPPRESSION OF ENDOGENOUS GROWTH HORMONE SECRETION WITH SOMATOSTATIN

We have estimated the half-life of serum growth hormone (GH) in six subjects on 14 occasions following an intravenous bolus injection of either 50 or 500 mU of biosynthetic human growth hormone (B-hGH) while endogenous GH secretion was suppressed by a continuous infusion of somatostatin. The disappearance curve of serum GH was mono-exponential and the mean half-life was 8.9 min (SD 1.5). This is less than previously reported and has important implications for the performance of GH profiles, which should be performed with 10-15 min sampling intervals, and the calculation of pituitary GH secretion rates.     

THE EFFECT OF PULSATILE FOLLICLE STIMULATING HORMONE ON THE. ENDOGENOUS LUTEINIZING HORMONE SURGE IN WOMEN

The effect of pulsatile administration of 'pure' FSH on the endogenous LH surge was investigated in 10 infertile but otherwise normal women. In each woman the LH surge in the spontaneous cycle preceding the treatment cycle was characterized in blood samples taken every 6 h. FSH was injected s.c. via a pump (28 IU every 3 h) starting on cycle day 2. Only five of the FSH-treated women displayed an endogenous LH surge, and this was markedly attenuated in four of them. The LH surge occurred significantly earlier in the FSH-treated than in the corresponding spontaneous cycle (cycle day 10.2 +/- 0.5 vs 13.6 +/- 0.8 mean- +/- SEM, P less than 0.05), although it tended to occur later in the FSH-treated cycles with a higher total follicular fluid volume of follicles 12-15 mm in diameter. This volume was even greater in the FSH-treated cycles without an endogenous LH surge. Serum progesterone levels increased significantly in all five FSH-treated cycles after the onset of the LH surge and ovulation was confirmed by ultrasound in four of them. These results suggest that the LH surge during superovulation induction with pulsatile FSH in normally cycling women is a variable event. We postulate that unknown inhibitory substances secreted be small growing follicles antagonize the positive feedback effect of E2 on LH secretion.     

THYROTROPHIN, PROLACTIN AND GROWTH HORMONE RESPONSES TO TRH IN BARBITURATE COMA AND IN DEPRESSION

The effects of 200 microgram thyrotrophin-releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear-cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderated rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TRH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.     

EFFECT OF SOMATOSTATIN ON ABNORMAL GROWTH HORMONE AND PROLACTIN SECRETION IN PATIENTS WITH THE CARCINOID SYNDROME

Growth hormone (GH) secretion has been studied in two patients with the carcinoid syndrome during glucose loading and growth hormone-release inhibiting hormone (GHRIH, somatostatin) infusion. Both patients had elevated fasting GH levels which were not suppressed by glucose; GH levels fell rapidly during GHRIH infusion. One patient also had hyperprolactinaemia with galactorrhoea and the prolactin (PRL) levels were unaltered by GHRIH. The association between carcinoid tumours and abnormalities of GH and PRL secretion is discussed.     

MATERNAL SERUM PROLACTIN AND ITS RESPONSE TO TRH IN NORMAL AND COMPLICATED EARLY PREGNANCY

Maternal serum prolactin levels (PRL) were measured by radioimmunoassay in thirty-four women with either normal or complicated early pregnancy. The basal PRL level (mean +/- S.D.) of 33.4 +/- 16.4 ng/ml in normal pregnancy (n = 15) was similar to the level of 32.7 +/- 18.8 ng/ml in threatened abortion (n = 11) and 32.8 +/- 16.9 ng/ml in hyperemesis gravidarum (n = 8). Two patients, one with blighted ovum and the other with subsequent spontaneous abortion, demonstrated PRL levels lower than the range of 20-63 ng/ml in the control group. The PRL response to 200 microgram of synthetic thyrotropin releasing hormone (TRH) administered intravenously was similar throughout the patient groups. The basal level of PRL in the whole series was more closely related to the level of serum oestradiol (r = 0.778, P less than 0.001) than to that of serum progesterone (r = 0.442, P less than 0.05). However the increments of PRL following TRH administration did not correlate with either oestradiol or progesterone.     

THE EFFECT OF PLASMA GLUCOSE ON THE GROWTH HORMONE RESPONSE TO HUMAN PANCREATIC GROWTH HORMONE RELEASING FACTOR IN NORMAL SUBJECTS

Pituitary responsiveness to 44 amino acid human pancreatic growth hormone releasing factor was tested under conditions of euglycaemia and hyperglycaemia in six normal subjects. A 100 μg dose of growth hormone releasing factor was given at a fasting blood glucose of 5.1 ± 0.4 mmols/1 (mean ± S.D.), and at a blood glucose level of 10.9 ± 1.5. Under conditions of hyperglycaemia, the GH response to releasing factor was significantly depressed when compared to results obtained at fasting blood glucose ( n = 6, t = 3.902, P = 0.0114). This is in keeping with the hypothesis that hyperglycaemia, mediated by the hypothalamus, causes decreased pituitary sensitivity to natural growth hormone releasing hormone.     

THE PROLACTIN RESPONSE TO SUCKLING

Changes in prolactin concentration during single suckling episodes in twenty breast-feeding women from four to 40 weeks post partum have been investigated. Basal prolactin concentration and the increase in prolactin secretion in response to single suckling episodes and amount of milk taken by the infant were both independent of time post partum until the introduction of supplementary feeds, when a significant decrease with time was apparent. Basal concentrations of prolactin were dependent upon the interval between suckling episodes, and the magnitude of the prolactin response varied with the time of day when suckling took place. The relationship between acute suckling episodes and the long term pattern of prolactin secretion over time post partum is discussed.     

FAILURE OF ADRENERGIC α AND β RECEPTOR BLOCKADE TO ELEVATE THE TSH AND PROLACTIN RESPONSE TO TRH IN HYPERTHYROIDISM

The effects of adrenergic alpha and beta receptor blockade on the thyrotrophin and prolactin responses to TRH were studied in groups of hyperthyroid patients who received either oral propranolol and phenoxybenzamine or intravenous propranolol and rogitine. The flat TSH and prolactin responses to TRH in the untreated hyperthyroid patients were not altered by oral or intravenous adrenergic alpha and beta receptor blockade suggesting that catecholamines do not play a major role in the feedback suppression of TSH and prolactin in hyperthyroidism.     

THE HIGHER THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE THE LOWER THE RESPONSE TO BROMOCRIPTINE AND THYROTROPHIN RELEASING HORMONE IN ACROMEGALY

In acromegaly a direct relationship has been demonstrated between GH responsiveness to TRH and to the dopaminergic agent bromocriptine (Br). Recent data show an inverse relationship between GH responsiveness to Br and to GH releasing hormone (GHRH), but not between the GH responses to GHRH and TRH. Thirty-one acromegalic patients, 18 women and 13 men (age 46.2 +/- (SD) 13 years) were studied. Four patients had been treated, but all still had active disease. The GH responses to GHRH (hpGHRH1-44, Bachem 100 micrograms i.v. bolus), TRH (Thyroliberin, Hoechst 200 micrograms i.v. bolus) and Br (Parlodel 5 mg orally) were assessed in most of the patients. The GH responses to GHRH showed a wide interindividual variation (delta GH 1-995 ng/ml), which correlated significantly with the basal GH levels (r = +0.85, P less than 0.0001, n = 31). GH increments in response to GHRH were inversely related to the responses to Br, i.e. the lower the GH increase after GHRH the greater the GH decrease after Br (r = -0.49, P less than 0.01, n = 30). This decrease correlated with the basal PRL level (r = +0.45, P less than 0.02, n = 29) and also the GH response to TRH (r = +0.66, P less than 0.0001, n = 30). An inverse correlation was also found between the GH responses to TRH and to GHRH (r = -0.43, P less than 0.02, n = 29). The data are consistent with the existence of GH-secreting adenomas which are more sensitive to GHRH and less to Br and TRH (pure somatotroph adenomas) and of mixed (lactotroph-like adenomas) responsive to TRH and Br but less responsive to GHRH.     

THE EFFECT OF GROWTH HORMONE ON THE LEYDIG CELL RESPONSE TO CHORIONIC GONADOTROPHIN IN BOYS WITH HYPOPITUITARISM

Eleven boys with growth hormone (hGH) deficiency received human chorionic gonadotrophin (hCG) stimulation tests for the assessment of Leydig cell function before, during, and after 1 year of treatment with somatotrophin. Two patients entered puberty during the course of the study protocol. Analysis of the data in nine prepubertal boys revealed an augmentation of testosterone (T) responses to hCG in the presence of hGH. In six of these individuals in whom dihydrotestosterone (DHT) was determined, a similar augmentation in responsiveness of this steroid was found in the presence of hGH. Three prepubertal boys exhibited poor T responses to the basal hCG test with only partial improvement following hGH. In man growth hormone may be an important permissive factor in Leydig cell activity during periods of changing testicular function such as occur in utero or during puberty.     

CHANGES IN SERUM PROLACTIN LEVELS DURING THE FOLLICULAR PHASE AND THE ENDOGENOUS LUTEINIZING HORMONE SURGE OF CYCLES HYPERSTIMULATED WITH FOLLICLE STIMULATING HORMONE

The pattern of serum PRL levels during superovulation induction with pulsatile 'pure' FSH was investigated in 10 normally ovulating women. They were studied in two consecutive cycles, i.e. an untreated spontaneous and an FSH stimulated cycle. An endogenous LH surge occurred in all 10 spontaneous cycles and in five of the FSH cycles. Midcycle PRL levels were significantly higher in the FSH stimulated than in the spontaneous cycles (P less than 0.01). In both groups of cycles, circadian periodicity of serum PRL levels during the LH surge was different from that during the late follicular phase with higher levels at midnight, although in the FSH cycles PRL secretion showed a sustained increase over 24 h. A nadir of PRL levels was found between 0900 h and 1200 h. In contrast, progesterone secretion during the LH surge showed a nocturnal increase with the highest value between 0600 h and 1200 h and the lowest at midnight. In the FSH cycles without an LH surge, PRL levels increased as long as FSH administration was continued and showed a significant positive correlation with the increasing serum oestradiol levels (r = 0.77). We conclude that ovarian hyperstimulation is a potent stimulus of PRL secretion in women. It is suggested that the midcycle endogenous LH surge facilitates the evening PRL secretion, while induction of multiple folliculogenesis amplifies the 24 h pattern of PRL secretion.     

TRH INJECTION DURING LABOUR: EFFECT ON MATERNAL AND FETAL PROLACTIN SECRETION

The effect of TRH injection on PRL levels in maternal serum and in serum of umbilical vein (UV) and artery (UA) was investigated in forty-six women. Twenty-two of them, with normal singleton term pregnancy, were given i.v. either saline solution (nine women, control group 1) or 200 μg of synthetic TRH (thirteen women, group 2) 30–45 min before normal delivery. Group 1 PRL values (mean ± SE) (ng/ml) in UV (428 ± 41) and UA serum (434 ± 45) were significantly higher than in maternal serum either before (285 ± 39) or after saline injection (331 ± 14) (P < 0·05). In group 2, TRH induced a marked increase in maternal serum PRL (544 ± 33 v. 285 ± 39, P < 0·001) (difference from corresponding maternal serum PRL of group 1 significant, P < 0·001) but not in UV (409 ± 41) and UA (406 ± 48) PRL values (difference from the corresponding PRL values in UV and UA serum of group 1 non-significant, P > 0·1). Group 2 maternal serum PRL values after TRH were significantly higher than in UV and UA serum (P < 0·05). A significant positive correlation was found between UV and UA serum PRL values in both group 1 (r=0·858, P < 0·01) and group 2 (r=0·870, P < 0·001). Twelve of the remaining twentyfour women were given TRH either 10–20 min (four women), 60–75 min (four women), or 90–110 min (four women) before delivery. UA serum PRL values did not differ significantly from corresponding controls (twelve women). It is suggested, from these findings in women, that TRH injected into the mother in a single dose of 200 μg stimulates maternal but not fetal pituitary in late pregnancy during labour. This is possibly due to inability of TRH to cross the human placenta.