High PRL Research Articles

Effect of sulpiride on plasma prolactin levels in women with puerperal or pathological hyperprolactinaemia.

The effect of 100 mg im sulpiride on plasma Prl levels was studied in 10 normal females, 21 patients with galactorrhoea and normal plasma Prl, 10 women with puerperal hyperprolactinaemia and 27 patients with amenorrhoea-galactorrhoea and high plasma Prl levels. The response to sulpiride in patients with galactorrhoea but normal PRL was slightly higher (P < 0.05) than that observed in normal women, but only if expressed in per cent. Women with puerperal hyperprolactinaemia respond to the drug with a marked increase in Prl (mean +/- SEM: 563.0 +/- 142.8%), even though their baseline values are already very high (mean +/- SEM: 133.6 +/- 23.8 ng/ml). By contrast, there is a lower or no response to sulpiride in 13 women with pituitary tumour. The same was true in 11 patients with hyperprolactinaemia of uncertain aetiology but also 10 of these subjects presented signs suggestive of a tumour. In the last 3 patients with pathological hyperprolactinaemia in whom a consistent Prl increase after sulpiride was observed, hyperprolactinaemia was probably not of tumourous origin. On the basis of these results, the sulpiride test appears promising for discriminating between organic and 'functional' cases of enhanced Prl secretion.

The clinical and biochemical features in 26 patients with prolactinoma before and after transsphenoidal microresection.

Abstract. Twenty-six women, 16 to 40 years of age, with amenorrhoea with or without galactorrhoea and abnormal pituitary fossa tomogram were studied before and after transsphenoidal resection of their pituitary adenomas. The immunoreactive serum prolactin (Prl) was abnormally high both before and after intravenous (iv) administration of thyrotrophin-releasing hormone (TRH) but the rise was blunted. The serum Prl level returned to normal post-operatively in 20 patients, but the subnormal rise after TRH persisted in 23 patients. The basal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were normal before and after surgery. The peak serum level of LH after administration of the luteinizing hormone-releasing hormone (LRH) was normal but the peak FSH was significantly high before surgery (P &lt; 0.001) and returned to normal post-operatively. Plasma oestradiol (Oe2) was significantly low compared to that after surgery (P &lt; 0.001). Plasma testosterone (T) was significantly higher before surgery than that found in normal women (P &lt; 0.001) and the level fell post-operatively. Plasma androstenedione (A) was higher before surgery than found in normals, but the difference was not significant (P &lt; 0.2). Post-operatively, 23 patients regained their normal menses. Three of these 23 patients continued to have high serum Prl but the serum Oe2 returned to normal. Sixteen of 20 patients who desired pregnancy became pregnant post-operatively. None of the patients required hormonal replacement after surgery. These data indicate that the measurement of LH or FSH at basal and after LRH stimulation, may not be of significant prognostic importance compared with serum Prl and plasma Oe2. Regular menses and pregnancy can occur in some patients in spite of moderately high serum Prl but normal plasma Oe2 levels. Surgical resection of prolactinoma has low morbidity with a high incidence of success resulting in return of normal menses and fertility. The persistent subnormal rise of Prl after TRH post-operatively in the majority of the patients suggests that long-term follow-up for evidence of recurrence is indicated.

Effect of estrogen on thyrotropin-releasing hormone-induced release of prolactin in intact, ovariectomized, and stalk-sectioned female rhesus monkeys.

The effects of estrogen treatment on basal and TRH-induced serum PRL concentrations were studied in three groups of four female rhesus monkeys; intact monkeys, ovariectomized animals, and monkeys in which the pituitary gland had been isolated from direct hypothalamic influences by pituitary stalk section. The TRH tests (50 microgram, iv) were performed before and 7 and 21 days after the sc implantation of one or two 3-cm long silastic capsules containing 17 beta-estradiol. Treatment with estradiol significantly increased the PRL response to TRH in the three groups of animals. The highest PRL response to TRH was observed after stalk section. The estrogen treatment also increased basal PRL concentrations in stalk-sectioned monkeys but no statistically significant increase was observed in intact or ovariectomized animals. These results indicate that physiological amounts of estradiol increase the magnitude of TRH-induced PRL release in rhesus monkeys, and that this estrogen effect is probably enacted directly at the level of the anterior pituitary gland.

Reduction of elevated prolactin levels in neonatally androgenized female rats by corticomedial amygdaloid lesions.

The effect of corticomedial amygdaloid lesions on serum PRL levels was investigated in adult female rats neonatally androgenized (NA) on day 3 of life with 1.25 mg testosterone propionate. NA animals exhibiting constant vaginal estrus were studied at 4 and 6 months of age in a series of three experiments. Basal (1100 h) PRL levels were elevated in adult NA females compared to levels in control females that were ovariectomized and estrogen primed. Four-month-old NA rats, decapitated at 1100 and 1700 h, had statistically significant diurnal fluctuations in serum PRL levels (118.1 ± 14.8 and 207.8 ± 13.7 ng/ml, respectively). Ablation of the corticomedial amygdala 1 month before sacrifice significantly reduced these elevated levels. A second group of NA females, decapitated at 1100 h at 6 months of age to determine if the elevated basal PRL levels in NA rats were affected by increasing age, had high serum PRL levels, similar to those of younger NA rats, which were significantly reduced by corticomedial amygd...

The Inability of Bromocriptine to Inhibit Prolactin Secretion by Transplantable Rat Pituitary Tumors: Observations on the Mechanism and Dynamics of the Autofeedback Regulation of Prolactin Secretion*

The effect of several ergot alkaloids on the growth of transplantable rat PRL- and GH-secreting tumors MtTW15 and 7315α was measured. In vivo administration of ergotamine and ergocryptine caused a significant decrease in tumor growth and decreased the serum PRL concentration. Tumor regression was not blocked by the concomitant administration of haloperidol, a dopamine antagonist. The administration of bromocriptine (0.8-40 mg/kg daily) did not cause tumor regression nor did it suppress the elevated serum PRL levels. Since ergotamine and ergocryptine but not bromocriptine are potent vasoconstrictor agents, it is suggested that the former ergot derivatives decrease the capillary blood supply to the tumors and thereby decrease tumor growth and PRL secretion. High serum PRL concentrations are known to produce atrophy of the hosts' pituitary gland and to decrease its synthesis and release of PRL. Since ergotamine significantly decreased the PRL secretion by the tumor, less of a tonic inhibitory signal was pres...

A Pregnancy in an Acromegalic Woman during Bromocriptine Treatment: Effects on Growth Hormone and Prolactin in the Maternal, Fetal, and Amniotic Compartments*

An unexpected 20-week-old pregnancy was found in a young acromegalic who had been treated with 10 mg bromocriptine/day for 10 months. The drug was continued throughout the period of gestation. No growth of the pituitary adenoma was noticed. The intrauterine development of the fetus was normal. Bromocriptine therapy had no discernible effect on the expected patterns of secretion of placental hormones, but inhibited completely the increase of PRL in the serum of the mother. Maternal plasma GH concentrations were very high in spite of the treatment and progressively declined after delivery. The plasma GH level was normal in the child, but PRL was very low at birth and increased in the following days. The expected high PRL concentration was found in the amniotic fluid. This case study suggests that bromocriptine crosses the human placenta and affects the fetal pituitary, maternal GH does not influence fetal or amniotic GH, and amniotic fluid PRL correlates poorly with either maternal or fetal blood levels and is not affected by bromocriptine.

Heterogeneity of Pituitary and Plasma Prolactin in Man: Decreased Affinity of “Big” Prolactin in a Radioreceptor Assay and Evidence for Its Secretion*

Molecular heterogeneity of immunoreactive human PRL (IR-hPRL) plasma was assessed by exclusion chromatography on Sephadex G-100 in blood drawn from 4 normal adults, 3 newborn infants, 2 late gestational women, 3 patients with primary hypothyroidism and high PRL levels, 2 with functional hyperprolactinemia, 3 with acromegaly, and 10 with PRLsecreting tumors. Three forms of PRL, each of different apparent molecular weight, were detected: the so-called big-big hPRL eluted with the void volume, big hPRL appeared after the albumin peak, and little hPRL eluted as monomeric hPRL. In normal subjects, the proportion of big-big, big, and little hPRL components was 5.1 ± 1.7%, 9.1 ± 0.9%, and 85.8 ± 2.3%, respectively, without significant change in the distribution of the different forms after TRF stimulation. In 8 of 10 patients with PRL-secreting tumors, we detected 3.9 ± 0.8%, 14.3 ± 1.1%, and 81.8 ± 1.1%, respectively, a significantly higher proportion of big PRL. In 2 additional patients with prolactinomas, the...

Growth Hormone Causes Rapid Induction of Lactogenic Receptor Activity in the Snell Dwarf Mouse Liver

The Snell dwarf mouse (dw/dw) has no detectable PRL-binding sites in the microsomal fractions of its liver. Both bGH and bPRL, purified by preparative gel electrophoresis, induce PRL-binding sites when injected into dw/dw. Intraperitoneal injection of 100 micrograms bGH every 8 h results in the appearance of a high affinity PRL receptor 8--16 h after initiation of treatment. This induced binding capacity plateaus after 32 h of treatment and subsequently decreases to nondetectable levels 48 h after the last injection. [125I]Iodo-ovine PRL is displaced from the induced receptor equally well by similar concentrations of ovine PRL, human GH, and bovine PRL, but is displaced by bovine GH (bGH) only at approximately 100-fold higher concentrations. While untreated dw/dw livers do possess high affinity bGH-binding sites, treatment with bGH did not alter the bGH-binding activity. Treatment of dw/dw with cycloheximide does not prevent induction of PRL receptors by bGH injections. These observations indicate that bGH induces the PRL receptor by interacting with the cell at some point distal to the induced receptor site and does not require the synthesis of new proteins.

Hypothalamic-pituitary-ovarian function in hyperprolactinemic women.

Hypothalamic-pituitary-ovarian function, as well as other pituitary tropic hormone secretions, was examined in 27 hyperprolactinemic patients (17 with PRL-secreting tumor and 10 with so called functional hyperprolactinemia). Serum PRL levels ranged between 39 and 108 ng/ml in functional cases and between 34 and 2500 ng/ml in patients with pituitary adenoma. Basal serum LH, FSH and 17 β-estradiol levels did not differ from those recorded between days −14 and −10 in normally cycling women in functional cases, and were lowered in patients with pituitary tumor. LH response to GnRH (25μg iv) was normal in 7, impaired in 1 and exaggerated in 2 functional cases, and appeared normal in 9 and impaired in 8 tumoral cases. Two exaggerated FSH responses were seen in functional patients and 4 in patients with pituitary tumor. Estradiol benzoate administration (1 mg im) caused a significant fall in serum FSH and LH within 24 hr, but failed to induce serum LH increase within 96 hr in 11 out of 12 examined patients while a definite LH peak occurred within 48–72 hr in 7 patients retested after serum PRL normalization. Clomiphene citrate (100 mg/day for 5 days) administration caused a normal rise in serum LH, FSH and 17β-estradiol in 5 functional cases and in 1 case with pituitary tumor out of 9 patients tested. Normal pulsatility of serum LH was observed in 3 examined patients. In 3 normogonadotropic patients with PRL-secreting tumor, hCG + hMG administration (5000 + 150 IU im for 3 days) did not cause any significant increase in plasma 17β-estradiol while inducing a sharp rise in the same patients retested after serum PRL normalization. No abnormal changes in TSH, GH and ACTH secretion both in the basal state and after provocative stimuli were observed in patients with functional hyperprolactinemia, whereas in patients with pituitary tumors TSH secretion was impaired in 53% of cases, GH secretion in 71% and ACTH secretion in 29%. The present data along with previous reports in the literature suggest that high serum PRL can induce anovulation and amenorrhea by acting at both hypothalamic and ovarian levels.

The effect of pinealectomy on the pattern of prolactin secretion in conscious freely moving male rats.

Plasma prolactin (Prl) titers were determined by radioimmunoassay in conscious, freely moving male rats which had either had sham operations or had been pinealectomized. Values were determined during the day and during the night in animals on a reversed light cycle. During the day plasma Prl levels were low in both groups with small bursts and a tendency for greater elevation toward the end of the collection period at 17.00 and 18.00 h. There were only 2 significant effects of pinealectomy on these daytime values, one of which was a reduction in the elevation of Prl at 17.30 h. There were also more frequent very low values, less than 5 ng/ml, after pinealectomy. At night there was greater variation of plasma Prl in sham-operated rats and in general the animals showed a sudden elevation just prior to the time the lights were turned on. The values remained elevated for some time thereafter. After pinealectomy the elevation when the lights were turned on was slightly delayed and the responses were smaller in magnitude or even absent. There were significantly more high Prl values in the controls than in the pinealectomized animals in darkness and the area under the curve of Prl release, which was greater at night than in the daytime, was significantly lowered by pinealectomy.

Further evidence on the role of the hypothalamic afferents on the estrogen-induced prolactin release.

Serum prolactin (Prl) concentrations in ovariectomized rats were low without significant differences between morning and afternoon values. These levels were not affected by either frontal or caudal hypothalamic deafferentation. However, they increased after lesioning the hypothalamic median eminence (ME). Three days after the injection of 20 microgram estradiol benzoate (EB) into ovariectomized non-lesioned rats, a rise in serum Prl occurred in the afternoon but not in the morning. In animals with ME lesions estrogen enhanced both morning and afternoon values. The animals with caudal hypothalamic deafferentation and those which had undergone sham operation showed the same pattern as the normal animals. On the contrary, after estrogen treatment of rats with frontal hypothalamic deafferentation high serum Prl concentration during the morning and low levels in the afternoon were observed. It is concluded that estrogen effects on Prl secretion are in part mediated by frontal neural afferents to the hypothalamus. They would facilitate Prl inhibiting factor (PIF) secretion in the morning and inhibit PIF secretion in the afternoon.

Influence of dopaminergic agonists and antagonists on serum prolactin concentrations in the rat.

Inhibitors of dopaminergic neurotransmission, such as reserpine (RES), given alone or combined with alpha-methyl-p-tyrosine (alpha-MpT)or Ro 4-4602, as well as haloperidol (HAL) and sulpiride (SUL), induced highly elevated serum prolactin (Prl) concentrations in intact rats. In contrast, the dopaminergic agonists apomorphine (APO), lisuride hydrogen meleate (LHM), D-amphetamine (AMPH), piribedil and L-dopa greatly lowered the high serum Prl concentrations in female rats induced by i.p. pretreatment with 2 mg/kg RES. Additional inhibition of catecholamine synthesis in RES-treated animals by alpha-MpT abolished the effect of AMPH, which indicates that the effect of this compound is mediated through newly synthesized dopamine (DA), while the effect of APO and LHM remained unchanged. Inhibition of dopa decarboxylation by Ro 4-4602 within the whole body abolished the effect of L-dopa, while lower dosages of Ro 4-4602, which do not penetrate the blood-brain barrier, had less effect. The noradrenergic receptor-stimulating agent clonidine (CLON) had no Prl-lowering effect in RES-treated female rats. In hypophysectomized rats bearing 4 pituitaries transplanted under the kidney capsule, APO and LSM still lowered serum Prl concentrations, while AMPH had no effect; SUL produced a strong increase. These results support the hypothesis that DA has a dominant role as an inhibitor of Prl secretion by acting itself as the Prl inhibiting factor (PIF) on dopaminergic receptors located within the pituitary.