Rise In Serum PRL Research Articles

Effects of cocaine–amphetamine regulated transcript (CART) on hormone release

Objective: Cocaine- and amphetamine-regulated transcript (CART) is a recently described neuropeptide widely expressed in the rat brain. CART is abundant in hypothalamus nuclei controlling anterior pituitary function. In the paraventricular nucleus CART mRNA is colocalized with vasopressin and corticotrophin-releasing factor containing neurons. The data may suggest that CART plays a role in hypothalamic regulation of neuroenocrine functions. Material and methods: Male Wistar–Kyoto rats were investigated. Experiment I: CART was administered intracerebroventricularly (i.c.v.) in a dose of 0.5 μg dissolved in 5 μl vehicle. At 60, 120 min after the infusion of CART or vehicle animals were decapitated and trunk blood was collected until hormonal estimations. Experiment II: CART in a dose of 10 μg was injected intravenously (i.v.). At 60, 120, 240 min the rats were decapitated and the trunk blood was collected. Serum rLH, rFSH, rPRL, rTSH, rGH and plasma leptin, NPY concentrations were measured by RIA methods. Results: CART administered centrally (i.c.v.) simulated significantly GH release after 60 min ( p<0.05) and after 120 min ( p<0.01). CART increased also PRL after 60 min ( p<0.05). A marked increase of corticosterone level was observed at 60 and 120 min ( p<0.01, p<0.01). We did not observe significant changes in LH, FSH and TSH. We found an increase of serum leptin concentrations at 60 min after CART administration ( p<0.01). However, serum NPY levels did not change. After intravenous injection (i.v.) of CART an increase of GH was observed at 120, 240 min ( p<0.01, p<0.01, respectively). A rise in serum PRL was found at 240 min ( p<0.05). Corticosterone concentrations were enhanced at 60, 120, 240 min ( p<0.01, p<0.01, p<0.01, respectively). We did not observe significant changes in LH, FSH and TSH. Conclusions: CART may play a modulating role in the mechanism of pituitary hormone release.

Does alpha-melanocyte-stimulating hormone from the pars intermedia regulate suckling-induced prolactin release? Supportive evidence from morphological and functional studies

Recent evidence suggests that substances derived from the hypophyseal intermediate lobe (IL) play a crucial role in the regulation of suckling-induced PRL secretion. The purpose of the present study was to explore this possibility further by determining whether the suckling stimulus acutely increases the secretory activity of the IL and whether alpha MSH, a major secretory product of the IL, plays a specific role in suckling-induced PRL release. Light microscopic morphometric analysis of serial pituitary sections obtained from lactating rats revealed that as little as 1 min of suckling caused a significant increase in the proportion of the IL that was in secretory configuration (11.8 +/- 0.7% vs. 6.7 +/- 0.5%; 1-min suckled vs. nonsuckled control; mean +/- SE). Moreover, the fraction of the IL in secretory configuration continued to increase after 5 and 10 min of nursing (to 16.0 +/- 0.8% at 5 min and 18.2 +/- 0.7% at 10 min). In contrast, serum PRL was not significantly elevated above the control level after 1 min of suckling (18.1 +/- 13.5 vs. 9.9 +/- 6.5 ng/ml, 1-min suckled vs. control). In fact, a significant rise in PRL levels (to 314.4 +/- 19.4 ng/ml) could be detected only after 10 min of nursing. Thus, secretion by the IL in response to suckling preceded the release of adenohypophyseal PRL, suggesting that a secretory product(s) from the pars intermedia is involved in the modulation of nursing-induced PRL release. Having established a sequential temporal relationship between these two phenomena, we next investigated whether alpha MSH was the IL factor involved in the regulation of suckling-induced PRL secretion. To this end, lactating rats were injected either with antiserum to alpha MSH or preimmune serum and then allowed to nurse their pups. Serial blood samples were taken from the mothers 15, 30, 60, and 90 min after the litters were returned, and serum PRL was measured by RIA. We found that the suckling-induced rise in serum PRL was severely attenuated in animals that received anti-alpha MSH serum. This suppression was most evident at 15 min (70.1 +/- 13.4 vs. 323.5 +/- 127.0 ng/ml, antibody treated vs. preimmune serum control) and persisted throughout the entire 90-min test period. When taken together, our results suggest that suckling-induced PRL secretion is mediated at least in part by alpha MSH released from the hypophyseal IL.

Does alpha-melanocyte-stimulating hormone from the pars intermedia regulate suckling-induced prolactin release? Supportive evidence from morphological and functional studies.

Recent evidence suggests that substances derived from the hypophyseal intermediate lobe (IL) play a crucial role in the regulation of suckling-induced PRL secretion. The purpose of the present study was to explore this possibility further by determining whether the suckling stimulus acutely increases the secretory activity of the IL and whether alpha MSH, a major secretory product of the IL, plays a specific role in suckling-induced PRL release. Light microscopic morphometric analysis of serial pituitary sections obtained from lactating rats revealed that as little as 1 min of suckling caused a significant increase in the proportion of the IL that was in secretory configuration (11.8 +/- 0.7% vs. 6.7 +/- 0.5%; 1-min suckled vs. nonsuckled control; mean +/- SE). Moreover, the fraction of the IL in secretory configuration continued to increase after 5 and 10 min of nursing (to 16.0 +/- 0.8% at 5 min and 18.2 +/- 0.7% at 10 min). In contrast, serum PRL was not significantly elevated above the control level after 1 min of suckling (18.1 +/- 13.5 vs. 9.9 +/- 6.5 ng/ml, 1-min suckled vs. control). In fact, a significant rise in PRL levels (to 314.4 +/- 19.4 ng/ml) could be detected only after 10 min of nursing. Thus, secretion by the IL in response to suckling preceded the release of adenohypophyseal PRL, suggesting that a secretory product(s) from the pars intermedia is involved in the modulation of nursing-induced PRL release. Having established a sequential temporal relationship between these two phenomena, we next investigated whether alpha MSH was the IL factor involved in the regulation of suckling-induced PRL secretion. To this end, lactating rats were injected either with antiserum to alpha MSH or preimmune serum and then allowed to nurse their pups. Serial blood samples were taken from the mothers 15, 30, 60, and 90 min after the litters were returned, and serum PRL was measured by RIA. We found that the suckling-induced rise in serum PRL was severely attenuated in animals that received anti-alpha MSH serum. This suppression was most evident at 15 min (70.1 +/- 13.4 vs. 323.5 +/- 127.0 ng/ml, antibody treated vs. preimmune serum control) and persisted throughout the entire 90-min test period. When taken together, our results suggest that suckling-induced PRL secretion is mediated at least in part by alpha MSH released from the hypophyseal IL.

The mRNA encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin.

During lactation, a dramatic rise in serum PRL stimulates milk production, resulting in a substantial rise in calcium mobilization from gut and bone. We found that the production of a newly characterized calcium-mobilizing PTH-like peptide (PTH-LP) by mammary tissue was tightly linked to lactation, suggesting a possible role for PRL in the expression of PTH-LP. Here it is shown that suckling results in both an elevation in serum PRL and the appearance of PTH-LP mRNA in mammary tissue. Bromocriptine, a potent inhibitor of PRL secretion, blocked the suckling-associated rise in serum PRL and the subsequent induction of PTH-LP mRNA in mammary gland. Furthermore, injection of PRL dramatically induced PTH-LP mRNA in unsuckled puerperal glands, but not in glands on day 21 of pregnancy. Thus, the correlation between serum levels of PRL and the expression of PTH-LP mRNA in mammary tissue extends the role of PRL in milk production and suggests a possible mechanism for the PRL effects on calcium metabolism.

Gradual recovery of lactotroph responsiveness to dynamic stimulation following surgical removal of prolactinomas: Long-term follow-up studies

Prolactin-secreting pituitary adenomas were selectively removed through a transsphenoidal approach from 120 women. Basal serum PRL levels (measured one to six months after surgery) were normal in 96 patients and decreased appreciably but not to normal in the remaining 24 patients. Dynamics of PRL secretion were studied at three to four months in 81 patients who had normal basal PRL level. Two different patterns of response to provocative stimuli were noted in these patients. In one group (group I, n = 65), patients had >100% rise in serum PRL following TRH or perphenazine (Pz) administration. However, when analyzed as a group, the mean ± SEM incremental responses (ΔPRL) to TRH and Pz in these patients (29.9 ± 1.9, 20.4 ± 1.5 ng/mL) were significantly less ( P < 0.005 and P < 0.001) than those of normal women (38.8 ± 5, 33 ± 5 ng/mL, respectively). Nineteen of these patients were restudied 12 to 72 months after surgery. The responses to provocative stimulation at that time were improved and similar to normal women. In contrast, in the second group (n = 16) of patients (group II), the responses to stimulation with the same agents were blunted or absent and remained so during subsequent studies. Recurrence of the hyperprolactinemia was noted in 11 of the 16 patients in group II and in only two of 65 patients in group I. The daily serum PRL levels in the immediate postoperative period were higher in patients from group II than those from group I. We conclude that transsphenoidal surgery is an optimal form of therapy for patients with PRL-secreting adenomas. The dynamics of PRL secretion are helpful in evaluating the outcome of surgery and in predicting patients at risk for recurrences. Following complete removal of the adenoma, lactotrophs of the normal pituitary recover gradually and their responsiveness to stimulation becomes normal months to years later. These findings are consistent with the concept that PRL-secreting pituitary adenomas are primary pituitary disorders.

Long term follow-up of women with surgically treated prolactin-secreting pituitary tumors.

To examine the long term effectiveness of transsphenoidal microsurgery for patients with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. Hyperprolactinemia recurred in 12 of 31 patients (39%) who had normal PRL concentration 6 weeks after surgery. None of the patients with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 weeks after surgery occurred more frequently in cured patients than in those who had a recurrence. PRL responses to TRH were normal in cured patients 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. The PRL responses to chlorpromazine- and insulin-induced hypoglycemia were blunted in patients with normal as well as elevated PRL levels. Patients with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in serum PRL 5 yr after surgery. The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for patients with PRL-secreting tumors.

Dermorphin stimulates prolactin secretion in the rat.

The effect of dermorphin, a new opioid peptide originally isolated from amphibian skin, on the release of prolactin (Prl) was studied in vivo and in vitro. In vivo experiments: subcutaneous administrations of different doses of dermorphin ranging from 0.1 to 5 mg/kg body weight to normal male rats induce a statistically significant, dose-related increase in serum Prl levels. Pretreatment with the specific opioid antagonist, naloxone (2 mg/kg i.p.) completely prevents the rise in serum Prl, induced by 2 mg/kg of dermorphin. In normal male rats, the intraventricular injection of 0.25 micrograms/kg of dermorphin is not able to induce any significant changes in serum Prl levels 10 min after injection. Serum Prl levels show a significant enhancement 30 min after the administration of this dose of dermorphin, and return to control values at 60 min. On the contrary, 1 microgram/kg of dermorphin significantly elevates Prl concentrations 10 min after injection, leaving serum Prl levels unchanged 30 and 60 min after the administration. Naloxone (25 and 100 micrograms/kg) alone does not substantially modify serum Prl concentrations at any time interval considered. Treatment with either dose of naloxone performed together with either 0.25 or 1 microgram/kg of dermorphin completely counteracts the stimulatory effect of the peptide at all time intervals in which dermorphin was active when given alone. In orchidectomized (3 weeks) rats, the intraventricular administration of dermorphin at the dose of 0.25 micrograms/kg appears effective in enhancing Prl levels only 30 min after treatment. No statistically significant modifications are observed at 10 and 60 min with this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Down-Regulation of Prolactin Secretion in Men during Continuous Thyrotropin-Releasing Hormone Infusion: Evidence for Induction of Pituitary Desensitization by Continuous TRH Administration

TRH was administered as a 5-h constant rate iv infusion (5 micrograms/min) to seven healthy adult men. Serum samples were collected at regular intervals for measurement of PRL, TSH, and T3. Serum levels of PRL during TRH infusion increased sharply to maximum level by 40 min, and then, despite continued TRH stimulation, PRL levels declined gradually to a plateau value after 100 min. No further rise in serum PRL was observed when a bolus of 200 micrograms TRH was administered to three subjects after 240 min of infusion. Conversely, an iv bolus of sulpiride (25 mg), a dopaminergic antagonist, given to four subjects after 240 min, brought about a marked increase in serum PRL values above the plateau level. These results are consistent with the interpretation that down-regulation in PRL secretion which follows the initial peak of response most likely represents pituitary desensitization to TRH. During the infusion serum TSH increases in two phases. A first phase of secretion was observed by 40 min followed by a plateau, with a second phase of increase occurring between 80-180 min.

Recovery of pituitary function following surgical removal of large nonfunctioning pituitary adenomas.

SUMMARYPituitary function was evaluated in eleven patients with large nonfunctioning pituitary adenomas before and 3 months after surgical adenomectomy. The longest anteroposterior dimension from the anterior wall to the dorsum of the sella on a lateral skull x‐ray ranged between 22 and 45 mm. All adenomas were confirmed histologically and had negative immunostaining for GH, PRL, ACTH and HCG.Based on the pre‐ and post‐operative pituitary function, the patients were divided into two groups. Group I included eight patients who had hypopituitarism pre‐operatively of whom five had partial recovery of pituitary function while three had persistent hypopituitarism. Group II included three patients who had normal pituitary function pre‐ and post‐operatively. Five patients of group I had high normal or slightly elevated serum PRL levels while one had a normal level and two patients had low levels pre‐operatively. TRH but not perphenazine resulted in a variable but definite rise in serum PRL preoperatively in patients with normal or elevated PRL level.In contrast, neither stimulus resulted in a rise in serum PRL in two patients with low basal levels. Serum PRL levels were normal in six patients and low in two others post‐operatively. Serum TSH levels were low in all eight patients with hypothyroidism. TRH resulted in a sustained release of TSH in three patients and was without effect in two patients pre‐operatively. Of eight patients with pre‐operative hypothyroidism, five recovered normal function and three remained hypothyroid. Of six patients with adrenal insufficiency pre‐operatively, two recovered normal pituitary—adrenal function while only two of eight patients recovered gonadal function post‐operatively. None of the eight patients recovered GH responsiveness to stimulation. All patients that recovered pituitary function had normal or slightly elevated serum PRL pre‐operatively. Our data indicate that recovery of pituitary function in patients with large pituitary adenomas and hypopituitarism may occur after surgical removal of the adenoma. One of the possible mechanisms of hypopituitarism in this setting would be interruption of the hypothalamic pituitary portal circulation by the large adenoma. An additional factor might be pressure necrosis and destruction of normal pituitary cells by the expanding adenoma. The extent of that might determine the degree of recovery of pituitary function.

Prolactin and calcitonin responses to parathyroid hormone infusion in hypoparathyroid, pseudohypoparathyroid, and normal subjects.

Since parathyroid hormone (PTH) has been reported to release PRL in normal humans, we studied the effects of exogenous PTH infusion (150 U) on the secretion of PRL, TSH, and calcitonin in 10 normal subjects, 5 with hypoparathyroidism, and 10 with pseudohypoparathyroidism, type I (PHP). PTH produced a rise in serum PRL in the normal subjects from 5.1 +/- 0.8 ng/ml (SE) to 14.9 +/- 3.0 ng/ml (P less than 0.01), while levels similarly rose from 4.0 +/- 0.2 to 8.5 +/- 0.8 ng/ml (P less than 0.01) in the patients with hypoparathyroidism. In 6 PHP patients with deficient PRL responses to TRH, the PRL response to PTH was also blunted (basal, 3.2 +/- 0.81 ng/ml; peak, 4.1 +/- 1.3 ng/ml; P greater than 0.1). Three of 4 PHP patients with normal PRL responses to TRH demonstrated a normal PRL increment in response to PTH infusion. Serum TSH and calcitonin were not changed by PTH infusion in any of the groups. These findings demonstrate that the resistance to PTH seen in PHP does not extend to the pituitary gland.

Opiates, Prolactin, and the Dopamine Receptor*

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

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.