Rise In Prolactin Research Articles

Localisation of insulin-like growth factor receptors in skin follicles of sheep ( Ovis aries) and changes during an induced growth cycle

Pelage growth cycles are regulated by circulating prolactin in many mammals, but the intercellular mediators of this signaling are unknown. Binding sites for insulin-like growth factors (IGFs) were examined in sheep skin to show changes in distribution and abundance of IGF receptors associated with a prolactin stimulus and the subsequent hair follicle growth cycle. Follicle cycles were induced in New Zealand Wiltshire ewes by a surge in plasma prolactin following a 4-month period of prolactin suppression with bromocriptine. Eight treated and three control sheep were slaughtered at intervals over 43 days during the follicle growth cycle. At 12–20 days after the elevation of prolactin, wool follicles passed through brief catagen and telogen phases, followed by a return to anagen. IGF binding sites were localized in skin sections by incubation with 125I-IGF-I or 125I-IGF-II. Displacement with competitive binding inhibitors (unlabeled IGF-I, IGF-II, des(1–3)IGF-I, des(1–6)IGF-II, or insulin) and affinity cross-linking showed that these binding sites were predominantly IGF type 1 and type 2 (mannose-6-phosphate) receptors. The radiologands bound especially to follicle germinal cells and prekeratinocytes. Increases in specific binding of both radioligands were observed after the rise in prolactin, but prior to anatomical changes in follicles associated with cessation of growth. For IGF-I, highest binding density was observed during catagen in the germinal matrix and dermal papilla cells. For IGF-II, peak density occurred during late anagen/early catagen in the germinal matrix and during telogen in the dermal papilla. These cycle associated changes in receptor availability suggest that IGF receptors are involved in control of the wool growth.

Relationship between mesial temporal seizure focus and elevated serum prolactin in temporal lobe epilepsy.

We evaluated the relationship between mesial temporal seizure focus and serum prolactin (PRL) in patients before and after they underwent anterior temporal lobectomy (ATL) for medically intractable temporal lobe epilepsy (TLE). These patients had a confirmed unilateral epileptogenic focus in mesial temporal structures, a postictal rise in serum PRL 15 to 20 minutes after onset of complex partial seizures, and were refractory for more than 2 years to antiepileptic drugs. Presurgical interictal serum PRL levels were significantly elevated (16.47 +/- 0.85 ng/mL, n = 62) and declined after ATL to normal values (patients, 9.63 +/- 0.55 ng/mL, n = 54; normal subjects, 8.99 +/- 0.57 ng/mL, n = 52). Serial evaluations indicated that normalization was seen 3 months after surgery (9.42 +/- 1.22 ng/mL, n = 9). The postsurgical reduction in serum PRL was similar in men and women, in patients with epileptogenic focus on either side of mesial temporal structures, and was unaffected by antiepileptic medication. We conclude that PRL is elevated following seizures and that a seizure focus in mesial temporal structures may exert a sustained excitatory influence on PRL release in patients with medically intractable TLE.

Serum Prolactin Response to Stressors in Children. • 67

To further describe the relationship between prolactin and behavior in children, sequential serum prolactins were obtained in the course of a follow-up study of iron deficiency in infancy. 167 of the original 191 Costa Rican children (87%) were assessed at 10-13 years of age (mean=12 yr); prolactins were available for 164 subjects. At the time of venipuncture for iron status measures, a catheter was placed indwelling for 4 hours to determine the initial rise and decline of prolactin with venipuncture (0, 15, 30 and 45 min) and prolactin response to a psychological task involving blindfolding, IQ testing, a socially stressful situation and routine dental examination (no fillings). Sera were separated, stored at - 20°C and later assayed by double-antibody RIA for prolactin. Using each child's lowest value as the reference for that child, IQ testing produced trivial changes in serum prolactin. In contrast, serum prolactin rose, on average, 34% after a socially stressful encounter, 62% after a dental exam and 177% after venipuncture. These responses all differed significantly from each other (p<0.1). Males had a greater increase than females after the dental exam (77% vs 39%, p<0.01) but there were no other gender differences. Serum prolactin response to physical or psychological stress has been inconsistently observed in previous studies. Addressing methodologic problems, this study used a larger sample, both genders, varying stressors, and sequential sampling immediately post-stressor. The results show that serum prolactin is a sensitive stress response hormone in children and the degree of the response appears related to the severity of the stressor.

Prolactinomas Resistant to Bromocriptine

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15-30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5-17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 +/- 185 micrograms/l (mean +/- SEM) and decreased to 291 +/- 154 micrograms/l after a 6-21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150-300 micrograms/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 +/- 180 micrograms/l) was 16 +/- 2 micrograms/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150-450 micrograms/day quinagolide. Their initial PRL levels (606 +/- 298 micrograms/l) were reduced to 343 +/- 187 micrograms/l (versus 463 +/- 265 micrograms/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3-4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 micrograms/l and from 65 to 192 micrograms/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240-400 micrograms/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observed in a limited series, justify the careful follow-up of pregnancies in this subclass of patients at risk. Finally, in the whole population, long-term control of hyperprolactinemia by quinagolide was obtained in 11/28 patients (39%) previously resistant to bromocriptine, and 15/20 women (75%) resumed normal gonadal function with a quinagolide daily dose of 300 micrograms in most of them.

Effect of Nω‐nitro‐l‐arginine methyl ester, a nitric oxide synthesis inhibitor, on stress‐ and morphine‐induced prolactin release in male rats

1. The effect of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was investigated on stress- and morphine-induced prolactin (PRL) secretion in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Three doses of L-NAME were tested (1, 10 and 30 mg kg-1) and were given intraperitoneally one hour before blood sampling; control rats received saline. After the first blood sample, rats received an initial intravenous injection of morphine (3, 6 or 12 mg kg-1) or were subjected to immobilization stress. In the case of a morphine administration, rats received a second dose of morphine (3, 6 or 6 mg kg-1, respectively) 90 min later, when tolerance had developed, while rats subjected to immobilization stress received 6 mg kg-1 morphine 90 min after onset of stress. 3. L-NAME had no effect on basal plasma PRL concentration. However, it potentiated acute morphine-induced PRL secretion and attenuated the subsequent tolerance in a dose-dependent way. Immobilization stress-induced PRL secretion was inhibited dose-dependently by L-NAME, as was its subsequent tolerance to morphine; however, in this case, in a reversed dose-dependent way. 4. When the highest dose of morphine (12 mg kg-1) was combined with the highest dose of L-NAME pretreatment (30 mg kg-1), all rats showed a dramatic potentiation of the morphine-induced PRL rise compared to controls. Moreover, all of these rats died within 90 min after the administration of morphine. 5. These results show that NO plays a role in the acute opioid action on PRL release during stress as well as in the development of tolerance to the opioid effect, and some possible mechanisms are discussed.

Prolactinomas resistant to bromocriptine: long-term efficacy of quinagolide and outcome of pregnancy.

Resistance to bromocriptine, defined as the absence of normalization of prolactin (PRL) levels despite a 15-30 mg daily dose of bromocriptine during at least 6 months, has been observed in 5-17% of the prolactinomas according to the literature. The recent availability of a new potent dopamine agonist, quinagolide, prompted us to analyze its long-term therapeutic effects in 28 patients with prolactinomas resistant to bromocriptine. Before bromocriptine, their PRL levels were 520 +/- 185 micrograms/l (mean +/- SEM) and decreased to 291 +/- 154 micrograms/l after a 6-21 month period of bromocriptine treatment. All the women (N = 20) remained amenorrheic and hypogonadism was not improved in men (N = 8). Subsequently, after 1 year of 150-300 micrograms/day quinagolide, 12/28 patients of the present series recovered normal gonadal function and their initial mean baseline PRL value (404 +/- 180 micrograms/l) was 16 +/- 2 micrograms/l after 1 year of treatment. A significant tumor shrinkage was observed in 5/8 macroadenomas (62%). During the 3-year follow-up period under quinagolide, a similar good control was achieved in these patients, with the exception of one man presenting with a secondary rise of PRL under quinagolide. In contrast, 15 other patients (one patient interrupted quinagolide at 6 months because of poor tolerance) were not normalized under 150-450 micrograms/day quinagolide. Their initial PRL levels (606 +/- 298 micrograms/l) were reduced to 343 +/- 187 micrograms/l (versus 463 +/- 265 micrograms/l under bromocriptine after the same duration of treatment). Despite such a partial inhibitory effect of quinagolide, 7/12 women resumed menstrual cycles and three pregnancies occurred. In no case was any tumor shrinkage noticed during the 3-4-year follow-up. Three patients even presented, after 2 years of quinagolide treatment, with a secondary rise of PRL values associated with a further tumor growth in two patients. During the 3-year follow-up period, nine pregnancies occurred in seven women. In five women, after quinagolide withdrawal, the plasma PRL baseline values ranged from 52 to 158 micrograms/l and from 65 to 192 micrograms/l, respectively, at the first trimester and at the end of uneventful pregnancies. In contrast, in two women a rapid increase of PRL (240-400 micrograms/l) correlated with tumor growth during the first trimester. Such a tumor progression was blocked by quinagolide treatment but not by bromocriptine. These data, although observed in a limited series, justify the careful follow-up of pregnancies in this subclass of patients at risk. Finally, in the whole population, long-term control of hyperprolactinemia by quinagolide was obtained in 11/28 patients (39%) previously resistant to bromocriptine, and 15/20 women (75%) resumed normal gonadal function with a quinagolide daily dose of 300 micrograms in most of them.

498. - Course of psychotic disorders in women: Influence of menstrual cycle phase

are few data from studies that more directly examined serotonerglc responses in POD. We carried out such a stud)' u~ing the serotoninreleasing drug, dl-fenfluramine. We recruited 9 women with a prospecrive diagnosis of PDO and II healthy female controls. Each woman underwentu fenfluramlne challenge lest (60 mg p.o.) and a single-blind placebochallenge. Rise in plasma prolactin was the outcome measure of interest. The peak prolactin response to fenflurnrnlne was significantly less (p<O.04) in the POD group after controlling for effects of age and weight.This bluntedresponse is independent of pharmacokinetlc effects. This pilot study provides more direct evidenceof serotonerglcdysfunction in women with POD,

Nocturnal melatonin and luteinizing hormone rhythms in women with hyperprolactinemic amenorrhea.

To examine the role of melatonin in pathological hyperprolactinemia we compared untreated young females (N = 5) with hyperprolactinemic amenorrhea owing to pituitary microadenoma to healthy female controls (N = 6). Serum samples for melatonin, prolactin, and luteinizing hormone (LH) concentrations were obtained every 15 min from 1900 hr to 0700 hr in a controlled light-dark environment with simultaneous sleep recordings. The mean (+/- SD) light-time period, dark-time period, and the integrated nocturnal melatonin secretion values (area under the curve, or AUC) in patients (51 +/- 11 pmol/L, 157 +/- 33 pmol/L, and 102 +/- 19 pmol/min.L x 10(3), respectively) were similar to the values obtained in controls (79 +/- 39, 165 +/- 44, 111 +/- 31, respectively). The onset of the nocturnal melatonin rise, peak level, and peak time were similar in the two groups. A significant nocturnal prolactin rise was observed in patients (112 +/- 9 vs. 65 +/- 11 micrograms/L, P < 0.006) and controls (19 +/- 2 vs. 10 +/- 3 micrograms/L, P < 0.006). The time of prolactin peak was similar in patients and controls (0424 +/- 3:36 vs. 0350 +/- 2:21) and paralleled that of melatonin (0354 +/- 1:46 vs. 0337 +/- 1:30). The mean +/- SD light-time period, dark-time period, and the AUC values of LH were similar in patients and controls. The number of LH pulses in patients (7.2 +/- 1.9 per 12 hr) were not different from those in controls (7.7 +/- 2.1). The LH pulse interval was 100 +/- 22 min in patients compared with 94 +/- 23 min in controls. The mean (+/- SD) nocturnal estradiol (E2) levels were significantly lower in patients (84 +/- 15 pmol/L) than in controls (224 +/- 77) (P < 0.005). Analysis of LH and melatonin secretory profiles revealed significant pulses for both hormones. No significant relationship was observed between the LH and melatonin pulses. However, a negative correlation between LH pulse amplitude and the number of melatonin pulses (P < 0.04) and a positive correlation between LH amplitude and duration of melatonin pulses (P < 0.04) were observed. Taken together, these data suggest that the suppression of normal ovarian cycles in women with hyperprolactinemic amenorrhea owing to pituitary microadenoma may be mediated by blocking of gonadotropin action by prolactin at the ovarian level; yet it remains possible that chronically elevated prolactin might prevent the LH surge and thus lead to amenorrhea. Pulsatile melatonin secretion is unaltered in these patients, and frequent occurrence of amenorrhea in this population is not mediated by melatonin.

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam.

Inhibitory effect of increased photoperiod on wool follicle growth.

The relationships between circulating prolactin (PRL), wool follicle growth and daylength were investigated in 24 New Zealand Wiltshire ewes housed indoors from September 1989 to May 1991. Twelve control (C) ewes were maintained under natural photoperiod. Two other groups were held in short days (SD; 8 h light: 16 h darkness) commencing from the winter solstice (22 June 1990) for either three (group SD3, n = 7) or six (group SD6, n = 5) months before reversion to natural daylength. Skin was sampled at one- to four-week intervals for histological determination of percentages of growing primary and secondary follicles. Hourly blood samples over 24 h were collected via jugular cannulae from C sheep in March and July and then monthly from all animals until December 1990 for estimation of mean monthly PRL concentrations for each treatment group. Between autumn (March 1990) and winter (July) primary follicle activity (PFA) and secondary follicle activity (SFA) declined in C ewes (PFA: 97 to 43%, SFA: 100 to 57%). Follicle regrowth during July and August in eight C ewes preceded the initial rise in plasma PRL from the winter minimum (1.6 ng/ml). Across the three groups, four instances of decreased follicle activity were observed, closely following or concurrent with increases in plasma PRL concentrations. The resumption of spring growth in four C sheep was temporarily checked by falls in follicle activities during September and October as PRL concentrations began to increase (3.4 to 8.9 ng/ml). Follicle activity also declined in November and December in eight C sheep, coincident with the rapid rise in PRL to a seasonal maximum in late November (165.4 ng/ml). The increase in SD3 follicle activity over spring was not delayed by short days but during October, after release from treatment, PRL concentrations rose (1.8 to 12.0 ng/ml) and follicle activity declined (PFA: 65 to 38%, SFA: 68 to 43%). In SD6 ewes, PRL concentrations were suppressed (2.1 ng/ml) and relatively constant levels of follicle activity (PFA: 73%, SFA: 95%) were maintained throughout short-day treatment. Release of SD6 ewes into summer photoperiod in January 1991 temporarily interrupted follicle growth (PFA: 68 to 17%, SFA: 96 to 19%) and caused out-of-season shedding in March and April. Contemporary C follicle activities were high (PFA: 95%, SFA: 98%). These data suggest that natural and experimental increases in daylength have a short-term inhibitory effect on growing wool follicles which could be mediated through rising concentrations of plasma prolactin.

Effect of mating season and body condition on ovulation, fertilization and pregnancy rates in crossbred ewes

In three experiments, ewes kept under the ambient photoperiod at 57 °N were given daily at 15:00 h from March onwards an oral dose of 3 mg of melatonin in a 4:1 mixture of water and ethanol or, in the case of controls, the vehicle alone. All ewes were challenged daily with a vasectomized ram for the detection of behavioural oestrus. In Experiment 1, the mean interval (± standard error of the mean (s.e.m.)) from the start of melatonin treatment on 5 March to first behavioural oestrus for Border Leicester × Scottish Blackface ewes that had remained barren over the winter period was 87 ± 5.8 days (n = 8) compared with 222 ± 10.3 (n = 7) for controls. Corresponding intervals from the start of melatonin treatment on 24 March for the same breed of ewe in Experiment 2 were 80 ± 3.7 (n = 6) and 211 ± 9.4 (n = 6) days. In Experiment 3, 22 Scottish Blackface ewes that lambed between 11 January and 22 February were paired by lambing date for weaning at either 6 or 14 weeks. All ewes received melatonin from 22 March until 5 August. Apart from one ewe from the 14 week group that failed to show oestrus, all other ewes responded to melatonin and exhibited first behavioural oestrus at mean intervals from initial dosing of 77 ± 4.6 days and 75 ± 3.2 days for the 6 week and 14 week groups, respectively. Melatonin suppressed prolactin in both dry (Experiments 1 and 2) and lactating ewes (Experiments 1, 2 and 3), but in the only experiment in which it was tested (Experiment 1), its continuous administration throughout pregnancy failed to prevent the late-pregnancy rise in prolactin. It had no effect on gestation length or the subsequent growth rate of lambs; its effect on lamb birth weight was equivocal, causing a significant decrease in twin lambs in Experiment 2 and no effect in Experiment 1. Detailed sequential measures of the nature of the episodic release of luteinizing hormone (LH) (Experiment 2) provided no evidence that melatonin induced a progressive increase in the activity of the gonadotrophin releasing hormone (GnRH) pulse generator.The ovarian response to the daily oral administration of melatonin from March onwards contrasts with literature reports on the failure of continuous-release implants of melatonin to stimulate behavioural oestrus when inserted as early as April or May.

Plasma Prolactin and Luteinizing Hormone during Termination and Onset of Photorefractoriness in Intact and Pinealectomized European Starlings ( Sturnus vulgaris)

Plasma levels of prolactin and luteinizing hormone have been examined in intact and pinealectomized European starling ( Sturnus vulgaris) during termination and onset of photorefractoriness. Photorefractory starlings exposed to long (18L:6D) daily photoperiods for 10 weeks were pinealectomized. One week after pinealectomy these birds, along with the intact and sham-operated birds, were transferred to short (8L:16D) daily photoperiods. After 10 weeks on short day lengths the daily photoperiod was switched to long (18L:6D) and the birds remained on this regime for a further 10 weeks. Plasma prolactin and luteinizing hormone were determined prior to pinealectomy and then weekly throughout the experiment. Molt scores were also recorded. Profiles of both the hormones and the molt pattern were similar in pinealectomized, sham-operated, and intact control starlings. In European starlings the pineal gland does not seem to exert significant effects on the photoinduced rise in plasma prolactin and luteinizing hormone seen in photosensitive birds. It is also suggested that pinealectomy has no significant effect on the dissipation and onset of photorefractoriness assessed from plasma luteinizing hormone secretion in this bird.

Arecoline reverses dexamethasone suppression of cortisol in normal males: A pilot study

Six normal controls participated in two or three individual, intravenous challenges (each separated by 1 week) of saline or one of two doses of arecoline at 8 AM following ingestion of 1 mg dexamethasone at 12 midnight the previous evening. Individuals differed in their subjective and neuroendocrine responses to arecoline. At 2.1 micrograms/kg (n = 4) or 2.8 micrograms/kg (n = 1), four of five subjects evidenced dexamethone suppression test (DST) nonsuppression, which followed the rise in prolactin. Cholinergic side effects and nausea were minimal. At a dose of 4.2 micrograms/kg, four of five subjects evidenced cortisol escape from dexamethasone suppression, which was associated with a substantial rise in prolactin, some subjective cholinergic symptoms, and little to modest nausea. These data are consistent with the notion that cholinergic mechanisms are involved in the escape from dexamethasone suppression. Further, arecoline may be preferable to physostigmine as a cholinergic agonist, since it appears less likely to cause marked cholinergic side effects and significant nausea.

Reduced prolactin release during immobilization stress in thyrotoxic rats: role of the central serotoninergic system.

Adult Wistar male rats in a thyrotoxic state T4 increases rats) induced by administration of T4 (350 micrograms/kg/day, i.p. for 7 days) as well as their euthyroid controls were submitted to immobilization stress during forty minutes. Prolactin (PRL) secretion during stress was significantly lower in T4 increases rats as compared to control animals. Treatment with MK 212, a serotoninergic agonist, entirely reverts this situation. The effect of MK 212 seems to be due to its interaction with 5-HT2 receptors since it is blocked by LY 53857, a selective 5-HT2 antagonist. Furthermore, the blockade of 5-HT2 receptors by LY 53857, a selective 5-HT2 antagonist, significantly diminishes prolactin (PRL) response to stress in euthyroid rats but has no effect in T4 increases animals. It is suggested that an increased concentration of thyroid hormone in plasma disrupts an endogenous serotoninergic brain input necessary to trigger stress-induced PRL rise.

Prediction of recurrence in operable breast cancer by postoperative changes in prolactin secretion.

It has been demonstrated that breast surgery may induce prolactin (PRL) increase. Because of the potential stimulatory role of PRL on breast cancer cells, its postoperative increase may influence the prognosis of breast cancer patients. This study was performed to evaluate the influence of surgery-induced hyperprolactinemia on recurrence rate in operable breast cancer. The study included 250 consecutive breast cancer patients, clinical stage T1-3 N0-2M0, who were observed for a median follow-up of 72 months. Surgery-induced hyperprolactinemia occurred in 108/250 patients (43%). Irrespectively of node involvement, hormonal receptor, type of surgery and adjuvant therapies, the relapse rate was significantly higher in patients who had no surgery-induced hyperprolactinemia than in those with postoperative PRL increase (64/142 vs. 23/108; p < 0.001). This difference was also significant in relation to node status (N0:22/63 vs. 5/56, p < 0.001; N+:42/79 vs. 18/52, p < 0.05). The present study shows that a surgery-induced rise of PRL, despite its potential stimulation of cancer cell growth, is paradoxically associated with a longer disease-free survival in operable breast carcinoma in both patients with or without axillary node involvement. Moreover, this study suggests that the prognosis of node-negative patients who did not show postoperative hyperprolactinemia tends to be similar to that of patients with node involvement and surgery-induced PRL enhancement. Therefore, the lack of surgery-induced hyperprolactinemia would have to be grouped together with the unfavorable prognostic factors of breast cancer.

Stimulated thyrotropin and prolactin secretion in lactating and non-lactating women.

During the postpartum period, lactation is initiated by a massive release of prolactin which, in turn, reflects reduced dopaminergic inhibition of the pituitary lactotrophs. This postpartum prolactin rise can be prevented by administration of dopamine agonists. The release of thyrotropin (TSH) is also controlled by dopaminergic inputs and, therefore, TSH secretion may also be affected by postpartum alterations in dopaminergic activity. To gain further insight into the regulation of TSH and prolactin secretion during the postpartum period, we compared the basal and stimulated TSH and prolactin levels of postpartum lactating (n = 10) and non-lactating women (treated with 5 mg bromocriptine daily, n = 9) with those of normal cycling women (n = 9). Frequent blood samples were obtained on postpartum day 5 or in the early follicular phase before and after administration of thyrotropin-releasing hormone (TRH) for serial determination of TSH and prolactin by immunoradiometric assay (IRMA). Based serum prolactin levels were high (p < 0.001) in lactating women and low in both non-lactating and normal cycling women. When these differences in the basal prolactin concentrations were taken into account, the stimulated prolactin release (relative prolactin increase and area under the prolactin curve) was found to be highest (p < 0.05) in non-lactating women and lowest in lactating women. Basal TSH secretion was not significantly different between the groups of women (p > 0.2). Yet, both the relative TSH increases and the response curves following TRH stimulations were high (p < 0.05) in normal cycling women and low in both lactating and non-lactating postpartum women. These observations confirm a difference in the basal and stimulated prolactin release between lactating and non-lactating women. They also indicate that the TRH-stimulated TSH release is greatly affected by the postpartum state, irrespective of lactation or therapeutic weaning. The observation of a decreased sensitivity of pituitary thyrotrophs in concert with unchanged basal TSH secretion is suggestive of changes in hypothalamic TRH secretion and/or in the TSH metabolic half-life during the postpartum period.

Effects of sleep deprivation on serotonin function in depression

There is considerable evidence that antidepressant treatments enhance serotonin (5-HT) function. In order to evaluate whether sleep deprivation (SD) produces alterations in 5-HT function, the increase in prolactin (PRL) produced by intravenous tryptophan (TRP) was assessed in depressed patients following SD and undisturbed sleep (US). Eleven depressed patients received mood ratings and TRP infusions after either SD or US, 1 week apart. In five women, but not six men, the TRP-induced PRL rise was markedly enhanced after SD compared to US. Mood score changes were not significantly different between US and SD and there was no significant relationship of mood changes to the TRP induced PRL response. The data suggests that SD produces an increase in 5HT function in female depressed patients. The lack of identified SD-induced changes in 5-HT function in men may be due to lower sensitivity of the TRP-induced PRL rise in depressed men than women.

Opioid modulation of the gamma-aminobutyric acid-controlled inhibition of exercise-stimulated growth hormone and prolactin secretion in normal men

The possible involvement of endogenous opioids in the gamma-aminobutyric acid-controlled (GABAergic) inhibition of growth hormone (GH) and prolactin (PRL) during physical exercise was evaluated in normal men. After fasting overnight, seven subjects were tested on four mornings at least 1 week apart. Exercise was performed on a bicycle ergometer. The workload was gradually increased at 3-min intervals until exhaustion and lasted about 15 min in all subjects. Tests were carried out under administration of placebo, the opioid antagonist naloxone (10 mg as an iv bolus injection), the GABAergic agonist sodium valproate (600 mg in three divided doses orally) or naloxone plus sodium valproate. During exercise, plasma GH and PRL levels rose 5.5- and 1.9-fold, respectively. The administration of naloxone did not modify, whereas sodium valproate significantly reduced the plasma GH and PRL rise during exercise. In the presence of sodium valproate, GH and PRL levels rose 3- and 1.5-fold, respectively, in response to exercise. When naloxone was given together with sodium valproate, both GH and PRL responses to exercise were abolished completely. These data suggest the involvement of a GABAergic mechanism in the regulation of GH and PRL responses to physical exercise in men. Furthermore, the data argue against a role of naloxone-sensitive endogenous opioids in the control of these hormonal responses to exercise, whereas they suggest a modulation by opioids of the GABAergic inhibitory action.

Serum levels of insulin-like growth factor-I in operable breast cancer in relation to the main prognostic variables and their perioperative changes in relation to those of prolactin.

In addition to estrogens, prolactin (PRL) and IGF-I have also appeared to stimulate breast cancer growth. The present study was performed to evaluate IGF-I blood levels in operable breast cancer in relation to PRL values and the main prognostic variables. The study included 40 patients, clinical stage T1-3NO-2MO. Venous blood samples were collected before and 7 days after surgery. PRL and IGF-I were measured by radioimmunoassay. The control group consisted of 50 healthy women. Mean serum levels of IGF-I were significantly higher in patients than in controls, without any apparent relation to the main prognostic variables, including estrogen receptor and node status. Surgery-induced hyperprolactinemia occurred in 22/40 patients. IGF-I mean concentrations observed in the postoperative period in patients with surgery-induced hyperprolactinemia were significantly lower than those seen in patients showing no postoperative PRL rise. The study showed that operable breast cancer may be associated with abnormally high levels of tumor growth factor IGF-I, and that surgery was followed by an IGF-I decline only in patients who showed surgery-induced hyperprolactinemia. Our previous studies have shown that postoperative hyperprolactinemia is a favorable prognostic factors for operable breast cancer. The present study, by showing that a postoperative PRL rise is associated with a fall in IGF-I, would suggest that surgery-induced hyperprolactinemia may determine a lower tumor relapse rate by determining a diminished secretion of breast tumor growth factor IGF-I.

Effects of morphine on hypothalamic tyrosine hydroxylase mRNA levels in dopaminergic neurons and on preoptic DOPAC levels measured by microdialysis

Morphine not only suppresses norepinephrine-induced increases in LHRH mRNA levels but, in these same animals, it simultaneously amplifies norepinephrine (NE)-induced LH release. These observations suggest that NE may activate parallel mechanisms which independently increase LHRH mRNA levels and LHRH release and suggest that some of these effects could be mediated indirectly via morphine's action on different components of the hypothalamic dopamine (DA) system. Accordingly, in the present studies we examined the effects of morphine on various components of this dopamine system using as our index of altered DA neuronal activity, the changes which occur in tyrosine hydroxylase (TH) mRNA levels following morphine. As an ancillary index of changes which occur in dopamine neuronal activity, we measured, by microdialysis, the changes which occur in preoptic dihydroxyphenylacetic acid (DOPAC) levels after either subcutaneous injections or following microinfusions of morphine into the zona incerta (ZI). In a final study, we evaluated whether DA when given alone (icv infusion) or prior to icv NE would altered LH release. Single cell levels of TH mRNA in preoptic A15 and periventricular anterior hypothalamic A14 DA neurons were not affected by morphine 1, 5 and 24 h later. In contrast, within 1 h after morphine, TH mRNA levels in ZI A13 neurons were significantly elevated and they remained high at 5 and 24 h compared to controls. Morphine also resulted in a significant rise in TH mRNA levels in tuberoinfundibular DA neurons (TIDA) (A12) within 1 h and these levels remained high to 5 h. Thereafter, by 24 h, message levels had returned to control values. Morphine also resulted in a rapid rise in plasma prolactin (Prl) with peak values occurring at 20 min and then returning to baseline by 90 min. When morphine was given sc it resulted, within 15 min, in a rapid rise in preoptic DOPAC levels and these levels continued to rise such that they were 217% higher than pretreatment values by 105 min. Preoptic 5-hydroxyindoleacetic acid (5-HIAA) levels also increased by 25–75% after sc morphine. The microinfusion of morphine into ZI also resulted in elevated preoptic DOPAC but not 5-HIAA levels within 15 min. The icv infusion of DA alone had no effect on plasma LH whereas, NE (icv) produced a modest but significant increase in plasma LH. When DA was given 15 min prior to the infusion of NE, neither amplification nor inhibition of NE-induced LH release occurred. From these and other studies we conclude that the morphine-induced suppression of TIDA neuronal activity may allow NE to release greater amounts of LHRH from axon terminals in the median eminence. On the other hand, we doubt that the rise in preoptic DA (DOPAC) which occurs after morphine plays a role in augmenting the action of NE on LHRH release since icv DA does not alter the patterns or concentrations of plasma LH which occur after NE alone.