Reduced Serum Prolactin Levels Research Articles

Correlations Among Maternal and Infant Factors, Lead Exposure, and Serum Prolactin Levels During Lactation: A Cross-sectional Study in Indonesia.

Prolactin is vital for breastfeeding and milk production, and its secretion is influenced by factors related to the mother, infant, and environment. To date, no study has concurrently investigated the correlation of these factors with serum prolactin levels during lactation. Therefore, the objective of this study was to investigate the correlations among maternal and infant factors, lead exposure, and serum prolactin levels during lactation. A cross-sectional approach was employed in Surabaya, Indonesia, among 110 exclusively lactating mothers. The mothers' daily diets were determined using multiple 24-hour recalls, while blood lead levels were measured with inductively coupled plasma mass spectrometry. Serum prolactin levels were assessed using the electrochemiluminescence immunoassay. For bivariate analysis, we employed the Spearman correlation, Mann-Whitney, and Kruskal-Wallis tests, while for multivariate analysis, we utilized multiple linear regression. The average serum prolactin level of the lactating mothers was 129.19±88.96 ng/mL. Positive correlations were found between serum prolactin levels and breastfeeding frequency (p < 0.001), protein intake (p < 0.001), and calcium intake (p = 0.011) but had negative correlation with blood lead levels (p < 0.001) and vitamin B6 intake (p = 0.003). Additionally, prolactin levels were not significantly associated with maternal age; parity; intake of calories, vitamin D, vitamin E, zinc, folic acid, magnesium, or iron; infant age; or infant sex. Breastfeeding frequency had a stronger positive relationship with serum prolactin levels than protein and calcium intake. However, lead exposure was associated with reduced serum prolactin levels during lactation. Consequently, specific interventions from policymakers are necessary to manage breastfeeding in mothers exposed to lead.

Prolactin signaling modulates stress-induced behavioral responses in a preclinical mouse model of migraine.

The aim of this study was to determine if prolactin signaling modulates stress-induced behavioral responses in a preclinical migraine model. Migraine is one of the most complex and prevalent disorders. The involvement of sex-selective hormones in migraine pathology is highly likely as migraine is more common in women and its frequency correlates with reproductive stages. Prolactin has been shown to be a worsening factor for migraine. Normally prolactin levels are low; however levels can surge during stress. Dopamine receptor agonists, which suppress pituitary prolactin release, are an effective migraine treatment in a subset of patients. Previously, we showed that administration of prolactin onto the dura mater induces female-specific behavioral responses, suggesting that prolactin may play a sex-specific role in migraine. The effects of prolactin signaling were assessed using a preclinical migraine model we published recently in which behavioral sensitization is induced by repeated stress. Plasma prolactin levels were assessed in naïve and stressed CD-1 mice (n=3-5/group) and transgenic mice with conditional deletion of the Prlr in Nav1.8-positive sensory neurons (Prlr conditional knock-out [CKO]; n=3/group). To assess the contribution of prolactin release during stress, naïve or stressed male and female CD-1 mice were treated with the prolactin release inhibitor bromocriptine (2mg/kg; n=7-12/group) or vehicle for 5days (8-12/group) and tested for facial hypersensitivity following stress. Additionally, the contribution of ovarian hormones in regulating the prolactin-induced responses was assessed in ovariectomized female CD-1 mice (n=6-10/group). Furthermore, the contribution of Prlr activation on Nav1.8-positive sensory neurons was assessed. Naïve or stressed male and female Prlr CKO mice and their control littermates were tested for facial hypersensitivity (n=8-9/group). Immunohistochemistry was used to confirm loss of Prlr in Nav1.8-positive neurons in Prlr CKO mice. The total sample size is n=245; the full analysis sample size is n=221. Stress significantly increased prolactin levels in vehicle-treated female mice (39.70±2.77; p<0.0001). Bromocriptine significantly reduced serum prolactin levels in stressed female mice compared to vehicle-treated mice (-44.85±3.1; p<0.0001). Additionally, no difference was detected between female stressed mice that received bromocriptine compared to naïve mice treated with bromocriptine (-0.70±2.9; p=0.995). Stress also significantly increased serum prolactin levels in male mice, although to a much smaller extent than in females (0.61±0.08; p<0.001). Bromocriptine significantly reduced serum prolactin levels in stressed males compared to those treated with vehicle (-0.49±0.08; p=0.002). Furthermore, bromocriptine attenuated stress-induced behavioral responses in female mice compared to those treated with vehicle (maximum effect observed on day 4 post stress [0.21±0.08; p=0.03]). Bromocriptine did not attenuate stress-induced behavior in males at any timepoint compared to those treated with vehicle. Moreover, loss of ovarian hormones did not affect the ability of bromocriptine to attenuate stress responses compared to vehicle-treated ovariectomy mice that were stressed (maximum effect observed on day 4 post stress [0.29±0.078; p=0.013]). Similar to CD-1 mice, stress increased serum prolactin levels in both Prlr CKO female mice (27.74±9.96; p=0.047) and control littermates (28.68±9.9; p=0.041) compared to their naïve counterparts. There was no significant increase in serum prolactin levels detected in male Prlr CKO mice or control littermates. Finally, conditional deletion of Prlr from Nav1.8-positive sensory neurons led to a female-specific attenuation of stress-induced behavioral responses (maximum effect observed on day 7 post stress [0.32±0.08; p=0.007]) compared to control littermates. These data demonstrate that prolactin plays a female-specific role in stress-induced behavioral responses in this preclinical migraine model through activation of Prlr on sensory neurons. They also support a role for prolactin in migraine mechanisms in females and suggest that modulation of prolactin signaling may be an effective therapeutic strategy in some cases.

Safety and Efficacy of High-Dose Vitamin B6 as an Adjunctive Treatment for Antipsychotic-Induced Hyperprolactinemia in Male Patients With Treatment-Resistant Schizophrenia.

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 μg/L to 30.43 ± 18.65 μg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 μg/L to 55.78 ± 7.39 μg/L). During weeks 1–4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP.Trial Registration: ChiCTR1800014755

A safety evaluation of aripiprazole in the treatment of schizophrenia

ABSTRACT Introduction Aripiprazole is a third generation antipsychotic approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. Aripiprazole is available as oral and long-acting injectable (LAI) depot formulations, with a unique mechanism of action comprising partial D2 and serotonin 5-HT1A agonism and antagonism at serotonin 5-HT2A receptors. Areas covered We review short-and-long-term clinical trials, meta-analyses of clinical trials and product information pertaining to the safety and efficacy of aripiprazole in adults with schizophrenia. Formulations of aripiprazole reviewed include oral aripiprazole, Aripiprazole monohydrate LAI (Abilify Maintena©) and Aripiprazole lauroxil LAI (Aristada©). Clinical studies and product information were collected from PubMed, Psychinfo, Embase, and other web sources. Expert opinion Aripiprazole is a generally well-tolerated third-generation antipsychotic with low rates of motor side effects and metabolic adverse effects that occur commonly with several alternative antipsychotics. Akathisia and tremor appear to occur at higher rates with aripiprazole compared to placebo but are still generally uncommon with incidences of 10–11% or less. Uniquely, aripiprazole treatment is associated with reduced serum prolactin levels and QTc interval. A variety of LAI options with dosing intervals as infrequent as every 8 weeks provide a compelling reason to select aripiprazole in patients with limited oral treatment adherence.

The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots. Effects of extracts of chasteberry (Vitex agnus-castus) as a solution

The dried fruits of the chaste tree Vitex agnus-castus (VAC) were traditionally used by monks as a substitute for pepper and was therefore also called Monk’s pepper. For the last 50 years it is commercially provided for the treatment of premenstrual symptoms, particularly to prevent premenstrual mastodynia (mastalgia). Most studies were performed with the preparation containing an aqueous/ethanolic ectract BNO 1095. A number of placebo controlled studies gave proof that extracts of VAC had beneficial effects on premenstrual breast pain. This breast sensation is induced by latent hyperprolactinemia which is characterized by secretory episodes of prolactin release by the pituitary in response to stress and deep sleep phases. This latent hyperprolactinemia induces also often a corpus luteum insufficiency which is a common reason for infertilty. It is well accepted that prolactin release can be reduced by dopamine and dopaminergic drugs. The efficacy of VAC extracts to ameliorate prolactin induced premenstrual mastodynia was therefore suggestive that VAC may contain dopaminergic compounds. Indeed, a number of diterpenes were identified that bound to recombinant Dopamine receptors of the 2 subtype which are present in pituitary lactotropes and which mediate the inhibitory effects of dopamine and dopaminergic drugs on pituitary prolactin release. Consequently, prolactin release in vitro from dispersed pituitary cells and in vivo in rats and postmenopausal women was inhibited by VAC 1095. Placebo controlled studies proved also the efficacy of VAC extracts to ameliorate premenstrual symptoms. In several placebo-controlled studies a clear relation between reduction of breast pain and reduction of serum prolactin levels could be established. In addition VAC extracts was also highly effective in women suffering from fibrocystic mastopathy. In many of these women serum prolactin levels were also elevated and reduced by VAC extracts. The results from all trials suggested that VAC extracts ameliorated premenstrual symptoms including mastodynia, premenstrual dysphoric disorder and latent hyperprolactinemia. Cystic mastopathy and sterility due to corpus luteum insufficiencies were also beneficially influenced. Adverse events with VAC were mild and generally infrequent.

Giant prolactinoma, germline BRCA1 mutation, and depression: a case report

BackgroundGiant prolactinomas are very rare pituitary tumors that may exhibit an aggressive behavior and present with a life-threatening condition.Case presentationA 25-year-old white woman was admitted to our hospital with a headache, psychomotor retardation, reduced vision, and loss of autonomy in daily activities. Her past medical history was significant for having oligomenorrhea and a depressive syndrome since her mother’s death. She also had a breast cancer gene 1 (BRCA1) mutation and a family history of breast cancer. She had marked hyperprolactinemia (7615 ng/dL), central hypocortisolism, growth hormone deficiency, and a giant pituitary tumor (52 × 30 × 33 mm) which was shown in magnetic resonance imaging with obstructive hydrocephalus, requiring emergency surgery. Treatment with cabergoline led to a 99.8% reduction in serum prolactin levels and significant tumor shrinkage. Her depressive symptoms progressively improved and psychiatric drugs were withdrawn after 3 months of cabergoline treatment. Currently, she is being followed in Endocrinology, Neurosurgery, and Neurophthalmology out-patient clinics and in a breast cancer unit. Careful monitoring, support, and follow-up will be essential throughout this patient’s life.ConclusionsThis case is a rare presentation of a giant prolactinoma in a young woman, who presented a life-threatening event. She also had an unexpected association between diseases or symptoms that may have contributed to the delay in diagnosis. Given the concomitant presence of a giant prolactinoma, a BRCA1 mutation, and depressive symptoms, a possible association was hypothesized. The breast cancer risk in a BRCA1 mutation carrier and the possible interference of hyperprolactinemia and life events were also discussed. However this hypothesis requires further investigation.

A pilot phase II trial of cabergoline in the treatment of metastatic breast cancer.

e12568 Background: The prolactin receptor can be overexpressed in breast cancer, and pre-clinical data indicate that it contributes to the pathobiology of breast cancer. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary prolactin secretion resulting in reduced serum prolactin levels. Methods: A pilot phase II study of cabergoline in patients with metastatic breast cancer was conducted with primary end point of best overall response rate (ORR) among patients with measurable disease. Eligible patients had metastatic breast cancer, any receptors status was allowed, and there was no limit of prior lines of therapy. Both measurable and unmeasurable diseases (RECIST 1.1) were allowed. Cabergoline 1mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. Immunohistochemistry prolactin receptor staining was performed on available baseline tumor tissue, and serum prolactin levels were serially assessed. Results: A total of 20 women were enrolled, 19 of whom were evaluable for response (one patient died on C1D7 of unrelated causes). Mean age was 62 (range 42-83); 15 (75%) were Caucasian; mean number of prior lines of therapy 5 (range 0-14). Tumor receptor statuses were distributed as follows: HR+/HER2+ 1(5%), HR+/HER2- 18 (80%), HR-/HER2+ 1 (5%). Analysis was performed after a median follow-up of 6.8 months (0.2-26.2). Best ORR was 8.3% among 12 patients with measurable disease. Results for secondary endpoints were as follows: 4-month CBR = 26% (including patients with measurable and non-measurable disease), median PFS = 1.9 months, and median OS = 10.4 months. Most common treatment related AEs were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). The highest-grade AE was a single grade 3 treatment-related pain in extremity. Nine patients had sufficient baseline tissue for analysis, there was no correlation between baseline tumor prolactin receptor expression and clinical benefit ( p= 0.24). Additional correlative work is ongoing. Conclusions: Cabergoline was well tolerated and associated with modest anti-tumor activity. Clinical trial information: NCT01730729.

The first report of cabergoline-induced immune hemolytic anemia in an adolescent with prolactinoma

Prolactinomas are common pituitary tumors that can cause gonadal dysfunction and infertility related to hyperprolactinemia. Dopamine agonists are the first-line treatment in these patients. Cabergoline leads to significant reduction in serum prolactin levels and tumor size in patients with prolactinoma. Dopamine agonists have been associated with adverse effects such as nausea, vomiting and psychosis. We report here a case with cabergoline-induced immune hemolytic anemia. The patient had cabergoline treatment history for prolactinoma and presented with weakness, fatigue, nausea, and paleness. Laboratory findings revealed severe anemia-related immune hemolysis. There were no causes identified to explain hemolytic anemia except cabergoline. Therefore, cabergoline therapy was stopped and subsequently hemolytic anemia resolved and did not occur again. This is the first reported pediatric case with prolactinoma and cabergoline-induced hemolytic anemia. Clinicians should be watchful for this rare side effect induced by cabergoline.

Central Prolactin Modulates Insulin Sensitivity and Insulin Secretion in Diabetic Rats

Background: Prolactin secretion is self-regulating as it acts upon hypothalamic dopaminergic systems which inhibit prolactin release from the anterior pitutary. Circulating prolactin improves glucose homeostasis by increasing insulin action and secretion, but central prolactin effects on glucose homeostasis have not been examined. Here, we determined that chronic central infusion of prolactin modulates insulin resistance and β-cell function and mass in 90% of pancreatectomized diabetic male rats. Methods: Diabetic rats were divided into three groups according to the dose of intracerebroventricular infusion of prolactin during 4 weeks: (1) low-dose prolactin (Low-PRL; 0.1 µg/h), (2) high-dose prolactin (High-PRL; 1 µg/h) and (3) vehicle only (cerebrospinal fluid). Nondiabetic rats were centrally infused with the vehicle. Results: Chronic intracerebroventricular infusion of Low-PRL lowered body weight and epididymal fat pads by increasing hypothalamic dopamine levels that reduced serum prolactin levels and potentiated leptin signaling. However, High-PRL slightly exacerbated energy dysregulation, decreased hypothalamic dopamine levels, and elevated serum prolactin levels. Both dosages promoted β-cell mass but in a different manner: Low-PRL decreased β-cell apoptosis, whereas High-PRL increased its proliferation. However, only Low-PRL enhanced first-phase insulin secretion and improved insulin sensitivity at a hyperglycemic state in comparison to the control. Low-PRL also increased glucose infusion rates and decreased hepatic glucose output in hyperinsulinemic states, signifying an improvement in hepatic insulin sensitivity. However, High-PRL exacerbated hepatic insulin resistance compared with the control diabetic rats. Conclusions: In contrast to the exacerbation of insulin resistance caused by High-PRL, Low-PRL may improve energy and glucose metabolism by increasing hypothalamic dopamine levels in diabetic rats.

Prolactin differentially modulates the macrophage activity of lactating rats: possible role of reproductive experience

Reproductive experience (i.e., pregnancy and lactation) induces physiological changes in mammals. We recently showed that a previous reproductive experience can modulate the activity of dopaminergic hypothalamic systems while decreasing serum prolactin (PRL) levels and oxidative burst activity in peritoneal macrophages. Dopamine receptor antagonists increase serum PRL levels, and both PRL and dopamine receptors might be involved in the modulation of macrophage activity, providing a means of communication between the nervous and immune systems. The present study evaluated the in vitro effects of PRL and the dopamine receptor D2 antagonist domperidone (DOMP) on the peritoneal activity of macrophages from primiparous and multiparous female rats during lactation. Oxidative bursts and phagocytosis in peritoneal macrophages were evaluated by flow cytometry. Primiparous and multiparous Wistar rats, during the period of lactation (i.e., days 5-7 after parturition) were used. Samples of peritoneal fluid from these rats were first incubated with PRL (10 and 100 nM) for different periods of time. The same procedure was repeated to evaluate the effects of DOMP (10 and 100 nM). Our results showed that macrophages from multiparous rats respond more effectively to in vitro incubation with PRL, especially with regard to oxidative bursts and the percentage of phagocytosis. Additionally, these effects were more pronounced after 30 min of incubation. These data suggest that reproductive experience is associated with a reduction in serum PRL levels, and cells in experienced female animals, including their macrophages, become more sensitive to the effects of PRL.

Casticin, a flavonoid isolated from Vitex rotundifolia, inhibits prolactin release in vivo and in vitro

to investigate the anti-hyperprolactinemia activity of casticin, a flavonoid isolated from Vitex rotundifolia, and elucidate its molecular mechanism. hyperprolactinemia (MIHP) was induced by administration of metoclopramide dihydrochloride (50 mg/kg, tid, ip, for 10 d) in SD rats and the primary pituitary cells were prepared from the pituitary glands of the SD rats. Prolactin concentrations were measured using a radioimmunoassay. Cell viability was measured using an MTT assay. The mRNA expression of estrogen receptor alpha and beta in rat pituitary cells was measured using semi-quantitative RT-PCR analysis. the level of serum prolactin in the MIHP model group was 2.1 fold higher than that in the untreated control group (P<0.01). Casticin (10, 20, and 40 mg/kg, ip, for 7 d) reduced serum prolactin levels by 33.9%, 54.3%, and 64.7%, respectively (P<0.01). The positive control drug bromocriptine 1 mg/kg decreased the serum prolactin concentration in MIHP rats by 44.9%. 17β-Estradiol (E2) significantly increased the proliferation of pituitary cells and casticin (1 and 10 micromol/L) markedly inhibited E2-induced pituitary cell proliferation by 27.7% and 42.1%, respectively. Stimulation of pituitary cells with E2 increased prolactin secretion into the cell culture supernatants, and casticin (0.1, 1, and 10 micromol/L) significantly inhibited the prolactin release stimulated by E2 in a concentration-dependent manner. Casticin (1 and 10 micromol/L) significantly inhibited ERα mRNA expression in pituitary cells stimulated with E2 (P<0.01) but increased ERβ mRNA expression at a concentration of 10 micromol/L (P<0.01). However, casticin had no effects on proliferation and prolectin release of the unstimulated primary pituitary cells in vitro. casticin inhibited the release of prolactin from pituitary cells of SD rats stimulated with E2 in vivo and in vitro. These effects might be related with inhibiting the ERα mRNA expression and increasing the ERβ mRNA expression.

Olanzapine, not resperidone, exacerbates β-cell function and mass in ovariectomized diabetic rats and estrogen replacement reverses them

The effect of risperidone and olanzapine on beta-cell function and mass was investigated in 90% pancreatectomized and ovariectomized female rats, of which some were treated with estrogen replacement and some were not. Ovariectomized diabetic rats were divided into two groups: one group received daily estrogen replacement (30 mug 17beta-estradiol/kg body weight) and the other group received a vehicle. Each group was further divided into three subgroups and orally given either a placebo, risperidone (0.5 mg/kg body weight), or olanzapine (2 mg/kg body weight) each day in conjunction with a high-fat diet for eight weeks. Ovariectomy reduced serum prolactin levels, while risperidone and estrogen replacement increased them. Olanzapine, not risperidone, increased body weight gain and epididymal fats, and impaired glucose tolerance in ovariectomized diabetic rats, while estrogen replacement improved them. This was related to changes in insulin secretion capacity. Ovariectomized rats had decreased beta-cell mass, due to decreasing beta-cell proliferation, compared with Sham rats, and olanzapine, but not risperidone, caused further reduction. Olanzapine reduced IRS2 protein levels in the islets of ovariectomized rats. Decreased IRS2 attenuated the phosphorylation of Akt and, subsequently, PDX-1 protein levels were lowered in olanzapine-treated rats. Estrogen replacement activated insulin/IGF-1 signaling regardless of treatment. In conclusion, olanzapine, but not risperidone, exacerbated glucose homeostasis partly by attenuating beta-cell function and mass in ovariectomized diabetic rats, while estrogen replacement reversed its negative impact. Further human studies are needed to support the claim that olanzapine should be avoided in the treatment of schizophrenic postmenopausal patients with diabetes.

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Clinical efficacy of novel unidirectional buccoadhesive vs. vaginoadhesive bromocriptine mesylate discs for treating pathologic hyperprolactinemia

To test the clinical effectiveness of new bioadhesive unidirectional buccal and vaginal bromocriptine methylate discs in hyperprolactinemic patients. A preliminary randomized comparative study. A pharmaceutical phase at the departments of Pharmaceutics, Faculties of Pharmacy, Assiut and El-Minea universities and a clinical phase at the Infertility Out-patient Clinic of Women's Health University Center, Assiut University, Assiut, Egypt. A total of 42 patients with pathologic hyperprolactinemia. Patients were randomly divided into two groups. Group A comprised 21 patients who used unidirectional buccoadhesive bromocriptine methylate discs once daily for 1 month. Group B included 21 patients who used vaginoadhesive bromocriptine methylate discs once daily for 1 month. Serum prolactin (PRL) was measured before and after therapy in all cases. Decline of serum PRL level after 1 month of therapy. Pharmaceutically, tests for swelling, surface pH, in vitro and in vivo bioadhesion and in vitro release expressed satisfactory results. The in vitro release of vaginal bromocriptine from the discs is increased in pH 4.5 media. Both groups showed a highly statistically significant reduction of serum PRL levels after 1 month of therapy without any significant difference between both groups. The decline of serum PRL was not correlated with age, parity, or indication of entering into this study. Both buccoadhesive and vaginoadhesive discs containing bromocriptine are of equal efficacy for treating pathologic hyperprolactinemia. Buccoadhesive discs have the advantages of being gender nonspecific (i.e., could be used by men), avoiding manipulating the vagina, which could be inconvenient to some patients, such as virgins; not being dependent on cyclic estrogen (E) levels; and could be easily used during menstruation.

Inhibition of prolactin secretion by American ginseng is mediated by ginseng polysaccharide‐induced nitric oxide production

Rats treated with American ginseng exhibit an approximate 50% reduction in serum prolactin levels and a compensatory decrease in hypothalamic dopamine activity. To investigate whether ginseng has direct pituitary effects, anterior pituitaries collected from random cycling female rats were dispersed and cultured for 1 week prior to treatment with water soluble ginseng extract (0 – 2 mg/ml) for 24 hr. Ginseng produced a dose‐dependent decrease in prolactin with maximum suppression (∼50%) within 6 hr at ≥1mg/ml; there was no change in media LH levels. When the ginsenoside and polysaccharide components in ginseng were examined, ginseng polysaccharides (12.5μg/ml) inhibited prolactin whereas ginsenosides had no effect in the pituitary cultures. Ginseng and its polysaccharides both stimulated nitric oxide (NO) production from cultured cells at 24 hr and induced iNOS gene and protein expression at 12 and 24 hr, respectively. The specific iNOS inhibitor 1400W blocked the ginseng/polysaccharide effects on NO production and prolactin release, whereas eNOS and nNOS inhibitors had no effect. Together, these results suggest that the reduction in circulating prolactin levels following ginseng ingestion is due to polysaccharide‐induced pituitary iNOS and NO production and subsequent prolactin suppression.

Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats

The aim of this study was to investigate the effects of Ginkgo biloba extract (EGb 761) on male copulatory behavior in rats. EGb 761 (1 mg/ml) induced significant production of testosterone (T) in rat Leydig cells in vitro. Its effects on sexual behavior were then tested in Long–Evans male rats after 7, 14, 21, or 28 days of oral gavage of vehicle (distilled water) or EGb 761 at doses of 10, 50, or 100 mg/kg. Administration of 50 mg/kg of EGb 761 for 28 days and of 100 mg/kg for 14 or 21 days significantly increased intromission frequency compared to controls on the same day. An increase in ejaculation frequency was seen after treatment with 50 mg/kg of EGb 761 for 14, 21, or 28 days when compared to either the control group on the same day or the same group on day 0. A reduction in ejaculation latency was only seen after administration of 50 mg/kg of EGb 761 for 14 days compared to the vehicle-treated group. After treatment for 28 days, no significant difference was seen in mount latency, intromission latency, serum T levels, reproductive organ weight, sperm number, or levels of the metabolite of dopamine, 3,4-dihydroxyphenylacetic acid in the brain with any dose of EGb 761, but significantly reduced serum prolactin levels and increased dopamine levels in the medial preoptic area and arcuate nucleus were seen at the dose of 50 mg/kg. These findings show that EGb 761 (especially at the dose of 50 mg/kg) enhances the copulatory behavior of male rats and suggest that the dopaminergic system, which regulates prolactin secretion, may be involved in the facilitatory effect of EGb 761.

57-jähriger Patient mit Doppelbildern und Kopfschmerzen

A 57-year old patient presented with an 8 week history of headache and diplopia. Left-sided incomplete oculomotor nerve paresis was found, whereas further clinically relevant visual impairment was not seen. Magnetic resonance imaging of the head showed an extensive intra-, para- and suprasellar tumor which in combination with a markedly elevated serum prolactin level was identified as a macroprolactinoma. The symptoms began 7 years ago with a loss of libido and virility. The application of a dopamine agonist lead to a reduction of serum prolactin level to 0.5% of the initial value and a considerable tumor regression within three months. The development of oculomotor nerve paresis is an unusual manifestation of prolactinoma. By contrast, long-term medical history with slowly developing signs and symptoms of hypogonadotropic hypogonadism are often to be found in men. The delayed diagnosis is responsible for the high percentage of macroprolactinomas in male subjects.

Regulation by endogenous opioids of suckling-induced prolactin secretion in pregnant and lactating rats: role of ovarian steroids.

Evidence suggests that endogenous opioid peptides are implicated in the suckling-induced prolactin rise. We explored the role of the opioid system and the participation of ovarian hormones in the regulation of prolactin induced by the suckling stimulus at the end of pregnancy in rats with developed maternal behavior, and during lactation. Suckling for 24 h induced a significant increase in serum prolactin on day 19 of pregnancy, which was increased more than three times when naloxone (2 mg/kg s.c.) or mifepristone (2 mg/kg) was administered. The combination of naloxone and mifepristone did not increase serum prolactin more than either compound alone. Administration of tamoxifen (500 microg/kg orally) on days 14 and 15 of pregnancy completely abolished the effect of naloxone, indicating a role for estrogens in establishing this inhibitory role of opioids. To examine the participation of the opioid system during lactation, we used groups of rats on days 1, 3, 5, 12 and 19 postpartum either (i) isolated from the pups for 4 h, or (ii) isolated from the pups for 3.5 h and reunited with them and suckled for 30 min. Naloxone, given just before replacing the pups, prevented the increase in serum prolactin levels observed in the suckled group of rats but had no effect on the basal levels of the isolated rats. To examine whether the participation of the opioid system in the release of prolactin is dependent on the variation of progesterone levels, rats on day 20 of pregnancy were implanted with two cannulae containing progesterone (that blocked postpartum ovulation) or cholesterol, and cesarean surgery was performed on day 21. To maintain lactation, pups (1-3 days old) were replaced every 24 h, and 4 days after the cesarean eight pups were placed in the cage at 1800 h to maintain a strong suckling stimulus during the following 24 h. Naloxone administration significantly reduced serum prolactin levels in control (cholesterol) rats but progesterone implants prevented the inhibitory effect of naloxone and this effect was not modified by treatment with estrogen. These results indicate that the opioid system modulates suckling-induced prolactin secretion, passing from an inhibitory action before delivery to a stimulatory action during lactation. This regulatory shift seems to be dependent on the fall in progesterone concentration at the end of pregnancy and the subsequent increase after the postpartum ovulation and luteal phase.

Increased exocytosis of secretory granules in contrast to reduced serum hormone levels in pituitary adenomas of humans and rats treated with dopamine agonist.

The release of secretory granules outside the cells increased in frequency, in inverse proportion to the marked decrease in serum prolactin (PRL) levels in human prolactin-secreting adenomas (PRLomas) treated with bromocriptine (CB), a dopamine agonist. Rat pituitary adenomas induced by diethylstilbestrol also showed an increase in exocytosis of the granules despite a reduction in serum PRL levels after CB treatment. To elucidate this curious phenomenon, which is contrary to current general knowledge that serum hormone levels are sustained by the exocytosis of the secretory granules, we combined morphometric analysis with analyses using a cell fractionation technique and immunocytochemistry. The results indicated that the proteins in secretory granules consisted of 90% nonhormonal proteins and 10% PRL. CB treatment did not change the levels of the former, while the levels of the latter were markedly reduced. Immunocytochemistry, using a protein-A gold method, revealed that the secretory granules in rats treated with CB contained fewer PRL molecules than the controls. Serum PRL elevation caused by the exocytoses, estimated by counting the exocytotic granules, were markedly lower (less than 10%) in CB-treated rats than in the controls. It was suggested that, after CB treatment, the composition of secretory granules altered, or that nonhormonal constituents in the granules disintegrated more slowly, and that the granules became detectable at the site of release for a longer period. Consequently, although granules that appear ultrastructurally similar to those in untreated adenomas are observed to be more frequently released in treated adenomas, it seems that they no longer contribute to raising the serum PRL levels.

Participation of the opioid system in the regulation of prolactin secretion in androgenized rats: effect of ovarian steroids

We examined the role of the opioid system on the regulation of prolactin secretion in neonatally androgenized rats and evaluated the participation of ovarian steroids in this regulation. Androgenized rats exhibited an increase of prolactin secretion with higher serum circulating levels in the afternoon (1800) than in the morning (1000). The administration of the opioid antagonist naloxone (2 mg/kg, 30 min before decapitation) reduced serum prolactin levels in both groups. To identify the opioid receptor subtypes involved in this regulation, opioid agonists were administered i.c.v. 15 min before the decapitation (1000). The μ-opioid receptor agonist DAMGO ([ d-Ala 2, NMe-Phe 4, Gly 5-ol]-enkephalin) caused a significant increase in serum prolactin concentration. The selective κ-opioid receptor agonist U-50, 488H ( trans-(±)-3,4-dichloro- N-[2(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methane sulfonate salt) induced a small but significant increase in serum prolactin levels but no effect was observed after administration of the δ-opioid agonist DPDPE ([ d-Pen 2, d-Pen 5]-enkephalin). The role of oestradiol and the opioid system in the continuous secretion of prolactin was also study. Chronic gonadectomy (3–4 weeks) reduced serum prolactin concentrations measured at 1000 but the administration of naloxone had no effect. Three days of oestrogen treatment (2 μg/rat in oil) restored serum prolactin levels compared with ovariectomized animals and this effect was abolished by naloxone treatment. Interestingly, acute ovariectomy or administration of tamoxifen to intact androgenized rats did not prevent the continuous secretion of prolactin observed in these animals and naloxone treatment reduced serum prolactin levels in both groups of rats. We also examine the participation of adrenal progesterone and the endogenous opioid peptides on the regulation of prolactin levels in androgenized rats. After adrenalectomy, no changes in serum prolactin levels (1000) were observed compared with the control animal and naloxone treatment significantly reduced circulating prolactin levels. Progesterone treatment to intact androgenized rats significantly increased prolactin levels and the administration of naloxone blocked the stimulatory effect of the steroid. These results suggest that the opioid system play a role in the regulation of prolactin secretion in androgenized rats modulated by the persistence of oestrogen action. Moreover, the presence or absence of progesterone did not modify the regulation of prolactin secretion by the opioids. The μ- and κ-opioid receptor subtypes are the ones involved in the modulation of pituitary prolactin secretion.