Serum PRL Concentrations Research Articles

Gonadotropin profile in experimentally induced hypothyroid and hyperthyroid cyclic female rats

The current study examined the association of thyroid disorders with reproductive dysfunction by determining its effect on gonadotropin secretion in cyclic female rats. Sixty cyclic females were assigned to three groups (20 each) and supplemented, for 30 days plus two consequent estrous cycles, with drinking water (control), methimazole in drinking water (0.02% w/v) (hypothyroid group), and thyroxine in drinking water (0.002% w/v) and gastric gavage of 200 μg/kg body weight (hyperthyroid group). At late proestrus, ten females from each group (for each cycle) were anesthetized and dissected. Blood samples were obtained to assess thyroid-stimulating hormone, free and total triiodothyronine, free and total thyroxin, follicle-stimulating hormone, luteinizing hormone, and prolactin concentrations. Ovarian and pituitary tissue samples were obtained for molecular analysis of ovarian thyroid receptor genes and pituitary TSH, FSHβ, and LHβ genes. In comparison with control, the Hypo group revealed increased serum concentrations of TSH and PRL and the expression levels of pituitary TSH and ovarian TRsTRs genes and significant decrease of FT3, TT3, FT4, TT4, FSH, and LHLH concentrations and the expression levels of pituitary FSHβ and LHβ genes. In contrast, the Hyper group showed increased serum FT3, TT3, FT4, TT4, and LHLH concentrations and the expression levels of pituitary LHβ and ovarian TRsTRs genes and decreased serum TSH FSH and PRL concentrations and pituitary FSHβ and TSH gene expression levels. It is concluded that thyroid dysfunction is associated with altered serum gonadotropin secretion and reproductive failure.

Retinal layers in prolactinoma patients: a spectral-domain optical coherence tomography study.

Prolactinomais a type ofpituitary tumourthat produces an excessive amount of the hormone prolactin. It is the mostcommontype of hormonally-activepituitary tumour. These tumours can cause ocular complications such as vision loss and visual fields (VF) defect. In this study, we aimed to evaluate the thickness of chorioretinal layers in patients with prolactinoma. We enrolled 63 eyes of 32 prolactinoma patients and 36 eyes of 18 age and gender-matched healthy controls. All participants underwent complete hormonal and ophthalmological examination, including spectral-domain optical coherence tomography (SD-OCT) and VF test.The complete biochemical response was defined as serum PRL concentration ≤ 20ng/mL at the time of evaluation.The seven layers were retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE). The results of prolactinoma patients were compared with the control group. The mean RNFL, GCL, IPL, INL, ONL, and RPE were thinner in prolactinoma patients than the control group (p < 0.05) while OPL was similar between groups (p > 0.05).None of the patients had VF defect.The thickness of retinal layers was similar in patients with and without complete biochemical response (p > 0.05). To our knowledge, this is the first study that evaluates the thickness of chorioretinal layers in patients with prolactinoma.Most of the layers were thinner than the control group.Therefore, detailed eye assessment should be a routine component of the follow-up visits of prolactinoma patients and further studies related to this condition are required.

Effects of silymarin supplementation during transition and lactation on reproductive performance, milk composition and haematological parameters in sows.

Silymarin has been shown to be a multiple-functional plant extract having antioxidant, hepatoprotective, hypolipidemic, antihypertensive, antidiabetic and anti-obesity effects. In recent years, the galactagogue effects of silymarin in animals and humans have also been revealed. This research was conducted to test whether dietary inclusion of silymarin during transition and lactation could impact reproductive performance of sows and to explore the underlying mechanisms. From day 108 of gestation to weaning, sows were randomly assigned to receive dietary treatment of silymarin (40g/day) or not and were designated as control group (CGP, n=55) or treatment group (TGP, n=55). The results showed that piglets' average daily gain and average weaning weight were higher in TGP than CGP sows. In comparison with the CGP sows, the TGP sows had higher serum concentrations of catalase (CAT) on day 18 of lactation and glutathione peroxidase (GSH-Px) on day 7 of lactation. The TGP sows had lower concentration of TNF-α on day 7 of lactation and significantly lower concentration of IL-1β on day 18 of lactation than CGP sows. There was significantly higher serum concentration of PRL on day 7 of lactation in sows consuming silymarin than sows from the CGP group. On day 18 of lactation, the protein and urea contents in milk were significantly increased while the serum urea concentration was significantly decreased in TGP sows. In summary, our results indicate that silymarin supplementation during transition and lactation can increase circulating concentrations of PRL transiently, reduce oxidative stress, increase feed intake and enhance protein metabolism, thereby significantly increasing milk yield of sows and subsequently improving growth performance of their offsprings.

159 Relationships among circulating prolactin concentrations, hair coat score, and weights of grazing cows

Abstract Prolactin (PRL) is a pleiotropic protein hormone synthesized and released from the anterior pituitary. Concentrations of PRL can serve as a biomarker of cattle exposure to ergot alkaloids. Our objective was to determine relationships among prolactin concentrations, hair coat score, and body weights of non-lactating crossbred beef cows (n = 71). Cows were weighed, hair coat scored (1 = 100% shed, and 5 = 0% shed), and blood samples collected in May, June, and July. Cows were grazing mixed grass pastures that included native endophyte-infected tall fescue. Serum PRL concentrations were determined by validated RIA. Based on May samples, cows were categorized as high (n = 11; 159 ± 29 ng/mL PRL), medium (n = 48; 51 ± 4 ng/mL PRL), or low (n = 12; 21 ± 4 ng/ mL PRL). Data were analyzed with Pearson correlations, and repeated measures ANOVA with month and prolactin category (PRLCAT) as main effects. Concentrations of PRL were correlated (r &amp;gt; 0.53; P &amp;lt; 0.0001) over the three months, and May PRL concentrations were correlated (r &amp;gt; 0.29; P &amp;lt; 0.02) with cow body weights in May, June, and July. Cows in the low PRLCAT had lower (P &amp;lt; 0.01) concentrations of PRL in all three months. Hair coat score decreased (P &amp;lt; 0.0001) each month (4.3, 2.7, and 1.3; respectively, May, June, July), and was higher (P &amp;lt; 0.05) for cows with low PRLCAT (3.3 vs. 2.7 and 2.4 for low, medium, and high, respectively). Cow body weight increased (P &amp;lt; 0.0001) from May to July. Cows in the low PRLCAT had lower (P &amp;lt; 0.05) body weights than medium and high PRLCAT cows (484 vs. 555, and 575 kg; respectively). Concentrations of PRL in May could be useful in identifying cattle with slick hair coats and heavier body weights.

Impact of slick hair trait on physiological and reproductive performance in beef heifers consuming ergot alkaloids from endophyte-infected tall fescue1.

Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue. The objective of this study was to evaluate the impact of the slick hair trait on physiological and reproductive parameters in heifers experiencing fescue toxicosis. Angus × Senepol heifers (n = 31) were blocked by weight (393.5 ± 17.3 kg) and phenotype relative to hair coat at birth, and randomly fed novel endophyte fescue (EN) or endophyte-infected fescue (EI) haylage in a total mixed ration for 91 d. Weekly measurements were collected to monitor heifer growth and response during ergot alkaloids exposure. Following 28 d of treatment, estrus was synchronized and heifers were inseminated. Ovary mapping and AI pregnancy rate were examined via transrectal ultrasonography. Blood samples were taken for genotyping: slick (S) or wildtype (W). Data were analyzed using repeated measures in PROC MIXED of SAS including fescue treatment (EN vs. EI), genotype (S vs. W), and sample collection time as main effects. Body condition scores were decreased for W heifers compared with S heifers (5.48 vs. 5.66, respectively; P < 0.0001). Surface temperature was greater for EI-W heifers (37.2 °C) compared with other groups (36.4, 36.6, 36.7 °C for EN-S, EN-W, EI-S, respectively; P < 0.05). Serum PRL concentrations were reduced for EI heifers compared with EN heifers (133.5 vs. 163.1 ng/mL, respectively; P < 0.05). The average number of 2 to 4 mm follicles were greater in EI-W heifers (13.8 follicles) compared with other groups (12.2, 10.6, and 11.1 for EN-S, EN-W, and EI-S, respectively; P < 0.0001). However, the average number of preovulatory follicles (≥9 mm) were reduced in EI-W heifers (0.52 follicles) compared with other heifer groups (0.94, 0.88, and 0.85 ± 0.04 for EN-S, EN-W, and EI-S, respectively; P < 0.05). Ovulatory follicle size was smaller in EI-W heifers compared with EN-W heifers (9.14 vs. 11.57 mm, respectively; P = 0.05). Corpus luteum area was reduced in EI-W heifers (235.1 mm2) compared with other heifer groups (297.2, 272.7, and 276.8 mm2 for EN-S, EN-W, and EI-S, respectively; P < 0.05). Concentrations of P4 were greater for EN heifers compared with EI heifers (2.7 vs. 1.8 ng/mL, respectively; P < 0.05). Pregnancy was not established in EI-W heifers (0%) compared with other heifer groups (37.5%, 57.1%, and 62.5% for EN-S, EN-W, and EI-S, respectively; P < 0.05). Overall, the slick hair mutation appears to aid in offsetting the physiological symptoms associated with fescue toxicosis and helps to improve reproductive performance.

Suppression of Prolactin Secretion Partially Explains the Antidiabetic Effect of Bromocriptine in ob/ob Mice.

Previous studies have shown that bromocriptine mesylate (Bromo) lowers blood glucose levels in adults with type 2 diabetes mellitus; however, the mechanism of action of the antidiabetic effects of Bromo is unclear. As a dopamine receptor agonist, Bromo can alter brain dopamine activity affecting glucose control, but it also suppresses prolactin (Prl) secretion, and Prl levels modulate glucose homeostasis. Thus, the objective of the current study was to investigate whether Bromo improves insulin sensitivity via inhibition of Prl secretion. Male and female ob/ob animals (a mouse model of obesity and insulin resistance) were treated with Bromo and/or Prl. Bromo-treated ob/ob mice exhibited lower serum Prl concentration, improved glucose and insulin tolerance, and increased insulin sensitivity in the liver and skeletal muscle compared with vehicle-treated mice. Prl replacement in Bromo-treated mice normalized serum Prl concentration without inducing hyperprolactinemia. Importantly, Prl replacement partially reversed the improvements in glucose homeostasis caused by Bromo treatment. The effects of the Prl receptor antagonist G129R-hPrl on glucose homeostasis were also investigated. We found that central G129R-hPrl infusion increased insulin tolerance of male ob/ob mice. In summary, our findings indicate that part of Bromo effects on glucose homeostasis are associated with decrease in serum Prl levels. Because G129R-hPrl treatment also improved the insulin sensitivity of ob/ob mice, pharmacological compounds that inhibit Prl signaling may represent a promising therapeutic approach to control blood glucose levels in individuals with insulin resistance.

Giant Prolactinoma in Men: Clinical Features and Therapeutic Outcomes.

The aim of the study was to evaluate the clinical features and long-term therapeutic outcome of giant prolactinoma (gPRLoma) in men and to compare them with those of a group of male patients with non-gPRL macroprolactinomas (non-gPRLomas). A retrospective and multicenter study of gPRLomas in men diagnosed in a 20-year period was performed. Clinical data and treatment outcome were registered. The diagnosis of gPRLoma was established when the maximal tumor diameter was ≥40 mm or the tumor had ≥20 mm of suprasellar extension associated to hyperprolactinemia (PRL>1000 ng/ml). Non-gPRLoma was considered when tumor diameter was ≥ 10 mm and<40 mm associated to hyperprolactinemia (PRL≥200 ng/ml). Twenty-three patients with gPRLoma (age 38.3±13.5 years) followed for at least 3 months (follow-up 87.1±60.5 months, range 3-211 months) were evaluated. A group of 42 patients with non-gPRLoma (age 42±16.6 years; NS; follow-up 89±65.9 months, range 3-222 months; NS) served as a control group. More than half (56.5%) of the gPRLoma patients were younger than 40 years at diagnosis. Visual disturbances were significantly more common in gPRLoma than in non-gPRLoma patients (65.2 vs. 25.6%; p=0.004). Prevalence of hypopituitarism was similar in both groups of patients (73.9% vs. 80.9%; gPRLoma vs non-gPRLoma; NS). Serum PRL concentrations were significantly higher in gPRLoma than in non-gPRLoma patients [median (IR), 3978 ng/ml (1179-9012) vs. 907 ng/ml (428-3119); p<0.001]. Maximum tumor diameter in gPRLomas was 4.8±0.8 cm and 2.4±0.7 cm in non-gPRLoma (p<0.001). All patients were treated with dopamine agonists (DA). Twelve (52.2%) gPRLoma patients and 32 (73.8%) non-gPRLoma patients were treated with DA as monotherapy (p=0.045). Surgery was used in 12 (52.2%) gPRLoma patients and in 12 (28.6%) non-gPRLoma patients (p=0.054). Lastly, radiotherapy was used in 5 (21.7%) gPRLoma patients and in 6 (14.2%) non-gPRLoma patients (NS). At last visit, PRL was similar in both groups of patients [16 ng/ml (4-30) vs. 11 ng/ml (4-25); gPRLomas vs. non-gPRLomas; ns] and tumor size decreased significantly (p<0.001) in both groups of patients. Clinical cure (maintained normoprolactinemia without therapy for>1 year and no radiological evidence of pituitary tumor) was achieved in 2 (8.7%) gPRLoma patients and in 2 (4.8%) non-gPRLoma patients (NS). gPRLomas in men are usually diagnosed at a mean age of 40 years, an age similar to that of non-gPRLomas. The only clinical difference with non-gPRLomas is their greater prevalence of visual disturbances. The therapeutic approaches and tumor outcomes were similar to those obtained in patients with non-gPRLomas. Complete cure in gPRLoma is rare, but similar to that achieved in non-gPRLomas, reached in less than 10% of patients.

Serum sex hormones concentrations in young women in the early period after successful kidney transplantation.

Hormonal disorders are frequently present in hemodialysed patients with chronic kidney disease (CKD). In women with CKD sex hormones abnormalities may lead to irregular, often anovulatory cycles, sexual dysfunction and infertility. Kidney transplantation done in young women tends to ameliorate most of the aforementioned disorders and improve fertility. The aim of this study was to assess the changes of serum sex hormones concentration in young women before, and after the first 6 months after successful KTx Material and methods: Fourteen chronic hemodialysis women with CKD undergoing kidney transplantation and 46 apparently healthy women in similar age (control group) were enrolled into the study. In all women serum concentration of: FSH, LH, PRL and estradiol determined. Measurements in the transplanted group were done four times: immediately before surgery, in the 14th - and 30th - day and 6 months after the transplantation. The results are presented as means and 95% CI. All of the women that have finished the study presented an excellent function of the transplanted kidney - mean serum creatinine concentration was 92.54 (74.85 - 110.23) µmol/l. After successful KTx a significant decrease in the serum concentrations of FSH and LH was observed. Decrease of serum PRL concentration after KTx did not reach statistical significance in the multiple comparisons analyses, but returned to the values observed in healthy controls. KTx did not significantly influence serum estradiol concentration. Successful kidney transplantation leads to the normalization of serum concentrations of hormones linked to fertility disorders in women with chronic kidney disease. < p > < /p >.

Serum prolactin concentration at presentation of non-functioning pituitary macroadenomas.

Serum PRL levels at presentation may be useful in distinguishing between disconnection hyperprolactinemia in non-secretory pituitary adenomas and prolactinomas in order to guide appropriate therapy; however, there is a debate regarding the discriminatory PRL thresholds. We aimed to examine PRL concentrations at presentation in a cohort of histologically proven non-functioning pituitary adenomas (NFPA). Retrospective case note analysis was performed. Clinical, biochemical, histopathological and radiological data were recorded and analyzed. Complete data were available for 250 subjects with NFPA. Of the study population, 44.8% were hyperprolactinemic at presentation, 55.3% of whom were female. Of those with hyperprolactinemia, 73.2% had PRL<1000 mIU/l on presentation, 24.1% had PRL between 1000 and 1999 mIU/l. Only 2.7% (no.=3 females, 1.2% whole cohort) had PRL>2000 mIU/l (94.3 ng/ml), 2 of whom were pregnant. No male subject and no subjects with an intrasellar macroadenoma had serum PRL>1000 mIU/l (47.2 ng/ml). Overall, serum PRL was not higher among 43 subjects taking medications known to raise PRL. Our data support recent evidence that the serum PRL concentration is rarely >1000 mIU/l in males, or >2000 mIU/l in females, with non-functioning macroadenomas and that, once other contributing factors to the hyperprolactinemia have been excluded, a trial of dopamine agonist therapy for such lesions is indicated.

A Th1-Type Cytokine Named Prolactin. Facts and Hypotheses

Evidence supporting the role of PRL as a Th1-type cytokine and its potential therapeutic implications in human immunodeficiency virus (HIV) infection, graft-versus-host disease (GVHD), chronic hepatitis C (CHC) and preeclampsia is reviewed. In patients with HIV infection, dopaminergic adaptive mechanisms maintain PRL at a high but physiological con- centration, which stimulates CD4 + T lymphocyte proliferation and increases viral apoptosis attempting to survive. In patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation complicated by chronic GVHD, the dopaminergic adaptive mechanisms tend to decrease the high normal serum PRL concentrations. On the contrary, in transplan- tations complicated by acute GVHD, donors with a Th1 cytokine profile may be prone to induce acute GVHD in their recipients, but a mild sustained rise in PRL concentrations after transplantation in these patients may reduce the severity of the disease. In patients with CHC, mild, drug-induced hyperprolactinemia is associated with increased peripheral lymphocytes and natural killer cell cytotoxicity that induces apoptosis in the infected hepatocytes. In early pregnancy, endogenous low-molecular-weight PRL (14-16 kDa) may act as a Th1-cytokine participating in the faulty trophoblastic invasion of the placenta in women with subse- quent severe preeclampsia. In conclusion, PRL may participate as an important immunoregulatory factor in the pathophysiology of HIV infection, GVHD, CHC and preeclampsia through its Th1-type cytokine-like actions.

Prevalence of macroprolactinaemia in regularly menstruating women with non-toxic goitre or autoimmune thyroid disease

BackgroundThe so called “big-big” prolactin (Prl), also known as macroprolactin is formed by Prl-immunoglobulin (Prl-IgG) complexes and may cause elevation of serum Prl concentrations measured by standard assays, potentially leading to unnecessary investigations and/or treatment. In our study, we have endeavoured to assess the prevalence of macroprolactinaemia in euthyroid, regularly menstruating women with thyroid disease, as well as to assess whether autoimmune thyroid disease may result in an increased prevalence of macroprolactinaemia.Material and methodsWe measured serum Prl in 182 regularly menstruating women aged 32.7 ± 7.5 years (mean ± SD, range 17–46 years) who attended endocrine clinic either for investigation of non-toxic goitre (n = 86, age 33.2 ± 7.8 years) or with autoimmune thyroid disease (n = 96, age 32.3 ± 7.2 years). Autoimmune thyroid disease was defined as raised titre of at least one anti-thyroid antibody [anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-Tg) and/or anti-TSH-receptor (anti-TSH-R) antibodies]. All women were clinically and biochemically euthyroid, either without or on treatment with L-thyroxine. In those with raised Prl (i.e., above 530 mIU/l) we ruled out the presence of macroprolactinaemia by polyethylene glycol (PEG) precipitation method.ResultsThere was no significant age difference between women with and without autoimmune thyroid disease (p = 0.84). Raised Prl concentrations were found in 10 women with thyroid disease (5.5%), and of those a significant macroprolactinaemia (i.e., reduction of Prl concentrations of more than 60% after PEG precipitation) was found in 9 subjects (4.94%). There were no differences in the prevalence of macroprolactinaemia between women with autoimmune thyroid disease (4 out of 96), and without autoimmune thyroid disease (5 out of 86, p = 0.75).ConclusionsApproximately one out of twenty women with regular menses is likely to have raised serum Prl that is usually caused by the presence of macroprolactinaemia. Though structure of macroprolactin involves Prl-IgG complexes, there is no evidence that autoimmune thyroid disease is associated with raised prevalence of macroprolactinaemia.

Combined Treatment with Buserelin+Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma

Twelve years following hemicolectomy for colon adenocarcinoma, a 75-year-old patient with prostate cancer was treated for 4 weeks with the antiandrogen nilutamide and then with the long-acting GnRH agonist buserelin. The serum testosterone and prostate-specific antigen levels had decreased dramatically after 3 months of treatment. After 2 years of buserelin administration, the hormonal state was examined. Serum estradiol, testosterone, DHEA, DHEAS, FSH and LH levels proved to be suppressed, but the serum PRL concentration was extremely high (3 365 mIU/l). The pituitary MRI revealed a macroadenoma. The patient was treated with the dopamine agonist cabergoline, together with buserelin. After 9 months of this combined treatment, the prostate-specific antigen and testosterone levels were very low; the serum estradiol, DHEA, DHEAS, FSH and LH concentrations remained suppressed. The serum PRL level fell dramatically to 6.95 mIU/l, and a significant reduction in tumor size was observed on MRI. In conclusion: Combined buserelin + cabergoline treatment proved a highly successful procedure to cure this patient with prostate carcinoma and subsequent pituitary macroprolactinoma.

Effect of estradiol or calcium treatment on mammotrophs of female middle-aged rats

The effects of estradiol dipropionate (EDP) or calciumglucoheptonate (Ca) on the morphology and stereology of the PRLcellsin14-month-oldWistarfemaleratswerestudied.Theanimalsweretreated daily with EDP in the dose of 0.625 mg/kg b.w. or calciumglucoheptonate(Ca;11.4mg/kgb.w.)fortwoweeks.Thecontrolswereinjected with vehicle alone by the same schedule. Mammotrophs (PRLcells) were immunocytochemically localized by the PAP method. BloodPRL concentration was determined by Delfia procedure. In animalstreated with EDP the volume of both, PRL cells and their nuclei, as wellas the volume densities were significantly (p 0.05) decreased compared to control rats. Serum concentration ofPRL was significantly increased (p 0.05) changed by 2% compared to controls. Based on theseresults, it can be concluded that EDP expresses a strong stimulatoryeffect on the morphology and function of pituitary PRL cells.Keywords:PRL,mammotrophs,estradiol,calcium,middle-aged,female rats

Endothelin-3 and PRL levels in the maternal and fetal circulation at delivery

The aim of the present cross-sectional study was to test the hypothesis that endothelin-3 (ET-3) is involved in PRL secretion via systemic hormonal interaction during labor. Fifty healthy pregnant women with singleton pregnancies were included in the present study. At delivery, blood samples were drawn from umbilical vein and artery. At the same time, a blood sample was obtained from a peripheral vein of the mother. In all blood samples, plasma ET-3 and serum PRL concentrations were determined. The main outcome measures were the differences between maternal peripheral blood, umbilical artery and vein in terms of ET-3 and PRL levels, and the associations between ET-3 and PRL levels. ET-3 values (mean+/-SEM) in umbilical artery did not differ significantly from those in umbilical vein (4.94+/-0.27 vs 5.05+/-0.32 pg/ml) but were in both vessels significantly higher than in maternal vein (1.14+/-0.56 pg/ml, p<0.001). Serum PRL values showed similar patterns. There was a significant positive correlation of the ET-3 levels between umbilical artery and vein (r=0.906, p<0.001), but not between maternal peripheral venous blood and the umbilical vessels. Similar correlations were found for PRL values. However, no significant correlations were found between ET-3 and PRL levels in all vessels studied. The present study demonstrates for the first time that ET-3 levels are higher in fetal than in maternal circulation at term. The lack of correlation between ET-3 and PRL levels suggests that ET-3 does not play an important endocrine role in the control of maternal and fetal PRL secretion during labor.

Macroprolactinemia in women presenting with hyperandrogenic symptoms: Implications for the management of polycystic ovary syndrome

Eight of 109 consecutive hyperandrogenic patients had increased serum PRL levels; macroprolactinemia was diagnosed in 4 patients by measuring PRL levels after precipitation of serum with polyethylene glycol, and after detecting macroprolactinemia, these 4 patients were diagnosed with polycystic ovary syndrome (PCOS). Therefore, macroprolactinemia must be ruled out in women presenting with hyperandrogenic symptoms and increased serum PRL concentrations to avoid misdiagnosis (hyperprolactinemia is an exclusion criterion for the diagnosis of PCOS), unnecessary diagnostic tests, and inappropriate use of dopaminergic agonists.

Functional role of estrogen in pituitary tumor pathogenesis.

Pituitary hyperplasia and lactotroph replication are induced by estrogen. The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas. We now elucidate the role of estrogen in paracrine regulation of pituitary tumorigenesis by PTTG. Coincident with the circulating rat estradiol surge and maximal pituitary proliferation, pituitary pttg mRNA, bFGF, and VEGF expression increased approximately threefold during proestrus and estrus. Osmotic mini-pump coinfusion of estrogen and antiestrogen abrogated estrogen-induced pituitary pttg expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated prolactin-secreting pituitary tumor growth by 41% in rats. Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%. Pituitary pttg, bFGF, and VEGF are cyclically expressed during the rat estrus cycle, concordantly with estrogen levels. Because anti-estrogens reduced PTTG expression in human pituitary tumors in vitro and suppressed experimental tumor growth in vivo, concomitantly with reduced PRL secretion, these results indicate a role for selective antiestrogens in treating pituitary tumors.

Functional role of estrogen in pituitary tumor pathogenesis

Pituitary hyperplasia and lactotroph replication are induced by estrogen. The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas. We now elucidate the role of estrogen in paracrine regulation of pituitary tumorigenesis by PTTG. Coincident with the circulating rat estradiol surge and maximal pituitary proliferation, pituitary pttg mRNA, bFGF, and VEGF expression increased approximately threefold during proestrus and estrus. Osmotic mini-pump coinfusion of estrogen and antiestrogen abrogated estrogen-induced pituitary pttg expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated prolactin-secreting pituitary tumor growth by 41% in rats. Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%. Pituitary pttg, bFGF, and VEGF are cyclically expressed during the rat estrus cycle, concordantly with estrogen levels. Because anti-estrogens reduced PTTG expression in human pituitary tumors in vitro and suppressed experimental tumor growth in vivo, concomitantly with reduced PRL secretion, these results indicate a role for selective antiestrogens in treating pituitary tumors.

Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b.

PRL secretion from the anterior pituitary gland is inhibited by dopamine produced in the tuberoinfundibular dopamine neurons of the hypothalamus. The activity of tuberoinfundibular dopamine neurons is stimulated by PRL; thus, PRL regulates its own secretion by a negative feedback mechanism. PRL receptors are expressed on tuberoinfundibular dopamine neurons, but the intracellular signaling pathway is not known. We have observed that mice with a disrupted signal transducer and activator of transcription 5b gene have grossly elevated serum PRL concentrations. Despite this hyperprolactinemia, mRNA levels and immunoreactivity of tyrosine hydroxylase, the key enzyme in dopamine synthesis, were significantly lower in the tuberoinfundibular dopamine neurons of these signal transducer and activator of transcription 5b-deficient mice. Concentrations of the dopamine metabolite dihydroxyphenylacetic acid in the median eminence were also significantly lower in signal transducer and activator of transcription 5b-deficient mice than in wild-type mice. No changes were observed in nonhypothalamic dopaminergic neuronal populations, indicating that the effects were selective to tuberoinfundibular dopamine neurons. These data indicate that in the absence of signal transducer and activator of transcription 5b, PRL signal transduction in tuberoinfundibular dopamine neurons is impaired, and they demonstrate that this transcription factor plays an obligatory and nonredundant role in mediating the negative feedback action of PRL on tuberoinfundibular dopamine neurons.

Activation of AMPA receptors inhibits prolactin and estradiol secretion and delays the onset of puberty in female rats

Previous experiments have evidenced the neuroendocrine role of AMPA receptors. Present studies were carried out to obtain information on the role of these receptors in the control of the onset of puberty. To this end, female rats were i.c.v. injected with vehicle or AMPA (agonist of AMPA receptors: 0.1 or 0.5 nmol/day) between 26 and 30 days (Experiment 1), or 30 and 34 days (Experiment 2) of age. Serum concentrations of PRL, LH and estradiol were measured before drug administration, 10 min after the last injection, at vaginal opening (VO) and at first estrus (FE) presentation. In both experiments, AMPA administration inhibited PRL and estradiol secretion without affecting LH release. When AMPA was administered between 26 and 30 days a significant delay in the day of vaginal opening was observed. These results confirmed the inhibitory effect of AMPA on PRL secretion and suggests a role of AMPA receptors in the control of puberty onset.

ROLES OF PROLACTIN AND GONADOTROPIN-RELEASING HORMONE IN RHEUMATIC DISEASES

PRL is capable of influencing immune responses and is a cytokine in all likelihood. Circulating PRL is elevated in a number of autoimmune diseases, and about 20% of SLE patients are hyperprolactinemic. The serum PRL concentration often does not reflect disease activity in SLE. The PRL-suppressing drug bromocriptine has been reported to benefit small numbers of patients with reactive arthritis and inflammatory eye disease, and bromocriptine may be beneficial in treating SLE. In NZB/NZW mice, bromocriptine was beneficial and prolonged life. Bromocriptine therapy favorably modified disease in human SLE. In a preliminary open-label study, SLE patients treated with bromocriptine for 6 months had significant improvement in disease activity. These responses were corroborated by masted therapeutic studies. Daily treatment with low-dose bromocriptine prevented lupus flares, and bromocriptine was as effective as hydroxychloroquine in treating active nonorgan-threatening disease. The reports of the efficacy of bromocriptine treatment of SLE are encouraging. Additional studies may confirm the findings reported in this review and may lead to further use of hormonal modification to treat lupus and other autoimmune diseases. For the present, it is important to understand that treatment with dopamine agonists such as bromocriptine is experimental and best confined to therapeutic trials. In the experience of the authors, bromocriptine should not be relied on to treat severe life-threatening autoimmune disease. If bromocriptine is used to treat SLE and is then discontinued, the patient should be observed carefully for rebound hyperprolactinemia and the development of a lupus flare. GnRH is produced by lymphocytes and exerts immunomodulatory actions. Thus, GnRH resembles a cytokine. GnRH can be shown to exert gender-restricted immune actions in vitro and in vivo. The authors' preliminary observations are consistent with the possibility that gender-related differences in expression of the GnRH receptor or in GnRH signal transducers may contribute to gender-related differences in immune responsiveness to GnRH. These differences in G proteins may contribute to the gender-related differences in immunity and expression of autoimmune disease.