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Background: Resistance to dopamine agonists is not uncommonly seen in prolactinomas. However, development of resistance to dopamine agonists after an initial period of robust treatment response is rare, and only 39 cases have been reported in the past four decades. We describe a Chinese man with this rare condition and explored the postulated mechanisms that may explain this phenomenon. We compiled similar cases that were previously reported and compared their etiology, progress, and response to treatment. On the basis of these cases, we derived a list of differential diagnoses to consider in patients with secondary resistance to dopamine agonists. Case presentation: A 63-year-old Chinese man presented with blurred vision and was subsequently diagnosed with a macroprolactinoma. He had initial response to cabergoline but developed secondary resistance to it after 5 years. The prolactinoma continued to grow, and his serum prolactin remained markedly elevated despite adherence to escalating dosages of cabergoline up to 6 mg/week. The patient finally underwent transsphenoidal surgery and was found to have a sparsely granulated lactotroph tumor with Ki-67 index of 5%. Postoperatively, there was improvement in his serum prolactin level, although he still required treatment with cabergoline at 6 mg/week. Conclusions: Surgery can facilitate disease control in patients with prolactinomas that develop secondary resistance to dopamine agonists. Malignant prolactinoma is an important differential diagnosis in this group of patients, especially when serum prolactin remains markedly elevated despite resolution or stability of the primary pituitary lesion, suggesting a metastatic source of prolactin secretion. [ABSTRACT FROM AUTHOR]

PurposeThree dopamine agonists [bromocriptine, cabergoline, and quinagolide (CV)] have been used for hyperprolactinemia treatment for decades. Several studies have reviewed the efficacy and safety of bromocriptine and cabergoline. However, no systematic review or meta-analysis has discussed the efficacy and safety of CV in hyperprolactinemia and prolactinoma treatment.MethodsFive medical databases (PubMed, Web of Science, Embase, Scopus, and Cochrane Library) were searched up to 9 May 2022 to identify studies related to CV and hyperprolactinemia. A meta-analysis was implemented by using a forest plot, funnel plot, sensitivity analysis, meta-regression, and Egger’s test via software R 4.0 and STATA 12.ResultsA total of 1,211 studies were retrieved from the five medical databases, and 33 studies consisting of 827 patients were finally included in the analysis. The pooled proportions of patients with prolactin concentration normalization and tumor reduction (>50%) under CV treatment were 69% and 20%, respectively, with 95% confidence intervals of 61%–76% and 15%–28%, respectively. The pooled proportion of adverse effects was 13%, with a 95% confidence interval of 11%–16%.ConclusionOur study showed that CV is not less effective than cabergoline and bromocriptine in treating hyperprolactinemia, and the side effects were not significant. Hence, this drug could be considered an alternative first-line or rescue treatment in treating hyperprolactinemia in the future.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42022347750.

What is known and objective: Hyperprolactinemia is a neuroendocrine disease that is responsible for a quarter of cases of secondary amenorrhea, which can lead to infertility in women. Dopaminergic agonists (bromocriptine, cabergoline, quinagolide) can be used in the treatment. However, there is a lack of secondary studies that compare their efficacy and safety, especially through a network meta‐analysis. Thus, to contribute to the decision‐making, a systematic review and network meta‐analyses (NMA) were performed to evaluate the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. Methods: Randomized clinical trials (RCT) were retrieved through PubMed, Web of Science and Scopus databases. The efficacy and safety of the drugs were compared, considering the following outcomes: prolactin (PRL) levels, number of patients with galactorrhoea, menstrual irregularities and adverse drug reactions. NMA was built for each outcome. Results were reported as odds ratios (OR) with 95% credibility intervals. Ranking probabilities were calculated by surface under the cumulative ranking analysis (SUCRA) and Stochastic multicriteria acceptability analysis (SMAA). Results and discussion: Seventeen RCTs were included in the systematic review and fifteen in the meta‐analyses. The drugs had similar efficacy, considering the PRL levels. The SUCRA analysis showed that quinagolide (0.075 and 0.05 mg/day) was superior for reducing irregular menstruation, whereas bromocriptine was the best (97%) for galactorrhoea. Cabergoline proved to be the safest drug, except for abdominal pain at a dose of 1 mg/week. The SMAA demonstrated similar results to SUCRA. What is new and conclusion: This is the first network meta‐analysis that evaluated the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. The results of this review revealed that these drugs have similar efficacy, but cabergoline has a better safety profile. [ABSTRACT FROM AUTHOR]

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.

Accumulating evidence supports that the hormone prolactin (PRL) is galactopoietic in dairy ruminants. Accordingly, the inhibition of PRL secretion by the dopamine agonists quinagolide and cabergoline causes a sharp decline in milk production and could be useful in several critical periods. First, PRL inhibition may reduce the incidence during the periparturient period of metabolic disorders caused by the abrupt increase in energy demand for milk production. Metabolic disturbances can be lessened by reducing milk output by milking once a day or incompletely in the first few days of lactation. The injection of cows with quinagolide for the first 4 days of lactation reduced milk production during the first week of lactation without any residual effects. Blood glucose and calcium concentrations were higher and β-hydroxybutyric acid concentration was lower in the quinagolide-treated cows. Second, PRL inhibition may help sick or injured lactating cows, considering that they can fall into severe negative energy balance when they are unable to consume enough feed to support their milk production. This leads to a weakened immune system and increased susceptibility to diseases. When cows were subjected to feed restriction and were treated with quinagolide, the decrease in milk production was accelerated without any residual effects. The quinagolide-treated cows had higher glucose and lower β-hydroxybutyric acid and non-esterified fatty acid concentrations than the control cows did. Third, PRL inhibition may facilitate drying-off in high-yielding cows, because they are often dried off while still producing significant quantities of milk, which delays mammary involution and increases risk of mastitis. Therefore, strategies that reduce milk production before drying-off and accelerate mammary gland involution could be an important management tool. In this context, inhibition of PRL was utilised to accelerate mammary gland dry-off. Quinagolide decreased milk production within the first day of treatment, and both quinagolide and cabergoline induced more rapid changes in several markers of mammary gland involution after drying-off. In addition, quinagolide improved the animals’ resistance to intramammary infection. These results suggest that the inhibition of PRL could be a strategy for facilitating drying-off, reducing metabolic stress during the postpartum period, and alleviating acute nutritional stress during illness without compromising the overall productivity of dairy ruminants.

Accumulating evidence supports that the hormone prolactin (PRL) is galactopoietic in dairy ruminants. Accordingly, the inhibition of PRL secretion by the dopamine agonists quinagolide and cabergoline causes a sharp decline in milk production and could be useful in several critical periods. First, PRL inhibition may reduce the incidence during the periparturient period of metabolic disorders caused by the abrupt increase in energy demand for milk production. Metabolic disturbances can be lessened by reducing milk output by milking once a day or incompletely in the first few days of lactation. The injection of cows with quinagolide for the first 4 days of lactation reduced milk production during the first week of lactation without any residual effects. Blood glucose and calcium concentrations were higher and β-hydroxybutyric acid concentration was lower in the quinagolide-treated cows. Second, PRL inhibition may help sick or injured lactating cows, considering that they can fall into severe negative energy balance when they are unable to consume enough feed to support their milk production. This leads to a weakened immune system and increased susceptibility to diseases. When cows were subjected to feed restriction and were treated with quinagolide, the decrease in milk production was accelerated without any residual effects. The quinagolide-treated cows had higher glucose and lower β-hydroxybutyric acid and non-esterified fatty acid concentrations than the control cows did. Third, PRL inhibition may facilitate drying-off in high-yielding cows, because they are often dried off while still producing significant quantities of milk, which delays mammary involution and increases risk of mastitis. Therefore, strategies that reduce milk production before drying-off and accelerate mammary gland involution could be an important management tool. In this context, inhibition of PRL was utilised to accelerate mammary gland dry-off. Quinagolide decreased milk production within the first day of treatment, and both quinagolide and cabergoline induced more rapid changes in several markers of mammary gland involution after drying-off. In addition, quinagolide improved the animals' resistance to intramammary infection. These results suggest that the inhibition of PRL could be a strategy for facilitating drying-off, reducing metabolic stress during the postpartum period, and alleviating acute nutritional stress during illness without compromising the overall productivity of dairy ruminants. [ABSTRACT FROM AUTHOR]

The discovery of dopamine inhibitory effects on prolactin secretion has led to an era of successful dopaminergic therapy for prolactinomas. Herein we provide an overview of the evolution of dopamine agonists and their use in patients with PRL-secreting pituitary tumors, starting from the 1970s up to today, highlighting that normalization of PRL levels, restoration of eugonadism, and reduction of tumor mass can be achieved in the majority of patients by treatment with dopamine agonists. [ABSTRACT FROM AUTHOR]

Résumé La prolactine est une hormone polypeptidique synthétisée et sécrétée par les cellules lactotropes de l’antéhypophyse. En endocrinologie, il existe quatre inhibiteurs de la prolactine : la bromocriptine, le lisuride, la cabergoline et le quinagolide. Summary Prolactin is a synthesised polypeptide hormone secreted by the lactotroph cells of the anterior pituitary. In endocrinology, there are four prolactin inhibitors: bromocriptine, lisuride, cabergoline and quinagolide. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine whether the responsiveness of the mammary gland to prolactin (PRL) is affected by the concentration of the hormone. After 1 pre-experimental week (d -7 to -1), 18 Holstein cows in mid to late lactation were injected intramuscularly twice daily with either 0.5 mg of quinagolide (QN) or 2 mL of water (control) for 2 wk (d 1 to 14; treatment period). After the treatment period, all cows received daily subcutaneous injections of 300 mg of domperidone (DOMP) for 3 wk (d 15 to 35; DOMP period). The cows were monitored for an additional 2 wk as a posttreatment period (d 36 to 49). Blood and milk samples were collected 3 times per week. Additionally, blood samples were collected during the a.m. milking on d -4, 14, and 35. Milk production was not affected by QN during the treatment period but was increased during the DOMP and posttreatment periods in the QN cows. With respect to milk composition, the treatments affected only the protein content, which was greater in the QN cows during the treatment period. Blood PRL concentration declined during QN injections and was lower in the QN cows than in the control cows between d 5 and 14. The basal concentration of PRL was increased by DOMP injections during the DOMP and posttreatment periods but was not affected by previous QN injections. Prolactin concentration in milk was not affected by the QN treatments but was increased by DOMP injections during the DOMP and posttreatment periods. Milking-induced PRL release was decreased by QN on d 14. On d 35, milking did not induce a significant release of PRL above the baseline for both treatments. In conclusion, the results of this experiment support the contention that the mammary gland's responsiveness to PRL is modulated by the previous level of the hormone. [ABSTRACT FROM AUTHOR]

Aim: The study aimed to investigate the efficacy of a dopamine agonist, quinagolide, on experimentally induced endometriosis in a rat model.Methods: Twenty female Wistar rats were used in this experiment. Endometriosis was surgically induced by transplantation of autologous endometrial tissue. A second laparotomy was performed 4 weeks after the first one to assess the pre-treatment implant volumes, and peritoneal lavage with saline solution was performed to assess the peritoneal cytokine levels. Rats were randomized to treatment with quinagolide or saline. At the end of the treatment period, a third laparotomy was performed to compare pre- and post-treatment implant volumes and cytokine levels within the groups. Implants were excised to compare glandular tissue (GT) and stromal tissue (ST) scores between the groups.Results: In the quinagolide group, post-treatment volume was statistically significantly reduced compared with pre-treatment volume (p = 0.01). There were significant decreases in interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) levels in peritoneal fluid samples in quinagolide-treated rats when compared to pre-treatment levels (p = 0.03 and p < 0.01). Histopathologically, both GT and ST scores were significantly lower in the quinagolide group compared to the control group (p = 0.01 and p = 0.02).Conclusions: Quinagolide caused a significant regression in endometriotic implants and it also significantly reduced the levels of IL-6 and VEGF in peritoneal fluid. [ABSTRACT FROM AUTHOR]

During the periparturient period, the abrupt increase in energy demand for milk production often induces metabolic and immunological disturbances in dairy cows. Our previous work has shown that reducing milk output by milking once a day or incompletely in the first few days of lactation reduces these disturbances. The aim of this study was to reduce metabolic and immunological disturbances by limiting milk production during the first week of lactation by inhibiting the lactogenic signal driven by prolactin. Twenty-two fresh cows received 8 i.m. injections of the prolactin-release inhibitor quinagolide (QUIN; 2 mg) or water as a control (CTL). The first injection was given just after calving, and the subsequent 7 injections were given every 12 h. Milk production was measured until d 28 after calving. Blood samples were taken from d 1 (calving) to d 5 and then on d 7, 10, 14, 21, and 28 to measure concentrations of urea, phosphorus, calcium, glucose, nonesterified fatty acids (NEFA), β-hydroxybutyrate, and prolactin. Other blood samples were taken on d 2, 5, 10, and 28 to analyze oxidative burst, phagocytosis, and the effect of the serum on the lymphoproliferation of peripheral blood mononuclear cells from donor cows. Blood prolactin concentration was lower from d 2 to 5 but higher from d 10 to 28 in the QUIN cows than in the CTL cows. Milk production was lower from d 2 to 6 in the QUIN cows than in the CTL cows (24.3 ± 6.4 and 34.8 ± 4.1 kg/d on average, respectively). We observed no residual effect of quinagolide on milk production after d 6. During the first week of lactation, blood glucose and calcium concentrations were higher and β-hydroxybutyrate concentration was lower in the QUIN cows than in the CTL cows. Blood NEFA, urea, and phosphorus concentrations were not affected by the treatment. At d 2 and 5, the phagocytosis ability of polymorphonuclear leukocytes was not affected by treatment; however, quinagolide injection enhanced the proportion of cells that entered oxidative burst, The mitogen-induced proliferation of peripheral blood mononuclear cells was greater when they were incubated with serum harvested from the CTL cows and was negatively correlated with the NEFA concentration in the serum. Reducing the prolactin peak at calving was effective in reducing milk production during the first week of lactation without compromising the dairy cow's overall productivity. Slowing the increase in milk production allowed a more gradual transition from pregnancy to lactation and led to a reduction in metabolic stress and an improvement in some immune system aspects during this period. [ABSTRACT FROM AUTHOR]

When cows are unable to consume enough feed to support milk production, they often fall into severe negative energy balance. This leads to a weakened immune system and increases their susceptibility to infectious diseases. Reducing the milk production of cows subjected to acute nutritional stress decreases their energy deficit. The aim of this study was to compare the effects on metabolism and immune function of reducing milk production using quinagolide (a prolactin-release inhibitor) or dexamethasone in feed-restricted cows. A total of 23 cows in early/mid-lactation were fed for 5 d at 55.9% of their previous dry matter intake to subject them to acute nutritional stress. After 1 d of feed restriction and for 4 d afterward (d 2 to 5), cows received twice-daily i.m. injections of water (control group; n = 8), 2 mg of quinagolide (QN group; n = 7), or water after a first injection of 20 mg of dexamethasone (DEX group; n = 8). Feed restriction decreased milk production, but the decrease was greater in the QN and DEX cows than in the control cows on d 2 and 3. As expected, feed restriction reduced the energy balance, but the reduction was lower in the QN cows than in the control cows. Feed restriction decreased plasma glucose concentration and increased plasma nonesterified fatty acid (NEFA) and β-hydroxybutyrate (BHB) concentrations. The QN cows had higher glucose concentration and lower BHB concentration than the control cows. The NEFA concentration was also lower in the QN cows than in the control cows on d 2. Dexamethasone injection induced transient hyperglycemia concomitant with a reduction in milk lactose concentration; it also decreased BHB concentration and decreased NEFA initially but increased it later. Feed restriction and quinagolide injections did not affect the blood concentration or activity of polymorphonuclear leukocytes (PMN), whereas dexamethasone injection increased PMN blood concentration but decreased the proportion of PMN capable of inducing oxidative burst. Incubation of peripheral blood mononuclear cells in serum harvested on d 2 of the restriction period reduced their ability to react to mitogen-induced proliferation, and injection of quinagolide or dexamethasone could not alleviate this effect. This experiment shows that prolactin-release inhibition could be an alternative to dexamethasone for reducing milk production and energy deficit in cows under acute nutritional stress, without disturbing immune function. [ABSTRACT FROM AUTHOR]

A cow's risk of acquiring a new intramammary infection during the dry period increases with milk production at drying-off. A method commonly used to reduce milk production is a drastic reduction in feed supply in the days that precede drying-off. Milk production can also be reduced by inhibiting the lactogenic signal driven by prolactin (PRL). This study aimed to compare the effects of these 2 drying-off procedures on milk production, metabolism, and susceptibility to intramammary infection in cows. A total of 21 Holstein cows in late lactation were assigned to 1 of 3 treatments based on milk yield, somatic cell count, and parity. The cows were fed a lactation diet until drying-off (control), only dry hay during the last 5 d before drying-off (DH), or the same diet as the control cows but with twice-daily i.m. injections of 4 mg of quinagolide, a specific inhibitor of PRL release, from 5 d before drying-off until 13 d after (QN). On d 1 to 7 after the last milking, the cows were challenged by daily teat dipping in a solution containing Streptococcus agalactiae at 5 x 107 cfu/mL. Quinagolide induced a decrease in PRL concentration in blood on all the injection days. Blood PRL was also depressed in the hay-fed cows before drying-off. Both the QN and DH treatments induced a decrease in milk production, which at drying-off averaged 12.0, 10.0, and 21.7 kg/d for the QN, DH, and control cows, respectively. The DH treatment decreased blood concentration of glucose and increased blood concentrations of β-hydroxybutyrate and nonesterified fatty acids before drying-off. Somatic cell count at drying-off was greater in the milk of the QN cows than in that of the control cows but after drying-off was greater in the mammary secretions of the control cows than in those of the QN cows. The number of S. agalactiae colonies found in mammary secretions on d 8 and 14 after the last milking was lower for the QN cows than for the control cows. The percentage of S. agalactiae-infected quarters was also lower in the QN cows than in the control cows and on d 14 averaged 17.2, 33.7, and 57.5% in the QN, DH, and control cows, respectively. No differences between the DH and control groups were observed for either bacterial count or infection rate. In conclusion, this experiment shows that PRL-release inhibition could be an alternative for reducing milk production and improving resistance to intramammary infection at drying-off. [ABSTRACT FROM AUTHOR]

A cow's risk of acquiring a new intramammary infection during the dry period increases with milk production at drying off and decreases as mammary gland involution progresses. A method commonly used to reduce milk production is a drastic reduction in feed supply in the days that precede drying off. Milk production can also be reduced by inhibiting the lactogenic signal driven by prolactin (PRL). This study aimed to compare the effects of these 2 drying-off procedures on metabolism, immunity, and mammary gland involution in cows. A total of 24 Holstein cows in late lactation were assigned to 1 of 3 treatments based on milk yield, somatic cell count, and parity. The cows were fed a lactation diet until drying off (control; n = 8), only dry hay during the last 5 d before drying off (DH; n = 8), or the same lactation diet as the control cows but with twice-daily i.m. injections of 4 mg of quinagolide, a specific inhibitor of PRL release, from 5 d before drying off until 13 d after (QN; n = 8). Quinagolide induced a decrease in PRL concentration in blood and in milk and mammary secretions on all the injection days. Interestingly, PRL was also depressed in the blood and milk of the hay-fed cows before drying off. Both the QN and DH treatments induced a decrease in milk production, which averaged 17.9 and 10.1 kg/d for the QN and DH cows, respectively, at drying off in comparison with 24.8 kg/d for the control cows. Both BSA concentration and Na+-to-K+ ratio increased faster in the mammary secretions of both the DH and QN cows than in those of the control cows, whereas citrate-to-lactoferrin ratio, another indicator of involution rate, decreased faster. The DH treatment decreased blood concentrations of glucose and most amino acids and increased blood concentrations of (3-hydroxybutyrate and nonesterified fatty acids. Quinagolide increased blood glucose but did not affect the other metabolites. The serum harvested on d - 1 from the hay-fed cows reduced peripheral blood mononuclear cell proliferation and IL-4 production, whereas the serum from the quinagolide-treated cows had no effect. In conclusion, this experiment shows that PRL-release inhibition could be a new alternative for reducing milk production before drying off and for hastening mammary gland involution without disturbing the metabolism of the cow. [ABSTRACT FROM AUTHOR]

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment. [ABSTRACT FROM AUTHOR]

The end of each lactation is a challenging period for high-yielding cows as they are often dried off while still producing significant quantities of milk and, consequently, are highly susceptible to new intramammary infections. Once involution is complete, the mammary gland becomes much more resistant to infection. Therefore, it is critically important to develop strategies aimed at reducing milk production before drying-off and to accelerate mammary gland involution. This study assessed the effect of inhibition of the lactogenic signal driven by prolactin (PRL) on milk production and concentrations of involution markers in mammary secretions. Sixteen Holstein cows in late lactation were assigned to treatments based on milk yield, somatic cell count, and parity. Of those cows, 8 received twice-daily intramuscular injections (2 mg per injection) of quina-golide, a specific inhibitor of PRL release, from 4 d before drying-off to 3 d after (Quin). The other 8 cows received injections of the solvent (water, control). Blood and milk (mammary secretion) samples were collected on the last 5 d before and on d 1, 3, 5, 7, 10, and 14 after the last milking. Additionally, on the day preceding the first injection and on the following day, several blood samples were collected around milking time. Quinagolide reduced basal serum PRL concentrations on all injection days as well as PRL released in blood during milking. The PRL inhibitor decreased milk production before drying-off, which averaged, over the last 3 d of lactation, 19.3 and 15.5 kg/d for the control and Quin cows, respectively. Quinagolide had no significant effect on milk citrate:lactoferrin and Na:K ratios, which decreased and increased, respectively, during the first 2 wk of the dry period. Nevertheless, the increases in the number of somatic cells and bovine serum albumin concentration during early involution were greater and matrix metalloproteinase-2 activity tended to be great-er in mammary secretions of the Quin cows compared with the control cows. This experiment shows that inhibition of PRL release decreases milk production of cows in late lactation. Changes in the composition of mammary secretions suggest that this approach also hastens mammary gland involution. [ABSTRACT FROM AUTHOR]

Dopamine agonists (DA) are the mainstay of treatment for patients with prolactinomas. To describe the efficacy of treatment and the outcomes of DA withdrawal. Retrospective review of electronic medical records of patients with prolactinomas from 1985 to 2009. Seventy-nine patients (17 men/62 women), aged 35.3 ± 1.6 years at diagnosis were studied. The mean follow-up time was 84.7 ± 9.2 months (range 0-336). The mean initial size of microadenomas was 0.74 ± 0.10 cm (range 2.41 ± 0.39) and of macrodenomas 2.41 ± 0.39 cm (range 1.1-8) and serum prolactin (PRL) levels were 112 ± 19 and 263 ± 59 ng/ml, respectively (normal range 0-40). Fifty-one (65%) prolactinomas were micro- and 28 (35%) were macroadenomas. DA led to a decrease in adenoma size in 71% of them, while 53% of microadenomas were not visible during follow-up. In 26 patients, DA withdrawal was decided. After therapy of >24 months and a mean follow-up time of 49 ± 11 months (range 3-168), 15 subjects (58%) showed no recurrence of hyperprolactinemia. Higher remission rates, although not statistically significant, were observed with cabergoline (75%). The mean PRL levels before DA discontinuation were 12.2 ± 2.3 ng/ml (range 0.5-44.7) and after discontinuation they were significantly lower than pre-treatment values. Recurrence of hypeprolactinemia was evident during the first year in all but one patient. Remission rates were not associated with age or size of adenoma at diagnosis, initial or before DA discontinuation PRL levels and duration of treatment. DA withdrawal was followed by remission of hyperprolactinamia in about half of patients after >2 years of treatment. [ABSTRACT FROM AUTHOR]

Background: Ovarian hyperstimulation syndrome (OHSS) seems to be induced by the ovarian release of vascular endothelial growth factor (VEGF), which increases vascular permeability. Dopamine agonists inhibit VEGF receptor phosphorylation and thereby decrease vascular permeability.Methods: A randomized, double-blind, placebo-controlled, multicentre study assessing three oral doses (50, 100, 200 microg/day) of the non-ergot derived dopamine agonist quinagolide started on the day of human chorionic gonadotrophin (hCG) and continued for 17-21 days without dose-titration in comparison to placebo in preventing moderate/severe early OHSS (onset < or =9 days after hCG administration) in 182 IVF patients with > or =20 but less than 30 follicles > or =10 mm.Results: The incidence of moderate/severe early OHSS was 23% (12/53) in the placebo group and 12% (6/51), 13% (7/52) and 4% (1/26) in the quinagolide 50, 100 and 200 microg/day groups, respectively. The moderate/severe early OHSS rate was significantly lower with all quinagolide groups combined compared with placebo [P = 0.019; OR = 0.28 (0.09-0.81)]. The incidence of ultrasound evidence of ascites among patients with no clinical pregnancy was significantly reduced from 31% (8/26) with placebo to 11% (8/70) with all quinagolide groups combined [P = 0.033; OR = 0.29 (0.10-0.88)], although there was no difference for those with clinical pregnancy. Quinagolide did not have a detrimental effect on pregnancy or live birth rates. The incidence of gastrointestinal and central nervous system adverse events increased with increasing doses of quinagolide.Conclusions: Quinagolide appears to prevent moderate/severe early OHSS while not affecting treatment outcome. The effect is more marked in patients who did not achieve a clinical pregnancy. Quinagolide administered in high doses without dose-titration is associated with poor tolerability. ClinicalTrials.gov Identifier: NCT00329693. [ABSTRACT FROM AUTHOR]

This review focusses on the epidemiology, diagnosis and treatment of prolactinomas. In particular, attention was given to recent data showing a high prevalence of these tumours in the general population, 3–5 times higher than previously reported. The diagnosis of hyperprolactinaemia has been simplified in recent years, and only prolactin (PRL) assay and magnetic resonance imaging of the sella are required. Nonetheless, macroprolactinaemia should be assessed in patients with hyperprolactinaemia in the absence of clinical symptoms of elevated PRL levels. The recent evidence that medical therapy with dopamine agonists should be continued lifelong has been confirmed by several studied. The patients achieving disappearance of the tumours and suppression of PRL levels during treatment are those showing the highest likelihood to have persistent remission of hyperprolactinaemia after treatment withdrawal. [Copyright &y& Elsevier]

The relationship between endocrine regulation and immune system has recently become the subject of intense investigations. The objective of this study was to determine the extent of selected serum acute phase proteins (APP), IL-6 and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) involvement in systemic lupus erythematosus (SLE) patients during quinagolide therapy. A further aim of this study was to evaluate the relationships between the above mentioned parameters. In 25 SLE patients treated with a low dose of quinagolide (12.5-50 μg per day) and in 25 healthy persons who constituted the control group, serum concentration of C-creative protein (CRP), alpha-1-antitripsin (AAT), ceruloplasmin (CER), IL-6 and prolactin (PRL) were estimated at entry and in patients after 3 months of treatment. Moreover, SLEDAI score was calculated at entry and after 3 months of therapy with quinagolide. IL-6 and PRL levels were significantly higher in SLE group whereas the concentrations of CRP, AAT and CER were higher than in the controls, but without statistical significance. After 3 month therapy statistically significant decrease of serum level of IL-6 and PRL was revealed. Statistically significant lower serum concentration of CER was also obtained after 3 months of therapy whereas serum CRP and AAT concentration was lower compared with the mean pretreatment level but the results did not reach statistical significance. A raised SLEDAI score at entry was significantly reduced after 3 month therapy and positive correlation with PRL level in examined group of patients with SLE was noted at entry. The decreased serum concentration of IL-6, APP and SLEDAI score observed during applied therapy with small dose of quinagolide confirms the hypothesis that quinagolide may become a valuable and safe drug in the therapy of patients with mild SLE. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the expression of transforming growth factor-beta1 messenger RNA (TGF-β1 mRNA) and the expression of mRNA for TGF-β receptors (TGF-β Rs mRNA) in whole peripheral blood of consecutive (treated from several months to several years) systemic lupus erythematosus (SLE) patients (21 women). A further aim of this study was to evaluate the association between expression of the above mentioned parameters in relation to the form of applied therapy (9 patients treated with quinagolide and 12 with quinagolide plus prednisone, azathioprine or cyclosporine A). The control group consisted of 15 healthy women. Most of the patients had mild SLE with SLE disease activity index (SLEDAI) score < 10 at time when blood samples were collected. Laboratory measurements included real-time polymerase chain reaction (RT-QPCR). The expression levels of TGF-β1 mRNA and mRNA for TGF-β RII and RIII were significantly lower in patients whereas the expression level of TGF-β RI was statistically significantly higher in SLE patients than in the controls. A very high positive correlation between TGF-β1 mRNA expression and expression levels of TGF-β Rs mRNA was found. In compared subgroups selected according to the form of the applied therapy no statistically significant differences were observed. We conclude that the TGF-β signaling pathway can be altered in circulating leukocytes derived from treated patients with SLE and that the assumed forms of the applied therapy in the group of patients under consideration are accompanied by similarity in the expression level of transcripts for TGF-β1 and TGF-β Rs determined in whole blood. In our investigations, we cannot exclude the influence of the disease itself on the obtained results. [ABSTRACT FROM AUTHOR]

Abstract: High prolactin levels can occur as a physiological condition in females who are pregnant or lactating. As a pathological condition, hyperprolactinaemia is associated with gonadal dysfunction, infertility and an increased risk of long-term complications including osteoporosis. The most frequent cause of persistent hyperprolactinaemia is the presence of a micro- (<10mm diameter) or macroprolactinoma (≥10mm). These pituitary tumours may produce an excessive amount of prolactin or disrupt the normal delivery of dopamine from the hypothalamus to the pituitary; prolactin secretion from the pituitary is inhibited by dopamine released from neurones in the hypothalamus. Medications including anti-psychotics can induce hyperprolactinaemia, while idiopathic hyperprolactinaemia accounts for 30–40% of cases. The prevalence of hyperprolactinaemia is difficult to establish as not all sufferers are symptomatic or concerned by their symptoms and may remain undiagnosed. Symptoms of hyperprolactinaemia include signs of hypogonadism, with oligomenorrhoea, amenorrhoea and galactorrhoea frequently observed. Pharmacological intervention should be considered the first line therapy and involves the use of dopamine agonists to reduce tumour size and prolactin levels. Bromocriptine has the longest history of use and is a well-established, inexpensive, safe and effective therapy option. However, bromocriptine requires multiple daily dosing and some patients are resistant or intolerant to this therapy. The two newer dopamine agonists, quinagolide and cabergoline, provide more effective and better tolerated treatments compared with bromocriptine and may offer effective therapies for bromocriptine-resistant or intolerant patients. Quinagolide can be used until pregnancy is confirmed and may result in improved compliance in females wishing to become pregnant. For patients with hyperprolactinaemia, pregnancy is safe and can frequently be beneficial, inducing a decrease in prolactin levels. There does not appear to be any increased risk of abortion, malformations or multiple births in pregnancies achieved with bromocriptine and this dopamine agonist can be used safely during pregnancy. Surgery should be considered only in certain circumstances, and for the majority of patients, dopamine agonists will be sufficient to alleviate symptoms and restore normal prolactin levels. [Copyright &y& Elsevier]

Hyperprolactinemia is commonly found in both female and male patients with abnormal sexual and/or reproductive function or with galactorrhea. If serum prolactin levels are above 200 μg/L, a prolactin-secreting pituitary adenoma (prolactinoma) is the underlying cause, but if levels are lower, differential diagnoses include the intake of various drugs, compression of the pituitary stalk by other pathology, hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia. When a pituitary tumor is present, patients often have pressure symptoms in addition to endocrine dysfunction, such as headaches, visual field defects, or cranial nerve deficits. The large majority of patients with prolactinomas, both micro- and macroprolactinomas, can be successfully treated with dopaminergic drugs as first-line treatment, with normalization of prolactin secretion and gonadal function, and with significant tumor shrinkage in a high percentage of cases. Surgical resection of the prolactinoma is the option for patients who may refuse or do not respond to long-term pharmacological therapy. Radiotherapy and/or estrogens are also reasonable choices if surgery fails. In patients with asymptomatic microprolactinoma no treatment needs to be given and a regular follow-up with serial prolactin measurements and pituitary imaging should be organized. Currently, the most commonly used dopamine agonists are bromocriptine, pergolide, quinagolide and cabergoline. When comparing the plasma half-life, efficacy and tolerability of these drugs, cabergoline seems to have the most favorable profile, followed by quinagolide. If prolactin levels are well controlled with dopamine agonist therapy, gradual tapering of the dose to the lowest effective amount is recommended, and in a number of cases medication can be stopped after several years. Evidence to date suggests that cabergoline and quinagolide appear to have a good safety profile for women who wish to conceive, but hard evidence proving that dopamine agonists do not provoke congenital malformations when taken during early pregnancy is currently only available for bromocriptine. Once pregnant, dopamine agonist therapy should be immediately stopped, unless growth of a macroprolactinoma is likely or pressure symptoms occur. At our institution patients with symptomatic prolactinomas, both micro- and macroadenomas, are treated with cabergoline as the first-line aproach. In the small group of patients who do not respond to this treatment, or who refuse long-term therapy, surgery is offered. Radiotherapy is given if both pharmacologic therapy and surgery fail. [ABSTRACT FROM AUTHOR]

The biology of social phobia has been little studied, but a possible role for dopamine has been implicated in this disorder. The aim of this study was to examine central dopaminergic function in patients with generalised social phobia using the prolactin response to quinagolide, a dopamine D2 receptor agonist, and to compare responses with those of normal controls. The study included 14 patients with moderate or severe generalised social phobia and 14 healthy age- and gender-matched comparison subjects. Quinagolide (0.5 mg) was administered orally and prolactin responses were measured over 4 h. There was no significant difference between prolactin responses in patients and healthy controls, nor was there a correlation between prolactin response and age, sex, or severity of illness. This would suggest that tuberoinfundibular dopamine D2 receptor sensitivity is normal in this disorder. [Copyright &y& Elsevier]

The objective of this study was to determine the effect of quinagolide (Norprolac) on serum level of cytokines in systemic lupus erythematosus (SLE) patients. In 20 SLE patients treated with a low dose of quinagolide, and in 17 healthy persons who constituted the control group, concentration of serum prolactin (PRL), interleukins (ILs), soluble tumor necrosis factor receptors (sTNF Rs) preceded by calculation of disease activity index (SLEDAI) were tested at entry and then after 3 months in 16 patients and after 6 months in 11 patients who completed the study. Serum PRL level was higher (though insignificantly) in the SLE group than in the controls and decreased significantly after 6 months of therapy. A raised SLEDAI score at entry was significantly reduced during therapy but a weak correlation with PRL level was revealed. A significant increase in IL-6 level in SLE group as compared to controls was observed (respectively 14.57±13.25 and 5.04±3.35 pg/ml) as well as a significantly decreased level after 6 months of treatment (4.30±2.51 pg/ml). There was a significant difference between sTNF RI concentration before and after 3 months of quinagolide treatment (respectively 1140.83±312.08 and 1454.58±465.54 pg/ml). After 6 months of treatment a statistically significant correlation between concentration of PRL and level of IL-6 and a negative correlation between PRL and sTNF RI was revealed. Quinagolide treatment may have a role in the management of SLE patients. [ABSTRACT FROM AUTHOR]

Objective: This study reports a six year experience with quinagolide (CV205-502) in the treatment of 40 patients with hyperprolactinemia or prolactinoma. Patients and Measurements: Forty patients with hyperprolactinemia were treated with quinagolide (CV 205-502, NorprolacTM) for 2–72 months (mean 31.6 months). The patient's ages ranged from 12 to 53 years and 90% were female. Seventeen had no radiologic evidence of tumor; 11 had microadenomas; and 12 had macroadenomas. Results: All patients had a reduction of the serum prolactin following quinagolide therapy with normalization in 82% with no tumor, 73% with microadenomas, and 67% with macroadenomas. Fifty-five percent of microadenoma and 75% of macroadenoma patients had a decrease in tumor size when assessed by a blinded reviewer. Ten of 38 female patients became pregnant while taking quinagolide. The dosage of quinagolide ranged from 75 to 400 μg/day with a median dose of 100μg/day. A comparison of side effects in a subgroup of 35 patients who had taken bromocriptine prior to quinagolide administration showed a greater than 75% reduction in nausea, vomiting, dizziness, and drowsiness during quinagolide administration. Conclusions: We conclude that quinagolide is a safe and effective long-term alternative to bromocriptine therapy, particularly in those individuals with bromocriptine intolerance. [ABSTRACT FROM AUTHOR]