Prolactin Response Research Articles

Failing Memory in Nonaffective Psychosis and Prolactin Response to 12.5 µg i.v. TRH.

The increase in plasma prolactin at 15 min following administration of 12.5 µg TRH i. v. (∆prol) was introduced in Pharmacopsychiatry as an inverse estimate of tuberoinfundibular dopamine (TIDA) activity 1. We used the unpublished data set in 20 participants with nonaffective psychosis from our 1991 study utilizing ∆prol 2 and here report new results with its association with memory.

19 Interaction of kisspeptin and the somatotropic and lactotropic axes in mares and geldings

Several experiments were conducted to investigate the interaction between kisspeptin and the somatotropic and lactotropic axes in mares and geldings. Light horse, diestrous mares and geldings, weighing approximately 500 kg and aged 6 to 24 years, were randomly assigned to treatment with 1 mg equine kisspeptin-10 (Kp10; n = 10) or 1 mL saline (n = 9), i.v. Blood samples were collected via jugular venipuncture −10, 0, 5, 10, 15, 20 and 30 min relative to treatment. Plasma concentrations of growth hormone (GH) and prolactin (PRL) were determined by RIA and means compared using ANOVA with repeated sampling. Neither GH nor PRL were stimulated by Kp10. In a second experiment, 30 mares and geldings were used to determine if pre-treatment with estradiol or progesterone would elicit a GH or PRL response to Kp10. Five mares and 5 geldings each were assigned to pre-treatment with 50 mg estradiol cypionate in oil (ECP), 600 mg long-acting progesterone, or oil only, i.m. Two days later, all horses received 1 mg Kp10 in saline, i.v., and blood sampling occurred 0, 5, 10, 15 and 20 min relative to Kp10 administration. Mean GH and PRL concentrations and area under the curve were compared by ANOVA. No stimulation of GH or PRL was observed. In a third experiment, 12 diestrous mares, confirmed by plasma progesterone and ultrasound findings, were randomly assigned to treatment with 1 mg Kp10 (n = 6) or 1 mL saline (n = 6) followed by the dopamine antagonist, sulpiride (0.01 mg/kg body weight), 5 min later. Blood sampling occurred 0, 5, 10 and 15 min relative to sulpiride administration. Sulpiride stimulated PRL ( P < 0.0001) in both groups of mares; however, PRL concentrations were lower ( P ≤ 0.01) in Kp10-treated mares compared with saline-treated mares. To determine if estrogen altered the PRL response to sulpiride, 12 seasonally anovulatory mares, confirmed by plasma progesterone and ultrasound findings, were used in a fourth experiment and randomly assigned to receive 50 mg ECP (n = 6) or oil (n = 6), i.m. The next day, mares were challenged with sulpiride. Treatment and blood sampling occurred as described in experiment 3. Plasma PRL was stimulated ( P < 0.001) in both groups of mares and responses were similar between treatments. In the described experiments, 1 mg Kp10 given as a bolus failed to stimulate circulating GH or PRL within 30 min in mares or geldings regardless of steroid milieu. This is in contrast to reports of GH stimulation in ruminants. Kp10 did alter the PRL response to sulpiride in diestrous mares, perhaps suggesting an interaction between Kp10 and dopaminergic input to the pituitary in a progesterone dominant environment.

Comparison of Prolactin and Cortisol Response to Magnetic Seizure Therapy and Electroconvulsive Therapy

Electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) induce therapeutic seizures by delivering current to the brain via scalp electrodes or high-intensity magnetic stimulation, respectively. The induced electric field and the subsequent seizure differ between ECT and MST. We measured peri-treatment serum prolactin and cortisol levels as indicators of the degree of seizure spread induced by the two modalities.

72 Endocrine and ovarian responses to combined estradiol benzoate-sulpiride in anestrous mares treated with kisspeptin

Abstract The objective of this study was to determine if incorporation of kisspeptin 10 (Kp10) into an estradiol benzoate (EB)-sulpiride treatment would result in greater endocrine responses, and a greater number of mares ovulating within 28 days of treatment compared to EB-sulpiride alone. Eighteen anestrous mares were blocked by horse type (light horse and pony crosses), body condition, and age, then randomly assigned to treatment or control. On day 0, all mares received 50 mg EB. On day 1, mini osmotic pumps containing saline (n = 9) or Kp10 (50 mg/hour; n = 9) were inserted subcutaneously in the neck and remained for 7 days. Serial blood sampling occurred for 24 hours after pump placement. On day 2, all mares received 3 g sulpiride. Serial blood sampling continued for 36 hours and daily for 28 days. Transrectal ultrasounds were performed regularly for detection of ovulation. Plasma was assayed for prolactin, luteinizing hormone (LH) and progesterone. Data were analyzed by ANOVA with repeated measures. Plasma prolactin increased (P &amp;lt; .001) in response to sulpiride in all mares and remained stimulated for 7 days. Prolactin responses tended to be greater (P = .09) in Kp10- treated mares compared to controls. No differences were detected in plasma LH during the first 24 hours after pump placement; however, LH increased in all mares beginning 5 days after sulpiride and were greater (P &amp;lt; .05) in Kp10-mares from day 7 to day 21. Eleven of 18 (61%) mares ovulated within 18 days of sulpiride treatment; however, no differences in ovulation dates were detected between Kp10 treated- and control- mares. No differences were detected in plasma progesterone during the first 5 days post ovulation. In conclusion, incorporation of Kp10 potentiated the prolactin and LH responses to EB-sulpiride, but did not further advance first ovulation in treated-mares.

Interleukin-6 response to insulin-induced hypoglycemia is associated with hypothalamic-pituitary-adrenal axis activation

Increased plasma levels of interleukin-6 (IL-6) in response to acute hypoglycemia have been well documented. Aiming to study the interaction between IL-6 and counter-regulatory hormones during hypoglycemic stress we conducted an exploratory single center study involving 26 adult patients undergoing insulin tolerance test. Insulin-induced hypoglycemia elicited a significant dynamic response of IL-6, adrenaline, noradrenaline, GH, prolactin, ACTH and serum and salivary cortisol (P < 0.001 for all variables). Patients with insufficient HPA axis response had lower hypoglycemia-induced IL-6 increase (median: 0.88 pg/mL) compared with individuals with intact HPA axis response (2.03 pg/mL, P = 0.007). IL-6 maximal increase correlated with the maximal increase of serum cortisol (rs = 0.48; P = 0.013), salivary cortisol (rs = 0.66; P = 0.012), plasma ACTH (rs = 0.48; P = 0.013) and with the increase in procedure-related symptoms of anxiety and hypoglycemia (rs = 0.57; P = 0.003). In conclusion, hypoglycemic stress-induced IL-6 increase is associated with activation of the HPA axis, suggesting that IL-6 response to hypoglycemic stress may be regarded as part of the counter-regulatory response, possibly contributing to the maintenance of glucose homeostasis.

Exercise-induced GH secretion is related to puberty.

Exercise represents a physiological stimulus that initiates the coordinated responses of hypothalamic-pituitary axis and sympathetic nervous system. Aims of the study were: 1) to analyze the response of GH, cortisol and prolactin to acute exercise in healthy children with normal GH response to stimulation tests 2) to evaluate the reliability of physical exercise as a screening test for GH secretion. Forty-four children (mean age 9.35 ± 2.69years, range 4-13.7) underwent standardized Bruce's test on treadmill. Twenty-nine children were pre-pubertal (nine females and 20 males) and 15 children were pubertal (ten females and five males). Exercise elicited a peak secretion of all the analyzed hormones. GH showed the highest mean percentage increase (558%), followed by prolactin (178%) and cortisol (23%). In 19/44 children (43.2%), GH peak did not reach the cut-off level of 8ng/ml, considered as the normal GH response to stimulation tests. Despite a wide inter-individual variability, both GH peak and GH increase from baseline were higher in pubertal children than in pre-pubertal ones (GH peak: 13.49 ± 10.28ng/ml versus 6.6 ± 4.09ng/ml-p < 0.001; GH increase: 12.02 ± 10.30ng/ml versus 5.28 ± 3.97ng/ml-p < 0.001). The impact of puberty on both GH peak and GH increase was independent of sex, age, BMI SDS and VO2max. No differences related to sex or pubertal status were found in cortisol and prolactin responses. Exercise-induced GH secretion should not be considered a valuable screening tool in the diagnostic work-up of GH deficiency, due to the wide inter-individual variability in GH response. As described for standard GH stimulation tests, puberty represents the key factor that enhances GH secretion in healthy children.

Copeptin response to hypoglycemic stress is linked to prolactin activation in children.

The physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents. We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia. Basal plasma levels of copeptin (median: 5.2pmol/L) increased significantly after hypoglycemia (median 9.7pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3pmol/L) compared with individuals with intact pituitary response (median: 5.2pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (rs = 0.30; P = 0.010), cortisol (rs = 0.33; P = 0.003), prolactin (rs = 0.25; P = 0.03), IL-6 (rs = 0.35; P = 0.008) and with BMI-SDS (rs = - 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004). Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.

Plasma prolactin, thyroid-stimulating hormone, melanocyte-stimulating hormone, and adrenocorticotropin responses to thyrotropin-releasing hormone in mares treated with detomidine and butorphanol

Stress or excitement is a concern when performing endocrine tests on fractious horses. Sedation may be a solution; however, perturbation of test results may preclude useful information. Thyrotropin-releasing hormone (TRH) is a known stimulator of prolactin, thyroid-stimulating hormone (TSH), melanocyte-stimulating hormone (MSH), and ACTH. Thyrotropin-releasing hormone–induced ACTH is a diagnostic tool for the assessment of endocrinopathies such as pituitary pars intermedia dysfunction. It is unknown if drugs commonly used for sedation alter endocrine responses. The objective of this study was to assess the effects of detomidine (DET) and butorphanol on endocrine responses to TRH. Nine light horse mares were used in a replicated 3 × 3 Latin square with the following treatments: saline, DET, and detomidine + butorphanol (DET/BUT), all administered intravenously at 0.01 mg/kg BW. A 1-wk washout period was allowed between phases, all of which were performed in December. Blood samples were collected at −10 and 0 min before treatment and 5 and 10 min post-treatment. Administration of 1 mg TRH occurred 10 min post-treatment, and blood sampling continued 5, 10, 20, and 30 min post-TRH. Data were analyzed by ANOVA as a replicated Latin square with repeated sampling. Plasma prolactin increased (P < 0.0001) after TRH in all groups, rapidly peaking at 5 min in drug-treated mares and 40 min in saline-treated mares. The peak prolactin response to TRH was 2-fold higher (P < 0.0001) in saline-treated mares compared with those drug-treated. A peak rise in plasma TSH was observed in DET/BUT-treated mares 10 min after TSH and was greater (P ≤ 0.007) compared with DET- and saline-treated mares. Plasma MSH was stimulated (P = 0.001) by DET and DET/BUT before TRH, and the peak MSH response to TRH was greater (P < 0.0001) in drug-treated mares, although not hastened as observed with prolactin and TSH. A peak rise in ACTH was observed in drug-treated mares 5 min after administration of TRH, whereas a peak rise was observed in control mares 10 min post-TRH and was almost 2-fold lower (P = 0.05) than the peak observed in DET and DET/BUT-treated mares. Basal ACTH concentrations were not affected by DET or DET/BUT, indicating that sedation with these compounds may be achieved when needing to measure basal plasma ACTH. Treatment with DET and DET/BUT did alter the prolactin, TSH, MSH, and ACTH responses to TRH; therefore, the use of these drugs may not be advisable when assessing endocrine responses to TRH stimulation.

Impaired prolactin transport into the brain and functional responses to prolactin in aged male mice.

Ageing is related to changes in a number of endocrine systems that impact on the central actions of hormones. The anterior pituitary hormone prolactin is present in the circulation in both males and females, with widespread expression of the prolactin receptor throughout the forebrain. We aimed to investigate prolactin transport into the brain, as well as circulating levels of prolactin and functional responses to prolactin, in aged male mice (23months). Transport of 125 I-labelled prolactin (125 I-prolactin) from the peripheral circulation into the brain was suppressed in aged compared to young adult (4months) male mice, with no significant transport into the brain occurring in aged males. We subsequently investigated changes in the negative-feedback regulation of prolactin secretion and prolactin-induced suppression of luteinising hormone (LH) pulsatile secretion in aged male mice. Feedback regulation of prolactin secretion appeared to be unaffected in aged males, with no change in levels of circulating prolactin, and normal prolactin-induced phosphorylated signal transducer and activator of transcription 5(pSTAT5) immunoreactivity in tuberoinfundibular dopaminergic (TIDA) neurones in the arcuate nucleus. There were, however, significant impairments in the ability of prolactin to suppress LH pulsatile secretion in aged males. In young adult males, acute prolactin administration significantly decreased LH pulses from 1.5±0.19 pulses of LH in 4hours to 0.5±0.27 pulses. In contrast, prolactin did not suppress LH pulse frequency in aged males, with prolactin leading to an increase in mean LH concentration. These data demonstrate the emergence of impairments in prolactin transport into the brain and deficits in specific functional responses to prolactin with ageing.

Maternal Motivation: Exploring the Roles of Prolactin and Pup Stimuli

Motherhood entails increased motivation for pups, which become strong reinforcers and guide maternal behaviours. This depends on steroids and lactogens acting on the brain of females during pregnancy and postpartum. Since virgin female mice exposed to pups are nearly spontaneously maternal, the specific roles of endocrine and pup-derived signals in the induction of maternal motivation remain unclear. This work investigates maternal motivation in dams and virgin female mice, using a novel variant of the pup retrieval paradigm, the motivated pup retrieval test. We also analyse the role of prolactin (PRL) and of stimuli derived from a litter of pups and its mother, in the acquisition of maternal motivation. Experimental design included female mice in 3 conditions: lactating dams, comothers (virgins housed and sharing pup care with dams) and pup-naïve virgins. Females underwent 3 motivated-pup-retrieval trials, with pups displaced behind a 10-cm-high wire-mesh barrier. Dams retrieved with significantly lower latencies than comothers or virgins, indicating that full maternal motivation appears only after pregnancy. Although initially comothers and virgins showed no retrieval, comothers significantly improved throughout the experiment, suggesting an induced sensitization process. Lengthening exposure of comothers to the dyad pups-dam (from 2 to 5 days at the beginning of testing) had no strong effects on maternal sensitization. PRL responsiveness was analysed in these animals using immunohistochemical detection of phosphorylated signal transducer and activator of transcription 5 (pSTAT5, PRL-derived signalling marker). As expected, dams showed significantly higher pSTAT5 expression in most of the analysed nuclei. Moreover, comothers displayed significantly higher PRL responsiveness than pup-naïve virgins in the medial preoptic nucleus, even if they display similar circulating PRL levels, which are significantly lower than those of dams. Given the instrumental role of this nucleus in the relay and integration of pup-derived stimuli to facilitate proactive maternal responses, this increase in PRL responsiveness likely reflects the mechanism underlying the maternal sensitization process reported in this work. Since the analyses of maternal motivation and PRL signalling in the brain were performed in the same animals, we were able to explore correlation between both set of data. The results shed light on the neuroendocrine mechanisms underlying maternal motivation and other aspects of maternal behaviour.

Reduced dopaminergic tone during lactation is permissive to the hypothalamic stimulus for suckling-induced prolactin release.

Dopamine from tuberoinfundibular dopaminergic (TIDA) neurones tonically inhibits prolactin (PRL) secretion. Lactational hyperprolactinaemia is associated with a reduced activity of TIDA neurones. However, it remains controversial whether the suckling-induced PRL surge is driven by an additional decrease in dopamine release or by stimulation from a PRL-releasing factor. In the present study, we further investigated the role of dopamine in the PRL response to suckling. Non-lactating (N-Lac), lactating 4hour apart from pups (Lac), Lac with pups return and suckling (Lac+S), and post-lactating (P-Lac) rats were evaluated. PRL levels were elevated in Lac rats and increased linearly within 30 minutes of suckling in Lac+S rats. During the rise in PRL levels, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME) and neurointermediate lobe of the pituitary did not differ between Lac+S and Lac rats. However, dopamine and DOPAC were equally decreased in Lac and Lac+S compared to N-Lac and P-Lac rats. Suckling, in turn, reduced phosphorylation of tyrosine hydroxylase in the ME of Lac+S. Domperidone and bromocriptine were used to block and activate pituitary dopamine D2 receptors, respectively. Domperidone increased PRL secretion in both N-Lac and Lac rats, and suckling elicited a robust surge of PRL over the high basal levels in domperidone-treated Lac+S rats. Conversely, bromocriptine blocked the PRL response to suckling. The findings obtained in the present study provide evidence that dopamine synthesis and release are tonically reduced during lactation, whereas dopamine is still functional with respect to inhibiting PRL secretion. However, there appears to be no further reduction in dopamine release associated with the suckling-induced rise in PRL. Instead, the lower dopaminergic tone during lactation appears to be required to sensitise the pituitary to a suckling-induced PRL-releasing factor.

Pituitary-thyroid Hormone Responses Following Resistance Exercise Performed At Submaximal Movement Velocity

Acute hormonal changes can be elicited by mechanical overloading of skeletal muscle, which are potentially involved in muscle adaptation following resistance exercise. In particular, previous studies have shown that resistance exercise at maximal velocity induces acute changes in circulating levels of pituitary-thyroid (P-T) hormones. PURPOSE: This study investigated the responses of thyrotropin (TSH), free thyroxine (fT4) and prolactin (PRL) in young volunteers after a bout of resistance exercise performed at 70% of the maximal velocity of movement. METHODS: Nine healthy males (age: 22.5 ± 3.3 years, height: 181 ± 5 cm, body mass: 81.6 ± 5.6 kg) underwent a protocol of resistance exercise of the knee extensors of both legs (4 sets squat and 4 sets leg press, 8 repetitions/set, with a load corresponding to that of 10-repetition maximum). A recovery period of 3 minutes was allowed between sets. Blood samples were collected before, immediately after and at 20 and 40 min post-exercise. Plasma levels of TSH, fT4 and PRL were measured by ELISA. One-way ANOVA was used for statistics and data are presented as mean±SE. RESULTS: TSH showed a slight gradual increase up to 12% at 40 min post exercise, which failed to reach significance (p>0.05) due to a large variability shown between the subjects’ responses (3.63±0.89 ng/dl, 3.53±0.71 ng/dl, and 3.70±0.88 ng/dl, immediately after, at 20 and 40 min after exercise, respectively, compared to 3.26±0.65 ng/dl at baseline). Plasma fT4 levels exhibited also a no significant increase post exercise (1.33±0.09 ng/dl, 1.18±0.10 ng/dl, and 1.33±0.15 ng/dl, immediately after, 20 and 40 min after exercise, respectively, compared to 1.23±0.10 ng/dl at baseline; p>0.05). PRL levels showed a significant decrease up to 17% 20 min after exercise (18.39±1.23 ng/ml, 17.3±1.24 ng/ml and 17.46±1.10 ng/ml, immediately after, at 20 and 40 min post-exercise, respectively, compared to 21.59±2.29 ng/ml at baseline; p<0.05). CONCLUSION: Our findings suggest that resistance exercise at a submaximal velocity induces mild acute pituitary-thyroid hormone responses. Further studies are needed to characterize the mechanisms by which those responses are triggered and regulated during recovery after resistance exercise.

SAT-LB4 Novel Hormonal and Metabolic Markers of Recovery From Overtraining Syndrome Unveiled by the Longitudinal ARM of the Eros Study - the Eros-Longitudinal Study

Background: Overtraining Syndrome (OTS) is an unexplained underperformance syndrome triggered by excessive training, insufficient caloric intake, inadequate sleep, and excessive cognitive and social demands. Investigations of markers of the challenging recovery from OTS have not been reported to date. The objective of the present study is to describe novel markers, and biochemical and clinical behaviors during the restoration process of OTS.Design: A 12-week interventional protocol in 12 athletes affected by OTS was conducted, including increased food intake, transitory interruption of the trainings, improvement of sleep quality, and management of stress.Methods: We assessed 50 parameters, including hormonal responses to an insulin tolerance test (ITT), basal hormonal and non-hormonal biochemical markers, body metabolism and composition. Results: In response to an ITT, early cortisol (p = 0.026), early GH (p = 0.004), and late GH (p = 0.037) improved significantly. Basal estradiol (p = 0.0002) and nocturnal urinary catecholamines, (p = 0.043) reduced, while testosterone (p = 0.014), testosterone:estradiol (T:E) ratio (p = 0.0005), freeT3 (p = 0.043), IGF-1 (p = 0.003), and cortisol awakening response (CAR) (p = 0.001) increased significantly. All basal parameters and early responses to ITT normalized, when compared to healthy athletes. Basal metabolic rate, fat oxidation, body fat, muscle mass, and hydration status had partial but non-significant improvements. Conclusion: After 12 weeks, athletes affected by actual OTS demonstrated substantial improvements, remarkably IGF-1, freeT3, CAR, testosterone, estradiol testosterone:estradiol ratio, CK and catecholamines, and early cortisol, early prolactin, and overall GH responses to stimulations.

MON-LB305 The “Normal” Hormonal Levels in Athletes: Should Reference Ranges Be Adapted for the Physically Active Population?

Background:Despite the growing number of physically active subjects, including elite and amateur athletes, little is known regarding metabolic and hormonal chronic adaptations to exercises. While the elucidation of the hormonal and metabolic physiological adaptations to physical activity is of emerging importance, the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study have serendipitously unveiled the existence of multiple metabolic and endocrine physiological changes in male athletes, including chronic increase of testosterone with concurrent physiological increase of estradiol, enhanced GH and cortisol responses to stimulations,andincreased catecholamines, basal metabolic rate, fat oxidation, and hydration status. These findings were uncovered due to a novel methodological design in which athletes affected by overtraining syndrome (OTS) were compared to a two control groups, of healthy athletes (ATL) and healthy non-physically active controls (NPAC). Since none of the parameters were directly dependent on exercise or performance, differences between these two groups were unexpected. From the fact that several parameters were shown to be different between ATL and NPAC, we realized that the use of the reference ranges for general population to analyze results in athletes may potentially under- and over-diagnose a wide range of conditions. Our objective is therefore to determine whether athletes should be biochemically evaluated through specific adapted ranges, and propose preliminary adaptations in these ranges. Methods: A systematic review on the literature on endocrine and metabolic adaptations to exercise was performed, as well as a thorough analysis of the seven arms of the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study. Results:Multiple reference ranges were shown to be inaccurate for athletes. Among the parameters that should be adapted for athletes, and their respective adaptedranges include: 1. Cortisol response to an insulin stimulation test (ITT) (> 20.5 μg/dL); 2. GH response to an ITT (> 12 μg/L); 3. Prolactin response to an ITT (> 22 ng/mL); 4. Salivary cortisol at 8AM (> 450 ng/dL); 5. Total testosterone (> 450 ng/dL); 6. Estradiol (25-45 pg/mL) - and testosterone-to-estradiol ratio maintained > 13.7; 7. Total nocturnal urinary catecholamines (> 220 μg/12h); 8. Resting lactate (< 1.0 nMol/L); 9. Measured-to-predicted basal metabolic rate (BMR) (> 105%); 10. Fat oxidation (in relation to total BMR) (> 50%); and 11. Hydration status (body water > 62% of total body weight). Conclusion: Analysis of biochemical parameters in athleted should be interpreted with cautious, particularly hormonal and metabolic parameters, once many parameters likely undergo adaptive changes when under physical activity. Preliminary adaptations for the ranges have been proposed.

TAK‐906, a Novel D2/D3 Receptor Antagonist: First‐in‐Human Study of Single and Multiple Ascending Doses

IntroductionTAK‐906 (previously designated as ATC‐1906M, [3‐((1‐cyclohexyl‐4‐oxo‐8‐(4‐oxo‐4‐phenylbutyl)‐1,3,8‐triazaspiro[4.5]decan‐3‐yl)methyl)benzoic acid. maleate]) is in development for the symptomatic treatment of gastroparesis. TAK‐906 is designed to retain the dopamine receptor antagonist profile and minimal central nervous system (CNS) penetration of domperidone whilst avoiding the cardiac effects. This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of single and multiple ascending doses of TAK‐906 in healthy adults.MethodsThis Phase 1, randomized, double‐blind, placebo‐controlled, 2‐phase study was conducted in 72 healthy male and female subjects. In the single‐ascending dose (SAD) phase, TAK‐906 or placebo was administered orally, in the fasted state, to cohorts of 8 subjects each at doses of 5, 10, 25, 50, 100, 200, or 300 mg. Subjects in the 25‐mg cohort received a second 25‐mg dose in the fed state. In the multiple‐ascending dose (MAD) phase, TAK‐906 was administered orally to successive cohorts of 8 subjects each at 50 or 100 mg twice daily (BID) for 4 days with a single dose on Day 5.Results and ConclusionsPharmacokineticsTAK‐906 was rapidly absorbed (median plasma TAK‐906 Tmax ~1.1 hours across all cohorts) and rapidly eliminated (mean plasma TAK‐906 t1/2 ~4.0 hours [SAD cohorts], and 11.0 and 6.2 hours at the 50‐ and 100‐mg BID doses, respectively, on Day 5 [MAD cohorts]). Elimination was monophasic over the first 12 hours after dosing. With single oral doses, TAK‐906 exposure increased proportional to dose (mean Cmax ~2 ng/mL [5‐mg dose] and ~190 ng/mL [300‐mg dose]); CL/F, Vz/F, and t1/2 were not dose dependent. Accumulation was minor with BID dosing for 5 days (&lt;40% for Cmax; &lt;30% for AUC0–12). Food significantly reduced exposure to TAK‐906 25 mg.PharmacodynamicsSerum prolactin concentration, a biomarker for D2 antagonism, increased substantially following administration of single doses of TAK‐906 compared to placebo; the increase was rapid (median Tmax ~0.7 to 1.1 hours) and short‐lived (mean t1/2 10.82 hours). Serum prolactin concentration did not increase in proportion to dose; the prolactin response was maximal at the single 10‐mg dose level (mean TAK‐906 Cmax ~6 ng/mL), with little accumulation with BID dosing for 5 days.Cardiac SafetySingle doses of TAK‐906 between 5 and 300 mg, resulting in plasma concentrations of up to 170 ng/mL, did not have a clinically meaningful effect on placebo‐corrected change from baseline corrected QT interval using Frederica’s method (QTcF).SafetyMonitoring of adverse events, vital signs, clinical laboratory evaluations, CNS and general physical examinations indicated that oral administration of single or multiple doses of TAK‐906 was well tolerated in healthy male and female subjects.Support or Funding InformationThis study was sponsored by Altos Therapeutics, LLC. Formatting and editing support were provided by Oxford PharmaGenesis, Oxford, UK and funded by Takeda Pharmaceutical Company Ltd

Prolactin-Responsive Circular RNA circHIPK3 Promotes Proliferation of Mammary Epithelial Cells from Dairy Cow.

The highly expressed circHIPK3 is a circular RNA that has been previously reported to regulate the growth of human cells. In this study, we found an increased expression of circHIPK3 in bovine mammary epithelial cells treated with prolactin (PRL) in high-throughput sequencing data. Thus, we further investigated the effect of circHIPK3 on the proliferation and differentiation of mammary epithelial cells. We used qRT-PCR/Cell Counting Kit-8 (CCK-8) and a Western blotting analysis to evaluate the effects on cell proliferation. We found that circHIPK3 promotes the proliferation of mammary epithelial cells. The STAT5 signaling pathway was previously associated with the prolactin response and when the STAT5 was suppressed, the expression of circHIPK3 decreased. The results suggest that the response to prolactin and the associated STAT5 signaling pathway affect the expression of circHIPK3, which subsequently affects the proliferation of mammary epithelial cells in dairy cows.

Prolactin response to antipsychotics: An inpatient study.

BackgroundAntipsychotic medication, stress, gender, and age are factors that influence prolactin levels in patients with psychosis. The aim of the study was to investigate the level of prolactin response to antipsychotic treatment in acute patients, taking into account the total duration of psychosis.Methods and findingsThe study was conducted on 170 acute patients with schizophrenia spectrum disorders and bipolar disorder. Subjects were divided into three subgroups according to the duration of the psychosis (less than 5 years, between 5 and 10 years and more than 10 years of disorder duration). The initial prolactin response under antipsychotic treatment was measured, while the severity of the psychiatric symptoms was assessed with the BPRS (Brief Psychiatric Rating Scale). Hyperprolactinemia was found in 120 (70.6%) patients, amongst which 80 (66.7%) were females and 40 (33.3%) were males. The average increase in prolactinemia was 2.46 times the maximum value in women, and 1.59 times in men. Gender (β = 0.27, p<0.0001), type of antipsychotic medication according to potency of inducing hyperprolactinemia (β = -0.23, p<0.003), and the duration of psychosis over 10 years (β = -0.15, p = 0.04) significantly predicted prolactin levels, when age, diagnosis, antipsychotic category (conventional/atypical/combinations of antipsychotics), and BPRS total scores were controlled for.Conclusions and relevanceProlactin levels in patients treated with antipsychotic medication appeared to depend on patients’ gender, on the type of antipsychotic medication according to potency of inducing hyperprolactinemia, and on the duration of the psychosis. An increase in prolactin levels was associated with female gender, while the use of prolactin sparing antipsychotics and a duration of psychosis over 10 years were associated with lower prolactin levels.

Inter-correlations Among Clinical, Metabolic, and Biochemical Parameters and Their Predictive Value in Healthy and Overtrained Male Athletes: The EROS-CORRELATIONS Study.

Objectives: The Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study identified multiple hormonal and metabolic conditioning processes in athletes, and underlying mechanisms and biomarkers of overtraining syndrome (OTS). The present study's objective was to reveal independent predictors and linear correlations among the parameters evaluated in the EROS study to predict clinical, metabolic, and biochemical behaviors in healthy and OTS-affected male athletes.Methods: We used multivariate linear regression and linear correlation to analyze possible combinations of the 38 parameters evaluated in the EROS study that revealed significant differences between healthy and OTS-affected athletes.Results: The testosterone-to-estradiol (T:E) ratio predicted the measured-to-predicted basal metabolic rate (BMR) ratio; the T:E ratio and total testosterone level were inversely predicted by fat mass and estradiol was not predicted by any of the non-modifiable parameters. Early and late growth hormone, cortisol, and prolactin responses to an insulin tolerance test (ITT) were strongly correlated. Hormonal responses to the ITT were positively correlated with fat oxidation, predicted-to-measured BMR ratio, muscle mass, and vigor, and inversely correlated with fat mass and fatigue. Salivary cortisol 30 min after awakening and the T:E ratio were inversely correlated with fatigue. Tension was inversely correlated with libido and directly correlated with body fat. The predicted-to-measured BMR ratio was correlated with muscle mass and body water, while fat oxidation was directly correlated with muscle mass and inversely correlated with fat mass. Muscle mass was directly correlated with body water, and extracellular water was directly correlated with body fat and inversely correlated with body water and muscle mass.Conclusions: Hypothalamic-pituitary responses to stimulation were diffuse and indistinguishable between the different axes. A late hormonal response to stimulation, increased cortisol after awakening, and the T:E ratio were correlated with vigor and fatigue. The T:E ratio was also correlated with body metabolism and composition, testosterone was predicted by fat mass, and estradiol predicted anger. Hydration status was inversely correlated with edema, and inter-correlations were found among fat oxidation, hydration, and body fat.

Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning

BackgroundExercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study.MethodsIn this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18–50 years old, males, with BMI 20–30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT.ResultsResponses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 μg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1–38.1) vs 4.80 (0.33–27.36) μg/L; p = 0.015], and prolactin [24.3 (10.5–67.45) vs 10.50 (6.21–43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL.ConclusionsWe found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of “hormonal conditioning” in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.

Investigating the Role of Prolactin as a Potential Biomarker of Stress in Castrated Male Domestic Dogs.

Simple SummaryAlthough cortisol is usually considered the main reference for the assessment of stress, in some animal species it has been shown that prolactin can be used as a biomarker of both acute and chronic stress. Behavioural parameters can also be used to assess the state of welfare and stress. This study was aimed at evaluating the possible relationship between serum prolactin, serum cortisol and behavioural signs of stress in domestic dogs. To reduce the possible influence of some factors, the study was performed on a homogeneous sample formed by 40 castrated male Spanish Greyhound dogs housed in a dog shelter. The weak negative correlation found between serum cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response.Prolactin has been recently regarded as a potential biomarker of both acute and chronic stress in several species. Since only few studies until now have focussed on domestic dogs, this study was aimed at evaluating whether prolactin, cortisol and stress behaviour correlated with each other in sheltered dogs. Both cortisol and prolactin analysis were performed in serum samples through a hormone-specific ELISA kit. For each dog, a stress score was calculated by summing the number of occurrences of stress-related behaviours. The presence/absence of fear during the time spent in the collection room was also scored for each individual. Results revealed a weak negative correlation between cortisol and prolactin levels. Neither of the hormones was correlated with the stress score, nor did their values seem to be influenced by showing fear in the collection room. The weak negative correlation found between cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response. This, together with the high serum prolactin levels compared to those reported by other authors for healthy domestic dogs, may indicate that prolactin might be a good biomarker of chronic stress, and although further studies are needed to better understand the potential role of prolactin in the evaluation of canine welfare.