Prolactin, metabolic and immune parameters in naïve subjects with a first episode of psychosis
Introduction
Prolactin (Prl) is a pleiotropic hormone widely studied initially for its effects on the lactation process in mammals. However further research describing specific receptors in abdominal fat (Ruiz-Herrera et al., 2017), cerebral cortex and hypothalamus (Cabrera-Reyes et al., 2017), immune cells (Brown et al., 2017) has delved on its effects on metabolism, low-grade inflammation, immunity (Tang et al., 2017), stress response and human behavior (Brown et al., 2017). Regarding the brain, its importance relies on the physiological responses related to reproduction, stress adaptation, neurogenesis, and neuroprotection (Torner, 2016). Disruption of its different pathways has been related with abnormal cellular proliferation, reproductive abnormalities, and diabetes (Gorvin, 2015). Prl affects metabolic homeostasis by regulating key enzymes and transporters associated with glucose and lipid metabolism in several target organs (Schwetz et al., 2017). The pancreatic prolactin receptor has been related with maternal glucose homeostasis during pregnancy (Nteeba et al., 2019), an extremely important in psychiatry finding as gestational diabetes is a well replicated risk factor for schizophrenia in the offspring (Van Lieshout and Voruganti, 2008).
Hyperprolactinaemia is a common consequence of antipsychotics as a result of the blockade of D2 receptors at the tuberoinfundibular pathway (Halbreich et al., 2003). Prl values have been described to be increased in naïve subjects with a first episode of non-affective psychosis in a specific sex pattern (Garcia-Rizo et al., 2012). This initial finding was later confirmed in a meta-analysis, where despite differences between patients and controls, females presented, as expected, higher Prl values compared with males (González-Blanco et al., 2016). Surprisingly a later study did not find significant sex differences despite higher values in both females patients and controls (Del Cacho et al., 2019). Nevertheless and despite its medical side effects, current literature highlights the clinical importance of Prl on the cognitive function of patients (Delgado-Alvarado et al., 2020; Delgado-Alvarado et al., 2019; Labad, 2019; Labad et al., 2015; Montalvo et al., 2014; Penadés et al., 2015; Tost et al., 2020). Moreover, the interaction with the hypothalamic-pituitary-gonadal axis points out to the complex role of Prl in the pathogenesis of schizophrenia, and suggests that there might be potential differences between sexes (Riecher-Rössler, 2017).
Regarding its medical consequences, high Prl levels have been related to diverse co-morbidities in the general population. Initial studies have described a correlation between Prl and interleukin-6 values, and white blood cell (WBC) count, however no significant correlation was found with high-sensitivity C-reactive protein (hsCRP) and fibrinogen (Friedrich et al., 2011). A later study described an inverse correlation between Prl and type 2 diabetes mellitus (T2DM) supporting the role of Prl as a protective marker of the later development of T2DM, with similar non-significant findings with the metabolic syndrome (Balbach et al., 2013). Finally, in another study, Prl was associated with cardiovascular death in both sexes, but for cancer death, only in men (Haring et al., 2014). Later specific studies have confirmed previous results from other samples; in women affected by polycystic ovary syndrome, Prl was associated with low-grade inflammation measured with chemokines and growth factors (Hatziagelaki et al., 2019). However, these findings have not been replicated by all the studies. A small case-control study in older subjects reported no association between Prl and diverse cardiovascular risk factors, such as C-reactive Protein (CrP) or creatinine clearance (Bekić et al., 2018). Previous data has settled the basis for an interesting theoretical proposal suggesting that the dopamine-prolactin pathway might contribute to the co-morbidity between schizophrenia and type 2 diabetes (Gragnoli et al., 2016). Nevertheless previous studies suggest that there are also sex differences in the association between the immune system and Prl, as healthy women but not healthy men show increased Prl secretion after endotoxin administration (Engler et al., 2016).
With the previous rationale from studies in the general population and its pathophysiological background, we aimed to test whether Prl is associated with immune and metabolic parameters in a cohort of antipsychotic-naïve patients with a first episode of non-affective psychosis. We presume that Prl values will correlate directly with inflammatory and metabolic parameters suggesting that Prl might partially contribute to the pro-inflammatory state described in naïve patients. We also aimed to explore whether sex was a moderator of the relationship between Prl and inflammatory or metabolic parameters.
Section snippets
Subjects
The sample for the present study was recruited from 2001 to January 2018 and formed part of a larger prospective longitudinal study on first episode non-affective psychosis, called PAFIP (Crespo-Facorro et al., 2007). These patients were referred to the program when presenting a first episode of non-affective psychosis and were admitted if they fulfilled the following criteria: (1) aged 15–60 years; (2) met the DSM-IV criteria (according to the Structured Clinical Interview for DSM-IV, SCID-I)
Results
Clinical, sociodemographic and biochemical and hematological variables are described in Table 1.
For Prolactin, significant correlations in women were described for CrP (N = 150, r = 0.206, p = 0.012), LDL (N = 201, r = −0.180, p = 0.011) and AST (N = 206, r = 0.193, p = 0.006) while a trend towards significance was obtained for ALT (N = 210, r = 0.116, p = 0.093). The rest of the correlations were not significant.
Significant correlations in men were described for eosinophils (N = 111,
Discussion
Our results displayed a significant association between Prl and inflammatory, lipid profile and hepatic profile parameters. Prl was significantly associated with CrP, HDL and LDL, AST and ALT despite potential confounding variables such as sex, age, BMI and smoking status. We did not find a different pattern by sex in the adjusted models, as no significant sex by Prl interactions were found. Higher levels of Prl were correlated with higher levels of CrP and hepatic parameters: ALT and AST,
Conclusions
Our results do reflect interesting associations between Prl and low-grade inflammation and lipid metabolism while correlations with other immune parameters. Our results put forward the possibility of the prolactin physiology behaving as a possible factor in the increase morbidity found in patients with schizophrenia since onset. The fact that high levels of Prl correlate with higher levels of inflammatory and hepatic parameters while lower levels of immune parameters highlights its effect in
Acknowledgements
We are highly indebted to the participants and their families for their cooperation in this study. We also wish to thank all members of the PAFIP team for their clinical work.
Author contribution
The authors have contributed to the manuscript as follows: Drs. García-Rizo, Vázquez-Bourgon and Labad designed the study, interpreted the results and drafted the manuscript. Dr. Vázquez-Bourgon collected the clinical data and obtained funding. Drs. Marcos Gómez-Revuelta and María Juncal-Ruiz help in the interpretation of the results and reviewed the manuscript. Mr. Ortiz García de la Foz maintained the dataset and performed the statistical analyses. Prof. Crespo-Facorro collected clinical
Author agreement/Declaration
All authors have seen and approved the final version of the manuscript being submitted. We warrant that the article is an original work, hasn't received prior publication and isn't under consideration for publication elsewhere.
Potential conflicts of interest
Dr. García-Rizo has received honoraria/travel support from Adamed, Angelini, Janssen-Cilag and Lundbeck. Dr. Vázquez-Bourgon has received unrestricted research funding from Instituto de Investigación Marqués de Valdecilla (IDIVAL). He has also received honoraria for his participation as a consultant and/or as a speaker at educational events from Janssen-Cilag and Lundbeck. Dr. Labad has received honoraria for lectures or advisory boards from Janssen, Otsuka, Lundbeck and Angelini. Prof.
Financial disclosure
The present study was carried out at the Hospital Marqués de Valdecilla, University of Cantabria, Santander, Spain, under the following grant support: Instituto de investigación sanitaria Valdecilla, Spain INT/A20/04; Instituto de Salud Carlos III, Spain PI020499, PI050427, PI060507.
No pharmaceutical industry or institutional sponsors participated in the study conception and design, data collection, analysis and interpretation of the results, or drafting of the manuscript.
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These authors have contributed equally.