A Century of Prolactin: Emerging Perspectives as a Metabolic Regulator.

Prolactin, a hormone that has been studied for almost a century, has evolved from a reproductive regulator to a key player in metabolic health. Initially identified for its lactogenic role, the impact of prolactin on glucose and lipid metabolism became evident in the 1970s, leading to a paradigm shift in our understanding. Deviations in prolactin levels, including hyperprolactinaemia and hypoprolactinaemia, have been associated with adverse effects on glucose and lipid metabolism. Mechanistically, prolactin regulates metabolic homoeostasis by maintaining islet abundance, regulating the hypothalamic energy regulatory centre, balancing adipose tissue expansion, and regulating hepatic metabolism. Given the widespread use of pharmaceutical agents that affect prolactin levels, it is important to examine prolactin-related metabolic effects. Recently, a profound exploration of the intricate metabolic role of prolactin has been conducted, encompassing its rhythm-dependent regulatory influence on metabolism and its correlation with cognitive impairment associated with metabolic diseases. In this review, we highlight the role of prolactin as a metabolic regulator, summarise its metabolic effects, and discuss topics related to the association between prolactin and metabolic comorbidities.

Long-term proton pump inhibitors therapy and prevalence of hyperprolactinaemia: A cross-sectional study in outpatient gastroenterology clinics.

Objectives: To evaluate serum prolactin and macroprolactin levels in patients on long-term proton pump inhibitors therapy. METHODS: The cross-sectional study was conducted from January 2018 to November 2019 after approval from the ethics review committee of the Commission on Science and Technology for Sustainable Development in the South University, Abbottabad, Pakistan. The study included patients from two gastroenterology outpatient clinics in the Khyber Pakhtunkhwa province using proton pump inhibitors for ≥3 months either alone or in combination with either histamine receptor antagonists or prokinetics. Blood samples were collected from each patient for hormonal screening. Data was analysed using SPSS 25. RESULTS: Of the 166 patients, 101(60.8%) were females and 65(39.2%) were males. The overall mean age was 42.5±14.2 years, and the median serum prolactin level was 23.2ng/ml (interquartile range: 14.0-38.0ng/ml). There were 96(58%) patients with normoprolactinaemia and 70(42%) with hypreprolactinaemia. There were 19(11.4%) patients using combination therapy, while the rest were on proton pump inhibitors monotherapy. There was a significant increase in serum prolactin level with combination therapy compared to monotherapy (p=0.001). Patients having treatment duration 11-20 months (p=0.006) and >40 months (p=0.001) were at high risk of developing hyperprolactinaemia. CONCLUSIONS: Long-term use of proton pump inhibitors could increase serum prolactin levels, and appropriate evaluation is essential for clinical management.

No unfavorable effects on the menstruation recovery of early postoperative hypoprolactinemia after transsphenoidal surgery in patients with lactotroph pituitary neuroendocrine tumor.

OBJECTIVE: Transsphenoidal surgery for lactotroph pituitary neuroendocrine tumor (PitNET) lowers serum prolactin concentrations, occasionally below the normal range. However, the clinical significance of postoperative hypoprolactinemia is still unclear. In this study, we retrospectively reviewed the female patients with lactotroph PitNET who were treated with transsphenoidal surgery to elucidate the influence of postoperative hypoprolactinemia on regular menstruation restoration and endocrinological remission. RESULTS: The serum prolactin levels in all thirty three participating females had decreased following surgery. Serum prolactin levels in seven patients had decreased below the lower limit of normal ranges (hypoproactinemia group) and in the remaining twenty six patients, it was within the normal range (non-hypoproractinemia group). In hypoprolactinemia group, regular menstruation was restored in all patients with only lactotroph axis deficiency. Nine patients from the non-hypoprolactinemia group experienced re-elevation of serum prolactin concentration (27%). No patient in hypoprolactinemia group experienced the relapse of hyperprolactinemia. These data suggest that early postoperative hypoprolactinemia after transsphenoidal surgery for lactotroph PitNET is not only a good predictive factor for endocrinological remission but also no unfavorable effects on regular menstruation restoration.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

Significance of Duodenal Prolactin Receptor Modulation by Calcium and Vitamin D in Sulpiride-Induced Hyperprolactinemia.

Background and Objectives: Hyperprolactinemia, as a potential side-effect of some antipsychotic medications, is associated with decreased bone density and an increased risk of fractures. This study investigates whether calcium and vitamin D supplementation affects prolactin receptor (Prlr) gene expression in the duodenum, vertebrae, and kidneys of female rats with sulpiride-induced hyperprolactinemia. Materials and Methods: Twenty-one-week-old female Wistar rats were assigned to three groups: Group S consisted of ten rats who received sulpiride injections (10 mg/kg) twice daily for 6 weeks; Group D (10 rats) received daily supplementation of 50 mg calcium and 500 IU vitamin D along with sulpiride for the last 3 weeks; and Group C consisting of seven age-matched nulliparous rats serving as a control group. Real-time PCR was used to assess Prlr gene expression in the duodenum, vertebrae, and kidneys. Results: In Group S, Prlr gene expression was notably decreased in the duodenum (p < 0.01) but elevated in the vertebrae and kidneys compared to Group C. Conversely, Group D exhibited significantly increased Prlr expression in the duodenum (p < 0.01) alongside elevated expression in the vertebrae and kidneys. Conclusions: In sulpiride-induced hyperprolactinemia, decreased Prlr gene expression in the duodenum may lead to reduced intestinal calcium absorption. Consequently, prolactin may draw calcium from the skeletal system to maintain calcium balance, facilitated by increased Prlr gene expression in the vertebrae. However, vitamin D supplementation in sulpiride-induced hyperprolactinemia notably enhances Prlr gene expression in the duodenum, potentially ameliorating intestinal calcium absorption and mitigating adverse effects on bone health.

Sex-specific differences in the clinical profile among psychiatric patients with pulmonary Embolism: a hospital-based retrospective study.

BACKGROUND: Pulmonary embolism (PE) is a severe and life-threatening complication of venous thromboembolism. However, there is a lack of systematic studies on differences between female and male PE patients. This paper aimed to compare the sex-specific differences in clinical characteristics and laboratory indicators in psychotic patients with PE. METHODS: This retrospective study enrolled psychiatric patients with PE from June 2018 to June 2022 at Shenzhen Kangning Hospital (Shenzhen Mental Health Center). Demographic characteristics, factors associated with PE, and laboratory indices were collected to assess sex-specific differences. RESULTS: Of the 168 patients, 87 (51.8%) were female and 81 (48.2%) were male, with a mean age of 58 years for females and 46 years for male patients. The male group had higher ratio of hyperprolactinemia, more patients using antipsychotic medications, higher D-dimer levels at PE onset, greater D-dimer difference, and a higher rate of D-dimer elevation than the female group (p < 0.05). Female patients were significantly older, exhibited a higher prevalence of diabetes, and had a greater number of patients taking antidepressants and hypnotics/sedatives than male patients (p < 0.05). Schizophrenia spectrum disorders were more prevalent in male patients, while female patients had a higher incidence of mood disorders (p < 0.05). Among patients aged < 45 years, the male group had higher D-dimer levels at PE onset and greater D-dimer difference (p < 0.05). Among all 112 patients aged ≥ 45 years, male patients were more likely than female patients to have respiratory tract infections, higher D-dimer levels at PE onset, greater D-dimer difference, and a higher rate of D-dimer elevation (p < 0.05). The multiple linear regression analysis indicated that hyperprolactinemia and the use of first-generation antipsychotics (FGAs) were associated with D-dimer levels at PE onset in male patients, while the time of PE onset and protective restraints were associated with D-dimer levels at PE onset in female patients (p < 0.05). CONCLUSION: PE-associated clinical features differ between male and female patients. These differences may imply that the processes and mechanisms of PE onset are sex specific. Male patients are more likely to have respiratory tract infections and higher D-dimer levels at PE onset than female patients. The use of FGAs may be associated with increased D-dimer in male psychiatric patients, while protective restraints may be associated with increased D-dimer in female psychiatric patients.

Comparative efficacy of metformin combined with cabergoline versus metformin alone in patients with PCOS and hyperprolactinemia: A systematic review and meta-analysis of randomized controlled trials.

Isntroduction. Polycystic ovary syndrome (PCOS) is a multifaceted endocrine-gynecological condition affecting a substantial number of women during their reproductive years. Metformin (MET) has been shown to improve ovarian function in PCOS-related conditions, while cabergoline is recognized for its powerful and sustained ability to reduce prolactin levels. This study investigates the potential impact of combining cabergoline with metformin while comparing it with metformin alone in the treatment of PCOS alongside hyperprolactinemia. METHOD: To gather data, we searched PubMed, Google Scholar, ScienceDirect, and Cochrane Central. Eligible studies were randomized controlled trials involving patients with PCOS and hyperprolactinemia. Outcome measures included changes in the levels of prolactin, testosterone, DHEAS, BMI and menstrual irregularities. RevMan version 5.4 was used to analyze outcomes. RESULT: This study incorporated three Randomized Controlled Trials (RCTs) involving 405 participants in total. Patients receiving a combination of metformin and cabergoline experienced significant reductions in prolactin and testosterone levels (p= <0.0001 and p=<0.0001, respectively). Conversely, alterations in DHEAS levels and BMI did not reach statistical significance (p = 0.19 and p = 0.71, respectively). Notably, women solely prescribed metformin exhibited significantly higher rates of menstrual irregularities compared to those receiving both metformin and cabergoline (p=<0.0001). CONCLUSION: Our analysis underscores the synergistic effect achieved by pairing metformin and cabergoline in patients with PCOS and hyperprolactinemia. However, we encountered only a restricted number of studies meeting our criteria. It is imperative to consistently assess the combined effects of metformin and cabergoline to gain deeper insights into their effectiveness in addressing PCOS and hyperprolactinemia.

[Clinical study of Bushen Culuan Formula in treatment of ovulatory disorder infertility caused by hyperprolactinemia].

This paper aims to study the therapeutic effect and safety of Bushen Culuan Formula in the treatment of patients with infertility caused by hyperprolactinemia. Sixty patients with infertility caused by hyperprolactinemia of kidney deficiency and blood stasis were divided into the treatment group(Bushen Culuan Formula + Bromocriptine Mesylate Tablets placebo) and the control group(Bromocriptine Mesylate Tablets + Bushen Culuan Formula placebo), and ovulation rate, pregnancy rate, serum sex hormones, basal body temperature(BBT), and traditional Chinese medicine(TCM) symptom scores were observed. The results showed the clinical effective rate was 90.00% in the treatment group and 80.00% in the control group. The treatment group was able to significantly reduce the PRL level and increase the pregnancy rate, and it was superior to the control group in increasing the BBT biphasic ratio, improving the TCM symptom scores, and enhancing the ovulation rate. The results show that Bushen Culuan Formula is safe and reliable in treating ovulatory disorder infertility caused by hyperprolactinemia, with remarkable effects.

[Study on mechanism of regulation of sex hormones in treatment of hyperprolactinemia-induced ovulatory disorder infertility with Bushen Culuan Formula].

Transcriptomics was used to investigate the mechanism of action of Bushen Culuan Formula in the treatment of infertility caused by hyperprolactinemia(HPRL), and animal experiments were carried out to verify the results. After establishing an animal model of HPRL-induced infertility, the mice were divided into normal group, model group, Bushen Culuan Formula groups with high-, medium-, and low-doses, and bromocriptine group, and they were observed in terms of the estrous cycle, gonadal index, serum sex hormones, morphology of ovary and mammary gland, follicle count, and fertility. The results showed that the Bushen Culuan Formula could effectively restore the estrous cycle, down-regulate the levels of prolactin(PRL), follicle-stimulating hormone(FSH), and luteinizing hormone(LH), up-regulate the level of estradiol(E_2), increase the number of primordial follicles and sinus follicles, and improve the ovulation rate and fertility of mice. Through RNA sequencing combined with biosignature analysis, Bushen Culuan Formula may regulate the metabolism of lipids, antioxidant enzymes, and other substances in the cells of the ovary and pituitary gland through the signaling pathways of cAMP-PKA, Kiss-1/GPR54, and Hippo and exert therapeutic effects. The results of animal experiments showed that Bushen Culuan Formula could up-regulate serum dopamine(DA) level and pituitary DRD2 expression, down-regulate hypothalamus and ovary cAMP levels, as well as protein expressions of the pituitary gland and ovary PKA, CREB, and p-CREB, and treat HPRL-induced infertility by regulating the cAMP-PKA signaling pathway.

Diagnosis of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Hyperprolactinemia is a frequent cause of menstrual irregularity, galactorrhea, hypogonadism, and infertility. The most common etiologies of hyperprolactinemia can be classified as physiological, pharmacological, and pathological. Among pathological conditions, it is essential to distinguish prolactinomas from other tumors and pituitary lesions presenting with hyperprolactinemia due to pituitary stalk disconnection. Proper investigation considering clinical data, laboratory tests, and, if necessary, imaging evaluation, is important to identify the correctcause of hyperprolactinemia and manage the patient properly. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Societyof Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and medication-induced hyperprolactinemia in women.

Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM).

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.

Long-term outcome of surgically treated and conservatively managed Rathke cleft cysts.

OBJECTIVE: Rathke cleft cysts (RCC) are benign lesions of the sellar region that require surgical treatment in case of visual deterioration or progression of the cyst. However, the natural course is often stable and asymptomatic. We aimed to investigate the characteristics of patients with cyst progression during follow-up (FU) and to compare the natural history of patients with RCC with patients who underwent surgery. METHODS: Patients with an MR morphologic cystic sellar lesion classified as RCC between 04/2001 and 11/2020 were included. Functional outcomes, including ophthalmologic, endocrinologic, and MRI data, were retrospectively analyzed and compared between surgically treated patients, patients on a "watch and wait" strategy (WWS), and patients on a WWS who underwent secondary surgery due to cyst progression. RESULTS: One hundred forty patients (median age 42.8 years) with RCC on MRI were identified. 52/140 (37.1%) underwent primary surgery. Of 88 patients (62.9%) with initial WWS, 21 (23.9%) underwent surgery for secondary cyst progression. Patients on the WWS had significantly smaller cyst volumes (p = 0.0001) and fewer visual disturbances (p = 0.0004), but a similar rate of hormone deficiencies (p = 0.99) compared with surgically treated patients preoperatively. Postoperatively patients suffered significantly more often from hormone deficiencies than WWS patients (p = 0.001). Patients who switched to the surgical group were significantly more likely to have preoperative T1 hyperintense signals on MRI (p = 0.0001) and visual disturbances (p = 0.001) than patients with continuous WWS. Postoperatively, these patients suffered more frequently from new hormonal deficiencies (p = 0.001). Endocrine and ophthalmologic outcomes in patients with primary and secondary surgery were comparable. Multivariate analysis showed that WWS patients were at a higher risk of requiring surgery for cyst progression when perimetric deficits (p = 0.006), hyperprolactinemia (p = 0.003), and corticotropic deficits (p = 0.005) were present. CONCLUSION: Surgical treatment of RCC may cause new hormonal deficiencies, which are rare in the natural course. Therefore, the indication for surgery should be carefully evaluated. Hyperprolactinemia and corticotropic deficits were significant indicators for a secondary cyst progression in patients with RCC. However, a significant amount of almost 25% of initially conservatively managed cysts showed deterioration, necessary for surgical intervention.

Clinical and radiographic characteristics of patients with non-functioning pituitary adenomas categorized according to their serum prolactin concentration: novel predictors of postoperative transient diabetes insipidus following surgery.

PURPOSE: Non-functioning pituitary adenomas (NFPAs) are often associated with hyperprolactinemia, which is known as the "stalk effect". However, the relationships between hyperprolactinemia and the radiographic characteristics of the tumor that affects the pituitary stalk have not been well characterized. We aimed to identify the differences in the clinical and radiographic characteristics of patients with NFPA, with and without hyperprolactinemia. METHODS: We enrolled 107 patients with NFPA and allocated them to hyperprolactinemia and non-hyperprolactinemia groups using two different cut-off values: (1) the upper limit of the normal reference range, adjusted for sex and menopausal status, and (2) the upper quartile across the cohort, and compared their clinical and radiographic characteristics. These analyses were conducted to clarify the relationship between the "stalk effect" and the postoperative change in antidiuretic hormone secretion. RESULTS: The specific radiographic characteristics of the patients included the presence of a cystic or hemorrhagic tumor and the presence of pituitary stalk deviation, which were more frequent in the patients with hyperprolactinemia. Interestingly, the incidence of postoperative transient diabetes insipidus was statistically significantly higher in the hyperprolactinemia group (≥40 ng/mL) and in the group with radiologic evidence of stalk deviation, which were shown to be independent risk factors on multivariate analysis. CONCLUSION: The presence of a "stalk effect" was associated with a higher risk of postoperative transient diabetes insipidus, reflecting perioperative pituitary stalk dysfunction following NFPA surgery, especially in patients with serum prolactin concentrations ≥40 ng/mL and radiologic evidence of stalk deviation.

Macroprolactin over time: Is there any point in rechecking it in people with a persistently elevated serum prolactin?

OBJECTIVE AND DESIGN: Macroprolactinemia may influence the interpretation of serum prolactin levels-a recognised phenomenon since 1981. The degree of macroprolactinaemia over time is less well described. We determined how macroprolactin status (based on polyethylene glycol (PEG) precipitation) varied by analysing serial measurements in hyperprolactinaemic individuals over a period of 9 years. PATIENTS AND MEASUREMENTS: Results from 1810 individuals were included. All serum total prolactin results (measured using Roche Cobas 8000 analyser) were extracted from the laboratory information system for the period 1 January 2012 to 1 April 2021, along with relevant patient demographic/test data. Samples with a macroprolactin screening test performed (on samples with prolactin > 700 miu/L) were included in the main analysis. RESULTS: During the study period, 2782 macroprolactin checks were performed (12.5% of all prolactin tests) in 1810 individuals (599 males/2183 females, median-age: 35, interquartile range: 25-47, range: 16-93 years). Multiple macroprolactin checks were carried out on 465 patients (1437 measurements) with 94 patients (141 measurements) screening positive (<60% recovery). Only 19 patients (18 female) had at least one result above and one below the 60% screening cut-off, with 10 of these patients having results close to the 60% cut-off; in 9 patients, results were clearly different between repeat samples. In seven cases, the adjusted monomeric prolactin showed a potentially clinically significant difference. CONCLUSIONS: In this study, only 19/465 patients appeared to change macroprolactin status based on a 60% PEG recovery cut-off. The majority of these 19 patients were on antipsychotic/antidepressant medication(s) or had a prolactinoma; in only 7 did monomeric prolactin change significantly. This suggests that once macroprolactin status has been determined, clinical decision making is rarely affected by repeating it.

Tolerability and safety outcomes of first-line oral second-generation antipsychotics in patients with schizophrenia.

INTRODUCTION: Antipsychotics are the foundation of pharmacologic treatment for schizophrenia. There are many oral antipsychotics available and given that these medications are generally considered comparably efficacious when titrated to an adequate dose, their varied tolerability, and safety profiles become critically important for medication selection. AREAS COVERED: This paper reviews tolerability and safety considerations for first-line second-generation oral antipsychotics currently approved for the treatment of schizophrenia in the USA. Excluded from consideration are clozapine and non-oral formulations. EXPERT OPINION: Among antipsychotics, there are many differences in adverse reactions observed in clinical trials, such as variable likelihood to cause sedation vs insomnia, weight gain and abnormalities in glucose/lipid metabolism, hyperprolactinemia, potential for impact on the QT interval, and motoric adverse effects. Additional safety data that can help with medication selection include safety in pregnancy and lactation, and potential for drug-drug interactions. Ultimately, working with patients to personalize treatment by focusing on safety and individual tolerability considerations for various adverse effects can help in building a therapeutic alliance and improving patients' outcomes.

Gynura procumbens and selected metabolites: Amelioration of depressive-like behaviors in mice and risperidone-induced hyperprolactinemia in rats.

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.