Mechanisms of adverse mammary effect induced by olanzapine and therapeutic interventions in rat model.

BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented. METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed. RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen. CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

The homeo-FIT-prolactin hypothesis: the role of prolactin in metabolic homeostasis - association or causality?

The homeo-fit-prolactin hypothesis proposes a causal metabolic role for prolactin with hypoprolactinemia and hyperprolactinemia leading to adverse metabolic alterations. However, prolactin within the normal range and up to four times the upper reference limit may be a consequence of metabolic adaption and have a positive metabolic role similar to increased insulin in pre-diabetes. As a consequence, drugs that would increase prolactin levels within this threshold may hold promising effects, particularly for patients with type 2 diabetes. A documented positive metabolic effect of prolactin just above the normal threshold would not just be of benefit to patients with diabetes but assist in the decision to treat mild hyperprolactinemia in other patient groups as well, e.g. drug-induced hyperprolactinemia or idiopathic hyperprolactinemia. Prolactin receptors are present in the pancreas, liver, and adipose tissue, and pre-clinical studies suggest a positive and causal effect of prolactin on the gluco-insulinemic profile and lipid metabolism. This narrative review examines the evidence for the homeo-fit-prolactin hypothesis with a particular focus on results from human studies.

Traumatic brain injury and prolactin.

Traumatic brain injury (TBI) is a well-known etiologic factor for pituitary dysfunctions, with a prevalence of 15% during long-term follow-up. The most common hormonal disruption is growth hormone deficiency, followed by central adrenal insufficiency, central hypogonadism, and central hypothyroidism in varying order across studies. The prevalence of serum prolactin disturbances ranged widely from 0 to 85%. Prolactin release is mainly regulated by hypothalamic dopamine inhibition, and mediators such as TRH, serotonin, cytokines, and neurotransmitters have modulatory effects. Many factors, such as hypothalamic and/or pituitary gland injuries, as well as fluctuations in dopaminergic activity and other mediators and stress response, may cause derangements in serum prolactin levels after TBI. Although it is challenging to investigate the direct effects of TBI on serum prolactin levels due to many confounders, basal prolactin measurements and stimulation tests provide insight into the functionality of the hypothalamus and pituitary gland after TBI. Moreover, during the acute phase of TBI, prolactin levels appear to correlate with TBI severity. In contrast, in the chronic phase, hypoprolactinemia may function as an indirect indicator of pituitary dysfunction and reduced pituitary volume. Further investigations are needed to elucidate the pathophysiologic mechanisms underlying the prolactin trend following TBI, its significance, and its associations with other pituitary hormone dysfunctions. In this article, we re-evaluated our patients' TBI data regarding prolactin levels during prospective long-term follow-up, and reviewed the literature regarding the prevalence, pathophysiology, and clinical implications of serum prolactin disturbances during acute and chronic phases following TBI.

What do we know about abnormally low prolactin levels in polycystic ovary syndrome? A narrative review.

Hyper and hypoprolactinemia seem to be related to the occurrence of metabolic alterations in PCOS patients. In contrast, between significantly elevated and significantly low, prolactin levels seem to be protective against metabolic consequences. In the present review, we found 4 studies investigating hypoprolactinemia in patients with PCOS. We also identified 6 additional studies that reported low levels of PRL in PCOS patients. Although its prevalence is not considered high (13.2-13.9%), its contribution is certainly significant to the metabolic alterations observed in PCOS (insulin resistance, obesity, diabetes mellitus, and fatty liver disease). Dopamine inhibits the secretion of prolactin and GnRH. If dopamine levels are low or the dopamine receptor is less expressed or mutated, the levels of prolactin and GnRH increase, and consequently, LH also increases. On the other hand, hyperprolactinemia, in prolactinomas-typical levels, acting through kisspeptin inhibition causes GnRH suppression and hypogonadotropic hypogonadism. In situations of hypoprolactinemia due to excessive dopamine agonist treatment, dosage reduction is important to minimize the decrease in prolactin levels. Nevertheless, there is a lack of prospective studies confirming these hypotheses, as well as randomized clinical trials with appropriate drugs targeting both hyperprolactin and hypoprolactin in patients with PCOS.

The Diagnostic Value of Conventional MRI Combined With Diffusion-Weighted Imaging in Microprolactinomas.

BACKGROUND: Turbo spin-echo (TSE) diffusion-weighted imaging (DWI) sequences may reduce susceptibility artifacts and image distortion in sellar region, allowing better visualization of small pituitary lesions, and may be used to assist in the diagnosis of pituitary microadenomas. PURPOSE: To explore the application value of conventional MRI combined with DWI sequences in the diagnosis of microprolactinomas. STUDY TYPE: Prospective. POPULATION: Thirty-four patients in microprolactinomas with high signal on T2WI (HT2-PRL) group (34 females, 34 ± 7 years), 26 patients in microprolactinomas with equal or low signal on T2WI (ELT2-PRL) group (21 females, 34 ± 7 years), 35 patients with hyperprolactinemia (33 females, 32 ± 8 years), and 30 normal controls (25 females, 31 ± 7 years). FIELD STRENGTH/SEQUENCE: TSE sequence at 3 T. ASSESSMENT: Pituitary morphological parameters (such as length and volume), dynamic contrast-enhanced parameters (such as time to peak) and the apparent diffusion coefficients (ADCs) were measured in each group. STATISTICAL TESTS: ANOVA and Mann-Whitney U test were used to compare parameters among groups. Spearman's coefficient was used to evaluate the correlation between variables. ROC analysis was used to assess the performance of the parameters. A P-value <0.05 was considered statistically significant. RESULTS: The pituitary volume of patients in HT2-PRL, ELT2-PRL, and hyperprolactinemia group were 831.00 (747.60, 887.60), 923.63 ± 219.34, and 737.20 (606.40, 836.80) mm3. The pituitary maximum height in these three groups were 7.03 (6.43, 8.63), 8.03 ± 1.41, and 6.63 ± 1.28 mm, respectively. The lesion ADC value was significantly correlated with T2 relative signal intensity (the ratio of signal intensity of microprolactinoma or anterior pituitary to left temporal cortex) (r = 0.821). Compared with patients with hyperprolactinemia, the diagnostic efficacy of T2 relative signal intensity was higher in HT2-PRL group, with an AUC of 0.954, whereas the ADC value was the highest in ELT2-PRL group, with an AUC of 0.924. CONCLUSION: DWI sequences can be used to assist in the diagnosis of pituitary microadenomas. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Macroprolactin in mothers and their babies: what is its origin?

OBJECTIVES: Macroprolactinemia is one of the major causes of hyperprolactinemia. The aim of this study was to clarify the origin of macroprolactin (macro-PRL). METHODS: We examined macro-PRL in the sera of 826 pregnant women and in those of their babies' umbilical cords at delivery. Macro-PRL was evaluated by precipitation with polyethylene glycol (PEG), gel filtration chromatography (GFC), and absorption with protein G (PG). RESULTS: We detected macro-PRL in 16 out of the 826 pregnant women (1.94 %) and in 14 of their babies, which may indicate the possibility of hereditary origin of macro-PRL. However, the macro-PRL ratios of the babies correlated positively with those of their mothers (r=0.72 for GFC, p<0.001 and r=0.77 for PG, p<0.001), suggesting that the immunoglobulin (Ig)G-type anti-PRL autoantibodies might be actively transferred to babies via the placenta and form macro-PRL by binding to their babies' PRL or PRL-IgG complexes may possibly pass through the placenta. There were two cases in which only mothers had macro-PRL, indicating that the mothers had autoantibodies that did not pass through the placenta, such as IgA, PRL bound to the other proteins or PRL aggregates. No cases were found in which only the babies had macro-PRL and their mothers did not, suggesting that macro-PRL might not arise by non-hereditary congenital causes. CONCLUSIONS: Macro-PRL in women of reproductive age might be mostly IgG-type anti-PRL autoantibody-bound PRL. The likely origin of macro-PRL in babies is the transplacental transfer of IgG-type anti-PRL autoantibodies or PRL-IgG complexes from the mothers to their babies.

Skeletal fragility in pituitary disease: how can we predict fracture risk?

Pituitary hormones play a crucial role in regulating skeletal physiology, and skeletal fragility is a frequent complication of pituitary diseases. The ability to predict the risk of fracture events is crucial for guiding therapeutic decisions; however, in patients with pituitary diseases, fracture risk estimation is particularly challenging. Compared to primary osteoporosis, the evaluation of bone mineral density by dual X-ray absorptiometry is much less informative about fracture risk. Moreover, the reliability of standard fracture risk calculators does not have strong validations in this setting. Morphometric vertebral assessment is currently the cornerstone in the assessment of skeletal fragility in patients with pituitary diseases, as prevalent fractures remain the strongest predictor of future fracture events. In recent years, new tools for evaluating bone quality have shown promising results in assessing bone impairment in patients with pituitary diseases, but most available data are cross-sectional, and evidence regarding the prediction of incident fractures is still scarce. Of note, apart from measures of bone density and bone quality, the estimation of fracture risk in the context of pituitary hyperfunction or hypofunction cannot ignore the evaluation of factors related to the underlying disease, such as its severity and duration, as well as the specific therapies implemented for its treatment. Aim of this review is to provide an up-to-date overview of all major evidence regarding fracture risk prediction in patients with pituitary disease, highlighting the need for a tailored approach that critically integrates all clinical, biochemical, and instrumental data according to the specificities of each disease.

Breast Cancer risk in patients with dopamine agonist-treated hyperprolactinemia.

PURPOSE: Given prolactin's (PRL) multifaceted roles in mammary tissue, an association between hyperprolactinemia and breast cancer has been hypothesized. Despite previous studies not identifying this risk, we aimed to investigate whether a connection exists. METHODS: This retrospective cohort study compared breast cancer incidence in patients with dopamine agonist (DA)-treated hyperprolactinemia versus matched controls in a 1:5 ratio. The primary outcome was a breast cancer diagnosis following hyperprolactinemia diagnosis. RESULTS: The cohort consisted of 1484 female patients with DA-treated hyperprolactinemia matched to 7418 female controls (mean age at diagnosis 32.70 ± 11.12 years; BMI 25.60 ± 5.84 kg/m2). Breast cancer was diagnosed in 27 patients with hyperprolactinemia (1.82%) and 97 controls (1.31%) (HR 1.40, 95% CI 0.91-2.14, p = 0.12). Patients who developed breast cancer were diagnosed with hyperprolactinemia later in life than those who did not (median age 42.63 vs. 29.79 years; p < 0.0001). Patients with PRL < 5× upper limit of normal (ULN) at diagnosis developed breast cancer at a higher rate than controls (2.25% vs. 1.33%; HR 1.73, 95% CI 1.09-2.75), but the difference was not significant in patients with PRL ≥ 5×ULN. Patients who exhibited longer times to PRL normalization had higher incidence of breast cancer (median 2.60 vs. 1.41 years in those who did not develop breast cancer; p = 0.03). CONCLUSION: Overall, patients with DA-treated hyperprolactinemia did not show an increased risk for breast cancer compared to controls. However, the risk was significantly higher among those whose PRL levels were < 5×ULN, had advanced age of diagnosis, or prolonged time to PRL normalization.

Molecular mechanisms underlying the effects of hypo- and hyper-prolactinemia on spermatogenesis and fertility in male rats.

PURPOSE: Hypo- and hyper-prolactinemia have deleterious effects on male reproduction, yet there is a dearth of information regarding the underlying mechanisms. The aim of this study was to delineate the molecular mechanisms by which hypo- and hyper-prolactinemia affects spermatogenesis and fertility in male rats. METHODS: In vivo male rat models for hypo- and hyper-prolactinemia were established using dopamine receptor agonist, Bromocriptine (Brm), and antagonist, Fluphenazine (Flu), respectively. Effects on fertility and spermatogenesis were assessed by studying pre- and post-implantation loss, litter size, sperm parameters, hormonal profile, testicular histology, testicular cell population, and testicular transcriptome in rats. RESULTS: Treatment with Brm and Flu for 60 days led to subfertility, which was indicated by an increase in pre- and post-implantation loss and decrease in litter size, when mated with control female rats. Decreased sperm count was observed after both treatments, whereas reduced sperm motility was noted in Flu group. Serum FSH was unaffected, and LH was decreased by Flu treatment. Testosterone was decreased in both the groups, whereas estradiol was decreased in the Flu group. An arrest in spermatogenic cycle beyond round spermatids was observed in the Flu group. Additionally, testicular apoptosis in germ cells, mostly spermatocytes of Stage IX-XIV was noted in both the groups. Further, testicular RNA-Seq analysis revealed a total of 1539 and 824 differentially expressed genes/DEGs in Brm and Flu, respectively (Sequence Read Archive/SRA Database accession number: PRJNA1150513). Gene ontology and pathway analysis of DEGs highlighted enrichment of steroid metabolic pathway and ribosomal biogenesis pathway. Hub genes identified from the DEGs were validated by qPCR and the results showed that Uba52, Rps27a, Rpl23, Rps5, Rps16 were significantly down-regulated by Brm, whereas Rps27a, Rps29, Rps15, Rps27, Faul1 were significantly down-regulated by Flu. CONCLUSION: Hypo- and hyper-prolactinemia leads to subfertility and decreased sperm parameters possibly through an effect on steroid metabolism and ribosomal biogenesis pathway. Therefore, maintaining prolactin levels in physiological range is crucial.

The curious case of milk collection under skin graft over the breast: Lessons learned!

Raw area on the breast, especially when it is lactating, can lead to complications, including hyperprolactinemia and development of milk fistulae. A 25-year-old female presented with raw area over the left breast after 2 months of childbirth. She had history suggestive of necrotizing disease, which had primarily been managed elsewhere with debridement and dressings. We excised the raw area and applied split thickness skin grafts with minimal meshing. Bulky dressing prevented breastfeeding. On postoperative day 3, there were blebs containing milk underneath the graft. The blebs were drained and oral cabergoline was administered for 3 months. The skin graft healed well. If expression of breast milk is not possible then suppression of lactation should be considered before definitive cover of the raw area of breast.

Effect of Hyperprolactinemia on Bone Metabolism: Focusing on Osteopenia/Osteoporosis.

Prolactin is a hormone secreted from lactotroph cells in the anterior pituitary gland to induce lactation after birth. Hyperprolactinemia unrelated to lactation is a common cause of amenorrhea in women of a childbearing age, and a consequent decrease in the gonadotropin-releasing hormone (GnRH) by a high prolactin level can result in decreased bone mineral density. Osteoporosis is a common skeletal disorder characterized by decreased bone mineral density (BMD) and quality, which results in decreased bone strength. In patients with hyperprolactinemia, changes in BMD can be induced indirectly by the inhibition of the GnRH-gonadal axis due to increased prolactin levels or by the direct action of prolactin on osteoblasts and, possibly, osteoclast cells. This review highlights the recent work on bone remodeling and discusses our knowledge of how prolactin modulates these interactions, with a brief literature review on the relationship between prolactin and bone metabolism and suggestions for new possibilities.

Current Insights in Prolactin Signaling and Ovulatory Function.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

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.

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.

[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.

[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.

Successful medical management of a pituitary macroadenoma with features of resistant acromegaly and hyperprolactinemia using pasireotide.

BACKGROUND: The somatostatin analog, pasireotide, is used for the treatment of acromegaly after the failure of surgery and/or first-line medical treatment. CASE PRESENTATION: A 48-year-old male reported that during a workup for obesity in his home country, hyperprolactinemia was diagnosed and a 3.5 × 3.5 cm pituitary macroadenoma was identified on pituitary MRI. He received cabergoline for 6 months; then he was lost to follow-up. He presented at our Endocrine clinic 2 years later for treatment of obesity (BMI 49.5 kg/m2). Biochemical workup revealed that in addition to hyperprolactinemia (7,237 [normal: 85-323 mIU/L), he had acromegaly, evident by elevated insulin-like growth factor 1 (IGF-1) level (450 [normal: 88-210 µg/L]), and a positive growth hormone suppression test, secondary hypothyroidism, and secondary hypogonadism. Pituitary MRI showed that the adenoma encased parts of the left and right internal carotid arteries and encroached on the optic chiasm. Surgical excision was therefore not feasible. He was treated with cabergoline and later, long-acting release (LAR) octreotide. Prolactin levels were reduced with cabergoline, but IGF-1 levels did not respond to octreotide, and it was discontinued. The patient abandoned radiotherapy after two sessions. He was started on LAR pasireotide 40 mg every 4 weeks and continued on cabergoline 0.5 mg per week. His biochemical response was dramatic, with a near normalization of IGF-1 levels in 3 months. After 6 months from starting pasireotide, we increased cabergoline dose from 0.5 mg/week to 3 mg/week. Three months later, IGF-1 level was normalized. The patient developed type 2 diabetes as a side effect of pasireotide; however, this was well-controlled with medications. CONCLUSIONS: The case suggests that pasireotide can provide marked biochemical improvement in acromegaly after the failure of both cabergoline monotherapy and cabergoline plus octreotide. This further confirms a potentially efficacious treatment regimen in treatment-resistant acromegaly with hyperprolactinemia.

Hyperprolactinemia modifies extracellular matrix components associated with collagen fibrillogenesis in harderian glands of non- and pregnant female mice.

The harderian gland (HG) is a gland located at the base of the nictating membrane and fills the inferomedial aspect of the orbit in rodents. It is under the influence of the hypothalamic-pituitary-gonadal axis and, because of its hormone receptors, it is a target tissue for prolactin (PRL) and sex steroid hormones (estrogen and progesterone). In humans and murine, the anterior surface of the eyes is protected by a tear film synthesized by glands associated with the eye. In order to understand the endocrine changes caused by hyperprolactinemia in the glands responsible for the formation of the tear film, we used an animal model with metoclopramide-induced hyperprolactinemia (HPRL). Given the evidences that HPRL can lead to a process of cell death and tissue fibrosis, the protein expression of small leucine-rich proteoglycans (SLRPs) was analyzed through immunohistochemistry in the HG of the non- and the pregnant female mice with hyperprolactinemia. The SRLPs are related to collagen fibrillogenesis and they participate in pro-apoptotic signals. Our data revealed that high prolactin levels and changes in steroid hormones (estrogen and progesterone) can lead to an alteration in the amount of collagen, and in the structure of type I and III collagen fibers through changes in the amounts of lumican and decorin, which are responsible for collagen fibrillogenesis. This fact can lead to the impaired functioning of the HG by excessive apoptosis in the HG of the non- and the pregnant female mice with HPRL and especially in the HG of pregnancy-associated hyperprolactinemia.

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism.

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.

What is the optimal prolactin cutoff for predicting the presence of a pituitary adenoma in patients with polycystic ovary syndrome?

Objective: Hyperprolactinemia (HPRL) and polycystic ovary syndrome (PCOS) are common causes of infertility in women of reproductive age. A pituitary adenoma (PA) is the most common type of brain tumor that causes HPRL. In the neurosurgical field, the co-existence of PA and PCOS is not common. However, neurosurgeons often treat patients who are referred from gynecology. Because most of these patients are young and reproductive-aged, it is difficult for a neurosurgeon to come up with a treatment plan alone. In this study, we investigated the prevalence of PAs in PCOS patients, the cutoff prolactin (PRL) level to detect PAs, and the treatment strategy, then assessed the relationship between these diseases via a literature review. Methods: Medical records from November 2009 to March 2020 were reviewed at our institute. A total of 657 PCOS patients were enrolled. Initial prolactin levels were investigated and hyperprolactinemic patients were selected. As a result of sella magnetic resonance imaging (MRI), patients were divided into 2 groups of those with hyperprolactinemia but without PAs (group A) and those with both hyperprolactinemia and PAs (group B), respectively. We then compared and analyzed each group to find the characteristics and statistical differences. Receiver operating characteristic (ROC) curve analysis was performed to determine a cutoff value of the serum PRL level that could detect PAs in hyperprolactinemic PCOS patients. Results: Of 657 patients diagnosed with PCOS, 76 patients had hyperprolactinemia (76/657, 11.6%). Sella MRI was performed in 56 patients, excluding 20 patients for various reasons. Patients in groups A and B numbered 43 and 13, respectively, and the mean serum prolactin level significantly differed between the groups (39.89 ± 41.64 vs. 108.59 ± 60.70 ng/mL, P < 0.001). Based on the ROC curve analysis of the prolactin threshold level for predicting PAs in PCOS patients, the area under the ROC curve was 0.853 (95% confidence interval, 0.733-0.934; P < 0.001), and the sensitivity and specificity were 76.9% and 86.1%, respectively. Ultimately, the cutoff value for prolactin level was 52.9 ng/mL. Conclusion: PCOS and hyperprolactinemia are common causes of infertility in reproductive-age women. PCOS patients with a PRL level of ≥ 52.9 ng/mL may need to undergo sella MRI for detecting PAs. To help ensure a favorable clinical course for these patients, systematic diagnosis, treatment, and follow-up plan should be established. Therefore, a multidisciplinary approach involving both neurosurgery and gynecology is essential.