Pathological Hyperprolactinemia Research Articles

Hyperprolactinemia in Functional Dyspepsia: The Entangled Domperidone Link.

The commonest medications prescribed in functional dyspepsia are prokinetic agents, specifically domperidone. However, its administration at times elevates serum prolactin levels, which can lead to pathological hyperprolactinemia. The present study investigated the effect of 28 days of 30 mg domperidone therapy on prolactinemia in functional dyspepsia patients. We recruited 97 patients (60 men and 37 women, aged18-80 years) who had functional dyspepsia diagnosed as per the Rome IV criteria. After taking a preliminary clinical history, we measured and compared serum prolactin levels at day 'zero' and day 'twenty-eight'. We found increased prolactin levels from day '0' to day '28' after treatment with domperidone in functional dyspepsia patients, specifically in male participants aged less than 40 years, who are married and belong to middle socioeconomic status. The most common functional dyspepsia symptom found was pain in the epigastric region. To conclude, our pragmatic domperidone-induced-hyperprolactinemia link warrants this side effect to be robustly taken into account while treating functional dyspepsia patients with domperidone.

The utility of rested prolactin sampling in the evaluation of hyperprolactinaemia.

Serum prolactin levels may be elevated by venepuncture stress. We investigated the utility of a rested prolactin sample, obtained through an indwelling venous cannula, in preventing the overdiagnosis of hyperprolactinaemia. Patients at our institution undergo serial prolactin sampling, usually over 40 min, when investigating hyperprolactinaemia. We retrospectively reviewed all serial prolactin sampling performed during a 3-year period. Patients with possible medication-induced hyperprolactinaemia and macroprolactin interference were excluded. We assessed the effect of venepuncture-associated stress on hyperprolactinaemia with the main outcome being normalisation of serum prolactin at the end of serial sampling. Ninety-three patients with documented hyperprolactinaemia (range 360-1690 mU/L) were included in the analysis. Prolactin decreased during serial sampling in 73 patients (78%), suggesting a prevalent effect of venepuncture stress. The final prolactin sample was normal in 50 patients (54%), consistent with stress hyperprolactinaemia rather than pathological hyperprolactinaemia. Patients with a referral prolactin result greater than two times the upper reference limit (URL) were less likely (15%) to have a normal prolactin result on serial sampling. Measurement of a single rested prolactin sample from an indwelling cannula showed the same diagnostic utility as serial sampling. Serum prolactin results are frequently elevated by the stress of venepuncture. Confirmation of pathological hyperprolactinaemia in a rested sample obtained from an indwelling venous cannula is recommended in patients with mild hyperprolactinaemia, particularly when the referral prolactin is less than two times the URL.

Etiopathogenetic features of hyperprolactinemia in childhood

In recent years, the problem of hyperprolactinemia in children remains relevant because it is one of the most common pathologies of the hypothalamic-pituitary system, causing impaired fertility and reproductive function in adulthood. According to population studies, its incidence is 0.5 % in females, exceeding this figure in males by 10 times. Prolactin has: immunomodulatory effect, enhancing lymphocyte proliferation, phagocytic capacity of macrophages, IgA synthesis; analgesic effect; promotes postnatal growth of the body by inducing the activity of genes associated with growth; activates the proliferation of keratinocytes, epithelial cells of the prostate; participates in the regulation of metabolism, water-electrolyte balance, inhibiting the excretion of potassium and sodium ions by the kidneys; influences human behavior by accelerating neurogenesis, memory, learning and providing neuroprotection; induces surfactant production; stimulates lipogenesis. Prolactin levels increase due to physiological hyperestrogenemia, which blocks the inhibitory effect of dopamine on prolactin secretion and occurs during lactation, pregnancy and some other physiological states. Pathological hyperprolactinemia occurs in children with secondary hypogonadotropic hypogonadism, organic lesions of the suprasellar area of the brain and may be secondary (symptomatic). In the etiological structure of hyperprolactinemia syndrome, the largest proportion (60 %) in children and adolescents belongs to prolactinomas (pituitary adenomas that secrete prolactin), idiopathic hyperprolactinemia (22.7 %) and iatrogenic hyperprolactinemia induced by 6 drugs (4 % of cases). Given that the lion’s share of hyperprolactinemia in childhood is associated with the presence of pituitary prolactinoma, characterized by latent gradual progression of reproductive disorders, growth processes and neurological symptoms, the objective of this article is to focus on the pleiotropic effects of prolactin in the body, which controls more than 300 biological functions, epidemiological, etiological and pathogenetic mechanisms, on the features of the clinical classification of hyperprolactinemia to form a modern understanding of this problem.

Hyperprolactinemia in children and adolescents and longterm follow-up results of prolactinoma cases: a single-centre experience.

Hyperprolactinaemia refers to increased circulating prolactin and is divided into functional and pathological hyperprolactinaemia. Prolactinoma is the most common cause of severe hyperprolactinaemia. Prolactinomas are rare in children. Treatment outcomes and long-term follow-up data in children are insufficient. Dopamine agonists are the first step in the treatment of prolactinomas. There are no recommendations supported by a high level of evidence regarding the dose and duration of cabergoline treatment. Patients with hyperprolactinaemia were evaluated for etiological, clinical, and follow-up characteristics. The case files of patients with high prolactin levels who were followed up in our clinic between 2001 and 2019 were reviewed retrospectively. 27 cases (20 female, 7 male) with hyperprolactinemia were detected. The median age of the cases was 15 years (0.3-17.4). Prolactinoma was detected in 40.7% of the cases (n=11). Among these cases, six were macroadenomas. The median prolactin level was 118 ng/mL (34-4340) in those with prolactinoma and 60 ng/mL (22-200) in the hyperprolactinaemia group (p=0.007). In the prolactinoma group, the median age at presentation in macroadenoma cases (13.8 years) was lower than in microadenoma cases (17 years) (p=0.06). There was a negative correlation between prolactin level and height SDS (r=-0.770, p=0.06). In all cases, the median initial cabergoline dose was 0.5 mg/week, and prolactin levels returned to normal within an average of 2.6±2.4 months. Cabergoline treatment achieved a 50% reduction in adenoma size in the first year of treatment without high doses. Prolactinoma consists of an important group among hyperplolactinemia in children. In our study, prolactinoma was detected in 40.7% of children with hyperplolactinemia, and children with prolonged use (over 4 years) tolerated cabergoline well and prolactin levels normalized without high doses. Follow-up is required for relapse after discontinuing the treatment.

The prevalence rate of hypopituitarism in patients with pituitary macroadenomas with various hormonal activities

Rationale: According to the recent epidemiological studies, prevalence of pituitary tumors amounts to 1 per 865 to 2688 adults. The prevalence rates of hypopituitarism in pituitary macroadenomas are highly variable and comprise 37% to 85% among newly diagnosed non-functioning pituitary adenomas (NFPA). There is virtually no data on the prevalence of hypopituitarism in the cohort of newly diagnosed macroadenomas secreting prolactin and somatotropic hormone.Aim: To assess the prevalence of hypopituitarism in patients with pituitary macroadenomas with various hormonal activities and to identify its potential risk factors.Materials and methods: We analyzed data from 293 patients with pituitary macroadenomas with various hormonal activities: NFPA (n = 121), prolactinomas (n = 59), and somatotropinomas (n = 113). The patients had been examined before any treatment was commenced.Results: The prevalence rate of hypopituitarism was 59/121 (39.9%) among the patients with NFPA, 18/59 (27.3%) among those with prolactinomas, and 19/113 (14%) among those with somatotropinomas (р < 0.001). The symptoms of chiasmal compression and chiasmal syndrome were significantly more prevalent in the patients with hypopituitarism, than in those without it in all subgroups. The relative risk of hypopituitarism in the patients with chiasmal compression was 2.10 for NFPA (95% confidence interval (CI) 1.50-2.95, р=0.003), 1.667 for prolactinomas (95% CI 1.292.18, р = 0.005), and 1.45 for somatotropinomas (95% CI 1.56-2.48, р = 0.001). The relative risk of hypopituitarism in the patients with chiasmal syndrome was 1.66 for NFPA (95% CI 1.26-2.18, р=0.009), 2.08 for prolactinomas (95% CI 1.602.69, р = 0.001), and 1.97 for somatotropinomas (95% CI 1.56-2.48, р = 0.005). The NFPA subgroup had the highest rate of hypothyroidism (36/59, 61.0%), whereas the prolactinoma subgroup had the highest rate of secondary hypogonadism (34/59, 57.6%); however, hypogonadism is one of the manifestations of persistent pathological hyperprolactinemia typical for prolactinomas. In the somatotropinoma subgroup, secondary hypothyroidism was found in 11/19 (57.9%) of the patients. Conclusion: Identification of hypopituitarism before any treatment depended on the type of hormonal activity of a pituitary tumor and was most frequent in NFPA. The risk factors for hypopituitarism were chiasmal compression, chiasmal syndrome, vertical diameter of the pituitary tumor, and its volume. Secondary adrenal insufficiency, being the most hazardous component of hypopituitarism, manifested most rarely.

MicroRNA-7a2 Regulates Prolactin in Developing Lactotrophs and Prolactinoma Cells.

Prolactin production is controlled by a complex and temporally dynamic network of factors. Despite this tightly coordinated system, pathological hyperprolactinemia is a common endocrine disorder that is often not understood, thereby highlighting the need to expand our molecular understanding of lactotroph cell regulation. MicroRNA-7 (miR-7) is the most highly expressed miRNA family in the pituitary gland and the loss of the miR-7 family member, miR-7a2, is sufficient to reduce prolactin gene expression in mice. Here, we used conditional loss-of-function and gain-of-function mouse models to characterize the function of miR-7a2 in lactotroph cells. We found that pituitary miR-7a2 expression undergoes developmental and sex hormone-dependent regulation. Unexpectedly, the loss of mir-7a2 induces a premature increase in prolactin expression and lactotroph abundance during embryonic development, followed by a gradual loss of prolactin into adulthood. On the other hand, lactotroph development is delayed in mice overexpressing miR-7a2. This regulation of lactotroph function by miR-7a2 involves complementary mechanisms in multiple cell populations. In mouse pituitary and rat prolactinoma cells, miR-7a2 represses its target Raf1, which promotes prolactin gene expression. These findings shed light on the complex regulation of prolactin production and may have implications for the physiological and pathological mechanisms underlying hyperprolactinemia.

Hyperprolactinaemia.

Hyperprolactinaemia is one of the most common problems in clinical endocrinology. It relates with various aetiologies (physiological, pharmacological, pathological), the clarification of which requires careful history taking and clinical assessment. Analytical issues (presence of macroprolactin or of the hook effect) need to be taken into account when interpreting the prolactin values. Medications and sellar/parasellar masses (prolactin secreting or acting through “stalk effect”) are the most common causes of pathological hyperprolactinaemia. Hypogonadism and galactorrhoea are well-recognized manifestations of prolactin excess, although its implications on bone health, metabolism and immune system are also expanding. Treatment mainly aims at restoration and maintenance of normal gonadal function/fertility, and prevention of osteoporosis; further specific management strategies depend on the underlying cause. In this review, we provide an update on the diagnostic and management approaches for the patient with hyperprolactinaemia and on the current data looking at the impact of high prolactin on metabolism, cardiovascular and immune systems.

Prolactinomas in pregnancy: considerations before conception and during pregnancy.

Prolactinomas are the most common pituitary tumors and pathological hyperprolactinemia. Therefore, women harboring prolactinomas frequently present infertility due to the gonadal axis impairment. The gold-standard treatment is dopamine agonist (DA) which can reverse hyperprolactinemia and hypogonadism, and promote tumor shrinkage in the majority of cases. Therefore, reports of pregnancy in such cohort become more common. In this scenario, bromocriptine is still the DA of choice due to its shorter half-life and larger experience as compared to cabergoline. In DA resistant cases, transsphenoidal pituitary surgery is indicated. However, potential risks of DA-induced pregnancies include fetal exposition and symptomatic tumor growth. Dopamine agonist should be discontinued as soon as pregnancy is confirmed in microprolactinomas and intrasellar macroprolactinomas (MAC). Concerning expansive/invasive MAC, DA maintenance should be considered. Periodically clinical evaluation should be performed during pregnancy, being sellar imaging indicated if tumor symptomatic growth is suspected. In such cases, if DA treatment fails, neurosurgery is indicated.

The efficacy of high-dose cabergoline treatment of prolactinomas resistant to standard doses: a clinical observation

Hyperprolactinemia (HP) is one of the most common neuroendocrine disorders. In 60% of cases, pathological HP is caused by pituitary prolactin-secreting adenoma. Therapy with agonists of dopamine type 2 receptors (D2 receptor agonists) is a method of choice for the treatment of pathological HP which allows to achieve prolactin normalization and reduction of pituitary adenoma in most cases. However, 15-20% of patients are resistant to D2 receptor agonists, and the question of overcoming this resistance is highly relevant. Different approaches are considered to solve this problem, one - is to increase the dose of D2 receptor agonists up to the maximally tolerated. In this article, we present a clinical observation of a patient with a partial resistance to D2 receptor agonists who demonstrated a good response to treatment with high doses of cabergoline.

The prolactin-release inhibitor paeoniflorin suppresses proliferation and induces apoptosis in prolactinoma cells via the mitochondria-dependent pathway.

Prolactinomas are the most prevalent functional pituitary adenomas that cause chronic pathological hyperprolactinemia. Prolactin is known to promote cell growth and inhibit apoptosis in cells. Paeoniflorin is the principal component of radix Paeoniae alba (the main ingredient in some traditional herbal formulas clinically used for hyperprolactinemia-associated disorders). Recent findings from intensive studies have suggested that paeoniflorin regulates cell proliferation and apoptosis in many cell lines. However, the effects of paeoniflorin in pituitary tumor cells remain unknown. Here the results by the Cell Counting Kit-8 and colony formation assays showed that paeoniflorin concentration-dependently decreased cell viability in both MMQ and GH3 cells and colony formation in GH3 cells, suggesting inhibition of cell proliferation by paeoniflorin. By flow cytometry, paeoniflorin was found to increase apoptotic rate in MMQ cells. Mechanistically, Western blot results revealed that paeoniflorin enhanced protein expression of cleave caspase-9 and -3, and Bax, whereas it suppressed Bcl-2 protein expression in MMQ cells. Furthermore, paeoniflorin upregulated phosphorylated p53 protein expression, but it decreased prolactin concentration and prolactin protein expression in both MMQ and GH3 cells. Thus, the present results demonstrate that paeoniflorin inhibits cell proliferation and induces the mitochondrial pathway-mediated apoptosis in prolactinoma cells. These antitumor property is associated with inhibition of prolactin secretion. Our findings may provide new insight into the mechanisms underlying improving prolactinoma-associated disorders of paeoniflorin-enriched herbs and formulas.

Prolactinomas: how to handle prior to and during pregnancy?

Prolactinomas are the most common cause of pathological hyperprolactinemia, leading to central hypogonadism and, therefore, a frequent etiology of infertility. Treatment, usually with dopamine agonist (DA), can reverse hyperprolactinemia and hypogonadism, allowing pregnancy in the majority of cases. Bromocriptine is still the DA of choice for such purpose. Important issues in DA-induced pregnancies include fetal exposition, both malformations and neuropsychological development and tumor size increase. Regarding microprolactinomas and intrasellar macroprolactinomas, DA should be withdrawn as soon as pregnancy is confirmed. In expansive/invasive macroprolactinomas, DA maintenance should be individualized. Patient follow-up includes periodically clinical evaluation, sellar imaging only indicated in the presence of tumor mass effects related symptoms. Neurosurgery, both before and during gestation, is indicated in cases in which DA treatment failed. Breastfeeding is usually allowed. As tumor volume decrease and remission of hyperprolactinemia may occur after pregnancy, serum prolactin levels and tumor status should be reevaluated.

Amenorrhea without vasomotor symptoms in women over 40: A sign of pathological hyperprolactinemia?

Amenorrhea without vasomotor symptoms in women over 40: A sign of pathological hyperprolactinemia?

Interactions between prolactin and kisspeptin to control reproduction.

Prolactin is best known for its effects of stimulating mammary gland development and lactogenesis. However, prolactin is a pleiotropic hormone that is able to affect several physiological functions, including fertility. Prolactin receptors (PRLRs) are widely expressed in several tissues, including several brain regions and reproductive tract organs. Upon activation, PRLRs may exert prolactin's functions through several signaling pathways, although the recruitment of the signal transducer and activator of transcription 5 causes most of the known effects of prolactin. Pathological hyperprolactinemia is mainly due to the presence of a prolactinoma or pharmacological effects induced by drugs that interact with the dopamine system. Notably, hyperprolactinemia is a frequent cause of reproductive dysfunction and may lead to infertility in males and females. Recently, several studies have indicated that prolactin may modulate the reproductive axis by acting on specific populations of hypothalamic neurons that express the Kiss1 gene. The Kiss1 gene encodes neuropeptides known as kisspeptins, which are powerful activators of gonadotropin-releasing hormone neurons. In the present review, we will summarize the current knowledge about prolactin's actions on reproduction. Among other aspects, we will discuss whether the interaction between prolactin and the Kiss1-expressing neurons can affect reproduction and how kisspeptins may become a novel therapeutic approach to treat prolactin-induced infertility.

CABERGOLINE IN PRACTICAL MAMMOLOGY

Abnormal increase in prolactin hyperprolactinemia is one of the main signs of hypothalamic-pituitary-ovarian dysfunction. Consequently, the effect of dopamine on lactophores is attenuated resulting in their persistent hyperplasia and formation of functionally active microand macro-adenomas followed by an even greater prolactin level increase. According to statistics, prolactinomas are found in 25-30% of women with pathological hyperprolactinemia.

Signaling pathways regulating pituitary lactotrope homeostasis and tumorigenesis.

Dysregulation of the signaling pathways that govern lactotrope biology contributes to tumorigenesis of prolactin (PRL)-secreting adenomas, or prolactinomas, leading to a state of pathological hyperprolactinemia. Prolactinomas cause hypogonadism, infertility, osteoporosis, and tumor mass effects, and are the most common type of neuroendocrine tumor. In this review, we highlight signaling pathways involved in lactotrope development, homeostasis, and physiology of pregnancy, as well as implications for signaling pathways in pathophysiology of prolactinoma. We also review mutations found in human prolactinoma and briefly discuss animal models that are useful in studying pituitary adenoma, many of which emphasize the fact that alterations in signaling pathways are common in prolactinomas. Although individual mutations have been proposed as possible driving forces for prolactinoma tumorigenesis in humans, no single mutation has been clinically identified as a causative factor for the majority of prolactinomas. A better understanding of lactotrope-specific responses to intracellular signaling pathways is needed to explain the mechanism of tumorigenesis in prolactinoma.

GENDER FEATURES OF MANIFESTATION AND CLINICAL COURSE OF PROLACTINOMA

It was studied 40 patients (6 men and 34 women) with prolactinoma. It was conducted a quan-titative and qualitative analysis of complaints at the time of disease manifestation and examination.The main specific clinical manifestations of pathological hyperprolactinemia in women and men haveimpaired of sexual function. Severity of complaints of a general nature for men concealed clinicalsymptoms of hyperprolactinemia and complicates timely diagnosis of prolactinoma. The frequency ofneurological and neuro-ophthalmic complaints in patients with prolactinoma depends on the size ofthe hypophysis adenoma. In 15 % of patients prolactinomas characterized by a long asymptomaticand are diagnosed at a stage invasive macroadenomas.

Hyperprolactinemia

Prolactin (PRL) is an anterior pituitary hormone which has its principle physiological action in initiation and maintenance of lactation. In human reproduction, pathological hyperprolactinemia most commonly presents as an ovulatory disorder and is often associated with secondary amenorrhea or oligomenorrhea. Galactorrhea, a typical symptom of hyperprolactinemia, occurs in less than half the cases. Out of the causes of hyperprolactinemia, pituitary tumors may be responsible for almost 50% of cases and need to be investigated especially in the absence of history of drug induced hyperprolactinemia. In women with hyperprolactinemic amenorrhea one important consequence of estrogen deficiency is osteoporosis, which deserves specific therapeutic consideration. Problem in diagnosing and treating hyperprolactinemia is the occurrence of the ‘big big molecule of prolactin’ that is biologically inactive (called macroprolactinemia), but detected by the same radioimmunoassay as the biologically active prolactin. This may explain many cases of very high prolactin levels sometimes found in normally ovulating women and do not require any treatment. Dopamine agonist is the mainstay of treatment. However, presence of a pituitary macroadenoma may require surgical or radiological management.

Management of hyperprolactinemic infertility

Abstract Pathological hyperprolactinemia may cause defective ovulation and reduced fecundability. Abnormal prolactin (PRL) secretion is usually related to an idiopathic hypothalamic dysfunction or to the presence of a pituitary adenoma. The use of medication is the most common cause of functional hyperprolactinemia. Pituitary prolactin secreting adenoma is classified according to size: micro (the vast majority) being smaller than 10 mm in diameter or macroprolactinoma (very few) of larger size. An excessive PRL secretion decreases the pulsatile release of GnRH impairing the pituitary production of FSH and LH. Furthermore it may directly impair the endocrine activity of ovarian follicles. As a consequence: defective luteal phase, inconstant ovulation and chronic anovulation are conditions frequently observed in young hyperprolactinemic patients. In addition 5% of unselected, asymptomatic infertile women show hyperprolactinemia. In such patients fertility may be promoted with long-term use of dopaminergic drugs. The normalized PRL level induced by the treatment allows the occurrence of spontaneous ovulatory cycles or the normalization of the defective luteal phase. Treatment should be continued for at least one year since half of the pregnancies occurring during dopaminergic therapy start after the first 6 months of drug assumption. An ovarian stimulation with gonadotropin and the pulsatile administration of GnRH may also induce ovulatory cycles and fertility in the infertile hyperprolactinemic patients. Hyperprolactinemia either, due to hypothalamic dysfunction, as well as the presence of PRL secreting adenoma usually improves after delivery.

Prolactin levels independently predict major cardiovascular events in patients with erectile dysfunction

The physiological role of prolactin (PRL) in men is not completely clarified. We previously reported that in subjects consulting for sexual dysfunction, lower PRL plasma levels were associated with worse lipid and glycaemic profile, as well as with a higher prevalence of metabolic syndrome and arteriogenic erectile dysfunction (ED). The aim of this study was to assess possible associations between PRL levels and incident major cardiovascular events (MACE) in subjects with ED. When only subjects without pathological hyperprolactinaemia (PRL < 735 mU/L or 35 ng/mL) and pituitary diseases were considered, both unadjusted and adjusted analyses showed a significantly lower incidence of MACE in subjects with PRL levels in the highest PRL quintile (246-735 mU/L or 12-35 ng/mL) when compared with the rest of the sample. In particular, the risk of MACE was reduced by 5% (1-9%; p = 0.03) for each 10 ng/mL increment of PRL. Conversely, comparing patients with hyperprolactinaemia with matched controls, no significant difference was detected between cases and controls in MACE. In subjects at high risk for cardiovascular diseases, such as those with ED, a relatively high PRL plasma level is associated with an overall decreased chance of MACE, independently from other known risk factors.

Bromocriptine Response in Pathological Hyperprolactinemia: A 34 Year Follow-Up of a Homogeneous Population of 827 Patients

patients with symptomatic pathological hyperprolactinemia were treated with bromocriptine. The evaluation, treatment, and follow-up was by a single individual, making this a large and unique homogeneous group for purposes of treatment evaluation.