Frequency of Macroprolactin in Hyperprolactinemia.

OBJECTIVE: To determine the frequency of Macroprolactin (MaPRL) in patients with increased total prolactin and its clinical and financial impact. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from March to May 2015. METHODOLOGY: Patients with high total prolactin were screened by polyethylene glycol (PEG) precipitation for determination of MaPRL. Clinical history, imaging work-ups, and cost incurred in further investigations were collected by telephonic interview after verbal consent. Patients were stratified into true hyperprolactinemia and macroprolactinemia after PEG treatment, based on monomeric prolactin levels. Medical records of cases registered with AKUH were reviewed to confirm the diagnosis. RESULTS: Two hundred and thirty-nine patients were identified with high prolactin levels. Macroprolactinemia was identified in 145 (60.7%) and true hyperprolactinemia in 94 (39.3%) patients. Galactorrhea was significantly more in true hyperprolactinemic females (p=0.022), followed by visual disturbances (p=0.01) and headache (p=0.006). Moreover, as majority of population were females, the clinical features in the macroprolactinemia group as compared to true hyperprolactinemic group were mostly related to non-pituitary causes like drug intake [42.5% (54) vs. 37% (30)], heat intolerance due to thyroidal illness [41.7% (53) vs. 38.3% (31)] and surgery [26.8% (34) vs 22.2% (18)] in females. Further radiological workup (MRI, CT) were conducted in 35 (37.2%) patients with true hyperprolactinemia. Twenty-one (60%) of the patients were confirmed to have pituitary adenomas. In eight (5.5%) patients with MaPRL, only one had pituitary microadenoma on radiological workup. Total cost impact on the basis of investigations, was significantly higher in the group undergone imaging, despite 7 out of 8 individuals found to have normal imaging results. The median total cost in true hyperprolactinemic group undergone imaging was Rs. 4370 (IQR=2412.5, 22850) as compared to macroprolactinemic groups; Rs. 3,250 (IQR=2150, 4278). There was significant difference in the cost burden of both the groups (p <0.001). CONCLUSION: High frequency of MaPRL was identified in patients with hyperprolactinemia. Screening with PEG precipitation in hyperprolactinemic sera is simple and cost-effective.

Paraneoplastic Galactorrhea in Childhood T-ALL: An Evaluation of Tumor-derived Prolactin.

T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood leukemia. Although multiagent pulse chemotherapy has improved event-free survival in recent decades, the lack of reliable prognosticators and high rate of relapse remain a challenge. Described is a novel discovery of tumor-derived hyperprolactinemia in childhood T-ALL through a case associated with paraneoplastic galactorrhea. Prolactin production by tumor cells, although a rare phenomenon, is previously demonstrated in several adult cancers and 2 pediatric malignancies with unknown implications. This is the first report demonstrating tumor-derived prolactin in pediatric T-ALL and offers potential as a disease marker and therapeutic drug target.

The risk of elevated prolactin levels in pediatric patients exposed to antipsychotics for the treatment of schizophrenia and schizophrenia spectrum disorders: protocol for a systematic review and meta-analysis.

BACKGROUND: Antipsychotic medications, particularly second-generation antipsychotics, are increasingly being used to alleviate the symptoms of schizophrenia and other severe mental disorders in the pediatric population. While evidence-based approaches examining efficacy and safety outcomes have been reported, no review has evaluated prolactin-based adverse events for antipsychotic treatments in schizophrenia and schizophrenia spectrum disorders. METHODS/DESIGN: Searches involving MEDLINE, EMBASE, CENTRAL, PsycINFO, and clinical trial registries (ClinicalTrials.gov, Drug Industry Document Archive [DIDA], International Clinical Trials Registry Platform [ICTRP]) will be used to identify relevant studies. Two reviewers will independently screen abstracts and relevant full-text articles of the papers identified by the initial search according to the prospectively defined eligibility criteria. Data extraction will be conducted in duplicate independently. Pairwise random effects meta-analyses and network meta-analyses will be conducted on individual drug and class effects where appropriate. DISCUSSION: This systematic review will evaluate prolactin-based adverse events of first- and second-generation antipsychotics in the pediatric population with schizophrenia and schizophrenia spectrum disorders. It will also seek to strengthen the evidence base of the safety of antipsychotics by incorporating both randomized controlled trials and observational studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009506.

Clinical and radiological findings in macroprolactinemia.

Hyperprolactinemia is the most common abnormality of the hypothalamic-pituitary axis. The aim of this study was to investigate the clinical and radiological features of patients with macroprolactinemia. The study population consisted of patients with elevated serum prolactin (PRL) concentrations who presented to our Endocrinology outpatient clinic. Detection of macroprolactin (macroPRL) was performed using the polyethylene glycol precipitation method. Patients in which macroPRL made up more than 60% of total PRL levels were stratified into the macroPRL group, while the remaining patients were placed in the monomeric prolactin (monoPRL) group. A total of 337 patients were enrolled with a mean age of 33.8 ± 10.8 (16-66) years and a male/female ratio of 29/308. Eighty-eight of the patients (26.1%) had an elevated macroPRL level. The mean age in the monoPRL group was higher than in the macroPRL group (35.0 ± 10.1 vs. 30.7 ± 9.8, P = 0.016). The mean PRL levels (ng/ml) in the macroPRL and monoPRL groups were similar (168.0 ± 347.0 vs. 238.8 ± 584.9, P = 0.239). Frequency of amenorrhea, infertility, irregular menses, gynecomastia, and erectile dysfunction were also similar in both groups. More patients in the macroPRL group were asymptomatic compared to the monoPRL group (30.2 vs. 12.0%, P = 0.006). Compared to the macroPRL group, the monoPRL group had a higher frequency of galactorrhea (39.2 vs. 57.1%, P = 0.04) and abnormal magnetic resonance imaging findings (65.3 vs. 81.1%, P = 0.02). Elevated macroPRL levels should be considered a pathological biochemical variant of hyperprolactinemia that may present with any of the conventional symptoms and radiological findings generally associated with elevated PRL levels.

[Irregular secretion of prolactin in infertile women with normoprolactinemic galactorrhea]. / Secreción irregular de prolactina en mujeres infértiles con galactorrea normoprolactinémica.

BACKGROUND: Abnormal frequency and pulse amplitud of prolactin secretion in micro and macroprolactinomas has been atributed to a dysfunctional tumoral lactotrope. Previous evidence suggests that non tumoral hyperprolactinemia is caused by a hypothalamic dysfunction. The regularity of prolactin secretion has not been studied with cuantitative methods in patients with normoprolactinemic galactorrhea (NPG) which could be considered an entity that precedes non tumoral and tumoral hyperprolactinemia. OBJECTIVE: To analyze the 24-hour prolactin secretion pattern and its secretion regularity in a group of infertile women with normoprolactinemic galatorea. PATIENTS AND METHODS: A transversal-comparative study was carried out in 6 infertile women with normoprolactinemic galactorrhea and 4 healthy women as controls. The 24 hour prolactin profile, the ratio night time mean concentration/daytime mean concentrattion (NM/DM ratio) and apparent entropy (Ap En, Ap En ratio) were compared in the two groups. RESULTS: Blunting of the nyctohemeral rythm and nocturn hyperprolactinaemia occurred in patients with normoprolactinemic galactorrhea (NPG). NM/DM ratio was lower in patients with NPG than in controls (1.28 +/- 0.25 vs. 1.75 +/- 0.05; p= 0.01). Higher irregularity of prolactin secretion was found in patients with NPG (ApEn: 0.853 +/- 0.158 vs 0.608 +/- 0.171, p=0.04; Ap En ratio: 0.839 +/- 0.11 vs 0.661 +/- 0.14; p=0.04). CONCLUSIONS: The irregularity of prolactin secretion in patients with NPG is not dependant on the presence of a pituitary tumour which suggests that a hypothalamic dysfunction underlies this condition. An irregular secretion and a higher daily mass production of prolactin in patients with NPG could explain both galactorrhea and infertility.

Risperidone-induced symptomatic hyperprolactinaemia in adolescents.

Studies performed in adult patients unambiguously demonstrate a marked effect of risperidone on prolactin blood levels, with possible clinical effects related to hyperprolactinemia, such as gynecomastia and galactorrhea. However, the largest study performed in children and adolescents showed a weak effect of risperidone on prolactin concentrations during short-term treatment and a negligible effect during long-term treatment, which was probably because of the relatively low dosages of risperidone used [approximately 0.04 mg/(kg x d)]. Among the 10 psychotic adolescents treated with risperidone in our unit, we had 3 cases of gynecomastia in 3 male patients and 2 cases of galactorrhea in 2 female patients. The prolactin blood levels in these cases and in 3 other patients without apparent prolactin-related side effects were all above the normal range (median, 59 ng/mL; range, 30-123 ng/mL). Thus, risperidone administered to adolescents at doses commonly used for the treatment of psychotic symptoms can strongly increase prolactin levels, with clinical consequences such as gynecomastia and/or galactorrhea. Given that the long-term effects of antipsychotic drug-induced hyperprolactinemia are not well documented, especially regarding osteopenia, infertility, growth, and pubertal delay, risperidone should be administered with caution to children and adolescents.

Clinical and radiological features of patients with macroprolactinaemia.

OBJECTIVES: Macroprolactin is a complex of prolactin (PRL) and IgG and may account for a significant proportion of cases of 'idiopathic hyperprolactinaemia'. In this study, we sought to determine the prevalence and clinical features of macroprolactinaemia in patients diagnosed with hyperprolactinaemia in our region, with a view to determining how patients with macroprolactinaemia should be investigated and managed. PATIENTS AND METHODS: An Immuno-1 automated immunoassay system with polyethylene glycol (PEG) precipitation was used to identify macroprolactin, with a recovery of 700 mU/l. The clinical records of 51 (44 female) were available for retrospective review. RESULTS: The mean (range) age of patients was 39.5 (18-82) years. The median (range) concentrations for the various forms of PRL were: total PRL 1130 mU/l (728-5116), monomeric PRL 240 mU/l (50-656) and macroprolactin 895 mU/l (381-4854). Classical symptoms of hyperprolactinaemia were present in 39% of patients, although in many there were other possible explanations for their symptomatology. Pituitary adenomas were identified in six out of 36 people who underwent neuroimaging. Five of these patients had a microadenoma and one had a 10-mm macroadenoma (although, in this patient macroprolactin was identified after the discovery of the tumour). There was no relationship between macroprolactin concentrations and the presence of hyperprolactinaemic symptoms or neuroimaging abnormalities. CONCLUSIONS: Macroprolactinaemia is a common occurrence in patients with hyperprolactinaemia, but associated symptomatology may not necessarily be linked. The neuroimaging abnormalities were also probably incidental findings and it is questionable whether neuroimaging is necessary when significant macroprolactinaemia is identified and the concentration of monomeric PRL is not elevated (using the Immuno-1 assay system, following PEG precipitation).

Galactorrhea may be clue to serious problems. Patients deserve a thorough workup.

Three cases of nonphysiologic hyperprolactinemia associated with pituitary disease evidenced by galactorrhea are presented. Two patients had significant pituitary disease associated with low-level prolactin elevations. The third patient had only a history of infertility and expressible galactorrhea on examination. This patient was found to have high prolactin levels and a locally invasive pituitary tumor. Physicians need to be aware of the serious conditions associated with galactorrhea so that appropriate diagnostic studies can be done and treatment instituted.

Circulating nitric oxide levels in galactorrheic, hyperprolactinemic, amenorrheic women.

OBJECTIVE: To test the hypothesis that nitric oxide production is decreased in hyperprolactinemic, amenorrheic patients with estrogen (E) deficiency, augmenting the possible risk of cardiovascular disorders. SETTING: Cairo University Hospitals. DESIGN: Prospective, case-controlled study. PATIENT(S): Twenty-five galactorrheic, hyperprolactinemic patients with amenorrhea of more than 6 months and with low serum E2, as well as 30 healthy, fertile women (controls) matched for age and body mass index. INTERVENTION(S): Bromocriptine was administered orally to hyperprolactinemic patients, and blood samples were collected before and 6 weeks after treatment. MAIN OUTCOME MEASURE(S): Total nitric oxide production was determined photometrically using Greiss reagent after preliminary conversion of nitrate to nitrite by nitrate reductase. RESULT(S): Serum E2 and nitric oxide levels in hyperprolactinemic, amenorrheic patients (62.5 +/- 3.2 [SE] pg/mL [229 +/- 11.7 pmol/L] and 18.4 +/- 2.5 mumol/L, respectively) were significantly lower than E2 (114 +/- 6.4 pg/ml, [418 +/- 23.5 pmol/L]) and nitric oxide (41.2 +/- 4.1 mumol/L) levels observed in normal women during the follicular phase. The decrease of nitric oxide was associated with elevation of blood pressure. Treatment of hyperprolactinemia with bromocriptine restored normal values of serum nitric oxide and E2, and normal blood pressure. CONCLUSION(S): Hyperprolactinemia with E deficiency exhibits a significant decrease in nitric oxide production, and this decrease may subject the patient to certain cardiovascular disorders and disturbed ovarian function.

Two-step development of a pituitary adenoma: from hyperprolactinemic syndrome to Cushing's disease.

In this report we describe the case of a young female patient with amenorrhea-galactorrhea syndrome apparently due to pituitary PRL-secreting adenoma who, after three years of dopaminergic therapy without any shrinkage of the tumor, developed true Cushing's disease. Progression from hyperprolactinemia to hypersecretion of ACTH has been rarely described and it may be due to different possibilities. However, histopathological and immunohistochemical studies of the adenoma showed a pattern of PRL negative and ACTH positive cells, excluding mixed pituitary tumor. In order to explain the progression from hyperprolactinemia with amenorrhea-galactorrhea to an ACTH hypersecretion syndrome, it must be hypothesized either pituitary stalk compression or the influence of paracrine regulation factor(s) (such as Galanine) due to an "initially silent" corticotropinoma. This case confirms that the presence of hyperprolactinemia in a patient with pituitary tumor and amenorrhea-galactorrhea syndrome is insufficient to confidently conclude for prolactinoma. Furthermore, it underlines the importance both of clinically monitoring the patient with prolactin pituitary adenoma if dopaminergic therapy does not reduce tumor volume, and of accurately and repeatedly measuring the other pituitary hormonal secretions.

[Levels of progesterone, estrogen, FSH and LH in galactorrhea of unknown etiology]. / Nivo progesterona, estrogena, FSH i LH kod galaktoreje nepoznate etiologije.

Considering the frequent occurrence of idiopathic galactorrhea in the women of fertile age, the hormone status was investigated in 50 patients aged from 20 to 40 years. The FSH, LH, estradiol and progesterone hormones were tested. The hormone level was estimated from venous blood serum in the stage I of menstrual cycle (on 10th day) and in the stage II of cycle (on 22nd day). Patients were divided into 3 groups (related to menstrual cycle): with regular cycle, with irregular and with amenorrhea. Control group consisted of 21 healthy subjects. The changes in levels of FSH and LH were not found in the patients with galactorrheas of unknown etiology. Progesterone level was significantly lower (p < 0.05) in the patients with irregular cycle. Progesterone level was also significantly lower in the patients with amenorrhea and irregular cycle (0.01) and it was significantly raised in the patients with regular cycle (p < 0.05). Significantly higher estrogen (p < 0.05) was found in the patients with amenorrhea, and in the other groups there were no significant changes in estrogen level.

Euprolactinemic Galactorrhea. Response of bioassayable prolactin to thyrotropin-releasing hormone.

OBJECTIVE: To define whether the pathophysiology of euprolactinemic galactorrhea (EuG) involves hyperresponsiveness to thyrotropin-releasing hormone (TRH). STUDY DESIGN: Basal and TRH-induced prolactin (PRL) patterns were examined in women with EuG (n = 7) and compared to those in controls (n = 10) with normal menstrual cycles. PRL activity was measured by radioimmunoassay (RIA) and Nb2 lymphoma cell bioassay (BA). The response of BA-PRL, RIA-PRL, the BA/RIA-PRL ratio and lactogenic activity to TRH given intravenously were studied. RESULTS: The response of RIA-PRL, BA-PRL, lactogenic activity (representing both PRL and growth hormone in the Nb2 lymphoma cell bioassay) and BA/RIA-PRL ratio were not significantly different in EuG as compared to controls. In both groups the combined BA/ RIA-PRL ratio increased at 15 (P = .006), 30 (P = .011), and 90 minutes (P = .022) after TRH injection as compared to zero time. The level of serum progesterone at the time of TRH stimulation did not affect the response of any parameter studied. CONCLUSION: The response of BA-PRL, RIA-PRL and the BA/RIA-PRL ratio to TRH was not significantly different in EuG as compared to controls. The mechanism of EuG did not involve hyperresponsiveness of BA-PRL, RIA-PRL, the BA/RIA-PRL ratio or lactogenic activity to TRH.

Contribution to the problem of hyperprolactinaemia: experience with 4,199 prolactin assays and 117 prolactinomas.

OBJECTIVE: To help define the normal and pathological serum prolactin concentration ranges in adult females. PATIENTS AND METHODS: Serum prolactin was assayed in a mixed population of 4,199 women divided into five groups: (A) 753 with normal menses consulting for infertility (control group); (B) 2,523 with menstrual disorders; (C) 519 with hirsutism and normal cycles; (D) 201 with galactorrhoea and normal cycles; (E) 203 with galactorrhoea and menstrual disorders. RESULTS: In each group, a separate subset (2%, 3%, 1%, 15%, and 42.3%, respectively) was distinguished, with scattered prolactin values above 30 ng/mL, in which 117 prolactinomas were found, with an incidence ranging from 11 to 57% in cases with prolactin of 31-49 ng/mL and from 65 to 87.5% in those with prolactin > or = 50 ng/mL. The frequency distribution of values from 1 to 30 ng/mL was strikingly similar in the 753 subjects of group A and the 2,523 patients of group B: 91% and 92.6%, respectively, between 1 and 15 ng/mL, and 5.5% and 4.7% from 16 to 20 ng/mL. Values > 20 ng/mL were found in 4.4% of the subjects in group A, 5.5% in group B, 5.1% in group C, 21.8% in group D, and 18.7% in group E. CONCLUSIONS: (a) Normal prolactin values can be considered to include 1-15 ng/mL and 16-20 ng/mL, the former corresponding to the vast majority of normal subjects or patients, and the latter being the extreme limit of normal, for which from a clinical point of view repetition of the assay and a follow-up is advocated. (b) Values between 21 and 30 are rare and could be considered as hyperprolactinemia necessitating further investigation. (c) Values between 31 and 49 are suspect, and values > or = 50 ng/mL are suggestive of the presence of a prolactinoma, warranting thorough investigation.

Comparacao dos perfis hipofisario, esteroidiano e lipoproteico em pacientes com galactorreia normoprolactinemica e galactorreia hiperprolactinemica / Comparison of pituitary, steroid and lipoprotein profile in patients with hyperprolactinemic and normoprolactinemic galactorrhea

Objetivos: Avaliar o comportamento dos perfis hipofisario, esteroidiano e lipoproteico em pacientes com galactorreia hiperprolactinemica e galactorreia normoprolactinemica. Desenho: Foram estudadas 39 pacientes: 18 com galactorreia hiperprolactinemica e 21 com galactorreia normoprolactinemica. A avaliacao laboratorial constou das dosagens de PRL, FSH, LH e TSH (perfil hipofisario); estradiol, testosterona, androstenediona, deidroepiandrosterona e seu sulfato, 17-alfa-hidroxiprogesterona (perfil lipoproteico). O tratamento estatistico foi realizado atraves da comparacao das medias e dos respectivos desvios padrao. Resultados: O perfil hipofisario nao diferiu entre os dois grupos exceto em relacao a prolactina...

Low serum prolactin levels in native women at high altitude.

OBJECTIVES: To determine the serum prolactin levels in women at sea level and at high altitude, and the prevalence of hyperprolactinemia in both places. METHODS: The study included 303 normal women and 112 women with any reproductive dysfunction (menstrual abnormalities, galactorrhea or dysmenorrhea). From these, 228 were living in Lima at 150 m above sea level and 187 were living in Cerro de Pasco at 4340 m. Normal women included nonpregnant and pregnant women. Menstrual abnormalities included amenorrhea, oligomenorrhea and polymenorrhea. RESULTS: Serum prolactin levels were significantly lower in nonpregnant and pregnant women living at high altitude than at sea level. Prevalence of hyperprolactinemia, galactorrhea and menstrual abnormalities were significantly lower at high altitude than at sea level. CONCLUSIONS: It is concluded that menstrual abnormalities associated with hyperprolactinemia is a rare condition at high altitude. The low serum prolactin level observed at high altitude could be due to a high dopaminergic activity.

Serum prolactin levels in postpill amenorrheic patients.

OBJECTIVES: In this study, we evaluated the importance of the determination of serum prolactin levels in postpill amenorrheic patients. METHODS: Serum estradiol and prolactin levels were determined in 37 postpill amenorrheic patients. Bromocriptine was administered to the hyperprolactinemic group and clomiphene citrate to the normoprolactinemic group. RESULTS: Hyperprolactinemia was observed in 21 patients (56.7%) and serum estradiol levels < 50 pg/ml were found in 19 of these patients. The mean prolactin level was 71.90 +/- 23.05 ng/ml in the hyperprolactinemic group. While bromocriptine had a significant effect on the length of time for menstrual bleeding to return (P < 0.001), clomifene had no effect. CONCLUSIONS: No treatment is required for the postpill amenorrheic patients with normal estradiol and prolactin levels. If hyperprolactinemia is detected, bromocriptine may be used as a treatment to promote normal menstrual bleeding and ovulation.

Psychosocial aspects of hyperprolactinemia.

Fourteen mildly hyperprolactinemic women and 14 matched controls were compared with respect to biographical data, self-reported emotional and somatic well-being, and cortisol production. The patients had significantly more often experienced a separation from their parents in childhood. No differences were found for cortisol levels and emotional and somatic well-being. Future studies also should focus on personality, coping, and defense mechanisms in order to explain these contrasting findings.

The aetiology of galactorrhoea in women with regular menstruation and normal prolactin levels.

Fourteen primary infertile women with expressible galactorrhoea associated with regular ovulatory cycles and normal basal prolactin levels (group A) were matched for age and weight with 14 infertile women with regular menstruation but no galactorrhoea (group B). Both groups showed equivalent increases in prolactin levels after stimulation with 200 micrograms thyrotrophin-releasing hormone (TRH) during the follicular and luteal phases of the menstrual cycle. Patients in group A had a greater increase in luteinizing hormone levels after 100 micrograms i.v. injection of a luteinizing hormone-releasing hormone during the follicular phase (P less than 0.05). Following a 60 mg oral dose of buspirone hydrochloride on day 22 of the menstrual cycle, patients in group A had a greater increase in prolactin levels than patients in group B (P less than 0.01). This reflects hyper-responsive 5-hydroxytryptamine type 1A (5HT1A) receptors in group A patients and may explain the presence of galactorrhoea in these patients despite normal basal and post-TRH prolactin levels.