Galactorrhea during antipsychotic treatment: results from AMSP, a drug surveillance program, between 1993 and 2015.

Galactorrhea is a well-known adverse drug reaction (ADR) of numerous antipsychotic drugs (APD) and is often distressing for those affected. Methodological problems in the existing literature make it difficult to determine the prevalence of symptomatic hyperprolactinemia in persons treated with APDs. Consequently, a large sample of patients exposed to APDs is needed for more extensive evaluation. Data on APD utilization and reports of galactorrhea caused by APDs were analyzed using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2015. 320,383 patients (175,884 female inpatients) under surveillance were treated with APDs for schizophrenia and other indications. A total of 170 events of galactorrhea caused by APDs were identified (0.97 cases in 1000 female inpatient admissions). Most cases occurred during the reproductive age with the highest incidence among patients between 16 and 30 years (3.81 cases in 1000 inpatients). The APDs that were most frequently imputed alone for inducing galactorrhea were risperidone (52 cases and 0.19% of all exposed inpatients), amisulpride (30 resp. 0.48%), and olanzapine (13 resp. 0.05%). In three cases, quetiapine had a prominent role as a probable cause for galactorrhea. High dosages of the imputed APDs correlated with higher rates of galactorrhea. Galactorrhea is a severe and underestimated condition in psychopharmacology. While some APDs are more likely to cause galactorrhea, we identified a few unusual cases. This highlights the importance of alertness in clinical practice and of taking a patient's individual situation into consideration.

Efficacy and safety in the treatment of hyperprolactinemia: A systematic review and network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Hyperprolactinemia is a neuroendocrine disease that is responsible for a quarter of cases of secondary amenorrhea, which can lead to infertility in women. Dopaminergic agonists (bromocriptine, cabergoline, quinagolide) can be used in the treatment. However, there is a lack of secondary studies that compare their efficacy and safety, especially through a network meta-analysis. Thus, to contribute to the decision-making, a systematic review and network meta-analyses (NMA) were performed to evaluate the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. METHODS: Randomized clinical trials (RCT) were retrieved through PubMed, Web of Science and Scopus databases. The efficacy and safety of the drugs were compared, considering the following outcomes: prolactin (PRL) levels, number of patients with galactorrhoea, menstrual irregularities and adverse drug reactions. NMA was built for each outcome. Results were reported as odds ratios (OR) with 95% credibility intervals. Ranking probabilities were calculated by surface under the cumulative ranking analysis (SUCRA) and Stochastic multicriteria acceptability analysis (SMAA). RESULTS AND DISCUSSION: Seventeen RCTs were included in the systematic review and fifteen in the meta-analyses. The drugs had similar efficacy, considering the PRL levels. The SUCRA analysis showed that quinagolide (0.075 and 0.05 mg/day) was superior for reducing irregular menstruation, whereas bromocriptine was the best (97%) for galactorrhoea. Cabergoline proved to be the safest drug, except for abdominal pain at a dose of 1 mg/week. The SMAA demonstrated similar results to SUCRA. WHAT IS NEW AND CONCLUSION: This is the first network meta-analysis that evaluated the efficacy and safety of dopaminergic agonists in the treatment of hyperprolactinemia. The results of this review revealed that these drugs have similar efficacy, but cabergoline has a better safety profile.

Impact of macroprolactin on galactorrhea and the rate of patients possibly affected by macroprolactin.

The clinical influence of macroprolactin (MPRL) is not clearly understood and the rate of patients potentially affected by MPRL is unknown. We investigated the influence of MPRL on the onset of galactorrhea and estimated the rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea. Data of patients with obstetric or gynecological symptoms who had undergone PRL fractionation testing were retrospectively analyzed. To evaluate factors influencing galactorrhea, a multivariate logistic regression analysis was performed and the adjusted odds ratios of MPRL for galactorrhea were calculated. Cutoff values for the total PRL level and the proportion of MPRL fractions for galactorrhea were determined by ROC analysis using a multivariate logistic model. The prevalence of patients with a proportion of MPRL fraction greater than or equal to the cutoff value for galactorrhea was estimated. The median proportion of MPRL fraction was 30.1% and increased as PRL level increased. Total PRL and MPRL had a significant influence on the onset of galactorrhea and the adjusted odds ratio was 1.09 in total PRL and 0.94 in MPRL. The rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea was estimated to be 33.5% of the study population, and thus found to be twelve times or more the number of macroprolactinemia patients. Future prospects for hyperprolactinemia may require diagnostic criteria using free prolactin levels and so MPRL fraction measurement is important for the diagnosis and treatment of patients with obstetric and gynecological symptoms.

The prevalence of hyperprolactinemia and galactorrhea in patients with abnormal uterine bleeding.

BACKGROUND: Abnormal uterine bleeding is one of the most common gynecological problems in women aged 15-45 years. The relationship of hyperprolactinemia with reproductive disorders, amenorrhea and irregular menstrual cycles has been known. The aim of the present study was to determine the frequency of hyperprolactinemia and galactorrhea in 15-45-year-old females with abnormal uterine bleeding. METHODS: This analytic descriptive study was carried out on 100 women referred to a gynecology clinic for vaginal bleeding without any organic disorder. Consecutive sampling was performed. RESULTS: Among the cases 61% had hyperprolactinemia and galactorrhea was reported in 48% of these patients. There was a significant association between hyperprolactinemia and galactorrhea (p = 0.003); 46% of patients with galactorrhea and 75% of patients without galactorrhea had a high level of prolactin. Galactorrhea and hyperprolactinemia had no significant association with the type of abnormal uterine bleeding. Among patients with undiagnosed vaginal bleeding, hyperprolactinemia was present in more than 50% of them and in 46% it was associated with galactorrhea. CONCLUSION: Hyperprolactinemia that presents a gynecological problem may or may not be accompanied by galactorrhea, and galactorrhea cannot be a certain index for hyperprolactinemia.

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.

[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.

Incidence of galactorrhea in young women using Depot-Medroxyprogesterone Acetate.

Galactorrhea is rarely mentioned as a possible side effect of the use of Depot-Medroxyprogesterone Acetate (DMPA). Over the last few years, we have noticed an increased number of patients complaining of galactorrhea. A review of clinical data showed that between 1999 and 2005, 360 adolescents in our clinic used DMPA for at least 6 months. After medical follow-up, 13 (3.6%) of these patients were found to have developed galactorrhea. The mean age of the patients was 19.4 years with a range from 13-24. Prolactin levels in these patients were normal, and in all subjects, the galactorrhea resolved spontaneously within the next year in both patients who continued use and those who discontinued use of DMPA. It appears that galactorrhea is a benign side effect and as previous reports have suggested, it did not seem to be related to changes in Prolactin levels in our patients. It is thought that this is a progesterone-mediated effect. We believe that reassurance and education of patients is sufficient and there is no evidence of need for further intervention. Since the sample size is small in this study, additional research is recommended as to validate the presence of progesterone-mediated effects secondary to the use of DMPA.

Prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding.

OBJECTIVE: To evaluate the prevalence of hyperprolactinemia and thyroid disorders among patients with abnormal uterine bleeding (AUB) compared with matched controls. METHODS: In 2013-2014, an observational study of women with AUB (group A) and women with regular menstruation (group B) was undertaken at one center in Egypt and one in the United Arab Emirates. Eligible women were aged 20-35 years and were not obese. Participants underwent clinical examinations, vaginal ultrasonography, office hysteroscopy (in selected cases), and measurement of hormone levels. RESULTS: Hyperprolactinemia was present in 17 (16.2%) of 105 patients in group A and 4 (3.2%) of 125 patients in group B (P=0.009). In group A, a high thyroid-stimulating hormone (TSH) level was observed in 8 (7.6%) patients and low levels of free triiodothyronine/thyroxine were found in 5 (4.8%) patients, compared with 2 (1.6%) patients and 1 (0.8%) patient in group B (P=0.012 and P=0.008, respectively). Polymenorrhea was the most frequent presentation of AUB (n=60 [57.1%]). Five (29.4%) patients with hyperprolactinemia had galactorrhea. In group A, 8 (47.1%) patients with a high TSH had hyperprolactinemia, whereas 1 (1.1%) patient with a high TSH had a normal prolactin value (P=0.008). CONCLUSION: Screening by evaluating prolactin and thyroid hormone levels is recommended for all patients with AUB, even in the absence of galactorrhea.

Incidence of galactorrhea in ovulatory and anovulatory females.

The incidence of galactorrhea in 480 ovulatory females was compared to that in 383 anovulatory females. One percent of the ovulatory and 3.2% of the anovulatory patients had bilateral galactorrhea. The probability (P) of these two groups being from the same population was less than 0.02.

Nonpuerperal breast secretion. Its relation to the use of oral contracetpives.

The occurrence of breast secretion more than 1 year postpartum was studied in 800 healthy, parous women of childbearing age. Among of 418 women who were using a combination-type oral steroid contraceptive, the incidence of breast secretion was lower than among the nonusers. The incidence of bilateral secretion decreased with increasing duration of use of the oral contraceptives. Statistical material is presented for the incidence of breast secretion as related to age. time elapsed since last delivery, and duration of nursing the last child. Brownish secretion rather than white or yellowish is seen more often in women over 30 years of age. Various menstrual irregularities (excluding amenorrhea) do not appear to be associated with an increased incidence of breast secretion.

Hyperprolactinemia in women with paternal deprivation during childhood.

It was reported that most females with prolactinoma, idiopathic hyperprolactinemia, or euprolactinemic galactorrhea were reared either without their father or with an alcoholic, violent father. To gain further insight into this association, a group of sisters of patients with prolactinoma (generally exposed to the same environment as the patients') and a control group were studied. Women with paternal deprivation during childhood differed from the women who had normal childhoods in that they had: 1) higher mean serum prolactin concentration (14.7 versus 9.4 ng/mL; P less than .001); 2) higher incidence of hyperprolactinemia (12 of 50 versus three of 59; P less than .005); and 3) higher incidence of galactorrhea (14 of 50 versus seven of 59: P less than .03). These observations support the contention that paternal deprivation during childhood is associated, in a minority of women, with a predisposition to develop hyperprolactinemia and presumably, prolactinoma later in life. A hypothesis on the possible mechanisms of a casual relationship is presented.

Case-control study of galactorrhea and its relationship to the use of oral contraceptives.

A case-control study was performed to determine the relationship between galactorrhea and the use of oral contraceptives as well as other risk factors. The cases included all 109 Olmsted County residents who satisfied the diagnostic criteria for galactorrhea between 1970 and 1980. Control subjects were selected from a sampling frame of all medical registrations and matched to the cases by age, year, and residency. Pituitary adenomas were strongly associated with galactorrhea, as the relative risk was 23.2 (95% confidence interval 2.0 to 90.0). In galactorrhea cases without pituitary adenomas there was an association with oral contraceptives (ever use versus never use), as the relative risk was 2.3 (95% confidence interval 1.3 to 4.4). Among current users of oral contraceptives, the risk of galactorrhea was not increased, but there was a trend of diminishing risk with duration of use. The estimate of relative risk was 3.1 after discontinuation of oral contraceptive use and was highest for the first year after discontinuation (5.5), compared with a year or more after discontinuation (2.1). Thus, galactorrhea was associated with the cessation of oral contraceptives.

Nipple discharge.

The evaluation and management of nipple discharge can be undertaken with minimal difficulty by performing a careful history and examination and following a logical thought process in linking the type of discharge with the suitable mode of treatment. In this manner, the patient's discharge can be efficiently and thoroughly evaluated.

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.

Age and adverse drug reactions from psychopharmacological treatment: data from the AMSP drug surveillance programme in Switzerland.

QUESTION UNDER STUDY: The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years. METHODS: Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP. RESULTS: A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions. CONCLUSION: The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

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.

A case with euprolactinemic galactorrhea induced by escitalopram.

Endocrine and reproductive side effects of serotonergic antidepressants are uncommon and galactorrhea is only rarely mentioned among SSRI-related side effects. Perhaps through suppression of dopamine neurotransmission releasing prolactin from tonic inhibitor control of dopamine, serotonin-enhancing antidepressants may result in a rise in prolactin levels. However, we here describe a case of euprolactinemic galactorrhea induced by the SSRI escitalopram and discuss potential mechanisms of action.