Monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia.

The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac valvulopathy in this population of patients are low, fewer and fewer endocrinologists adhere strictly to the original medicines and healthcare products agency MHRA guidance of "at least" annual echocardiography. Strict adherence to this guidance would be costly in monetary terms (£5.76 million/year in the UK) and also in resource use (90,000 extra echocardiograms/year). This article reviews the proposed pathophysiological mechanism underlying the phenomenon of dopamine agonist valvulopathy, the characteristic echocardiographic changes seen, summarises the published literature on the incidence of valvulopathy with low dose cabergoline and examines the previous and current evidence-based screening guidelines.

Macroprolactinomas: longitudinal assessment of biochemical and imaging therapeutic responses.

PURPOSE: To assess biochemical and imaging therapeutic response rates, when these occur and their predictive factors in patients with macroprolactinomas treated with dopamine agonists (DA). METHODS: Retrospective, longitudinal study of patients with macroprolactinomas treated with DA for ≥12 months. OUTCOMES: prolactin normalization, reduction in maximum tumor diameter ≥50% and time until therapeutic responses. RESULTS: We included 67 patients; 49.3% females, with median age at diagnosis of 43 years, 61.2% only treated with bromocriptine, 10.4% only with cabergoline, and 28.4% with both DA. Median follow-up time was 73 months. Prolactin levels normalized in 87%, mostly during the first 2 years. Prolactin levels after 6 months (HR 0.994, p = 0.012), 1 year (HR 0.970, p = 0.003), and 2 years (HR 0.970, p = 0.015) predicted its normalization time. Only 62% of the patients achieved a ≥50% reduction in maximum tumor diameter. Percent tumor diameter reduction after 1 year (OR 1.098, p = 0.022) and 2 years (OR 1.102, p = 0.008) predicted a ≥50% size reduction. Size reduction occurred later than prolactin normalization. Initial tumor diameter (HR 1.050, p = 0.032) and its percent reduction at 6 months (HR 1.110, p = 0.002), 1 (HR 1.060, p < 0.001), 2 (HR 1.045, p < 0.001), 3 (HR 1.048, p = 0.002), and 4 years (HR 1.074, p = 0.042) predicted the time until imaging response. CONCLUSION: A significant number of patients did not obtain an imaging response. Biochemical and imaging responses were asynchronous and occurred mainly in the first 4 years of treatment. This may allow an earlier identification of partially resistant and resistant macroprolactinomas, with consequent change in the therapeutic approach.

Cost-Effectiveness Analysis of Microscopic and Endoscopic Transsphenoidal Surgery Versus Medical Therapy in the Management of Microprolactinoma in the United States.

BACKGROUND: Although prolactinomas are treated effectively with dopamine agonists, some have proposed curative surgical resection for select cases of microprolactinomas to avoid life-long medical therapy. We performed a cost-effectiveness analysis comparing transsphenoidal surgery (either microsurgical or endoscopic) and medical therapy (either bromocriptine or cabergoline) with decision analysis modeling. METHODS: A 2-armed decision tree was created with TreeAge Pro Suite 2012 to compare upfront transsphenoidal surgery versus medical therapy. The economic perspective was that of the health care third-party payer. On the basis of a literature review, we assigned plausible distributions for costs and utilities to each potential outcome, taking into account medical and surgical costs and complications. Base-case analysis, sensitivity analysis, and Monte Carlo simulations were performed to determine the cost-effectiveness of each strategy at 5-year and 10-year time horizons. RESULTS: In the base-case scenario, microscopic transsphenoidal surgery was the most cost-effective option at 5 years from the time of diagnosis; however, by the 10-year time horizon, endoscopic transsphenoidal surgery became the most cost-effective option. At both time horizons, medical therapy (both bromocriptine and cabergoline) were found to be more costly and less effective than transsphenoidal surgery (i.e., the medical arm was dominated by the surgical arm in this model). Two-way sensitivity analysis demonstrated that endoscopic resection would be the most cost-effective strategy if the cure rate from endoscopic surgery was greater than 90% and the complication rate was less than 1%. Monte Carlo simulation was performed for endoscopic surgery versus microscopic surgery at both time horizons. This analysis produced an incremental cost-effectiveness ratio of $80,235 per quality-adjusted life years at 5 years and $40,737 per quality-adjusted life years at 10 years, implying that with increasing time intervals, endoscopic transsphenoidal surgery is the more cost-effective treatment strategy. CONCLUSIONS: On the basis of the results of our model, transsphenoidal surgical resection of microprolactinomas, either microsurgical or endoscopic, appears to be more cost-effective than life-long medical therapy in young patients with life expectancy greater than 10 years. We caution that surgical resection for microprolactinomas be performed only in select cases by experienced pituitary surgeons at high-volume centers with high biochemical cure rates and low complication rates.

Toxicological assessment of drugs that affect the endocrine system in puberty-related disorders.

INTRODUCTION: Toxicologists must ensure that clinical risk-to-benefit analysis should be made both for genders and age groups, with any treatment. Puberty concerns physiological changes leading to organism's maturation. Pubertal growth disorders are increasing in last decades: besides causing physical and psychological distress, they may signal underlying endocrine-metabolic abnormalities with serious health consequences later on. Therapeutic approaches for some health conditions in childhood and adolescence are considered. AREAS COVERED: The authors discuss how some diseases and treatments can impact pubertal growth. The authors look at particular immunological disorders such as asthma and how both the disease and treatment affects pubertal growth. They also discuss how the provision of available data can help to assess the dose-response of the drug, in these cases, and minimize the chance of side effects. The authors also discuss pediatric inflammatory bowel disease and how both the disease and treatment can mitigate the growth delay. Last, but not least, the authors discuss how the effects of the drugs used in the treatment of psychiatric disorders may accentuate endocrine issues in juvenile patients. Hyperprolactinemia induction by some antipsychotics is highlighted as an example. EXPERT OPINION: Appropriate risk-benefit analysis of drugs prescribed during childhood and adolescence and intended to be used in the long term is required. Furthermore, future treatment strategies and safer compounds development should be supported by the knowledge of mechanisms underlying adverse side effects in pubertal growth and development.

Assessment of cardiac valve dysfunction in patients receiving cabergoline treatment for hyperprolactinaemia.

OBJECTIVE: Cabergoline is a highly effective medical treatment for patients with hyperprolactinaemia. There is an increased risk of valvular heart disease in patients receiving cabergoline for Parkinson's disease. This study examined whether cabergoline treatment of hyperprolactinaemia is associated with a greater prevalence of valvulopathy. DESIGN: Cross-sectional, two-dimensional echocardiographic study performed by a single echocardiographer. PATIENTS: Seventy-two patients (median age 36 years, 19 men) receiving cabergoline for hyperprolactinaemia, and 72 controls prospectively matched for age, sex and cardiovascular risk factors. Measurements Assessment of valvular mobility, regurgitation and morphology. RESULTS: Median cumulative dose exposure for cabergoline was 126 (58-258) mg, and patients had received cabergoline for 53 (26-96) months. The frequency of mild mitral regurgitation was identical (5/72, 7%) in patient and control groups. Mild aortic regurgitation was not significantly different between groups (4/72 [controls] vs 2/72 [patients], P = 0.681). There was only one case of tricuspid regurgitation, which was mild and observed in a cabergoline-treated patient. Nodular thickening of the right coronary cusp, noncoronary cusp or left coronary cusp of the aortic valve was observed at a similar frequency in both groups. There were no cases of extensive thickening of any valvular leaflet. CONCLUSION: Our data demonstrates that there is no association between cabergoline treatment for hyperprolactinaemia and valvulopathy. This study therefore supports continued use of low-dose cabergoline for patients with hyperprolactinaemia.

Prevalence of valvular heart disease in a cohort of patients taking cabergoline for management of hyperprolactinemia.

OBJECTIVE: To determine the prevalence of valvular heart disease in a cohort of patients taking cabergoline for the management of hyperprolactinemia. METHODS: A retrospective review of medical records identified patients with hyperprolactinemia who underwent evaluation at Vanderbilt University Medical Center between January and June 2007. The medical records of those patients who were prescribed cabergoline and who underwent elective echocardiography were reviewed for details pertaining to cardiac valvular abnormalities and cabergoline use. RESULTS: Forty-five patients (mean age, 41 +/- 10 years [SD]) taking 0.91 +/- 0.96 mg of cabergoline per week for a mean duration of 39 +/- 29 months underwent echocardiography. Abnormalities of the cardiac valves were present in 3 patients (7%): 1 patient exhibited mild mitral regurgitation, 1 patient had focal aortic valve thickening, and 1 patient demonstrated mitral valve thickening. We found no significant difference in either the cumulative dose of cabergoline (P = .800) or the duration of cabergoline therapy (P = .745) between those patients with and those without these echocardiographic abnormalities. CONCLUSION: We found echocardiographic valve abnormalities in 3 of 45 patients (7%) who had been prescribed cabergoline for the management of hyperprolactinemia. This prevalence of valvular heart disease after approximately 3 years of cabergoline treatment is no different from that previously reported in normal populations as determined by echocardiography.

[The assessment of the mental state of patients during simultaneous treatment with psychotropic drugs, antipsychotics included, and bromocriptine]. / Ocena stanu psychicznego pacjentek w trakcie jednoczesnego stosowania leków psychotropowych, w tym leków przeciwpsychotycznych, oraz bromokryptyny.

AIM: The aim of this study was to assess the mental state of patients treated with psychotropic drugs (LPT) and bromocriptine (BRC) at the same time. METHODS: 25 female patients in the stable mental state treated with antipsychotics (LPP) (13 patients were also treated with other LPT) with an average age of 25.56 years were included in the study. All patients presented clinical symptoms of HPRL: menstrual disturbances or galactorrhea and their serum PRL was increased or the test with metoclopramide was incorrect. BRC (1.25-8.75 mg per day) was ordered to eliminate HPRL and observation was conducted over a period of 3 months. Two weeks, a month, 2 months and 3 months after the BRC treatment had been started, an evaluation of the mental state of the patients was conducted. The patients' mental state was evaluated with the Clinical Global Impression Scale (CGI), the Hamilton Depression Rating Scale (HDRS) and the Positive and Negative Syndrome Scale (PANSS). RESULTS: After 3 months of the study in the whole group there was no significant change in the mental state evaluated with the CGI and the HDRS. There was a worsening in PANSS (p < 0.05) which was mainly due to the worsening (p < 0.01) in the subscale of general psychiatric symptomatology of PANSS (PANSS-G). There was no significant change in the subscales of positive and negative symptoms of PANSS (PANSS-P and PANSS-N respectively). CONCLUSIONS: The results show that during the 3 months of the BRC treatment there was no worsening in positive, negative and affective symptoms. The study suggests that adding BRC may be a safe option of management of psychotropic-induced HPRL in some psychiatrically stable patients, although further studies are necessary.

Ovulation induction--optimizing results and minimizing risks.

The aim of ovulation induction therapy should be, wherever possible, to correct the underlying disturbance and achieve safe, repeated unifollicular ovulation to achieve the live birth of singleton babies. This article outlines the main causes of anovulatory infertility but deals mostly with the management of anovulatory polycystic ovary syndrome (PCOS), which is the most common problem to confront specialists in reproductive medicine. PCOS is associated with insulin resistance, particularly in those who are overweight. Thus, strategies to achieve weight loss and improve insulin sensitivity, including the use of drugs such as metformin, enhance reproductive function. Therapies to induce ovulation involve first the use of the anti-oestrogen clomiphene citrate. For those who fail to ovulate in response to clomiphene citrate, the principal options include parenteral gonadotrophin therapy or laparoscopic ovarian diathermy.

Detecting dose-response using contrasts: asymptotic power and sample size determination for binomial data.

Recently, Stewart and Ruberg proposed the use of contrast tests for detecting dose-response relationships. They considered in particular bivariate contrasts for healing rates and gave several possibilities of defining adequate sets of coefficients. This paper extends their work in several directions. First, asymptotic power expressions for both single and multiple contrast tests are derived. Secondly, well known trend tests are rewritten as multiple contrast tests, thus alleviating the inherent problem of choosing adequate contrast coefficients. Thirdly, recent results on the efficient calculation of multivariate normal probabilities overcome the traditional simulation-based methods for the numerical computations. Modifications of the power formulae allow the calculation of sample sizes for given type I and II errors, the spontaneous rate, and the dose-response shape. Some numerical results of a power study for small to moderate sample sizes show that the nominal power is a reasonably good approximation to the actual power. An example from a clinical trial illustrates the practical use of the results.

Resistance to cabergoline as compared with bromocriptine in hyperprolactinemia: prevalence, clinical definition, and therapeutic strategy.

To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point). After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P < 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5-7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15-20 mg/d. In these resistant macro- and microprolactinomas, the maximal tumor diameter was reduced by 43.7 +/- 3.6% and 22.1 +/- 3.7% and by 59.3 +/- 7.1% and 4.3 +/- 2.1% after CAB and BRC, respectively (P < 0.001). In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion.

Abnormal LH pulsatility in women with hyperprolactinaemic amenorrhoea normalizes after bromocriptine treatment: deconvolution-based assessment.

OBJECTIVE: The present study examines the LH secretory process in hyperprolactinaemic women before, during and after bromocriptine therapy, using restrictive clinical selection criteria as well as improved methodological tools. PATIENTS AND DESIGN: Six women (aged 20-40 years) with microprolactinomas (mean +/- SE prolactin, PRL: 2478 +/- 427 mU/l, range: 1370-3800 mU/l) and four age- and sex-matched healthy controls were admitted to the study. After an overnight fast, all patients and controls had blood samples withdrawn at 10 minute intervals for 6 h (during saline infusion) from 0800 h to 1400 h to determine serum LH and PRL concentrations. After baseline evaluation, patients were treated with bromocriptine, which was started at a daily dose of 1.25 mg for 7 days; the dose was then increased to 2.5 mg daily for the next 7 days and subsequently to 2.5 mg twice daily. PRL levels were evaluated at weekly intervals after the beginning of bromocriptine therapy for the duration of the study. The 6 h pulsatility study was repeated on four patients during treatment at a time when PRL levels were decreased, although not normalized (PRL range: 450-1350 mU/l) and, on four patients, with the attainment of normal serum PRL levels (PRL < 450 mU/l) in the early follicular phase of the menstrual cycle (days 2-5). The LH instantaneous secretion rate was reconstructed by a nonparametric deconvolution method. In addition to pulse analysis made using the program DETECT, the evaluation of the secretion rate yielded the pulse frequency as well as the pulse amplitude distribution. RESULTS: Each time series was submitted to deconvolution analysis using a nonparametric method in order to estimate the instantaneous secretion rate (ISR). Hyperprolactinaemic patients had very few high-amplitude LH pulses above 0.2 IU/(l minutes) before treatment (average frequency: 0.83 +/- 0.40 pulses/6 h) and at the intermediate evaluation (0.25 +/- 0.25 pulses/6 h). In both cases, the pulse frequency was significantly lower than in controls (P < 0.05 and P < 0.01, respectively). When PRL was normalized, the number of high-amplitude LH pulses (4.25 +/- 1.03 pulses/6 h), became statistically different from the pulse number before (P < 0.01) and during (P < 0.01) therapy; in particular the pulse frequency after therapy rose to a level not statistically different from that in controls. CONCLUSION: The present study shows the presence of reduced LH pulsatility in hyperprolactinaemic women that recovers completely to within the physiological distribution when PRL levels are normalized by bromocriptine therapy.

Assessment of quality of life in recently post-menopausal women on dopaminergic therapy for pathological hyperprolactinaemia.

BACKGROUND: Psychological distress has been reported in pre-menopausal hyperprolactinaemic women. The aim of this study was to assess quality of life in a group of recently post-menopausal women with a long-term history of hyperprolactinaemia. METHODS: Thirty-one recently post-menopausal hyperprolactinaemic women (age range 46-59 years) and 37 control women matched for age and menopausal status. Hyperprolactinaemia had been diagnosed 2-22 years before the study. All hyperprolactinaemic women were on dopaminergic therapy. The self-rating Kellner Symptom Questionnaire (KSQ) and the Hamilton Depression Scale (HDS) were used to evaluate psychiatric profile. Evaluation of climacteric symptoms was performed with the ad-hoc self-rating 21-item Menopausal Rating Scale (MRS). Serum PRL, E2, LH, FSH, and free-thyroid hormones were evaluated. RESULTS: Hyperprolactinaemic women showed normal PRL on dopaminergic therapy. No difference was noted in PRL, LH, FSH, free-T4, and E2 levels between groups. Free-T3 was significantly (p = 0.001) lower in hyperprolactinaemic than in control women. There was no difference in overall scores on the MRS between the groups. Only the item "rapid and strengthened heart-beat" was significantly (p = 0.04) lower in hyperprolactinaemic than in control women. Control women showed a significant correlation between the score for this item and free-thyroid hormone levels. Overall KSQ scores and subsection analysis of items did not show significant differences between groups. On HDS evaluation, depressive symptoms were similar in hyperprolactinaemic and control women. CONCLUSIONS: Quality of life seems unchanged in recently post-menopausal women with a long-term history of hyperprolactinaemia currently on dopaminergic therapy. The present study does not therefore support the differences in psychological profile reported in literature between untreated hyperprolactinaemic and control women unselected for age.

Assessment of the implantation site by transvaginal ultrasonography.

OBJECTIVE: To investigate the implantation site in a singleton pregnancy. DESIGN: Transvaginal ultrasonography (US) was performed at the mid or late follicular phase and/or at very early gestation before 6 weeks. SETTING, PATIENTS: Ultrasound monitoring was performed on 21 women with spontaneous cycles or treated by administration of 2.5 mg/d bromocriptine mesylate (Parlodel; Sando Co., Tokyo, Japan) for occulted hyperprolactinemia at the Fertility Clinic of the Department of Obstetrics and Gynecology at Gunma University Hospital. MAIN OUTCOME MEASURES: The site of the ovary with a growing follicle and/or a corpus luteum of pregnancy, and the location of a gestational sac in longitudinal and transverse views were observed. RESULTS: When ovulation occurred in the right ovary, 12 of the 14 gestational sacs were located on the right wall, 1 on the midwall, and 1 on the left wall. Ovulation in the left ovary resulted in 5 gestational sacs located in the left wall and 2 on the midwall. That is, of 21 gestational sacs, 17 were located on the ipsilateral uterine wall to the ovulating ovary, 3 on the midwall, and only 1 on the contralateral. CONCLUSION: Implantation occurs on the ipsilateral uterine wall to the ovulating ovary.