A Genetic Assessment of Dopamine Agonist-Induced Impulse Control Disorder in Patients With Prolactinoma.

CONTEXT: Dopamine agonist (DA)-induced impulse control disorder (ICD) represents a group of behavioral disorders that are increasingly recognized in patients with prolactinoma. OBJECTIVE: We aimed to examine the genetic component of the underlying mechanism of DA-induced ICD. METHODS: Patients with prolactinoma receiving dopamine agonist (cabergoline) treatment were included in the study. These patients were divided into 2 groups: patients who developed ICD due to DA and patients who did not. Patients were evaluated for polymorphisms of the DRD1, DRD3, COMT, DDC, GRIN2B, TPH2, OPRK1, OPRM1, SLC6A4, SLC6A3, HTR2A genes. RESULTS: Of the 72 patients with prolactinoma using cabergoline, 20 were diagnosed with ICD. When patients with and without ICD were compared according to genotype frequencies, OPRK1/rs702764, DRD3/rs6280, HTR2A/rs6313, SLC6A4/rs7224199, GRIN2B/rs7301328, TPH2/rs7305115, COMT/rs4680, DRD1/rs4532 polymorphisms significantly increased in patients with DA-induced ICD. CONCLUSION: Our results show that multiple neurotransmission systems affect DA-induced ICD in patients with prolactinoma.

Cost-effectiveness of direct surgery versus preoperative octreotide therapy for growth-hormone secreting pituitary adenomas.

PURPOSE: The objective of this study was to compare the cost-effectiveness of preoperative octreotide therapy followed by surgery versus the standard treatment modality for growth-hormone secreting pituitary adenomas, direct surgery (that is, surgery without preoperative treatment) from a public third-party payer perspective. METHODS: We developed an individual-level state-transition microsimulation model to simulate costs and outcomes associated with preoperative octreotide therapy followed by surgery and direct surgery for patients with growth-hormone secreting pituitary adenomas. Transition probabilities, utilities, and costs were estimated from recent published data and discounted by 3% annually over a lifetime time horizon. Model outcomes included lifetime costs [2020 United States (US) Dollars], quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: Under base case assumptions, direct surgery was found to be the dominant strategy as it yielded lower costs and greater health effects (QALYs) compared to preoperative octreotide strategy in the second-order Monte Carlo microsimulation. The ICER was most sensitive to probability of remission following primary therapy and duration of preoperative octreotide therapy. Accounting for joint parameter uncertainty, direct surgery had a higher probability of demonstrating a cost-effective profile compared to preoperative octreotide treatment at 77% compared to 23%, respectively. CONCLUSIONS: Using standard benchmarks for cost-effectiveness in the US ($100,000/QALY), preoperative octreotide therapy followed by surgery may not be cost-effective compared to direct surgery for patients with growth-hormone secreting pituitary adenomas but the result is highly sensitive to initial treatment failure and duration of preoperative treatment.

Depression and Impulsivity Self-Assessment Tools to Identify Dopamine Agonist Side Effects in Patients With Pituitary Adenomas.

Background: Dopamine agonists (DA) are the first line therapy for prolactinoma and symptomatic hyperprolactinemia; use as an adjuvant treatment for acromegaly and Cushing's disease is rare. Some patients develop de novo psychiatric symptoms or have exacerbation of pre-existing conditions during DA therapy. A practical, clinically sensitive depression and impulse control disorders (ICD; particularly hypersexuality and gambling disorders) detection tool is important for identifying at risk patients. The Barratt Impulsivity Scale (BIS-11) and the 9-item Patient Health Questionnaire (PHQ-9) are sensitive in identifying impulsivity and depression. Objective: Detail use of the BIS-11 and PHQ-9 as screening tools for depression and ICD in patients with pituitary disease at a high-volume academic pituitary center. Methods: DA-treated and naïve patients with pituitary disease were included. Patients with a known history of depression or psychiatric disorder were excluded. PHQ-9 standardized interpretation criteria were utilized to classify depression severity. For BIS-11, threshold was established based on previous studies. Statistical analysis was with SPSS version 25. Results: Seventy-six DA-treated and 27 naïve patients were included. Moderate and moderately severe depression were more prevalent in DA-treated patients; severe depression only found in DA-treated patients. A normal BIS-11 score was noted in 76.69%; higher scores (not significant) were noted in DA-treated patients. There was a positive correlation between higher BIS-11 and PHQ-9 scores; higher in DA-treated patients (r = 0.52, p < 0.001) than DA-naïve patients. Patients with BIS-11 scores ≥60 were younger and received lower cumulative DA doses compared to patients with BIS scores <60. There was no association between male sex and BIS-11 ≥60 and male sex did not increase the odds of increased scores (OR = 0.66, CI95% 0.25-1.76, p = 0.41). No significant difference was found for macroadenoma, prolactin levels, testosterone levels, hypogonadism, testosterone replacement in men, and increased impulsivity or depression scores. Conclusion: Use of PHQ-9 and BIS-11 is practical for routine screening of depression and ICD during outpatient pituitary clinic visits for patients with pituitary disease both naïve to treatment and during DA therapy. We recommend close follow-up after initiation of DA therapy for younger patients, regardless of dose.

An Economic Analysis of Bromocriptine Versus Trans-Sphenoidal Surgery for the Treatment of Prolactinoma.

Prolactinomas account for ∼40% of all pituitary adenomas and are important causes of infertility and gonadal dysfunction. In general, most prolactinomas are treated medically with dopaminergic agonists, while surgery is reserved for patients intolerant or nonresponsive to these medications. The aim of this study was to carry out a comparative analysis of the cost-effectiveness of medical therapy with bromocriptine and surgical therapy with trans-sphenoidal surgery. A Markov model was developed based on retrospective data from 126 patients with prolactinoma treated in our hospital between October 2008 and May 2009, and from data published previously. For patients with microadenoma, the cost of medical treatment was estimated to be ¥20,555, while the cost of surgery was calculated to be ¥22,527. For patients with macroadenoma, the cost of therapy with bromocriptine was ¥31,461 in males and ¥27,178 in females, while the cost of surgery was ¥42,357 in males and ¥44,094 in females. Sensitivity analyses (carried our using variations in patient age, bromocriptine therapeutic dose, bromocriptine maintenance dose, and the success rate of bromocriptine withdrawal) indicated that our model showed good stability, although our results were most heavily influenced by variations in the bromocriptine maintenance dose. It is concluded that, from an economic viewpoint, medical therapy with bromocriptine should be the first-line treatment option for patients with prolactinoma, irrespective of whether this is a microadenoma or macroadenoma.

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.

Cost-effectiveness analysis of two therapeutic schemes in the treatment of acromegaly: a retrospective study of 168 cases.

PURPOSE: This study aimed to estimate the cost effectiveness of two therapeutic schemes, including preoperative medical therapy and surgery as primary therapy. METHODS: A total of 168 acromegaly cases were retrospectively investigated for a comparative evaluation of surgery and preoperative medical therapy. A Markov model was developed to simulate treatment cost-effectiveness and progression of acromegaly. RESULTS: Overall effectiveness of preoperative medical therapy was significantly higher than surgery in acromegalic patients with macroadenoma. In addition, life expectancy, and cost per life-year gained were slightly higher in the preoperative medical therapy group than in the initial surgery group when patients received surgery as a secondary treatment. Interestingly, preoperative medical therapy achieved a significant increase in life expectancy and reduced cost for patients who received long-term medical therapy as secondary treatment. CONCLUSIONS: In acromegalic patients with macroadenoma, the cost-effectiveness analysis revealed more satisfactory outcomes in preoperative therapy, compared with primary surgery.

Effects of T3 treatment on brown adipose tissue and energy expenditure in a patient with craniopharyngioma and hypothalamic obesity.

OBJECTIVE: Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. METHODS: Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. ¹²³I-MIBG and ¹8F-FDG-PET after induction of non-shivering thermogenesis for the assessment of sympathetic and metabolic activity of BAT as well as indirect calorimetry for assessment of resting energy expenditure were performed before and during T3 treatment. RESULTS: No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. CONCLUSION: We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma.

Surgical treatment of prolactinomas: cons.

Prolactinomas account for approximately 40 % of all pituitary adenomas. Over 95 % of prolactinomas are microadenomas (< 10 mm diameter). Treatment is indicated to correct hypogonadism, restore other hormonal deficits, and alleviate local mass effects. Dopamine agonists (DA) are highly effective in achieving these goals and are well-tolerated. The vast majority of prolactinomas will respond to conventional doses of cabergoline (≤2 mg/week) that do not carry an increased risk of cardiac valvular abnormalities. DA therapy may be successful withdrawn in a subset of patients and thus is not necessarily a lifelong commitment. Although transsphenoidal surgery (TSS) is an option for prolactinoma treatment, it is less effective than medical management, carries considerably more risk, and is more expensive. The benefit/risk ratio for DA therapy compared to TSS actually becomes increasingly more favorable as tumor size increases. Therefore DA should remain the clear treatment of choice for essentially all patients with prolactinomas, reserving TSS as a second-line option for the very small number of patients that do not tolerate or are completely resistant to DA therapy.

The role of primary pharmacological therapy in acromegaly.

BACKGROUND AND OBJECTIVES: Primary pharmacological therapy may be the only viable treatment option for many patients with acromegaly, especially those presenting with advanced disease with large inoperable tumors. Long-acting somatostatin analogs are currently the first-line treatment of choice in this setting, where they provide biochemical control and reduce tumor size in a significant proportion of patients. We herein present a brief overview of the role of primary pharmacological therapy in the treatment of acromegaly within the context of Latin America and support this with a representative case study. CASE DESCRIPTION: A 20 year old male presented with clinical and biochemical evidence of acromegaly. The glucose-suppressed growth hormone (GH) was 5.3 µg/L, his insulin-like growth factor-1(IGF-1) was 3.5 times the ULN and serum prolactin greater than 4,000 µg/L. Pituitary MRI revealed a large and invasive mass, extending superiorly into the optic chiasm and laterally into the left cavernous sinus. He was treated with a combination of octreotide and cabergoline with remarkable clinical improvement, normalization of GH and IGF-1 values and striking shrinkage of the adenoma. CONCLUSION: This case illustrates how effective the pharmacological therapy of acromegaly can be and yet at the same time, raises several important issues such as the need for life-long treatment with costly medications such as the somatostatin analogs. Access to these agents may be limited in regions where resources are restricted and clinicians face challenges in order to make the most efficient use of available options.

Update on pituitary surgery.

Transsphenoidal surgery has an important role in the management of pituitary tumors and remains the primary treatment for most adenomas, with the exception of prolactinomas. This update will review the recent neurosurgical literature; modifications to the traditional microscopic approach, including the potential utility of endoscopy and intraoperative magnetic resonance imaging, are discussed. The value of experienced surgical judgment and expertise remains clear, over and above the possible advantages of current technology. Preliminary data on the relative cost-effectiveness of surgery vs. medical treatment suggest that surgical approaches compare favorably. It will be important to incorporate future technological advances in surgical technique with new medical therapies in a combined multidisciplinary approach for improved treatment algorithms.

Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status.

BACKGROUND: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours. MATERIALS AND METHODS: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'. RESULTS: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response. CONCLUSIONS: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group.

[Cost-effectiveness analysis of two therapeutic methods for prolactinoma].

OBJECTIVE: To evaluate the therapeutic responses to transsphenoidal surgery and medical therapy in terms of normalization of prolactin (PRL), mortality, morbidity and the cost-effectiveness of PRL normalization in order to establish an individualized therapeutic protocol for the patients with prolactinoma. METHODS: A retrospective study was undertaken of a consecutive series of patients with prolactinoma who were followed for at least 1 year after transsphenoidal surgery or medical treatment. The clinical characteristics and the long-term outcomes (normalization of PRL, morbidity or mortality) were assessed. Utilizing the principle of medical economics and data from the two types of treatment, we worked out a Markov chain and calculated the lowest cost of two kinds of therapeutic protocols. RESULTS: (1) The success rate of normalizing serum PRL through surgical treatment in microadenoma was 85% (22/26), and that of medical treatment was 95% (19/20). There was no statistical difference between the two therapies (P > 0.05). The success rate of normalizing serum PRL through surgical treatment in macroadenoma was 45% (19/42), and that of medical treatment was 5/5. There was a statistical difference between the two therapies (P < 0.05). (2) According to the Markov model, it would cost a microprolactinoma patient 25,129.25 yuan to normalize serum PRL by surgical treatment. This is comparable to the cost of medical treatment which would be 24,943.99 yuan. Whereas for a macroprolactinoma patient surgery would cost 35,208.20 yuan and medical treatment would cost 25,344.38 yuan. CONCLUSIONS: Medical therapy is superior to surgical treatment in regard to complication rate and cost-effectiveness for macro- and extra big prolactinomas. Transsphenoidal surgery remains an option for patients with microadenomas. Markov model is an effective way to predict the treatment cost for patients with hyperprolactinoma at different ages and with different causes.

The assessment of cabergoline efficacy and tolerability in patients with pituitary prolactinoma type.

Prolactinoma is the most frequent type of secreting pituitary tumours. In the treatment, pharmacotherapy with dopamine agonists is considered the first-line option. For many years bromocriptine, a D1 and D2 dopamine receptor agonist, has been the standard medicine for hyperprolactinemic patients. However, the treatment is frequently associated with intolerance or resistance. Recently cabergoline, a long acting, ergoline-derived, selective D2 agonist has become available and has been promoted as the initial treatment. Therefore the object of four studies was to assess the efficacy and tolerability of cabergoline in patients with prolactin-secreting pituitary adenomas. 17 patients, 13 women at the age of 21-55 years (average 37.1) and 4 men at the age of 29-45 years (average 36.3), with pathological hyperprolactinemia due to pituitary tumours were involved in the study. In all patients the increased pretreatment concentration of PRL was observed, ranging from 1047 to 1678 mlU/ml (mean 1369 mlU/ml). MRI scans revealed microprolactinomas in 11 (64.7%) cases and macroadenomas in 6 (35.3%) cases. None of the patients had previously undergone pituitary surgery and all of them were newly diagnosed, previously untreated. The patients were treated with cabergoline for 6 months. Cabergoline therapy was started at a dose of 0.5 mg twice a week for the first two months, then the dose was decreased to a 0.25 mg twice a week and finally maintained at 0.25 mg a week. After 6 months of the therapy, the normalization of serum PRL concentrations (from mean 1358 mlU/ml to mean 420 mlU/ml; p < 0.001) was achieved in 13 (76.5%) patients (8 with microprolactinoma and 5 with macroprolactinoma). In the remaining 4 patients PRL levels remained elevated but were decreased from mean 1403 mIU/ml to mean 812 mIU/ml. There were no differences, regarding CAB efficacy in lowering PRL levels, between patients with micro- and macroadenomas (p > 0.05). About 90% women resumed menstrual cycles in our study. All the other clinical pretreatment symptoms disappear in the course of the therapy. The tumour shrinkage, confirmed by control MRI was noted in 2 patients (33%) with macroprolactinoma. Cabergoline was tolerated satisfactorily by all our patients. The results have confirmed a high efficacy and a very good tolerability of CAB in the treatment of patients with pituitary adenomas. Together with a very convenient administration, such therapy can provide a very good patient compliance thus should be considered the first line option in patients with prolactinomas.

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 gall bladder dynamics, cholecystokinin release and the development of gallstones during octreotide therapy for acromegaly.

The development of gallstones is a well recognized complication of therapy with the long-acting somatostatin analogue, octreotide in patients with acromegaly. A group of nine acromegalic patients was treated with octreotide at doses of 300-600 micrograms daily for 8 months and the changes in fasting and post-prandial cholecystokinin release, and gall bladder motor function (determined by a radiosotopic technique) were assessed at regular intervals. In addition the development of any gallstones was determined by serial ultrasonography. Fasting cholecystokinin levels showed no significant change over 6 months, whereas the post-prandial levels demonstrated a significant decrease (p less than 0.01) during therapy, yet remained significantly higher than fasting levels. Twenty-four hours after commencing therapy gall bladder ejection fraction was decreased by 57 +/- 23 per cent and gall bladder ejection rate decreased by 63 +/- 19 per cent compared to the pretreatment values, whereas after 6 months' therapy a marked reduction in gall bladder ejection fraction (greater than 35 per cent) and gall bladder ejection rate (greater than 40 per cent) persisted in only four of nine patients. Three of these four patients with persistently impaired gall bladder motor function were subsequently shown to have developed either gallstones or biliary sludge during the course of therapy. We conclude that treatment with octreotide is associated with an impaired post-prandial release of cholecystokinin in all acromegalic patients, but gallstones only develop in those patients who, in addition, have evidence of a persistently impaired gall bladder motor response to cholecystokinin.

Assessment by computed tomography of the response of pituitary macroadenomas to bromocriptine.

Eleven patients with large pituitary tumours and with extrasellar extension were studied prospectively to assess the response of these tumours to bromocriptine. Five out of the six patients with high serum prolactin due to prolactinomas showed rapid and dramatic reduction in tumour size when treated with bromocriptine. In contrast, none of the five patients with non-functioning tumours showed any change in tumour size on computed tomography.