The PRolaCT studies - a study protocol for a combined randomised clinical trial and observational cohort study design in prolactinoma.

BACKGROUND: First-line treatment for prolactinomas is a medical treatment with dopamine agonists (DAs), which effectively control hyperprolactinaemia in most patients, although post-withdrawal remission rates are approximately 34%. Therefore, many patients require prolonged DA treatment, while side effects negatively impact health-related quality of life (HRQoL). Endoscopic transsphenoidal resection is reserved for patients with severe side effects, or with DA-resistant prolactinoma. Surgery has a good safety profile and high probability of remission and may thus deserve a more prominent place in prolactinoma treatment. The hypothesis for this study is that early or upfront surgical resection is superior to DA treatment both in terms of HRQoL and remission rate in patients with a non-invasive prolactinoma of limited size. METHODS: We present a combined randomised clinical trial and observational cohort study design, which comprises three unblinded randomised controlled trials (RCTs; PRolaCT-1, PRolaCT-2, PRolaCT-3), and an observational study arm (PRolaCT-O) that compare neurosurgical counselling, and potential subsequent endoscopic transsphenoidal adenoma resection, with current standard care. Patients with a non-invasive prolactinoma (< 25 mm) will be eligible for one of three RCTs based on the duration of pre-treatment with DAs: PRolaCT-1: newly diagnosed, treatment-naïve patients; PRolaCT-2: patients with limited duration of DA treatment (4-6 months); and PRolaCT-3: patients with persisting prolactinoma after DA treatment for > 2 years. PRolaCT-O will include patients who decline randomisation, due to e.g. a clear treatment preference. Primary outcomes are disease remission after 36 months and HRQoL after 12 months. DISCUSSION: Early or upfront surgical resection for patients with a limited-sized prolactinoma may be a reasonable alternative to the current standard practice of DA treatment, which we will investigate in three RCTs and an observational cohort study. Within the three RCTs, patients will be randomised between neurosurgical counselling and standard care. The observational study arm will recruit patients who refuse randomisation and have a pronounced treatment preference. PRolaCT will collect randomised and observational data, which may facilitate a more individually tailored practice of evidence-based medicine. TRIAL REGISTRATION: US National Library of Medicine registry (ClinicalTrials.gov) NCT04107480 . Registered on 27 September 2019, registered retrospectively (by 2 months).

A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report.

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.

Anatomy, Physiology, and Laboratory Evaluation of the Pituitary Gland.

The pituitary gland functions prominently in the control of most endocrine systems in the body. Diverse processes such as metabolism, growth, reproduction, and water balance are tightly regulated by the pituitary in conjunction with the hypothalamus and various downstream endocrine organs. Benign tumors of the pituitary gland are the primary cause of pituitary pathology and can result in inappropriate secretion of pituitary hormones or loss of pituitary function. First-line management of clinically significant tumors often involves surgical resection. Understanding of normal pituitary physiology and basic testing strategies to assess for pituitary dysfunction should be familiar to any skull base surgeon.

Effect of risperidone on prolactinoma growth in a psychotic woman.

OBJECTIVE: The case of a psychotic woman is described in which risperidone use was found to correspond with an increase in the size of a prolactinoma and prevented the return of serum prolactin level to baseline. METHODS: Although the patient had been treated with a high dose of bromocriptine, her prolactin level remained elevated, causing persistent galactorrhea. The patient later was treated with olanzapine and carbamazepine successfully. RESULTS: This case report highlights the role of risperidone on prolactin and discusses alternative methods of treating psychosis when the etiology is unclear, especially in younger patients. CONCLUSIONS: The authors recommend that additional studies regarding the relationship between the growth of prolactinoma and atypical antipsychotics would be worthwhile.

Establishment of reference values for endocrine tests. II: Hyperprolactinemia.

BACKGROUND: In patients with hyperprolactinemia, the thyrotropin-releasing hormone (TRH) stimulation test is widely applied to distinguish prolactinoma from other causes of hyperprolactinemia. In the present study, we established reference values for the plasma concentration of prolactin (PRL) and its response to TRH. METHODS: Basal PRL and the PRL response to 400 micrograms TRH i.v. was determined in 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. PRL was determined by a fluoroimmunometric assay. Reference values are given as the observed range. RESULTS: Plasma concentrations of PRL were 4.0-25 micrograms/l (median: 10.0 micrograms/l) in women and 0.5-19.0 micrograms/l (median: 8.5 micrograms/l) in men (p = 0.11). The peak PRL concentration after stimulation with TRH was slightly higher in women (median: 51 micrograms/l) than in men (median: 41 micrograms/l; p = 0.04) and was reached at t = 20 min in all subjects. The relative increase in plasma PRL (median: 440%) did not show a statistically significant effect of age or sex. In 12 subjects (24%), the relative increase in plasma PRL was lower than 250%, which has traditionally been considered the minimum cutoff for a normal response. There were no effects of smoking and alcohol, but regular ingestion of liquorice was associated with lower basal (p = 0.03) and lower stimulated (p = 0.05) plasma concentrations of PRL. CONCLUSIONS: The present study provides reference values for basal and TRH-stimulated plasma concentrations of PRL.

Analyzing amenorrhea.

When menarche has failed to occur or menstrual cycles have stopped, the problem can be traced back to a functional or structural defect in the hypothalamus, pituitary, ovaries, or uterus. In most cases, the history is the principal source of diagnostic information. Necessary laboratory studies include one for the most common cause of amenorrhea: pregnancy.

Detection of pituitary microadenomas: comparison of dynamic keyhole fast spin-echo, unenhanced, and conventional contrast-enhanced MR imaging.

OBJECTIVE: Pituitary microadenomas may not be detected on conventional MR images. We supplemented conventional unenhanced and contrast-enhanced MR imaging with a dynamic keyhole fast spin-echo (kFSE) method in order to compare how frequently a microadenoma could be detected with the three different methods. SUBJECTS AND METHODS: Eighteen consecutive patients with clinical and laboratory evidence of pituitary microadenomas had unenhanced, dynamic kFSE, and conventional contrast-enhanced MR imaging of the pituitary gland. A control group of 13 subjects without pituitary disease also had dynamic kFSE MR imaging. Hard copies of all the studies were obtained in an identical fashion, and then the MR images of the patients and control subjects were randomly mixed. The studies were reviewed by a neuroradiologist who had no knowledge of the clinical status of the subjects. The presence or absence of any pituitary focal hypointensity consistent with the appearance of a microadenoma was noted. RESULTS: A pituitary lesion consistent in appearance with a microadenoma was detected on dynamic kFSE images in 13 of the 18 patients, on unenhanced images in nine patients, and on conventional contrast-enhanced images in 10 patients. In four patients, a microadenoma was detected on dynamic kFSE images only. Dynamic kFSE images showed a lesion in four of the 13 control subjects. CONCLUSION: Dynamic kFSE MR imaging is a useful supplemental sequence in patients undergoing MR imaging because of pituitary endocrinopathy. It may show lesions that would otherwise escape detection.

MR imaging of pituitary region lesions with gadodiamide injection.

Twelve patients with known or suspected pituitary lesions underwent MR imaging with gadodiamide injection at a dose of 0.1 (n = 5) or 0.3 (n = 7) mM/kg. Six of the patients were also studied with 0.1 mM/kg gadopentetate dimeglumine. Consistent with previous reports gadodiamide injection was found to be a safe and effective contrast medium for MR imaging of the pituitary region. No additional diagnostic information was obtained using 0.3 mM/kg gadodiamide injection compared to 0.1 mM/kg gadopentate dimeglumine in the same patients. The high dose (0.3 mM/kg) gadodiamide injection in 7 patients did not shorten the T2 value sufficiently to overwhelm the T1 shortening and leave pathologic lesions hypointense compared to precontrast studies. With the comparable relaxivities of gadodiamide injection and gadopentetate dimeglumine, similarities in results have to be expected when using these media for MR image enhancement.

Prolactinoma: avaliaçäo da eficácia dos métodos complementares para seu diagnóstico e da terapia com bromocriptina / Prolactinoma: effectiveness of the diagnostic methods and bromocriptine therapy

Os objetivos do presente trabalho foram de analisar os aspectos clínicos, radiológicos e laboratoriais do prolactinoma diagnosticado em 15 mulheres e correlacioná-los com a terapia com bromocriptina (BRC). Todas pacientes tinham PRL 50ng/ml sendo sete com microprolactinoma (Grupo I) e oito com macroprolactinoma (Grupo II). A queixa mais freqüente foi distúrbio menstrual (100 por cento) sendo a galactorréia presente em 60 por cento. Os sintomas e sinais independeram dos níveis de PRL. Estes foram superiores a 200ng/ml em cinco das pacientes do Grupo I e em apenas dois do Grupo II. A tomografia computadorizada foi efetiva para o diagnóstico dos tumores e o teste do TRH mostrou-se bastante sensível e até mesmo precedeu, em alguns casos, as alteraçöes radiológicas encontradas posteriormente. A BRC mostrou-se efetiva no tratamento tanto dos micro quanto dos macroprolactinomas, havendo melhora clínica, radiológica e laboratorial após seu uso.

Control of prolactin secretion.

1. Prolactin is a 21,500 Dalton single-chain polypeptide hormone but may occur in 50 kDa and 150 kDa molecular variants. 2. These large PRL variants may be secreted predominantly; this condition is termed "macroprolactinemia". It is characterized by high immunological and normal biological serum levels of prolactin, and lack of clinical symptoms of hyperprolactinemia. 3. The information on PRL is encoded on chromosome 6. Transcription can be enhanced and suppressed by a variety of hormonal factors. 4. PRL is secreted in a pulsatile fashion; it displays a circadian rhythm (with a maximum during sleep) and is stimulated by some amino acids. PRL also responds to mechanical stimulation of the breast. 5. PRL rises during pregnancy, and maintainance of hyperprolactinemia (and, thereby, physiological infertility) is dependent on the frequency and duration of breast feedings. 6. Hypothalamic regulation of prolactin mainly involves tonic inhibition via portal dopamine. The physiological importance of various stimulating factors present in the hypothalamus is still incompletely understood. In particular, there is still no place for TRH in PRL physiology. 7. PRL is released in response to stress; this response may be mediated by opioids. The low-estrogen, low-gonadotropin amenorrhea of endurance-training women is not mediated by prolactin, however. 8. Estrogens stimulate PRL gene transcription via at least two independent mechanisms. There are many clinical examples of this estrogen effect on prolactin serum levels, and also on the growth of prolactinomas. 9. Mild hyperprolactinemia remains an enigma which cannot satisfactorily be resolved by biochemical or radiological testing. The border between "normal" and "elevated" prolactin is ill-defined. The possibility of macroprolactinemia complicates this matter even further. 10. The number of drugs which suppress prolactin by acting on pituitary D2 receptors, and which are useful in the treatment of hyperprolactinemia, continues to increase. In the field of ergot alkaloids, parenteral application appears to be a logical solution to the problem of the high first-pass effect; in addition, this form of treatment is frequently better tolerated than the oral route. 11. Prolactinoma development is presently being studied employing molecular biological techniques; the question of whether tumorigenesis can be attributed to specific defects of gene regulation remains to be answered.