Patients with hyperprolactinemia clinical and epidemiological perspectives

Hyperprolactinemia (HPL) is the most common endocrine disorder of the hypothalamicpituitary axis and prolactinomas the most frequent pituitary tumour. A majority of the patients are women in reproductive age seeking health care for menstrual disorders or infertility. Because a majority of the patients are relatively young at diagnosis and the medical treatment often life-long, it is essential to study the efficacy of treatment and longterm results in these patients. Data are lacking in women with HPL concerning parity and there is still a void of studies evaluating cancer risk and whether the metabolic state is altered in patients with elevated prolactin (PRL) levels. This thesis, which contains four studies addressing these issues, is aimed to improve our knowledge and the quality of clinical management in patients with HPL. Long-term outcome of treatment: A total of 271 women with HPL were retrospectively evaluated. At diagnosis, 87% of the women presented with menstrual disturbances and 47% had galactorrhea. The outcome after up to 29 years of clinical follow-up (median 9.3 years) showed a good treatment result with restoration of menses and galactorrhea in 94% of the women. Medical therapy with dopamine (DA) agonists normalised PRL levels in 71% of the patients and 80% had a total or partial degree of tumour reduction. Fifty-three per cent (9 of 17) of the surgically treated patients and one third (three of nine) of the patients treated with radiotherapy exhibited long-term normalisation of PRL levels without medical treatment. Parity and pregnancy outcome: In this matched cohort study (271 women with HPL and 1084 comparison subjects) a reduced parity was found in HPL patients, mainly because there were more nulliparous women and fewer women with more than two children. Parity was inversely associated with HPL status (P for trend =0.0009). No increased risk of pregnancy or delivery complications was found. In addition, outcomes of the newborns did not differ between patients and controls. Cancer risk: A small, though significant, increased risk of overall cancer was found in 969 patients with HPL (668 women and 301 men) as compared with matched comparison subjects (hazard ratio [HR] 1.31; 95% CI 1.02-1.68) which was mainly due to increased risk of upper gastrointestinal cancer in all patients and hematopoietic cancer in females. Risk of breast cancer did not differ between patients and controls. Furthermore, a reduced risk of prostate cancer by 60% was found in HPL men (HR 0.40; 95% CI 0.16-0.99). Metabolic assessment: Evaluation of 14 consecutive patients with prolactinomas (eight women and six men) before and after normalisation of PRL levels by DA agonist therapy revealed that HPL men had an unfavourable metabolic profile at diagnosis. After therapy, a significant decrease of body weight, waist circumference and body fat% was found in the men. A positive correlation between PRL levels and low-density lipoprotein (LDL) cholesterol at diagnosis was seen and LDL cholesterol decreased after 2 months of DA agonist treatment. Furthermore, peripheral insulin sensitivity evaluated with a euglycemic hyperinsulinemic clamp tended to improve after therapy. This improvement was associated with a reduction in PRL levels. In conclusion, the results of this thesis show that HPL patients can be effectively treated with DA agonists in the long-term perspective and emphasise its role as first-line therapy. Women treated for HPL have a reduced parity, but there are no increased risks during pregnancy or for their offspring. The small increased risk of cancer that was found in HPL patients and the possible negative effect of elevated PRL levels on metabolic state need to be further evaluated; however, it implies the need for an active treatment approach and close follow-up of patients with HPL

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.Peer reviewe

National Incidence and Prevalence of TSH-Secreting Pituitary Adenomas in Sweden.

Context:TSH-secreting pituitary adenomas (TSHomas) are rare. Epidemiological data are scant and there are no reports on national incidence.Objective:The objective of the study was to estimate the national Swedish incidence and prevalence of TSHomas.Design:This was an observational study.Setting:The study was conducted at tertiary referral centers.Patients:The Swedish Pituitary Registry and World Health Organization International Statistical Classification of Diseases and Related Health Problems coding at all university hospitals were used to identify patients diagnosed with TSHomas 1990-2010. The identified patients' medical records were studied until the latest follow-up [median 5.0 years (range < 1-20 years)].Main Outcome Measurements:Incidence, prevalence, demographics, tumor characteristics, treatment outcome, and thyroid hormone level at diagnosis were measured.Results:The age-standardized national incidence of 28 TSHoma patients was 0.15 per 1 million inhabitants per year, with an increasing incidence over time (0.05 per 1 million per year in 1990-1994 to 0.26 per 1 million per year in 2005-2009). The national prevalence in 2010 was 2.8 per 1 million inhabitants, in which 0.85 per 1 million had active disease. Most patients (n = 22) underwent pituitary surgery, 5 had radiotherapy, and 6 had somatostatin analogues. Eighteen patients were considered cured at the latest follow-up; 25% remained uncontrolled. Subjects treated for putative primary hyperthyroidism prior to diagnosis had TSH levels more than double those with intact thyroid at diagnosis (P = .013). The median time to diagnosis was longer for women than men (4 vs < 1 year, P = .026). More women than men were treated surgically (94.1% vs 54.5%, P = .022).Conclusion:This is the first estimate of a national incidence of TSHoma. Additional epidemiological studies are needed to compare these results with other geographical areas. This study suggests an increased incidence of TSHomas, in agreement with reports on other pituitary adenomas

Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up : a nationwide study

CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment. OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. DESIGN: Nationwide longitudinal register-based study. SETTING: University Hospitals in Sweden. SUBJECTS: CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register. RESULTS: In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension. CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health

Circulating Hepcidin-25 Is Reduced by Endogenous Estrogen in Humans.

Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia.We used a sensitive and specific dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist.In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels.In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency

Pituitary Metastases : A Nationwide Study on Current Characteristics with Special Reference to Breast Cancer

Objective To investigate the contemporary presentation of pituitary metastases. Patients Thirty-eight patients diagnosed with pituitary metastases from 1996 to 2018 in Sweden. Methods Pituitary metastases were confirmed by histopathology (n = 27) or considered highly likely according to radiological findings, including rapid tumor progression (n = 11). Medical records were reviewed and sellar images reexamined centrally. Results Breast and lung cancers were the most common primary tumors, in 45% and 21% of patients, respectively. Sixty-seven percent of breast cancers overexpressed human epidermal growth factor receptor 2 (HER2); 53% of pituitary metastases from breast cancers appeared ≥10 years after diagnosis of the primary tumor. At presentation, 71% appeared to have ACTH deficiency, 65% had TSH deficiency, and 26% had diabetes insipidus. Fatigue, nausea/vomiting, loss of appetite, weight loss, myalgia, and/or arthralgia were reported in 47% of patients with morning cortisol <100 nmol/L vs 23% with cortisol ≥200 nmol/L. Sixteen patients had visual field defects, and eight had diplopia. Intrasellar and suprasellar tumor growth was the most frequent finding. Initially, a pituitary adenoma was considered the etiology in 18% of patients. Radiotherapy, pituitary surgery, and chemotherapy were used in 68%, 68%, and 11% of patients, respectively. One and 2 years after diagnosis of pituitary metastases, 50% and 26% of patients were alive. Conclusion Pituitary metastases may be mistaken for pituitary adenomas and can appear late, especially in breast cancer. Breast cancers overexpressing HER2 seem prone to metastasize to the pituitary. Hypocortisolism may be misdiagnosed as cancer-related malaise. An increased awareness of pituitary metastases and undiagnosed pituitary failure can improve management in these patients

Increased Mortality Persists after Treatment of Cushing’s Disease : A Matched Nationwide Cohort Study

Context: Whether biochemical remission normalizes life expectancy in Cushings disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.Funding agencies: Medical Research Council of Southeast SwedenUK Research &amp; Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-930862]</p

Long-term outcomes of patients with acromegaly : a report from the Swedish Pituitary Register

Objective: To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden. Design and methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85-1.33) nor between 2001 and2011, SMR: 0.87 (0.61-1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly

Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register

Objective: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA). Design and methods: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded. Results: Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm(3). Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P &lt; .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively. Conclusions: Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA

Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome

Objective: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST). Design and methods: Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves. Results: The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h. Conclusion: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better