112 research outputs found
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
Deaths Among Adult Patients with Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality.
Context:Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.Objective:To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.Design and Methods:All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed.Main Outcome Measures:Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.Results:An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy.Conclusion:Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease
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
Serum prolactin concentrations as risk factor of metabolic syndrome or type 2 diabetes?
Treatment of hyperprolactinaemia reduces total cholesterol and LDL in patients with prolactinomas
The effect of short-term metformin treatment on plasma prolactin levels in bromocriptine-treated patients with hyperprolactinaemia and impaired glucose tolerance: a pilot study
Windows 10 újdonságok - a Windows operációs rendszerek és azok tulajdonságainak bemutatása, elemzése
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