ACTA ENDOCRINOLOGICA (BUC)

Aims. Earlier studies suggested that patients with nonfunctioning pituitary adenoma (NFPA) experience premature mortality, mostly from vascular diseases. The present study aims to identify risk factors associated with mortality in patients with NFPA. Methods. All consecutive patients admitted to a tertiary neuroendocrinology center for pituitary adenoma during 2001-2010 were screened. Only those with a final diagnostic of NFPA were retained. All 196 NFPA subjects (57.7% males, mean age 52.7±0.9 years) were followed-up for allcause mortality until December 31, 2011 (1298 person-years of follow-up). PAMCOMP software was used to calculate standardized mortality ratio (SMR), using the corresponding general population as reference. Cox regression analysis evaluated the independent hazards for mortality. Results. There were 26 deaths among 196 patients as compared to 20 expected. Standard Mortality Ratio (SMR) was 1.2 (95% Confidence interval (CI) 0.83-1.86). Females had a doubled mortality ratio: SMR 2.03 (95%CI 1.01-3.64), but males had a mortality ratio similar with general population: SMR 0.87 (95%CI 0.48-1.44). More patients with hypopituitarism for at least one axis deceased (22/156, 14.10%), as compared with patients without pituitary failure (1/22 patient deceased –2.07%), p=0.03. Prednison replacement for corticotrophin insufficiency (HR 1.46 (95%CI 1.12-1.90)) was correlated to mortality in females, but not in males, and mortality rose progressively with prednison dose (log rank: p=0.01). In males, last known maximal pituitary tumour diameter (HR 1.04 (95%CI 1.001-1.08) and age at baseline (HR 1.1 (95%CI 1.05-1.1) were modestly related to mortality. Conclusions. Females with nonfunctioning pituitary adenomas and hypopituitarism had a reduced life expectancy as compared with general population, possibly related to glucocorticoid substitution or a more severe pituitary insufficiency.

We present a 18 year old phenotypic female patient who presented for primary amenorrhea. Pelvic ultrasound revealed a hypoplastic uterus and CT scan showed a hypoplastic right gonad and a left gonadal tumor with extrapelvic location. Karyotype was 46XY. Hormonal assessment indicated hypergonadotropic hypogonadism: FSH was 39.69 mUI/ml, estradiol was 28.07 pg/ml, testosterone was 0.17 ng/ml. DHEA level was high – 21 ng/ml. Gonadectomy was performed at 15 years and histologic examination diagnosed left gonadoblastoma and right teratoma in a dysgenetic gonad. The patient had a good postoperatory evolution. Menses were induced with estrogenic and then estroprogestogenic treatment. Plastic breast surgery was performed at 18 years. Establishing the genotypic sex in patients with primary amenorrhea represents a crucial step knowing that intersex disorders bearing Y chromosomal material have a high risk for gonadoblastoma and germ cell tumors.

Introduction: Prolactinomas may grow during pregnancy. Dopamine agonists (DA) prevent tumor growth, but usually suppress prolactin (PRL) both in mother and fetus. Possible long-term consequences on fetal development remain unknown.\r\nAim: to assess whether DA treatment throughout pregnancy in a dosage able to maintain physiological gestational serum levels of prolactin (PRL) still prevents prolactinoma growth.\r\nPatients and methods: We evaluated 68 pregnancies in 49 women with prolactinoma (PRM) and 46 pregnancies in healthy women as controls. Thirty-three pregnancies were recorded in 27 women treated throughout pregnancy with bromocriptine (BRC) (n = 25) or cabergoline (CAB) (n = 2) divided in 2 groups: group A (22 pregnancies in 18 patients) had suppressed serum PRL (below the 5th percentile of the control group Z during the last trimester); group B (11 pregnancies in 10 patients) had physiological serum PRL levels. Other 26 pregnancies in 21 patients were incompletely evaluated and included only in the pregnancy outcome and cure rate analysis. Treated patients were compared with the control group Y 8 women with PRM who discontinued DA after pregnancy induction (9 pregnancies) and a control group Z of 46 healthy pregnant women, randomly selected from two departments of Obstetrics. Patients with multiple pregnancies were recorded in each corresponding study group.\r\nResults: In the control group Y, tumor size showed an increase in 2 (intrasellar macroPRM) out of 8 cases (25%). DA treatment throughout gestation in 27 women with PRM prevented the growth in all cases and induced a shrinkage of more than 30% of tumor mass in 8/14 macroPRM (57.1%), i.e., in 4/7 (57.1%) of macroPRM with physiological serum PRL levels during pregnancy, and in 5/8 (62.5%) of macroPRM with suppressed PRL levels (p = NS) (1 patient had pregnancies in both groups). Low dose DA (BRC 2.5 ? 5 mg/day or CAB 0.5 mg/week) maintains physiological PRL levels in 6/12 (50%) macroPRM, but suppressed PRL in 80% of microPRM. Cure was recorded in 6/49 (12.2%) of patients. Two patients with PRM-induced neuroophthalmic syndrome were successfully treated with DA throughout 1 and respectively 3 pregnancies.\r\nConclusions: Some women with prolactinomas showed a tumour size increase if they were not treated with dopamine agonists throughout pregnancy. Maintaining physiological serum PRL levels during pregnancy (frequently with low doses of DA) prevented tumor growth, avoiding a PRL suppression that may have subtle influence on long-term foetal development.

Glycemic control can be impaired in active acromegaly and insulin sensitivity (IS) decreases with rising growth hormone (GH) levels.\r\nAim. To assess the short-term impact of transsphenoidal surgery for acromegaly on glycemic control. Methods. 11 patients with native active acromegaly due to pituitary macroadenoma were assessed before and after (2-3 months) transsphenoidal hypophysectomy. Serum glucose, GH and insulin levels were measured by immunoradiometric assay at 0, 30, 60 and 120 minutes during a 75 g OGTT before and after surgery. IGF-1 levels were measured by ELISA. Basal hepatic IS was assessed using HOMA-S% and QUICKI indexes and stimulated IS using OGTTISI. Basal and stimulated insulin secretion was assessed using HOMA-B% index and IGI respectively. Results. All patients had their acromegaly improved (mean?SD pretreatment nadir GH 34?24.7 ng/mL vs. 4.6?3.5 ng/mL postsurgery; p<0.001) but only one was cured (nadir GH<1 ng/mL, normal IGF- 1 level). Mean fasting serum glucose was lowered by 7.9 mg/dL (95% CI 1.3-14.4, p=0.03) and fasting serum insulin by 9.6 mU/mL (95% CI 1.0-18.1, p=0.02). IS increased after surgery as shown by HOMA-S% index which rose 0.25?0.18 to 0.5?0.36 (p<0.01), QUICKI which rose form 0.31?0.03 to 0.33?0.03 (p=0.001) and OGTTISI index which rose from 2.5?1.6 to 5.1 ? 3.5 (p=0.002). Insulin secretion was unchanged as shown by HOMA-B% index (313?229 presurgery vs. 227?139 postsurgery, p=NS) and IGI index (0.96 ? 0.86 presurgery vs. 0.55 ? 0.49, p=NS). Conclusions. Partial removal of the pituitary adenoma by transsphenoidal surgery in patients with acromegaly induces a significant increase in insulin sensitivity and an improvement in glycemic control at 3 months after surgery. This suggests that transsphenoidal surgery should be indicated even if complete removal of the pituitary adenoma is not achieved.

Aims: Prolonged exposure to a glucocorticoid excess leads to cognitive impairment in experimental animals as well as humans. The present study tries to identify the cognitive deficits in patients with Cushing’s syndrome and to evaluate the possible residual deficits in patients after treatment. Materials and methods: 19 patients (women) with a history of chronic endogenous hypercortisolemia were investigated for etiology using clinical and biochemical criteria. Cognitive functions were evaluated using a battery of psychometric tests: the Rey Auditory Verbal Learning Test (RAVLT), the BCR2 battery for general intellectual potential and the Prague test, for divided attention and resistance to psychic fatigue. The patients were divided into two groups (before surgical treatment– Cushing and after surgical treatment – postCushing) without differences in age or duration of studies between groups (p = ns). The controls were considered to belong to the general population for which the psychometric tests were standardized. Results: Both groups showed an altered pattern of incremental learning - scores below standard in the last two trials of the RAVLT (one sample t test, one tailed, p<0.05), and the total score (p<0.05 for PostCushing, p=0.07 for Cushing); both had very low total scores in the battery for intellectual potential. The PostCushing scores were significantly better than those of the Cushing group for only one nonverbal test (complex perceptual analysis), p<0.02. There appears to be no significant effect of cortisol exposure on distributive attention; there is however an alteration in the resistance to psychic fatigue. Daily average cortisol exposure was positively correlated with the number of errors in learning for both groups (r=0.65, p=0.058 for Cushing; r=0.85, p<0.005 for PostCushing) Duration of illness was negatively correlated with the total learning score in the PostCushing group (r=-0.68, p<0.05). For the Cushing group there was a strong negative correlation between the duration of illness, general performance (r=-0.81, p<0.05) and verbal scores (r=-0.77, p<0.07).

The subCarpathian areas of Arges county are now characterized by a moderate endemia of iodine deficiency disorders (IDD) due to salt iodization. However, we found some cases of endemic cretinism (EC), that is the major expression of anomalies in the physical and intellectual development caused by a severe iodine deficiency. There are presented 5 patients, 4 men and 1 woman, with neurological endemic cretinism (NEC) (n=2) and mixed forms of the disease (n=3), coming from 2 old endemic areas (medium urinary iodine excretion in the studied patients 20.8 g/day), diagnosed and treated in outpatients clinics or in hospitals. Four patients are members of the same family. The age of the patients is between 36 and 84 years old, the average age being 69. The intellectual capacity was assessed by using the Wechsler and Raven tests, the average intelligence quotient (IQ) value was of 20.8 points ? 1.47. The thyroid volumes (TV) were estimated by palpatory method and by ultrasonography and were between 8.7-200 ml. TSH values in studied patients ranged between 3.8-26 IU/ml and free T4 ranged between 0.272-1.22 ng/dl. Aggregation of more cases of endemic cretinism in the same family suggests the occurrence of some genetic factors. In conclusion, the old age (over 70 years old) of 4 cretins shows they are remnants of the old IDD endemia. However, there is also an isolated case of middle age (36 years old) suggesting an inadequate iodine intake, despite a law regarding salt iodization which has been operating since 1962. More attention to the universal salt iodization and to consumption of iodized salt in the rural areas is necessary.

An 18 years old, tall man presented for circumoral numbness, paresthesias, and hypocalcaemia, without carpopedal spasm or seizures. Previous medical history revealed bilateral cataract and osseous cysts on limbs at the age of 12. Hypocalcaemia resistant to calcium treatment and mild increased TSH levels were present. At diagnosis, we noticed a normal phenotype with tall stature, moderate hypocalcaemia (5.8 mg/dL), hyperphosphatemia (5.08 mg/dL) and significantly higher than normal intact parathormone (PTH) levels (518 pg/mL), in the presence of normal serum levels of 25-hydroxy vitamin D (53.56 ng/mL). The mother and the family members have been found in good health. All these data strongly suggested sporadic pseudohypoparathyroidism type Ib (PHP-Ib), but with some features of PHP - type Ia, like the osseous cysts. We were not able to perform molecular genetic tests. The nearly complete recovery of clinical and biochemical signs (normalization of PTH, calcaemia, phosphatemia, and a normal DXA osteodensitometry) after 2 years of chronic treatment with activated 1,25- dihydroxycholecalciferol (2.00-0.75 &#956;g/day) indirectly, but strongly confirmed the diagnosis of pseudohypoparathyroidism. The patient may have resistance to TSH evidenced by high TSH\r\n(range 4.8-7.5 mIU/L), with normal thyroid hormone levels, absence of goiter and normal TPO antibodies. The TRH test (400 &#956;g i.v.) showed a response of TSH, and also of serum thyroxine and triiodothyronine in a range that did not clarify the diagnosis. This association of the resistance to TSH with type Ib PHP was relatively recently reported by two groups (17,20) and before them it was reported only in PHP-Ia. Our patient also showed mild thrombocytopenia, with normal bleeding time, indicating also a possible Gs&#945; deficiency in platelets. In conclusion, our patient with sporadic pseudohypoparathyroidism without clinical phenotype of Albright hereditary osteodystrophy is highly suggestive for the type Ib PHP. A possible resistance to TSH and thrombocytopenia associated are features related to the genetic mechanisms found also in type Ia PHP. It is tempting to suggest that this case is one of the new variants of pseudohypoparathyroidism-Ib, recently reported.