Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor ß.

OBJECTIVE: The syndrome of resistance to thyroid hormone (RTH) is caused by a mutation of TH receptor ß (TRß) in 80% of cases. Patients without mutation (non-TR-RTH) may have a biochemical pattern that is difficult to differentiate from that of pituitary TSH-secreting adenoma (TSHoma). Herein, we report a large monocentric series of RTH focusing on patients with non-TR-RTH, to evaluate possible clinical or biochemical parameters able to distinguish them from TSHoma. DESIGN AND PATIENTS: We retrospectively reviewed the data of 99 consecutive patients with inappropriate TSH secretion (IST) syndrome referred to our Department between 1983 and 2011, identifying 68 patients with RTH and 31 patients with TSHomas. MEASUREMENTS: Patient records were reviewed for the main clinical, biochemical and imaging characteristics. RESULTS: Of our 68 patients with RTH, 16 (23·5%) did not show a TRß mutation and did not have affected family members. Of these 16 patients, three developed a TSHoma, during follow-up. To distinguish non-TR-RTH from TSHoma, we identified appropriate cut-off values for the main biochemical parameters that demonstrated the greatest sensitivity and specificity (T3 suppression test, α-subunit/TSH molar ratio, α-subunit assay and TRH test) and we calculated the probability for each patient to develop a TSHoma. CONCLUSIONS: The application of the identified cut-offs could become a very useful tool in the challenging differential diagnosis between sporadic non-TR-RTH and TSHoma. It would then be possible to select the patients at higher risk of developing a TSHoma and therefore needing a closer follow-up.

Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol.

OBJECTIVE: Several tests have been proposed to diagnose patients with Cushing's syndrome (CS). The aims of the study were: i) to evaluate the performance of salivary cortisol (SC) in hypercortisolism and ii) to compare SC with serum cortisol (SeC) and urinary cortisol. DESIGN AND PATIENTS: This was a diagnostic study. Twenty-seven patients with untreated Cushing's disease (CD untr), 21 women consuming oral contraceptive pill (OCP), 18 pregnant women, and 89 healthy subjects (controls) were enrolled. METHODS: SC and SeC at baseline and after the low-dose dexamethasone suppression test (LDDST) and urinary free cortisol (UFC) were measured. RESULTS: Midnight SC had a sensitivity of 100% in the CD untr group and a specificity of 97.7% in the controls. Specificity remained high (95.2%) in women taking OCP, while in pregnant women, it decreased to 83.3%. SC after the LDDST showed a sensitivity of 96.3% in the CD untr group; specificity was 97.7% in the controls and 90.5% in OCP women. Midnight SeC had a sensitivity of 100% in the CD untr group. SeC after the LDDST had a sensitivity of 100% in the CD untr group while specificity was 97.7% in the controls and 61.9% in women taking OCP. For UFC, sensitivity was 92.6% in the CD untr group while specificity was 97.7% in the controls and 100% in the OCP group. CONCLUSIONS: SC is a reliable parameter for the diagnosis of severe hypercortisolism, with high sensitivity and specificity. In women during pregnancy or taking OCP, the measurement of SC, identifying the free fraction, could be helpful to exclude CS.

A functioning FSH-secreting pituitary macroadenoma causing an ovarian hyperstimulation syndrome with multiple cysts resected and relapsed after leuprolide in a reproductive-aged woman.

Bioactive gonadotropin-secreting pituitary adenomas are very rare in fertile women and can cause an ovarian hyperstimulation syndrome (OHSS). A 31-year-old woman with oligo-amenorrhea, severe ovarian cystic swelling and high serum estradiol was submitted to the resection of ovarian cysts and then treated with long-acting leuprolide 11.25 mg. Two months later, the ovarian multicystic hyperplasia relapsed, thus a pituitary MRI was performed and a pituitary macroadenoma was detected. In January 2010, she was referred to our Endocrinology Department where her hormonal evaluation showed high serum estradiol, FSH, α-subunit and inhibin with low LH. In April 2010, she underwent a trans-sphenoidal pituitary adenomectomy, which rapidly regularized the hormonal profile, the ovary and pituitary morphology and the menses. The case presented confirms that gonadotrophinomas occurring in reproductive-aged women frequently produce symptoms of ovarian hyperstimulation and proves that the use of GnRH analogs is not indicated in this condition.

Impact of different cut-off limits of peak GH after GHRH-arginine stimulatory test, single IGF1 measurement, or their combination in identifying adult patients with GH deficiency.

OBJECTIVE: To evaluate the impact of different peak GH cut-off limits after GHRH-Arg test, IGF1 measurement, or their combination in identifying patients with GH deficit (GHD). DESIGN AND PATIENTS: Totally, 894 normal subjects (used for determining IGF1 normative limits) and 302 patients with suspected GHD were included. Different peak GH cut-off limits (used by European (depending on body mass index (BMI)) or North American (4.1 µg/l) Endocrine Societies, by HypoCCs (2.5 µg/l), or with 95% specificity (based on BMI), Method 1, 2, 3, or 4 respectively) and IGF1 were considered. METHODS: Peak GH after GHRH-Arg and IGF1. RESULTS: Different peak GH cut-off limits recognized different proportions of GHD (range, 24.8-62.9%). Methods 1 and 2 with high sensitivity recognized a higher proportion (95.5 and 92.5% respectively) of GHD among patients with three (T) pituitary hormone deficits (HD), whereas Method 4 (with high specificity) identified 96.7% normal subjects among those without pituitary HD; on the contrary, Method 4 identified only 75% GHD among patients with THD, whereas Method 1 recognized a high proportion (40%) of GHD among subjects without HD. Of the total patients, 82% with THD and 84.5% without HD were recognized as GHD or normal respectively by IGF1. Among the remaining patients with THD and normal IGF1, 75% was recognized as GHD by Method 1; among patients without HD and abnormal IGF1, 87.5% was identified as normal by Method 4. Overall, combination of IGF1 and Method 1 or Method 4 identified 95.5% GHD among patients with THD and 98.1% normal subjects among those without HD. CONCLUSIONS: Single peak GH cut-offs have limits to sharply differentiate GHD from normal subjects; IGF1 may be used for selecting patients to be submitted to the GHRH-Arg test; the peak GH cut-off limits to be used for identifying healthy or diseased patients depend mainly on the clinical context.

Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery.

OBJECTIVES: To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). DESIGN: Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. PATIENTS AND METHODS: Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. RESULTS: CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α(2) antiplasmin, P=0.0004, thrombin-antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α(2) antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (P=0.04). CONCLUSIONS: Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

Serum pituitary antibodies in normal pregnancy and in patients with postpartum thyroiditis: a nested case-control study.

OBJECTIVES: The aim of this study was to evaluate antipituitary antibody (APA) prevalence in a series of patients with postpartum thyroiditis (PPT) during pregnancy and in the postpartum. DESIGN: We conducted a nested case-control study on consecutive PPT and normal pregnant women at the Centre for Endocrine and Diabetes Sciences in Cardiff and at the Department of Endocrinology in Pisa. METHODS: We enrolled 30 women with PPT: 17 were hypothyroid (Hypo), 7 with hyperthyroidism (Hyper) and 6 with a transient hyperthyroidism followed by hypothyroidism (Biphasic). Twenty-one healthy pregnant women served as controls. APA (measured using indirect immunofluorescence), free thyroxine, free triiodothyronine, TSH, antithyroid autoantibodies, and thyroid ultrasound were performed during pregnancy and postpartum. The stored sera have been sent to Pisa, where serum APA, IGF1, and cortisol were measured. RESULTS: APA were found in 8 out of the 30 PPT patients (26.7%) and in one normal pregnancy (4.7%, P=0.063). Three out of the seventeen Hypo with PPT (17.6%), three out of the seven Hyper PPT (42.8%), and two out of the six Biphasic PPT (33.3%) were positive for APA. APA prevalence was not significantly different in the PPT subgroups (P=0.453). With one exception, APA all increased in the postpartum period (87.5%, P<0.016). Basal serum IGF1 and cortisol were in the normal range with the exception of two patients with positive APA who presented low serum IGF1 levels (36 and 45 ng/ml). CONCLUSIONS: APA are frequently present in the postpartum period in patients affected by PPT. Further studies are necessary to evaluate whether APA in PPT patients are associated with pituitary function impairment.