Irene Halperin

Hormone-treated transsexuals report less social distress, anxiety and depression.

INTRODUCTION The aim of the present study was to evaluate the presence of symptoms of current social distress, anxiety and depression in transsexuals. METHODS We investigated a group of 187 transsexual patients attending a gender identity unit; 120 had undergone hormonal sex-reassignment (SR) treatment and 67 had not. We used the Social Anxiety and Distress Scale (SADS) for assessing social anxiety and the Hospital Anxiety and Depression Scale (HADS) for evaluating current depression and anxiety. RESULTS The mean SADS and HADS scores were in the normal range except for the HAD-Anxiety subscale (HAD-A) on the non-treated transsexual group. SADS, HAD-A, and HAD-Depression (HAD-D) mean scores were significantly higher among patients who had not begun cross-sex hormonal treatment compared with patients in hormonal treatment (F=4.362, p=.038; F=14.589, p=.001; F=9.523, p=.002 respectively). Similarly, current symptoms of anxiety and depression were present in a significantly higher percentage of untreated patients than in treated patients (61% vs. 33% and 31% vs. 8% respectively). CONCLUSIONS The results suggest that most transsexual patients attending a gender identity unit reported subclinical levels of social distress, anxiety, and depression. Moreover, patients under cross-sex hormonal treatment displayed a lower prevalence of these symptoms than patients who had not initiated hormonal therapy. Although the findings do not conclusively demonstrate a direct positive effect of hormone treatment in transsexuals, initiating this treatment may be associated with better mental health of these patients.

Sorafenib in metastatic thyroid cancer

Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.

The Exon 3-Deleted Growth Hormone Receptor Is Associated with Better Response to Pegvisomant Therapy in Acromegaly

CONTEXT The deletion of exon 3 in the GH receptor (GHR) has been associated with a different biochemical picture and response to therapy in acromegaly. OBJECTIVE The aim of the study was to determine whether or not the GHR genotype influences the efficacy of pegvisomant treatment. DESIGN AND SETTING A cross-sectional study was conducted in six Spanish university hospitals. PATIENTS Forty-four acromegalic patients with active disease and resistance to somatostatin analogs participated in the study. RESULTS The prevalence of the full-length GHR and the exon 3-deleted GHR homozygous and heterozygous genotypes was 41, 2, and 57%, respectively. There were no differences in IGF-I or GH pre-pegvisomant levels related to GHR genotype. The exon 3-deleted patients required approximately 20% lower doses of pegvisomant per kilogram of weight (28 +/- 11 compared to 22 +/- 7 mg per kg of weight; P = 0.033) to normalize IGF-I. A stepwise multivariate linear regression analysis (R(2) = 0.27; P = 0.003) identified male gender (beta = -0.79; P = 0.03) and d3-GHR genotype (beta = -0.64; P = 0.007) as the only significant predictors of the dose of pegvisomant per kilogram of weight. In addition, d3-GHR carriers required fewer months for IGF-I normalization (P < 0.01). A stepwise multivariate linear regression analysis (R(2) = 0.40; P = 0.001) revealed that the only significant predictor of the time to IGF-I normalization was the dose of pegvisomant per kilogram of weight (beta = 0.451; P = 0.001). CONCLUSIONS The exon 3 deletion in the GHR predicts an improved response to pegvisomant therapy in acromegaly.

Long-term treatment of acromegalic patients resistant to somatostatin analogues with the GH receptor antagonist pegvisomant: its efficacy in relation to gender and previous radiotherapy

CONTEXT Pegvisomant is an effective treatment for somatostatin analogue-resistant acromegaly, but the determinants defining the response to this treatment are largely unknown. OBJECTIVE To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients (e.g. serum IGF1 at least 1.25 x upper normal limit) in a clinical setting and the factors conditioning this response. DESIGN AND SETTING A retrospective cross-sectional study performed in six Spanish University hospitals from 2004 to 2007. Patients Forty-four acromegalic patients (61.4% female, mean age: 49+/-14), 95% of whom had undergone pituitary surgery and 61% having received pituitary radiotherapy. The mean follow-up was 22.7+/-11.2 months. Main outcome measures IGF1 levels reflected treatment efficacy, and the influence of gender, age, weight, previous radiotherapy and duration of treatment was assessed. RESULTS IGF1 normalisation was achieved in 84% of the patients. Male gender (P<0.05), previous irradiation (P<0.05) and the treatment duration (r=0.364, P<0.02) were associated with a better response to pegvisomant therapy. There was a significant decrease in HbA1c (P<0.001) and in the mean insulin dose (P<0.01) in acromegalic diabetic patients. Although 25% of patients experienced mild adverse events, pegvisomant was only withdrawn in four patients due to side effects (two cases of tumour growth, one liver dysfunction and one headache). CONCLUSIONS Long-term pegvisomant is a very effective therapy in resistant acromegaly. Male gender and prior radiotherapy influence the therapeutic response rate.

Laparoscopic surgery in patients with sporadic and multiple insulinomas associated with multiple endocrine neoplasia type 1

There have recently been reports of a limited number of laparoscopic procedures in patients with clinically manifest hyperinsulinism. However, the precise role of laparoscopy remains unknown. Between January 1998 and September 2003, 11 consecutive patients (10 women and 1 man; mean age, 40 years; age range, 22–66 years) with sporadic insulinoma and two female patients (25 and 40 years old) with multiple insulinomas associated with multiple endocrine neoplasia type 1 (MEN-1) were operated on using the laparoscopic approach. Endoscopic ultrasonography was used to localize the tumor preoperatively in 90% of patients with sporadic insulinoma. In patients with MEN-1, computed tomography and octreoscan-111In demonstrated multiple tumors. Laparoscopic ultrasonography (LapUS) was performed in all patients for operative decision-making. Of 11 patients with sporadic insulinoma, laparoscopic enucleation (LapEn) was planned in 8 patients, but in 1 patient, the use of LapUS missed the tumor and the patient was converted to open surgery. Mean operating time after LapEn (seven patients) was 180 minutes, and the mean blood loss was 200 ml. The mean hospital stay was 5 days. In three of the 11 patients, laparoscopic spleen-preserving distal pancreatectomy (LapSPDP) was performed; the mean operative time was 240 minutes, and the mean blood loss was 360 ml. Postoperative complications occurred in three of seven patients after LapEn (three pancreatic fistulas managed conservatively, and one case of bleeding requiring reoperation). LapSPDP was performed in both patients with MEN-1; in one patient with splenic vessel preservation (SVP), the operating time was 210 minutes and blood loss was 650 ml, with a hospital stay of 6 days. In another patient without SVP, the operating time was 150 minutes and blood loss was 300 ml. The latter patient developed a 4-cm splenic infarct managed conservatively, and the hospital stay was 14 days. LapEn and LapSPDP are feasible and safe and achieved cure in patients with sporadic insulinoma and multiple insulinomas associated with MEN-1. However, the risk of pancreatic leakage after LapEn remains high, and LapSPDP without SVP may be associated with splenic infarct.

Cushing's disease and pregnancy: Report of six cases

We describe six pregnancies in five patients with Cushings disease --four had undergone transsphenoidal surgery, with improvement but no cure of their hypercortisolism; the other woman became pregnant during initial work up. At conception, none of the patients were receiving specific treatment for hypercortisolism. Mean free urinary cortisol (FUC) prior to pregnancy was 430 nmol/24 h (normal range: 51-280). In two patients, FUC throughout pregnancy increased significantly, but no clinical progression was observed. FUC measured in 20 healthy pregnant women was found to rise above the normal non-pregnant range ( < 280 nmol/24 h) in the second (mean +/- 2 S.D. = 463 +/- 256 nmol/24 h; P < 0.01) and third trimester (424 +/- 210 nmol/24 h; P < 0.05). However, in the Cushing patients values were higher. Two pregnancies ended in spontaneous abortions, one resulted in an ectopic pregnancy, and the remaining three were followed to term of which one developed third trimester gestational diabetes, and her baby developed neonatal sepsis which resolved uneventfully. We conclude that despite high abortion and ectopic pregnancy rates, a remarkably uneventful and uncomplicated outcome with no clinical progression of cushingoid symptoms, was observed in two of the three pregnancies followed to term, despite significant increases in FUC.

Magnetic Resonance Imaging as a Predictor of Response to Somatostatin Analogs in Acromegaly after Surgical Failure

CONTEXT Transsphenoidal surgery is considered first-line therapy for acromegaly; however, there is often a need for adjunctive therapy. Somatostatin analogs (SSA) have greatly improved the effectiveness of medical treatment, but one third of patients are resistant. OBJECTIVE The aim was to evaluate whether magnetic resonance imaging (MRI) signal could predict long-term response to SSA in patients with active acromegaly after neurosurgery. PATIENTS AND METHODS Sixty-two patients who were active acromegalic after surgery were included in this retrospective study. Remaining pituitary tumor was classified as hyper-, iso-, or hypointense by evaluating T2-weighted MRI signal. Treatment with SSA at maximal effective doses was prescribed and evaluated at 6 and 12 months by monitoring IGF-I, GH, and T2 MRI. RESULTS Complete response to SSA treatment (defined as normal IGF-I) at 6 months was observed in 30%, partial response (defined as IGF-I between 2 and 3 sd score) in 15%, and no response in 55% of patients. At 12 months, 28, 20, and 52% were observed, respectively. MRI signal was hypointense in 40%, hyperintense in 48%, and isointense in 12%. At 6 months, complete response to SSA was observed in 71% of cases having hypointense MRI signal and in 20% of hyperintense (P = 0.04). At 12 months, 62% of hypointense remained well controlled, whereas in the hyperintense group, good, partial, or no response results did not change from that observed at 6 months (P = 0.04). CONCLUSION In active acromegalic patients after surgery, a hypointense T2-weighted MRI signal is associated with a better response to SSA treatment at 6 and 12 months.

Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake

Background: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid neoplasia that have lost radioiodine (131I) uptake with heterogeneous results. Aim: Retrospective analysis of the recovery rate of 1311 uptake after RA treatment in patients from 11 Spanish hospitals. Methods: Twenty-seven patients (14 men, 13 women) with papillary [21], follicular [4], and oncocytic [2] thyroid cancer initially treated with total thyroidectomy plus 131I, and with 131I negative metastatic disease, were given 13-cis RA (0.66–1.5 mg/kg for 5–12 weeks) followed by a therapeutic 131I dose (3700–7400 MBq); 3 months later thyroglobulin levels and computed tomography imaging were performed. Results: In 9 out 27 cases (33%) (8 papillary, 1 follicular) optimal positive 131I scan was observed after RA treatment; in the remaining 18, 10 had a suboptimal uptake (7 papillary, 2 follicular, 1 oncocytic) and in the rest there was no 131I uptake recovery (6 papillary, 1 follicular, 1 oncocytic). In 17 positive responses to RA (either optimal or suboptimal) in which image follow-up was available, decrease or stabilization of metastatic growth was observed in 7, while tumor mass increased at short term in the remaining 10. No major side effects were detected. Conclusion: Quite a high rate of 131I uptake recovery after RA treatment may be obtained in advanced differentiated thyroid cancer, but the potential modification of the natural course of the disease is uncertain. A better biological characterization of these tumors allowing the identification of potential responders to RA may improve the outcome of RA coadjuvant therapy.

Successful treatment of vitamin D unresponsive hypoparathyroidism with multipulse subcutaneous infusion of teriparatide

OBJECTIVE Hypoparathyroidism is usually controlled with calcium and vitamin-D supplements; in very few cases this treatment fails and teriparatide may be an alternative. We report the first case of hypoparathyroidism refractory to vitamin-D therapy requiring multipulse teriparatide treatment. CASE REPORT A 53 year-old woman presented severe hypocalcemia and hypomagnesemia after thyroidectomy. Preoperatively, mild hypercalciuria was detected with parathyroid hormone (PTH) 69 pg/ml (normal 10-45) and 25-OH-vitamin D 9 ng/ml (normal 20-40) and normal levels of magnesium. No response was seen with oral and i.v. calcium and magnesium, or even with 5 microg calcitriol/day, suggesting a vitamin-D resistance status. Calcium sensor and vitamin-D receptor gene mutation studies were negative. INTERVENTIONS AND RESULTS The following treatments were tried: i) s.c. recombinant human PTH (rhPTH) 1-34 plus oral calcitriol, calcium, and magnesium, was partially effective, but symptoms resumed 4 h after the injection of 20 microg rhPTH; stable calcemia was not achieved even with 4-6 injections/day of teriparatide; ii) two trials of heterologous parathyroid transplant were performed but rejection was detected 3 months after; iii) i.v. magnesium decreased rhPTH requirements but i.m. administration was not tolerated and iv) multipulse s.c. infusion of teriparatide achieved complete normalization of serum calcium, phosphate, magnesium, calciuria and magnesuria with relatively low rhPTH doses (25-35 microg/day) for more than a year. CONCLUSIONS Vitamin-D unresponsiveness leads to uncontrolled hypocalcemia when postsurgical hypoparathyroidism occurs; in situations of no response to usual or higher doses of vitamin-D and s.c. injections of rhPTH, treatment with teriparatide multipulse s.c. infusor is an effective and safe alternative.

Androgen treatment effects on memory in female-to-male transsexuals

INTRODUCTION It has been hypothesized that cognitive and memory-related brain function in transsexuals during cross-sex hormonal treatment might be activated towards that of the subjective gender. However, research on this topic has produced inconsistent results, and to the best of our knowledge no studies have investigated memory changes in androgen-treated female-to-male (FM) transsexuals. METHODS A total of 33 FM transsexuals underwent neuropsychological testing in order to examine the effects of androgen on memory. We used a longitudinal design in which 14 FM transsexuals were tested twice, before and after receiving 6 months of testosterone treatment. In addition, a cross-sectional design was used to compare 10 individuals off treatment versus 9 individuals on testosterone treatment for at least 6 months. RESULTS Participants tested before and after 6 months of androgen treatment improved significantly their performance on a visual memory task (visual paired associates, immediate recall, WMS-R). The cross-sectional design confirmed that patients on androgen treatment for at least 6 months performed better than subjects off treatment on the same task and also on another visual memory task (Rey-Osterrieth complex figure test, ROCF; copy and delayed recall). No differences were found in any verbal memory test for either design. CONCLUSIONS The results indicate that androgen has an influence on visual memory, but not on verbal memory. Therefore, for FM transsexuals the data support an activating effect for androgens on visual memory, a domain that generally tends to favour males.