BMP15 "knockout-like" effect in familial premature ovarian insufficiency with persistent ovarian reserve.

Premature ovarian insufficiency (POI) affects 1% to 2% of women under 40 years. Bone morphogenetic protein 15 (BMP15) variants have been described in POI. We studied a family with 2 sisters compound heterozygous for deletions in the BMP15 gene on chromosome Xp11.22 yielding a human "knockout-like" effect: a c.151_152delGA deletion yielded a p.Glu51IlefsTer27 mutation transmitted by the hemizygous father and a c.189_198delAGGGCATTCAinsTG deletion/insertion yielded a p.Glu64AlafsTer12 mutation transmitted by the heterozygous mother. Both deletions resulted in frameshifts with premature stop codons at positions 78 and 76 in the proregion, precluding mature BMP15 production. One sister had primary amenorrhea and the other primo-secondary amenorrhea. No bone abnormality was observed. Despite streak ovaries devoid of follicles on ultrasonography, anti-Mullerian hormone (AMH) levels were low but detectable suggesting the presence of growing follicles. Five years later, AMH was undetectable in both sisters, 1 had received an egg donation. BMP15 did not seem critical for follicles to enter the growth phase. Genetic counselling should be performed and fertility preservation discussed before progressive loss of follicular reserve. The fertile heterozygous mother did not support previous reports of BMP15 haploinsufficiency and gene dosage in humans, as in bovine species. The hemizygous brother had asthenozoospermia, consistent with previous observations in bulls with a variant BMP15.

[Four cases of aldosterone synthase deficiency in childhood]. / Déficit en aldostérone-synthase : 4 observations pédiatriques.

Neonatal salt-wasting syndromes are rare but potentially serious conditions. Isolated hypoaldosteronism is an autosomal recessive inherited disorder of terminal aldosterone synthesis, leading to selective aldosterone deficiency. Two different biochemical forms of this disease have been described, called aldosterone synthase deficiency or corticosterone methyl oxydase, types I and II. In type I, there is no aldosterone synthase activity and the 18 hydroxycorticosterone (18 OHB) level is low, whereas in type II, a residual activity of aldosterone synthase persists and 18 OHB is overproduced. We report on four patients with isolated hypoaldosteronism. In 2 of them, who were recently diagnosed with aldosterone synthase deficit, we discuss the symptoms and treatment. The 2 other patients are now adults. We discuss the long-term outcome, the quality of adult life, aldosterone synthase deficits, as well as the pathophysiology and molecular analysis.

Unconjugated bisphenol A cord blood levels in boys with descended or undescended testes.

BACKGROUND: Human toxicity of bisphenol A (BPA), a weak estrogenic environmental endocrine disrupting compound, widely used in plastics, baby bottles, cans and dental sealants, is under investigation. Fetal or perinatal exposure in rodents is associated with programmed adult reproductive diseases. Human epidemiological studies remain scarce, especially concerning testicular development. We have investigated the relationship between fetal exposure to BPA and cryptorchidism. METHODS: Using a radioimmunoassay performed after extraction, validated by high-performance liquid chromatography and mass spectrometry, active levels of unconjugated BPA (uBPA) in cord blood (CB) were measured in 152 boys born after 34 weeks gestation, with cryptorchid or descended testes. RESULTS: Active uBPA was detectable in all CB samples, with values in the control group (n = 106) of 0.14-4.76 ng/ml, median: 0.9 ng/ml; mean ± SD: 1.12 ng/ml ± 0.86 ng/ml, which did not differ from cryptorchid boys (n = 46, 1.26 ± 1.13 ng/ml, P = 0.38). uBPA in controls correlated with CB inhibin B (P < 0.01) and total testosterone (P < 0.05), and with maternal milk polychlorinated bisphenyl 138 (P < 0.03). uBPA did not correlate with clinical maternal or fetal parameters or with other steroid or polypeptide CB hormones assessed. CONCLUSIONS: The presence of uBPA in all CB samples suggests placental transfer and fetal exposure. Similar uBPA levels in the control and cryptorchid groups make the participation of fetal exposure to uBPA in the physiopathology of undescended testes unlikely. However, the observed nanomolar uBPA concentrations support assessment of epidemiological relationships between CB uBPA and other human diseases.

Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society.

BACKGROUND: Hirsutism, defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body, is one of the most common disorders in women during reproductive age. METHODS: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of hirsutism. RESULTS: The prevalence of hirsutism is ~10% in most populations, with the important exception of Far-East Asian women who present hirsutism less frequently. Although usually caused by relatively benign functional conditions, with the polycystic ovary syndrome leading the list of the most frequent etiologies, hirsutism may be the presenting symptom of a life-threatening tumor requiring immediate intervention. CONCLUSIONS: Following evidence-based diagnostic and treatment strategies that address not only the amelioration of hirsutism but also the treatment of the underlying etiology is essential for the proper management of affected women, especially considering that hirsutism is, in most cases, a chronic disorder needing long-term follow-up. Accordingly, we provide evidence-based guidelines for the etiological diagnosis and for the management of this frequent medical complaint.

FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.

[Assessment of the outcome of anorexia nervosa: construction of a self-administered questionnaire based on the patients' perception]. / Evaluation du devenir de l'anorexie mentale: construction d'un autoquestionnaire basé sur la perception des patientes (étude préliminaire).

INTRODUCTION: Our working hypothesis is that a better insight into the outcome of patients suffering from anorexia nervosa should contribute to preventing relapses and further complications and assessing treatment efficiency. Through anorexia nervosa, the patients express the difficulty they have to view themselves as specific subjects. OBJECTIVE: The current classic outcome evaluation is based on the study of objective events, which only partially reflect the reality of the patients' outcome at a subjective level. The objective of this study was to set up a new assessing instrument of the outcome of patients suffering from anorexia nervosa, essentially based on the patients' perception of their experience. METHOD: The methodology used has been based on: (1) the conduct by the main investigator of unstructured interviews using "free association", with the help of an interview guide. The anorexia nervosa patients were recruited among those who were hospitalized on an isolation contract, or among outpatients under a psychiatrist/psychoanalyst's supervision, aged over 25 years old so that they may have started their reproductive life. The study included 30 patients; (2) the analysis of the interview contents backed by preexisting hypotheses and by new ones suggested by the expression of the patients' perception, so as to set up an inventory of new themes; (3) the construction of a self-administered questionnaire starting from the development of each theme into several questions taking up the patients' own words and offering 4 possible answers (disagree completely, disagree, agree, quite agree). RESULTS: The analysis of the interviews contents has led to the development of 11 themes. The self-administered questionnaire includes a total of 124 items stemming from the development of each theme into between 9 and 16 items that were mixed in the version submitted to patients. DISCUSSION: This original interpretation of the outcome of the patients through their experience provides a better understanding of their relation to desire and pleasure, and consequently of the evolution of their subjectivity. By integrating several aspects of the disease expression, our instrument constitutes an alternative to the combination of several non-specific tools in anorexia nervosa. It thus avoids the atomization of the pathology and respects the specificity of its structure. The analysis of the disease function in the emergence of their subjectivity rather than the static observation of its symptoms has led to the development of new themes. CONCLUSION: The validation of this new methodological approach of the follow-up of anorexia nervosa based on the patients' perception of the evolution of their disease, aside from anthropometrical or physiological parameters, will have to be tested on a new population of patients. A quantitative score will be developed in association with the self-administered questionnaire. Its use in further epidemiological studies will enable a scientific assessment of the patients' outcome, and better prevent further complications and relapses, by screening patients with a pejorative risk. The ultimate aim is to improve these patients' care.

Recommendations for investigation of hyperandrogenism.

1. Total testosterone assay is recommended as the first-line approach. 2. Radioimmunological assay following prior treatment of the sample (extraction or extraction + chromatography) is the recommended method pending wider experience with mass spectrometry. 3. Where testosterone is twice the upper limit of normal, it is recommended that DHEAS assay be performed. DHEAS is primarily of cortico-adrenal origin in women. Thus, a DHEAS level over 600 mg/dl indicates a diagnosis of androgen-secreting adrenal cortical adenoma.. If DHEAS is normal, the diagnosis could be either ovarian hyperthecosis, normally associated with insulin resistance, or androgen-secreting ovarian tumour. 4. More rarely, elevated testosterone is associated with a marked elevation of SHBG possibly as the result of use of medication having an estrogenic effect (tamoxifen, raloxifene, Op'DDD), or of hyperthyroidism or liver disease. 5. Normal testosterone levels in patients with clear clinical symptoms of hyperandrogenism (hirsutism, seborrhoeic acne) must be interpreted with care. SHBG is normally reduced in the event of overweight, metabolic syndrome or familial history of diabetes.

Sex hormone-binding globulin predicts the incidence of hyperglycemia in women: interactions with adiponectin levels.

OBJECTIVE: Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia. DESIGN: We used a nested case-control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia > or = 6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years. RESULTS: At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels. CONCLUSIONS: These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

Ovarian hyperthecosis on grayscale and color Doppler ultrasound.

OBJECTIVES: To describe the grayscale and color Doppler ultrasound findings in women with ovarian hyperthecosis. METHODS: In a retrospective study, we reviewed the findings on ultrasound examination of the ovaries in 10 patients with proven hyperthecosis. Clinical features had been recorded and testosterone levels measured in all cases. The ovaries had been examined using grayscale ultrasound in all patients and color Doppler in six patients. Bilateral stromal hyperthecosis had been pathologically confirmed in all patients. RESULTS: The clinical features were polymorphic, with symptoms of virilization in four patients. Type 2 diabetes was present in four patients. Testosterone levels were greater than 2 ng/mL in four patients. On grayscale ultrasound examination, the ovaries were normal in two patients but showed bilateral abnormalities in eight; both ovaries were increased in size in seven patients and had a round shape in two patients, the ovary being both increased in size and round in shape in one of these patients. A very peculiar nodular stromal pattern was observed in two out of 10 patients, while a homogeneous stromal pattern was observed in eight patients. On color Doppler, performed in six patients, no areas of hypervascularization were observed. CONCLUSION: Findings on grayscale ultrasonography and on color Doppler examination, in association with clinical and biological findings, are useful in the diagnosis of ovarian hyperthecosis and in ruling out the presence of an androgen-secreting tumor.

Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features.

Familial pituitary adenoma is a rare syndrome which may present either as isolated lesions, or in association with other endocrine tumors, for example in the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The most frequently described forms of familial isolated pituitary adenoma (FIPA) are familial somatotropinomas or prolactinomas. Recently, some cases of familial isolated somatotropinoma have been associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The present report shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same family: somatotropinoma in the proband, giant prolactinoma in a brother, and gonadotroph cell macroadenoma in the father. A prospective survey also suggested the occurrence of a silent microadenoma in the proband's sister. Clinical screening was performed in the 3 affected members, the 4th suspected case, and 9 additional, asymptomatic relatives. They had no clinical evidence of associated endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2 affected members. In conclusion, these data suggest that familial pituitary adenomas can occur with a heterogeneous functional pattern that is distinguished from MEN-1 or CNC. The absence of mutation of the recently described AIP gene suggests the implication of other predisposing gene(s). Collaborative, multicentric studies are needed to further define the location of gene(s) involved in heterogeneous FIPA.

Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia.

CONTEXT: Because many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele affected by a severe mutation of CYP21, they are at risk for giving birth to infants with classic adrenal hyperplasia (CAH). OBJECTIVE: Our objective was to determine the frequency of CAH and NCAH infants born to mothers with 21-OH-deficient NCAH. DESIGN AND SETTING: We conducted an international multicenter retrospective/prospective study. PATIENTS AND METHODS: The outcome of 203 pregnancies among 101 women with 21-OH-deficient NCAH was reviewed. The diagnosis of 21-OH-deficient NCAH was established by a basal or post-ACTH-stimulation 17-hydroxyprogesterone level of more than 10 ng/ml (30.3 nmol/liter). When possible, genotype analyses were performed to confirm CAH or NCAH in the offspring. RESULTS: Of the 203 pregnancies, 138 (68%) occurred before the mother's diagnosis of NCAH and 65 (32%) after the diagnosis. Spontaneous miscarriages occurred in 35 of 138 pregnancies (25.4%) before the maternal diagnosis of NCAH, and in only four of 65 pregnancies (6.2%) after the diagnosis (P < 0.002). Four (2.5%; 95% confidence interval, 0.7-6.2%) of the 162 live births were diagnosed with CAH. To date, 24 (14.8%; 95% confidence interval, 9.0-20.6%) children, 13 girls and 11 boys, have been diagnosed with NCAH. The distribution of NCAH children and their mothers varied significantly by ethnicity (P < 0.0001, for both). CONCLUSIONS: The risk of a mother with 21-OH-deficient NCAH for giving birth to a child affected with CAH is 2.5%; at least 14.8% of children born to these mothers have NCAH.

Advances in growth hormone therapy: a new registry tool.

Growth hormone (GH) deficiency is a rare condition, and physicians may lack clinical experience of its treatment. Despite evidence for the efficacy and tolerability of GH therapy, a substantial proportion of patients remain untreated. Registries and other large-scale databases are an important tool for expanding the evidence base for GH treatment. Since the mid-1980s, registries have provided data on important aspects of the safety and efficacy of GH treatment. Registries have also allowed pooling of data from patients with rare conditions that could otherwise not be recruited in sufficient numbers for clinical trials. Importantly for patients and their relatives, use of registry data has allowed the development of prediction models that indicate the likely outcomes of treatment. MEGHA (Metabolic Endocrinology and Growth Hormone Assessment) is a recently developed, observational database with a number of features not found in existing registries, including its use as a day-to-day clinical management tool, the ability to create individual sub-studies, direct comparison of personal data against the full database, and a particular focus on the transition from childhood to adulthood. This creative registry is a promising instrument for further research into GH-related disorders that will improve GH therapy and thus provide benefits for patients.

[Contribution of bioavailable testosterone assay for the diagnosis of androgen deficiency in elderly men]. / Intérêt du dosage de testostérone biodisponible pour le diagnostic du déficit androgénique chez l'homme âgé

With age, some men develop symptoms resembling hypogonadism. Several cross-sectional and longitudinal studies have shown a decrease in testosterone levels with ageing in men. This finding has equally been observed in elderly men in good health. Testosterone levels decline progressively as of the thirties, at a rate which remains constant throughout life. While total testosterone levels decrease, sex hormone binding globulin (SHBG) levels on the contrary increase with age, with the result that the levels of free and non-SHBG-bound testosterone (corresponding to the fraction which is bioavailable to target cells) decrease more abruptly than that of total testosterone. Higher LH levels, decreased testosterone response to hCG and less Leydig cells all indicate that ageing induces partial testicular failure. However, the gonadotropic function is also affected in ageing. The hypothalamus-pituitary becomes more sensitive to gonad steroid feedback, LH pulse amplitude decreases, and the LH response to GnRH is blunted compared to the situation in young men. Thus LH level is not a valid index of androgen deficiency in elderly males. None of the androgen-dependent functions (libido, erection, sense of well-being, muscle mass and strength, fat mass, bone mass, erythropoiesis, etc.) are under exclusively androgen control, and there is no elderly male symptom which is completely specific to androgen deficiency. Thus, in elderly men, when clinical symptoms might indicate androgen deficiency, biological confirmation is needed. An assay which is independent of SHBG fluctuations is mandatory. Bioavailable testosterone assay by ammonium sulfate precipitation seems to us to be the optimum method for diagnosing androgen deficiency: it gives a reliable measurement for the testosterone fraction available to target cells, is adapted to clinical practice, and provides results that can be directly compared with current reference values for healthy young men.

Sex hormone-binding globulin levels and cardiovascular risk factors in morbidly obese subjects before and after weight reduction induced by diet or malabsorptive surgery.

One of the main goals of weight reduction in morbidly obese subjects is its benefit on coronary heart disease (CHD) risk. A cross-sectional study was designed to randomly assign 79 morbidly obese subjects (27 men and 52 women; age: 30-45 years) either to a diet protocol (20 kcal per kg fat-free mass (FFM); 55% carbohydrates, 30% fat, and 15% proteins) or to malabsorptive surgery (biliopancreatic diversion). Fatness parameters, measured by dual-energy X-ray absorptiometry, lipid profile, insulin, leptin, sex steroid hormones and sex hormone-binding globulin (SHBG) levels were compared at baseline and 1 year after the beginning of the study. The data showed that plasma SHBG levels, but not testosterone levels, correlated negatively to fasting insulin levels and positively to HDL-cholesterol in both men and women. Total leptin levels were significantly lower (P<0.0001) in post-BPD subjects of both sexes compared to dietary treated obese subjects. The logarithm of plasma leptin correlated significantly and positively with insulin but negatively with SHBG.A step-down regression analysis showed that FFM and SHBG, but not insulin levels, were the most powerful independent variables for predicting HDL-cholesterol levels in morbidly obese patients. The negative relationship between SHBG levels and CHD risk appears to be mediated by a concomitant variation in body fatness. Finally, in obese patients, SHBG levels seem to be an indicator of total adiposity rather than an index of an altered insulin/glucose homeostasis.

Study of the effect of changing glucose, insulin, and insulin-like growth factor-I levels on serum corticosteroid binding globulin in lean, obese, and obese subjects with glucose intolerance.

We have previously described that serum corticosteroid binding globulin (CBG) concentrations are associated with insulin secretion. The present study was designed to evaluate the effects of changing insulin concentrations, both endogenous and after exogenous insulin administration, on circulating CBG levels in vivo. Serum CBG concentrations were measured during an insulin-modified frequently sampled intravenous (IV) glucose tolerance test (FSIVGT) in 14 lean and 19 obese otherwise healthy subjects with varying degrees of glucose tolerance. Acute insulin response to glucose (AIRg) correlated significantly with serum CBG concentrations at time 0 (r = -.38, P =.029), 22 minutes (r = -.41, P =.01), 50 minutes (r = -.41, P =.01), and 180 minutes (r = -.39, P =.02). Insulin sensitivity (S(I)) was not associated with serum CBG concentration at time 0 (r = -.16, P = not significant [NS]), but correlated significantly with CBG concentration at 22 minutes (r = -.41, P =.02) and 50 minutes (r = -.35, P =.048) of the FSIVGT. In lean subjects, serum CBG concentration decreased significantly after IV insulin from 37.9 +/- 5.4 to 35.4 +/- 3 mg/L (P =.02) and returned to basal levels thereafter. In contrast, obese, glucose-tolerant subjects had lower CBG levels than lean and obese glucose intolerant subjects (33.8 +/- 3.0 v 37.9 +/- 5.4 and 39.8 +/- 4.4 mg/L, respectively), and their serum CBG concentrations remained unchanged during FSIVGT. Mean serum-free insulin-like growth factor-I (IGF-I) concentrations steadily declined from 1.21 +/- 0.81 to 0.8 +/- 0.36 microg/L during the FSIVGT, and this effect was restricted to lean subjects. Basal serum-free IGF-I did not correlate with CBG levels at time 0, but correlated inversely with the serum CBG concentrations at 22 minutes (r = -.36, P =.04). Stepwise multivariant analysis showed that AIRg (P =.035) and S(I) (P =.046), but not free IGF-I levels, independently contributed to 28% of CBG variance at 22 minutes. These results suggest that insulin, but not IGF-I, constitutes an important negative regulator of CBG liver synthesis. Endogenous and exogenous insulin do not affect serum CBG concentrations in insulin-resistant obese subjects with preserved or decreased insulin secretion. Obese glucose-tolerant subjects are hypothesized to exhibit tonically inhibited serum CBG levels. In contrast, in lean subjects, the higher the insulin secretion the lower the serum CBG concentration. The mechanisms of this CBG inhibitory effect exerted by insulin and its implication on cortisol homeostasis and fat distribution in humans await further investigations.

Efficacy of the long-acting octreotide formulation (octreotide-LAR) in patients with thyrotropin-secreting pituitary adenomas.

The presence of somatostatin receptors on TSH-secreting pituitary adenomas allows treatment of central hyperthyroidism with somatostatin analogs. Six women and 5 men (mean +/- SEM age, 43 +/- 3 yr) presented TSH-secreting pituitary adenomas (micro, n = 2; macro, n = 9). Seven patients had previously been treated with partial surgical removal (n = 6) and/or external radiation (n = 4) of their adenoma at least 1 yr before the study, whereas 4 patients had not been treated before somatostatin analog therapy. TSH, free T(4), and free T(3) levels were in the normal range during treatment with sc injections (n = 9) or continuous infusion (n = 2) of octreotide (280 +/- 25 microg/day). Mean thyroid hormone levels increased (P < 0.01) after the washout period (34 +/- 6 days). The patients received monthly im injections of 20 mg Octreotide-LAR. In patients with an elevated free T(4) level after 3 months (n = 1) the Octreotide-LAR dose was increased to 30 mg. After 3 months of Octreotide-LAR treatment, TSH, free T(4)/T(3), and alpha-subunit levels decreased, and 10 patients were euthyroid with normal free T(4) levels. These results remained at the same level over the next 3 months. There were no statistically significant differences in the TSH and free T(4) responses to sc octreotide or im Octreotide-LAR between previously untreated patients and patients who had undergone surgical resection and/or pituitary radiation before somatostatin analog treatment. During Octreotide-LAR treatment, minor digestive problems or moderate discomfort at the injection site, lasting less than 48 h, were reported in 6 and 5 patients, respectively. Gallbladder echographies did not reveal new gallstones during Octreotide-LAR treatment. In conclusion, this study shows that monthly im Octreotide-LAR is as effective as daily sc octreotide in controlling hyperthyroidism in patients with TSH-secreting pituitary adenomas, in both previously untreated patients and patients treated with surgery and/or pituitary radiotherapy. Octreotide-LAR is well tolerated, except for minor digestive problems or mild pain at the injection site. Therefore, Octreotide-LAR appears to be a useful therapeutic tool to facilitate medical treatment of TSH-secreting pituitary adenomas in patients who need long-term somatostatin analog therapy.