Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

STUDY QUESTION: What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION: A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE: Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS: Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER: NCT01150318.

Clinical practice guidelines on menorrhagia: management of abnormal uterine bleeding before menopause.

BACKGROUND: Normal menstrual periods last 3-6 days and involve blood loss of up to 80ml. Menorrhagia is defined as menstrual periods lasting more than 7 days and/or involving blood loss greater than 80ml. The prevalence of abnormal uterine bleeding (AUB) is estimated at 11-13% in the general population and increases with age, reaching 24% in those aged 36-40 years. INVESTIGATION: A blood count for red cells+platelets to test for anemia is recommended on a first-line basis for women consulting for AUB whose history and/or bleeding score justify it. A pregnancy test by an hCG assay should be ordered. A speculum examination and Pap smear, according to the French High Health Authority guidelines should be performed early on to rule out any cervical disease. Pelvic ultrasound, both abdominal (suprapubic) and transvaginal, is recommended as a first-line procedure for the etiological diagnosis of AUB. Hysteroscopy or hysterosonography can be suggested as a second-line procedure. MRI is not recommended as a first-line procedure. TREATMENT: In idiopathic AUB, the first-line treatment is medical, with efficacy ranked as follows: levonorgestrel IUD, tranexamic acid, oral contraceptives, either estrogens and progestins or synthetic progestins only, 21 days a month, or NSAIDs. When hormone treatment is contraindicated or immediate pregnancy is desired, tranexamic acid is indicated. Iron must be included for patients with iron-deficiency anemia. For women who do not wish to become pregnant in the future and who have idiopathic AUB, the long-term efficacy of conservative surgical treatment is greater than that of oral medical treatment. Placement of a levonorgestrel IUD (or administration of tranexamic acid by default) is recommended for women with idiopathic AUB. If this fails, a conservative surgical technique must be proposed; the choices include second-generation endometrial ablation techniques (thermal balloon, microwave, radiofrequency), or, if necessary, first-generation techniques (endometrectomy, roller-ball). A first-line hysterectomy is not recommended in this context. Should a hysterectomy be selected for functional bleeding, it should be performed by the vaginal or laparoscopic routes.

Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics.

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ss sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.

[Menometrorrhagia: to whom, why, on which criteria to propose a hormonal exploration?]. / Ménométrorragies : à qui, pourquoi, sur quels critères proposer une exploration hormonale ?

The hormonal exploration of menometrorrhagia concerns only the patients throughout their reproductive life, it is not indicated outside this period. In first intention at the woman in age to procreate, will be realized a determination of hCG, an inescapable determination to eliminate a pregnancy and a measure of serum TSH in the case of personal or family history for the screening of subclinical hypothyroidism. Further investigations can be carried out in second-based signs of appeal under the differential diagnosis of polycystic ovary syndrome (PCOS), as a measure serum prolactin, 17-hydroxyprogesterone and total testosterone and not bound to its binding protein the SHBG.

The tumor suppressor activity induced by adenovirus-mediated BRCA1 overexpression is not restricted to breast cancers.

The BRCA1 (breast cancer 1) breast cancer susceptibility gene is recognized as responsible for most familial breast and ovarian cancers and is suggested to be a tissue-specific tumor suppressor gene. In this report, we investigated the tissue specificity of tumor inhibitory activities induced by a recombinant adenovirus coding for wild-type BRCA1 (wtAdBRCA1). We demonstrated a pronounced in vitro antiproliferative effect on H1299 lung and HT29 colon cells upon infection with AdBRCA1. We describe a prolonged G1 cell cycle arrest associated with a decrease in the hyperphosphorylated form of Rb, suggesting that the Rb/E2F pathway is implicated in BRCA1-induced cell growth arrest. We also observed a significant antitumor effect in these pre-established subcutaneous tumors after in situ delivery of AdBRCA1, although these two tumors do not express wt p53, and also estrogen alpha and beta, progesterone and androgen receptors. Moreover, BRCA1 can induce a strong prolonged cell cycle arrest and apoptotic cell death but no significant antiangiogenic effect in H1299 tumors. Finally, our data indicate that intratumor administration of wtAdBRCA1 significantly inhibits growth of lung and colon steroid hormone-independent tumors.

Serotonin transporter promoter variants in autism: functional effects and relationship to platelet hyperserotonemia.

The well-replicated platelet hyperserotonemia of autism has stimulated interest in serotonin (5-HT) in autism. We have examined the effects of the serotonin transporter gene (5-HTT, locus SLC6A4) promoter polymorphism (5-HTTLPR) on platelet 5-HT physiology in autism. Platelet 5-HT uptake rates and affinities (V(max) and K(m)), uptake site densities (B(max)) and 5-HT levels were examined in 31 French individuals with autism genotyped with respect to the 5-HTTLPR. Platelet 5-HT uptake and 5-HT levels were measured using HPLC; uptake sites were determined by radioligand binding. A 1.5-fold increased rate (V(max)) of platelet 5-HT uptake was observed in ll genotype individuals compared to those with ls and ss genotypes (Mann- Whitney U-test, P = 0.022). However, no significant relationship was observed between genotype and uptake site density (U-test, P = 0.51). Although median levels of platelet 5-HT in platelet-rich plasma were higher in the ll group, only trend level significance was observed (U-test, P= 0.069); platelet 5-HT content measured in whole blood was similar across genotypes. Uptake rates were well correlated with B(max) values (r = 0.66, P = 0.002); correlations between uptake and platelet 5-HT levels and between B(max) values and 5-HT levels were somewhat lower. While 5-HTTLPR alleles had an appreciable effect on platelet 5-HT uptake rates, effects on 5-HT levels and uptake site density were smaller or absent. Based on these preliminary data and prior studies of allele frequencies, we conclude that the 5-HTTLPR is not a major determinant of the group mean platelet serotonin elevation seen in autism. However, a role for increased uptake in the hyperserotonemia of autism can not be ruled out. In addition, it appears that studies of platelet 5-HT measures in autism and other disorders should take account of the effects of 5-HTTLPR genotype on 5-HT uptake

Are serum inhibin concentrations new markers of placental tumours in the course of chemotherapy?

BACKGROUND: The study was conducted to evaluate whether the detection of serum molecular forms of inhibin (A and B) could be useful for the diagnosis, prognosis and follow-up of placental tumours. METHODS: A total of 17 patients with hydatidiform mole (n = 13), invasive mole (n = 1) or choriocarcinoma (n = 3) were studied; serum concentrations of inhibins A and B, human chorionic gonadotrophin (HCG) and its free beta subunit (HCGbeta) were measured before chemotherapy (after mole evacuation for eight patients) and also during the course of chemotherapy (for 10 patients). RESULTS: After evacuation or before chemotherapy for refractory disease, serum inhibin A and B concentrations were found to be increased in 10/17 and 4/17 patients, when HCG and HCGbeta were high in all patients. In 10 patients with a follow-up during treatment, nine had a high concentration of inhibin A which correlated with those of HCG and HCGbeta. Normalization of inhibin A was faster than that of HCG and HCGbeta for three and six patients respectively. There was no correlation between changes of inhibin B and HCGbeta concentrations. CONCLUSIONS: Our results suggest that inhibins A and B are not useful markers and that HCG determination still remains the most useful marker for diagnosis and follow-up of placental tumours.

The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred.

Detailed endocrinological studies were performed in the three affected kindred of a family carrying mutations of the GnRH receptor gene. All three were compound heterozygotes carrying on one allele the Arg262Gln mutation and on the other allele two mutations (Gln106Arg and Ser217Arg). When expressed in heterologous cells, both Gln106Arg and Ser217Arg mutations altered hormone binding, whereas the Arg262Gln mutation altered activation of phospholipase C. The propositus, a 30-yr-old man, displayed complete idiopathic hypogonadotropic hypogonadism with extremely low plasma levels of gonadotropins, absence of pulsatility of endogenous LH and alpha-subunit, absence of response to GnRH and GnRH agonist (triptorelin), and absence of effect of pulsatile administration of GnRH. The two sisters, 24 and 18 yr old, of the propositus displayed, on the contrary, only partial idiopathic hypogonadotropic hypogonadism. They both had primary amenorrhea, and the younger sister displayed retarded bone maturation and uterus development, but both sisters had normal breast development. Gonadotropin concentrations were normal or low, but in both cases were restored to normal levels by a single injection of GnRH. In the two sisters, there were no spontaneous pulses of LH, but pulsatile administration of GnRH provoked a pulsatile secretion of LH in the younger sister. The same mutations of the GnRH receptor gene may thus determine different degrees of alteration of gonadotropin function in affected kindred of the same family.

A single injection of a gonadotropin-releasing hormone (GnRH) antagonist (Cetrorelix) postpones the luteinizing hormone (LH) surge: further evidence for the role of GnRH during the LH surge.

OBJECTIVES: To assess the ability of a new third-generation GnRH antagonist, Cetrorelix (Asta Medica AG, Frankfurt am Main, Germany), to postpone the LH surge after a single injection during the late follicular phase. DESIGN: A single 5-mg (group 1, n = 7) or 3-mg (group 2, n = 3) dose SC of Cetrorelix was administered during the late follicular phase, on the day of the cycle when plasma E2 exceeded 150 pg/mL (550 pmol/L). Estradiol, LH, FSH, and P levels were measured daily from day 5 of the cycle until day 10 after antagonist administration. Transvaginal ultrasonographies were performed on the day of injection and after antagonist treatment. SUBJECTS: Ten normal women with regular ovulatory menstrual cycles. RESULTS: In group 1, Cetrorelix was administered on day 14.6 +/- 5 (mean +/- SD) of the cycle, when the mean plasma E2 level was 181 +/- 32 pg/mL (664 +/- 117 pmol/L) (mean +/- SD). Plasma LH and FSH decreased by 56% +/- 19% and 29.5% +/- 16% (mean +/- SD), respectively, reaching the nadir 24 hours after Cetrorelix administration. Estradiol decreased by 85% +/- 17%, reaching the nadir 48 hours after antagonist injection. In group 2, Cetrorelix was administered on day 14.3 +/- 1.2 of the cycle when the mean plasma E2 level was 169 +/- 21 pg/mL (618 +/- 77 pmol/L). Plasma LH and FSH decreased by 66% +/- 18% and 32% +/- 6%, respectively, reaching a nadir 24 hours after Cetrorelix administration. Estradiol decreased by 81% +/- 9%, reaching the nadir 24 to 48 hours after antagonist administration. The LH surge was interrupted in every case. In six of seven subjects from group 1, the LH surge was delayed, occurring 6 to 17 days after the antagonist injection. In the remaining woman, Cetrorelix was administered at the beginning of the LH surge (LH = 13 IU/L): the LH level fell immediately by 54%, and the surge was postponed by 3 days. In group 2, in three of three subjects, the LH surge was delayed, occurring 6 to 9 days after the antagonist injection. No adverse effects were observed, except for very slight and transient erythema and pruritus at the injection site. CONCLUSION: Cetrorelix is a very potent new GnRH antagonist. A single injection during the late follicular phase delays the LH surge, even if the latter has already begun. In addition, this new-generation GnRH antagonist is very well tolerated and simple to use. Our data reinforce the role of GnRH during the LH surge and point to a role for new GnRH antagonists in controlled ovarian hyperstimulation to avoid premature LH surges and subsequent luteinization.