Ap Athanasoulia

Twenty years of endocrinologic treatment in transsexualism: analyzing the role of chromosomal analysis and hormonal profiling in the diagnostic work-up

OBJECTIVE To demonstrate that adequate pubertal history, physical examination, and a basal hormone profile is sufficient to exclude disorders of sexual development (DSD) in adult transsexuals and that chromosomal analysis could be omitted in cases of unremarkable hormonal profile and pubertal history. DESIGN Retrospective chart analysis. SETTING Endocrine outpatient clinic of a psychiatric research institute. PATIENT(S) A total of 475 subjects (302 male-to-female transsexuals [MtF], 173 female-to-male transsexuals [FtM]). Data from 323 (192 MtF/131 FtM) were collected for hormonal and pubertal abnormalities. Information regarding chromosomal analysis was available for 270 patients (165 MtF/105 FtM). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pubertal abnormalities, menstrual cycle, and hormonal irregularities in relation to chromosomal analysis conducted by karyotype or hair root analysis. RESULT(S) In the MtF group, 5.2% of the patients reported pubertal irregularities and 5.7% hormonal abnormalities, and in the FtM group 3.8% and 19.1%, respectively. Overall chromosomal abnormality in both groups was 1.5% (2.9% in the FtM and 0.6% in the MtF group). The aneuploidies found included one gonosomal aneuploidy (45,X[10]/47,XXX[6]/46,XX[98]), two Robertsonian translocations (45,XXder(14;22)(q10;q10)), and one Klinefelter syndrome (47,XXY) that had already been diagnosed in puberty. CONCLUSION(S) Our data show a low incidence of chromosomal abnormalities and thus question routine chromosomal analysis at the baseline evaluation of transsexualism, and suggest that it be considered only in cases of abnormal history or hormonal examination.

Polymorphisms of the drug transporter gene: ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas

INTRODUCTION Treatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinsons disease is associated with central side effects. Central side effects may depend on a substances ability to pass the blood-brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by the ABCB1 gene. MATERIALS AND METHODS We aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encoding ABCB1 gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the human ABCB1 gene (Abcb1ab double knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case-control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selected ABCB1 gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy. RESULTS i) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood-brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found. DISCUSSION This is the first study demonstrating that individual ABCB1 gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

Clinical characteristics of pain in patients with pituitary adenomas.

OBJECTIVE Clinical presentation of pituitary adenomas frequently involves pain, particularly headache, due to structural and functional properties of the tumour. Our aim was to investigate the clinical characteristics of pain in a large cohort of patients with pituitary disease. DESIGN In a cross-sectional study, we assessed 278 patients with pituitary disease (n=81 acromegaly; n=45 Cushings disease; n=92 prolactinoma; n=60 non-functioning pituitary adenoma). METHODS Pain was studied using validated questionnaires to screen for nociceptive vs neuropathic pain components (painDETECT), determine pain severity, quality, duration and location (German pain questionnaire) and to assess the impact of pain on disability (migraine disability assessment, MIDAS) and quality of life (QoL). RESULTS We recorded a high prevalence of bodily pain (n=180, 65%) and headache (n=178, 64%); adrenocorticotropic adenomas were most frequently associated with pain (n=34, 76%). Headache was equally frequent in patients with macro- and microadenomas (68 vs 60%; P=0.266). According to painDETECT, the majority of the patients had a nociceptive pain component (n=193, 80%). Despite high prevalence of headache, 72% reported little or no headache-related disability (MIDAS). Modifiable factors including tumour size, genetic predisposition, previous surgery, irradiation or medical therapy did not have significant impact neither on neuropathic pain components (painDETECT) nor on headache-related disability (MIDAS). Neuropathic pain and pain-related disability correlated significantly with depression and impaired QoL. CONCLUSIONS Pain appears to be a frequent problem in pituitary disease. The data suggest that pain should be integrated in the diagnostic and therapeutic work-up of patients with pituitary disease in order to treat them appropriately and improve their QoL.

Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue 'Unresponsiveness' despite Adequate Estradiol Substitution

17-Alpha-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disorder resulting from mutations in the CYP17A1 gene, leading to impaired adrenal and gonadal steroidogenesis. We report for the first time a patient with a missense mutation at codon 96 (R96Q) of the CYP17A1 gene causing a 46,XY disorder of sexual development (DSD) that additionally showed lack of breast development despite highly dosed estradiol replacement treatment. This phenomenon could be attributed to irreversible breast tissue alterations following high serum progesterone levels.

Wie harmlos sind Kopfbälle? Hypogonadotroper Hypogonadismus nach leichten Schädel-Hirn-Traumata bei einem Profi-Fußballspieler

HISTORY AND CLINICAL PRESENTATION A 27-year-old man was admitted to our outpatient clinic with symptoms of loss at libido, erectile dysfunction and fatigue. He had been playing soccer from the age of 7, for the last 10 years as a high-level professional. During that time repeated mild head-trauma without loss of consciousness had occurred, mainly triggered by excessive header-training and occasional collisions. INVESTIGATIONS Serum levels of testosterone and luteinizing hormone were low. A gonadotropin releasing hormone loading test revealed significant gonadotropin responses, therefore pituitary gonadotropic insufficiency was unlikely. Further pituitary insufficiency of any other axis was also excluded by insulin hypoglycemia test. Magnetic resonance imaging of the brain revealed no significant abnormalities of the hypothalamic-pituitary unit. TREATMENT AND COURSE Testosterone substitution, at first applied transdermally, then intramuscularly, was initiated after approval by the National Anti Doping Agency. Four months later most of the symptoms had regressed. CONCLUSION Pituitary deficiency in the course of craniocerebral trauma is frequent and may be transient or permanent, mostly affecting somatotropic or gonadotropic function. Hormonal imbalances may also be observed after mild but repeated trauma without loss of consciousness and should be considered in cases of isolated pituitary dysfunction, since such traumas may often occur in contacts sports such as boxing or intensive soccer play.

Insights into the coexistence of two mutations in the same LHCGR gene locus causing severe Leydig cell hypoplasia

BACKGROUND: Leydig cell hypoplasia is a rare autosomal recessive condition that interferes with the normal development of male external genitalia in 46,XY individuals. It is mediated by mutations in the lutropin/choriogonadotropin receptor gene, resulting in the impairment of either the binding of hormone or signal transduction. OBJECTIVE/DESIGN: We report a 32-year-old female patient with severe Leydig cell hypoplasia due to a novel homozygote nonsense mutation in exon 10 (c.907C > T, p.Gln303Ter) of the lutropin/choriogonadotropin receptor gene. Interestingly, a second mutation was found (c.935A > G, p.Asn312Ser) downstream of the disruption of the gene sequence. CONCLUSIONS: This case report demonstrates the coexistence of a novel homozygote nonsense mutation with a second mutation in the same hormone binding domain, expanding the genotypic spectrum of lutropin-choriogonadotropic hormone receptor gene mutations. The first diagnosis of this mutation in an adult 46,XY female patient from Morocco underlines the importance of thorough clinical and genetic examination, not only in pre- and post-pubertal children but also in adults originating from conservative socio-cultural backgrounds.