RESUMO
BACKGROUND: Kallmann syndrome (KS) is a genetic disorder associating pubertal failure with congenitally absent or impaired sense of smell. KS is related to defective neuronal development affecting both the migration of olfactory nerve endings and GnRH neurons. The discovery of several genetic mutations responsible for KS led to the identification of signaling pathways involved in these processes, but the mutations so far identified account for only 30% of cases of KS. Here, we attempted to identify new genes responsible for KS by using a pan-genomic approach. METHODS: From a cohort of 120 KS patients, we selected 48 propositi with no mutations in known KS genes. They were analyzed by comparative genomic hybridization array, using Agilent 105K oligonucleotide chips with a mean resolution of 50 kb. RESULTS: One propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. This deletion cosegregated in the propositus' family with the KS phenotype, that was transmitted in autosomal dominant fashion and was not associated with other neurological or non-neurological clinical disorders. SEMA3A codes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been showed to have a Kallmann-like phenotype. CONCLUSIONS: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.
Assuntos
Deleção de Genes , Síndrome de Kallmann/genética , Semaforina-3A/genética , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Puberdade/genética , Puberdade/fisiologia , Semaforina-3A/fisiologia , Olfato/genética , Olfato/fisiologiaRESUMO
CONTEXT: In men with congenital hypogonadotropic hypogonadism (CHH), gonadotropin deficiency and testicular impairment exist since fetal development and persist throughout life. In a few reported cases of acquired HH (AHH), HH onset occurs mainly post pubertally. OBJECTIVE: This work aimed to compare the natural history and reproductive status in large series of CHH and lesional AHH evaluated in a single expert academic center. METHODS: We included 172 controls, 668 male HH patients (CHH: nâ =â 201 [age 16.9â ±â 9.0 years], lesional AHH: nâ =â 467 [age 45.6â ±â 18.4 years]) caused by hypothalamic and/or pituitary tumors (mainly adenomas and craniopharyngiomas) or infiltrative/traumatic diseases. RESULTS: At diagnosis, CHH were significantly younger, with 52.9% diagnosed before age 18 years, compared to only 9.6% of AHH patients. Cryptorchidism (21.9% vs 0.3%) and micropenis were more prevalent in CHH than AHH patients. Low testicular volume (TV) was present in 97% of patients with CHH (mean TV: 3.4â ±â 2.7 mL) but in only 30% of those with AHH (mean TV: 20.8â ±â 5.0 mL). Whereas no men with persistent CHH had spontaneous fertility, 70.4% of AHH men fathered at least one child without medical therapy. Total testosterone was lower both in CHH and AHH patients than in controls. Compared to controls, circulating gonadotropins and testicular peptides (insulin-like factor-3 and inhibin B) were decreased both in CHH and AHH, but were significantly higher in patients with AHH. CONCLUSION: In AHH patients, the HH has later onset and is less severe than in CHH and the phenotype can overlap with that of individuals with normal laboratory values. Our data suggest that age at diagnosis is a predictor of the reproductive phenotype in AHH.
Assuntos
Criptorquidismo , Hipogonadismo , Gonadotropinas , Humanos , Hipogonadismo/diagnóstico , Masculino , Fenótipo , TestosteronaRESUMO
CONTEXT: In patients treated with antipsychotics, the rare occurrence of a macroprolactinoma represents a therapeutic challenge. OBJECTIVE: Our aim was to evaluate the efficacy and psychiatric safety of dopamine agonists (DAs) prescribed for large macroprolactinomas in patients with psychosis treated with antipsychotics. DESIGN: This was a multicenter (France and Belgium) retrospective study. PATIENTS: Eighteen patients treated with antipsychotics were included. RESULTS: Under DA, median PRL levels decreased from 1247 (117-81 132) to 42 (4-573) ng/mL (P = 0.008), from 3850 (449-38 000) to 141 (60-6000) ng/mL (P = 0.037) and from 1664 (94-9400) to 1215 (48-5640) ng/mL (P = 0.56) when given alone (n = 8), before surgery (n = 7), or after surgery (n = 6), respectively. The prolactinoma median largest diameter decreased by 28% (0-57) in patients under DAs alone (P = 0.02) but did not change when given after surgery. Optic chiasm decompression was achieved in 82% of patients. Five patients (28%) were admitted for psychotic relapse while receiving DAs (but three of them had stopped antipsychotic treatment at that time). A more severe underlying psychosis, rather than the DA treatment itself, may explain such psychiatric admissions. CONCLUSIONS: Even if the DA efficacy on PRL levels and tumor volume in patients with macroprolactinoma under antipsychotic drugs is less impressive than that typically observed, it may be considered satisfactory for half of our patients, particularly in cases of optic chiasm compression. Psychotic exacerbation was unusual in these patients, occurring mostly in those with the most severe psychotic forms. DAs may therefore be used as antitumor treatment for macroprolactinoma in patients with visual involvement, severe headaches or invasion into the skull base who receive antipsychotics.
Assuntos
Antipsicóticos/uso terapêutico , Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adulto , Bélgica , Interações Medicamentosas , Feminino , França , Humanos , Masculino , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/psicologia , Prolactina/sangue , Prolactinoma/patologia , Prolactinoma/psicologia , Transtornos Psicóticos/complicações , Transtornos Psicóticos/tratamento farmacológico , Recidiva , Estudos RetrospectivosRESUMO
Classic forms of 21-hydroxylase deficiency (21OHD) are usually diagnosed at birth by salt wasting or precocious puberty in male patients. Here we report the case of a 32-year-old male patient who presented with azoospermia and bilateral testicular tumors. He was referred to our endocrine unit after testicular surgery. His gonadotropins were undetectable. Liquid chromatography-tandem mass spectrometry revealed a high serum progesterone level, high 17-hydroxyprogesterone (17OHP) (255 ng/mL), and high levels of 17OHP metabolites, suggesting a classic form of 21OHD. His blood pressure was normal. Molecular analysis showed a homozygous large 21-hydroxylase gene (CYP21A2) conversion. Furthermore, an adrenal CT scan revealed voluminous, heterogeneous bilateral and asymmetric adrenal masses containing calcifications. Our case report illustrates the fact that a classic form of 21OHD can be diagnosed in late adulthood, manifested by azoospermia and large adrenal tumors, associated with elevated 17OHP.
RESUMO
Thyrotropin-secreting pituitary adenomas are very rare tumors, known to present overexpression of somatostatin receptor subtype 2 and which may consequently demonstrate abnormal uptake on Ga-DOTA-TOC PET/CT. A 67-year-old woman with a history of operated pituitary macroadenoma presented with symptoms of hyperthyroidism including a large goiter. Her serum thyroid hormone levels were in favor of central hyperthyroidism. Pituitary MRI depicted an empty sella but visualized an ambiguous lesion centered on the left sphenoidal sinus. Complementary Ga-DOTA-TOC PET/CT finally demonstrated intense uptake by the sphenoidal lesion, confirming recurrence of the pituitary adenoma.
Assuntos
Adenoma/diagnóstico por imagem , Síndrome da Sela Vazia/complicações , Hipertireoidismo/complicações , Octreotida/análogos & derivados , Compostos Organometálicos , Neoplasias Hipofisárias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adenoma/sangue , Adenoma/complicações , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/complicações , Recidiva , Hormônios Tireóideos/sangueRESUMO
BACKGROUND: Papillary thyroid carcinomas (PTC) in the pT3 category constitute a heterogeneous group of tumors with a variable risk of recurrence. The objectives of this study were (i) to estimate disease-free survival (DFS) and identify prognostic factors associated with recurrence in a cohort of pT3 PTC, and (ii) to evaluate the concept of delayed risk stratification in a cohort of pT3 tumors. METHODS: A total of 560 patients with pT3 PTC, treated and followed at the authors' institution, were studied. They were divided into three groups: group 1, pT3 ≤10 mm; group 2, pT3 >10 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size >4 cm. DFS was estimated using the Kaplan-Meier method, and associated prognostic features were studied in univariate and multivariate Cox model-based analyses in each group. Then, DFS was studied for each group according to the six- to eight-month status (remission or not). RESULTS: DFS at 10 years was 75% for the entire cohort and was 89%, 67%, and 82% in groups 1, 2, and 3, respectively (p < 0.0001). Multivariate analysis identified three factors significantly associated with reduced DFS: lymph node (LN) involvement, male sex, and group 2 (>1 cm with ETI). A trend toward a worse prognosis in patients with pT3 N0/Nx PTC >10 mm with ETI was found in comparison with the other pT3 N0/Nx patients. When the six- to eight-month checkup was normal, the DFS at 10 years increased to 98%, 96%, and 91% in groups 1-3, respectively. Furthermore, in this case, initial LN involvement no longer seemed to affect the prognosis in those groups. CONCLUSION: PTC ≤10 mm with ETI and large tumors >4 cm without ETI both have a low-recurrence risk when there are no adverse associated prognostic features such as LN involvement. LN involvement, especially in the lateral compartment (N1b), is a strong prognostic factor of recurrence in pT3 PTC. Delayed risk stratification can be applied in pT3 PTC patients. Those cured at the first checkup, including those with limited LN involvement, have excellent outcomes, which should prompt clinicians to adapt subsequent management accordingly.
Assuntos
Carcinoma Papilar/diagnóstico , Medição de Risco/métodos , Neoplasias da Glândula Tireoide/diagnóstico , Carcinoma Papilar/terapia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Análise Multivariada , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia , Fatores de Tempo , Resultado do TratamentoRESUMO
Kallmann syndrome (KS) patients carrying FGFR1 mutations can transmit the disorder to their offspring as can asymptomatic female carriers of mutations in KAL1. We describe for the first time two cases in which KS was suspected during fetal life because of the family context and malformation detection by fetal ultrasound: syndactyly or unilateral renal agenesis in subjects with respectively FGFR1 and KAL1 mutations. In relevant family history, ultrasound monitoring can detect KS associated signs before birth and thus enable neonatal diagnosis and early management. These observations also underline the importance of genetic counselling for patients who may transmit KS to their offspring.
Assuntos
Proteínas da Matriz Extracelular/genética , Feto/metabolismo , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/genética , Proteínas do Tecido Nervoso/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Feminino , Humanos , Mutação , LinhagemRESUMO
CONTEXT: Both testicular and adrenal steroid secretions are impaired in men with panhypopituitarism (Hypo-Pit), whereas only testicular steroid secretion is impaired in men with isolated gonadotropin deficiency (IHH) caused by normosmic congenital hypogonadotropic hypogonadism or Kallmann syndrome. OBJECTIVE: The objective of the study was to compare the serum levels of sex steroids, precursors, and metabolites between men with complete IHH and those with Hypo-Pit. PATIENTS: We studied 42 healthy men, 16 untreated men with IHH (normosmic congenital hypogonadotropic hypogonadism/Kallmann syndrome) and 23 men with Hypo-Pit (14 with craniopharyngioma, 9 with congenital hypopituitarism) receiving hydrocortisone, thyroxine, and GH replacement therapy but not T. METHODS: Gas chromatography/mass spectrometry (GCMS) was used to measure the serum levels of sex steroids [T, dihydrotestosterone (DHT), and estradiol (E2)], their precursors (pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, androstenediol, progesterone, 17-hydroxyprogesterone, and androstenedione), and their metabolites (androsterone, estrone, and estrone sulfate) as well as pregnenolone and dehydroepiandrosterone sulfate esters. RESULTS: All the above-mentioned steroids, and notably T, DHT, and E2, were significantly lower in IHH patients than in controls but remained well above the detection limit of the relevant assays. In Hypo-Pit men, all these steroids were dramatically and significantly lower than in IHH. Interestingly, T, DHT, and E2, as well as pregnenolone and dehydroepiandrosterone sulfate esters, were undetectable or barely detectable in the Hypo-Pit men. CONCLUSIONS: Steroid deficiencies are marked but partial in men with complete IHH. In contrast, men with Hypo-Pit have a very severe overall steroid deficiency. These deficiencies could affect health and quality of life.
Assuntos
Di-Hidrotestosterona/sangue , Estradiol/sangue , Hipogonadismo/sangue , Hipopituitarismo/sangue , Testosterona/sangue , Adulto , Androstenodiona/sangue , Cromatografia Gasosa , Desidroepiandrosterona/sangue , Estrona/sangue , Humanos , Hipogonadismo/tratamento farmacológico , Hipopituitarismo/tratamento farmacológico , Masculino , Espectrometria de Massas , Progesterona/sangue , Adulto JovemRESUMO
BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a rare condition characterized by bone and joint pain and digital clubbing usually associated with bronchopulmonary diseases. Primary HOA is rare and the pathogenesis remains unclear. OBJECTIVES: Cases of HOA as a paraneoplastic syndrome associated with thyroid carcinoma are very rare - only 2 cases have been described in the literature. RESULTS: We present the first case of a 40-year-old patient affected by HOA associated with invasive differentiated follicular thyroid carcinoma operated in 2 stages. Both operations were followed by radioiodine ablation, and then a rapid unresectable local recurrence developed requiring cervical radiotherapy (70 Gy). A second treatment with 100 mCi of (131)I confirmed it was a refractory thyroid cancer. Further surgery confirmed a poorly differentiated follicular cancer and 12 cycles of chemotherapy by gemcitabine and oxaliplatin followed. During the 8 years of follow-up, cervical recurrence was stable, but severe episodes of hemoptysis occurred requiring iterative embolization of the bronchial and tracheal arteries. Other lung diseases were excluded. Digital clubbing appeared, which was associated with arthritis, bone pain and inflammatory syndrome. X-rays and magnetic resonance imaging found periosteal apposition in the long bones; bone scintigraphy confirmed the HOA diagnosis. Other causes of arthritis were eliminated. She was treated with colchicine, corticosteroids and nonsteroidal anti-inflammatory drugs, but only the combination of methotrexate and hydroxychloroquine reduced the morphine requirements. CONCLUSION: HOA is exceptionally associated with thyroid cancer and we raised the hypothesis of the secretion of a circulating factor in a patient with invasive and recurrent follicular thyroid cancer, refractory to radioiodine.
RESUMO
Men with Kallmann syndrome (KS) and those with congenital isolated hypogonadotropic hypogonadism with normal olfaction share a chronic, usually profound deficit, in FSH and LH, the two pituitary gonadotropins. Many studies indicate that this gonadotropin deficiency is already present during fetal life, thus explaining the micropenis, cryptorchidism and marked testicular hypotrophy already present at birth. In addition, neonatal activation of gonadotropin secretion is compromised in boys with severe CHH/Kallmann, preventing the first phase of postnatal testicular activation. Finally, CHH is characterized by the persistence, in the vast majority of cases, of gonadotropin deficiency at the time of puberty and during adulthood. This prevents the normal pubertal testicular reactivation required for physiological sex steroid and testicular peptide production, and for spermatogenesis. CHH/KS thus represents a pathological paradigm that can help to unravel, in vivo, the role of each gonadotropin in human testicular exocrine and endocrine functions at different stages of development. Recombinant gonadotropins with pure LH or FSH activity have been used to stimulate Leydig's cells and Sertoli's cells, respectively, and thereby to clarify their paracrine interaction in vivo. The effects of these pharmacological probes can be assessed by measuring the changes they provoke in circulating testicular hormone concentrations. This review discusses the impact of chronic gonadotropin deficiency on the endocrine functions of the interstitial compartment, which contains testosterone-, estradiol- and INSL3-secreting Leydig's cells. It also examines the regulation of inhibin B and anti-Mullerian hormone (AMH) secretion in the seminiferous tubules, and the insights provided by studies of human testicular stimulation with recombinant gonadotropins, used either individually or in combination.
Assuntos
Hormônios/fisiologia , Hipogonadismo/fisiopatologia , Síndrome de Kallmann/fisiopatologia , Testículo/fisiopatologia , Criptorquidismo/etiologia , Quimioterapia Combinada , Hormônio Foliculoestimulante/deficiência , Hormônio Foliculoestimulante/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Recém-Nascido , Inibinas/metabolismo , Hormônio Luteinizante/deficiência , Hormônio Luteinizante/uso terapêutico , Masculino , Pênis/anormalidades , Puberdade/fisiologia , Receptores do LH/fisiologia , Proteínas Recombinantes/uso terapêutico , Testículo/embriologia , Testículo/patologiaRESUMO
CONTEXT: Insulin-like factor 3 (INSL3) is a testicular hormone secreted during fetal life, the neonatal period, and after puberty. OBJECTIVE: To measure INSL3 levels in a large series of men with congenital hypogonadotropic hypogonadism (CHH)/ Kallmann syndrome (KS), in order to assess its diagnostic value and to investigate its regulation. PATIENTS: We studied 281 CHH/KS patients (91 untreated, 96 receiving T, and 94 receiving combined gonadotropin therapy [human chorionic gonadotropin, hCG, and FSH]) and 72 age-matched healthy men. METHODS: Serum INSL3 was immunoassayed with a validated RIA. RESULTS: Mean (±SD) INSL3 levels (pg/mL) were 659 ± 279 in controls and lower (60 ± 43; P < .001) in untreated CHH/KS patients, with no overlap between the two groups, when the threshold of 250 pg/mL was used. Basal INSL3 levels were lower in both untreated CHH/KS men with cryptorchidism than in those with intrascrotal testes and in patients with testicular volumes below 4 mL. Significant positive correlations between INSL3 and both serum total T and LH levels were observed in untreated CHH/KS. Mean INSL3 levels remained low in T-treated CHH/KS patients and were significantly higher in men receiving combined hCG-FSH therapy (P < .001), but the increase was lower cryptorchid patients. FSH-hCG combination therapy or hCG monotherapy, contrary to T and FSH monotherapies, significantly increased INSL3 levels in CHH/KS. CONCLUSIONS: INSL3 is as sensitive a marker as T for the evaluation of altered Leydig cell function in CHH/KS patients. INSL3 levels correlate with LH levels in CHH/KS men showing, together with the rise in INSL3 levels during hCG therapy, that INSL3 secretion seems not constitutively secreted during adulthood but is dependence on pituitary LH.
Assuntos
Hipogonadismo/diagnóstico , Insulina/sangue , Síndrome de Kallmann/diagnóstico , Adulto , Gonadotropina Coriônica/uso terapêutico , Quimioterapia Combinada , Hormônio Foliculoestimulante/uso terapêutico , Terapia de Reposição Hormonal , Humanos , Hipogonadismo/sangue , Hipogonadismo/congênito , Hipogonadismo/tratamento farmacológico , Síndrome de Kallmann/sangue , Síndrome de Kallmann/tratamento farmacológico , Hormônio Luteinizante/sangue , Masculino , Proteínas , Testosterona/sangue , Testosterona/uso terapêutico , Resultado do TratamentoRESUMO
CONTEXT: Mutations in CHD7, a gene previously implicated in CHARGE (coloboma, heart defect, choanal atresia, retardation of growth and/or development, genital hypoplasia, ear anomalies) syndrome, have been reported in patients presenting with Kallmann syndrome (KS) or congenital hypogonadotropic hypogonadism (CHH). Most mutations causing CHARGE syndrome result in premature stop codons and occur de novo, but the proportion of truncating vs nontruncating mutations in KS and CHH patients is still unknown. OBJECTIVE: The objective of the study was to determine the nature, prevalence, mode of transmission, and clinical spectrum of CHD7 mutations in a large series of patients. DESIGN: We studied 209 KS and 94 CHH patients. These patients had not been diagnosed with CHARGE syndrome according to the current criteria. We searched for mutations in 16 KS and CHH genes including CHD7. RESULTS: We found presumably pathogenic mutations in CHD7 in 24 KS patients but not in CHH patients. Nontruncating mutations (16 missense and a two-codon duplication) were more prevalent than truncating mutations (three nonsense, three frame shift, and a splice site), which contrasts with patients presenting with typical CHARGE syndrome. Thus, the clinical spectrum associated with CHD7 mutations may be partly explained by genotype/phenotype correlations. Eight patients also had congenital deafness and one had a cleft lip/palate, whereas six had both. For 10 patients, the presence of diverse features of the CHARGE spectrum in at least one relative argues against a de novo appearance of the missense mutation, and this was confirmed by genetic analysis in five families. CONCLUSION: Considering the large prevalence and clinical spectrum of CHD7 mutations, it will be particularly relevant to genetic counseling to search for mutations in this gene in KS patients seeking fertility treatment, especially if KS is associated with deafness and cleft lip/palate.
Assuntos
Síndrome CHARGE/epidemiologia , Síndrome CHARGE/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Síndrome de Kallmann/epidemiologia , Síndrome de Kallmann/genética , Adolescente , Adulto , Criança , Pré-Escolar , Saúde da Família , Feminino , Mutação da Fase de Leitura , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Prevalência , Adulto JovemRESUMO
CONTEXT: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that associates hypogonadotropic hypogonadism and anosmia. Various causative genes have been identified, but their respective involvement in different world regions is poorly documented. OBJECTIVE: We aimed to compare the prevalence of mutations in five routinely analyzed KS genes between Maghrebian and European patients. METHODS: Blood samples from 120 presumably unrelated Maghrebian patients were collected for DNA sequencing by the Sanger technique. The prevalence of the non-synonymous mutations in KAL1, FGFR1, FGF8, PROKR2, and PROK2 was determined for each gene, and compared with those previously obtained from the analysis of 712 European patients. RESULTS: Diverse mutations in PROKR2, a gene involved both in monogenic recessive and digenic/oligogenic KS transmission modes, were found in 23.3% of the Maghrebian patients, but only in 5.1% of the European patients (Fisher's exact test, P<0.001), whereas mutations in each of the other four KS genes were present either at similar frequencies in the Maghrebian and European patients (KAL1, PROK2, FGF8, from 6.6 to 0.8%; Fisher's exact test, P>0.4 for all comparisons) or at a lower frequency in Maghrebian patients (FGFR1, 5.0 vs 11.7%; Fisher's exact test, P<0.05). Homozygosity resulting from consanguineous marriages was not sufficient to account for the greater prevalence of PROKR2 mutations in the Maghrebian patients. CONCLUSIONS: The great prevalence of PROKR2 mutations in Maghrebian patients has practical consequences for molecular diagnosis of the disease and genetic counseling in the Maghrebian population.
Assuntos
Árabes/genética , Síndrome de Kallmann/genética , Mutação , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , População Branca/genética , Adulto , África do Norte , Idoso , Europa (Continente) , Éxons , Proteínas da Matriz Extracelular/genética , Feminino , Fator 8 de Crescimento de Fibroblasto/genética , Hormônios Gastrointestinais/genética , Frequência do Gene , Humanos , Íntrons , Síndrome de Kallmann/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Prevalência , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de DNARESUMO
OBJECTIVE: Evaluation of postmenopausal women with suspicion of androgen-secreting tumor. DESIGN AND PATIENTS: We retrospectively studied 22 postmenopausal women referred to our center for suspicion of androgen-secreting tumor. All patients had clinical, biological, and morphological evaluation. In absence of adrenal tumors, ovarian surgery was most often proposed and immunohistochemistry (IHC) studies were performed. RESULTS: Ovarian tumors were detected by ultrasound and/or magnetic resonance imaging in eight patients. Two adrenal androgen-secreting tumors were diagnosed by an adrenal computed tomography (CT) scan. The clinical presentation of the women with or without tumors was similar. Nevertheless, women with tumor exhibited significantly higher testosterone levels and lower basal FSH and LH levels than the other women (2.6±2.7 vs 0.9±0.9âng/ml, P<0.05; 26.5±22.9 vs 66.5±26.0âIU/l, P<0.01; and 12.0±8.6 vs 24.1±8.9âIU/l, P<0.05 respectively). Based on a likelihood ratio test, patients with a tumor had 8.4 and 10.8 times higher risk of having a testosterone level ≥1.4âng/ml or an FSH level ≤35âIU/l. Finally, IHC analysis with an anti-P450c17α antibody allowed the identification of an elevated number of ovarian androgen-producing cells in five patients in whom no tumor was found. CONCLUSIONS: Androgen-secreting tumors are clinically difficult to discriminate from other causes of postmenopausal hyperandrogenism. Testosterone and FSH were the two discriminative markers in a multivariate analysis. Ovarian and adrenal tumors were detected by imaging studies. However, ovarian non-tumoral causes of hyperandrogenism may be difficult to detect with conventional histology.
Assuntos
Hiperandrogenismo/diagnóstico por imagem , Hiperandrogenismo/metabolismo , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Pós-Menopausa/sangue , Idoso , Androgênios/metabolismo , Biomarcadores/química , Biomarcadores/metabolismo , Feminino , Humanos , Hiperandrogenismo/diagnóstico , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Radiografia , Estudos RetrospectivosAssuntos
Gonadotropinas/deficiência , Hormônio do Crescimento Humano/deficiência , Síndrome de Kallmann/patologia , Bulbo Olfatório/patologia , Hipófise/patologia , Azoospermia/etiologia , Azoospermia/patologia , Humanos , Masculino , Testículo/patologia , Testosterona/análogos & derivados , Testosterona/uso terapêutico , Adulto JovemRESUMO
Mutations in the prokineticin 2 peptide (PROK2) and its seven-transmembrane domain type 2 receptor PROKR2 are newly identified molecular culprits in autosomal Kallmann syndrome (KS). Prok2 and prokr2 gene knockout mice both have agenesis or hypoplasia of the olfactory bulbs, associated with hypogonadotropic hypogonadism linked to abnormal GnRH neuron migration. Prok2-/- and prokr2-/- mice are the first murine models of this human disease. KS patients of both sexes have a variety of point mutations, missense mutations, frameshifts and nonsense mutations in the PROK2 and PROKR2 genes that lead to a loss of peptide or receptor function. When only one allele is affected, penetrance of the two main clinical features of KS may be incomplete: subjects with only one mutant allele may have (1) no symptoms, with normal olfaction and complete pubertal development, (2) congenital isolated (idiopathic) hypogonadotropic hypogonadism (IHH) but normal olfaction, (3) anosmia/hyposmia but normal pubertal development and gonadal function or (4) the two cardinal clinical KS signs, anosmia and IHH. These phenotypic dissociations can be seen in family members with the same PROK2/PROKR2 mutations. By contrast, patients with two mutant alleles almost always have the cardinal signs of KS. Even when monoallelic PROK2/PROKR2 mutations are associated with full-blown KS, the reproductive phenotype in males is less severe than in KS associated with biallelic mutations, evidenced by significantly lower frequency of cryptorchidism and micropenis, greater testicular volume, and higher serum levels of LH, FSH and testosterone. Moreover, at least some of these monoallelic cases are in fact digenic, in that they also carry mutations of other KS/IHH genes. Overall, these observations point towards a combination of mendelian autosomal recessive transmission, with more complex oligogenic transmission. Patients with this genetic form of KS have been reported to have a possible increased prevalence of obesity and sleep disorders, which may be related to the role of PROK2 and PROKR2 in food intake and circadian rhythms. However, diurnal variation of serum cortisol levels appears to be physiologically maintained.
Assuntos
Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Sequência de Aminoácidos , Animais , Hormônios Gastrointestinais , Estudos de Associação Genética , Humanos , Síndrome de Kallmann/genética , Síndrome de Kallmann/fisiopatologia , Camundongos , Camundongos Knockout , Neuropeptídeos , Bulbo Olfatório/anormalidades , LinhagemRESUMO
CONTEXT: Both biallelic and monoallelic mutations in PROK2 or PROKR2 have been found in Kallmann syndrome (KS). OBJECTIVE: The objective of the study was to compare the phenotypes of KS patients harboring monoallelic and biallelic mutations in these genes. DESIGN AND PATIENTS: We studied clinical and endocrine features that reflect the functioning of the pituitary-gonadal axis, and the nonreproductive phenotype, in 55 adult KS patients (42 men and 13 women), of whom 41 had monoallelic mutations and 14 biallelic mutations in PROK2 or PROKR2. RESULTS: Biallelic mutations were associated with more frequent cryptorchidism (70% vs. 34%, P < 0.05) and microphallus (90% vs. 28%, P < 0.001) and lower mean testicular volume (1.2 +/- 0.4 vs. 4.5 +/- 6.0 ml; P < 0.01) in male patients. Likewise, the testosterone level as well as the basal FSH level and peak LH level under GnRH-stimulation were lower in males with biallelic mutations (0.2 +/- 0.1 vs. 0.7 +/- 0.8 ng/ml; P = 0.05, 0.3 +/- 0.1 vs. 1.8 +/- 3.0 IU/liter; P < 0.05, and 0.8 +/- 0.8 vs. 5.2 +/- 5.5 IU/liter; P < 0.05, respectively). Nonreproductive, nonolfactory anomalies were rare in both sexes and were never found in patients with biallelic mutations. The mean body mass index of the patients (23.9 +/- 4.2 kg/m(2) in males and 26.3 +/- 6.6 kg/m(2) in females) did not differ significantly from that of gender-, age-, and treatment-matched KS individuals who did not carry a mutation in PROK2 or PROKR2. Finally, circadian cortisol levels evaluated in five patients, including one with biallelic PROKR2 mutations, were normal in all cases. CONCLUSION: Male patients carrying biallelic mutations in PROK2 or PROKR2 have a less variable and on average a more severe reproductive phenotype than patients carrying monoallelic mutations in these genes. Nonreproductive, nonolfactory clinical anomalies associated with KS seem to be restricted to patients with monoallelic mutations.
Assuntos
Hormônios Gastrointestinais/genética , Síndrome de Kallmann/genética , Mutação , Neuropeptídeos/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Alelos , Índice de Massa Corporal , Ritmo Circadiano , Criptorquidismo/epidemiologia , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Fenótipo , Testículo/patologia , Testosterona/metabolismoRESUMO
Sex steroids are major determinants of bone mass, and hormonal contraceptives may affect bone mineral density (BMD) in women. Combination contraceptives probably have no impact on BMD, except perhaps when started within 3 years after the menarche. Progestogen-only contraceptives are being increasingly used. Injectable medroxyprogesterone acetate, a potent inhibitor of gonadotropin release, can induce bone loss, most notably in young women. Other progestogens are used in lower doses that have weaker antigonadotropin effects. Levonorgestrel and etonorgestrel implants have unclear effects on BMD but are probably safe. The impact of high- and low-dose oral progestogens on BMD has not been investigated, although no adverse effects would be expected.