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BACKGROUND: Reference intervals covering the whole life span for all the metabolites in the steroid hormone biosynthesis quantified by sensitive and robust analytical methods are sparse or not existing. OBJECTIVE: To develop a state-of-the-art LC-MS/MS method for simultaneous quantification of multiple steroid metabolites and to establish detailed sex- and age-specific reference intervals for 16 steroid metabolites. MATERIALS AND METHOD: An isotope diluted LC-MS/MS method was developed for simultaneous quantitation of 16 steroid hormones. Serum samples from cross-sectional cohorts of healthy infants, children, adolescents, and adults aged 0.17 months to 77 years (n = 2458) were analysed. RESULTS: With this novel, specific, and sensitive LC-MS/MS method, it was possible to quantify progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, testosterone, dihydrotestosterone, 11-deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, and cortisone in ≥90 % of the samples, while estrone sulfate, aldosterone and dehydroepiandrosterone were quantified in 77 %, 75 % and 60 % of the samples, respectively. 21-deoxycortisol was only detectable in 2.5 % of samples from healthy subjects. Sex- and age-dependent fluctuations observed in minipuberty, puberty and adulthood including the menopausal transition were modelled. This enabled us to establish valid reference intervals from birth to late adult life for both males and females. CONCLUSION: Detailed sex- and age-specific reference intervals of multiple, simultaneously quantified steroid metabolites by a novel and specific LC-MS/MS method provides a valuable tool for clinical practice and for future research.
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Esteroides , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/normas , Lactante , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto , Cromatografía Liquida/normas , Valores de Referencia , Adulto Joven , Anciano , Persona de Mediana Edad , Esteroides/sangre , Recién Nacido , Voluntarios Sanos , Factores de Edad , Estudios Transversales , Factores Sexuales , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cells lacked XIST expression and had only one X-chromosome. Sertoli cells supporting focal spermatogenesis also lacked XIST expression and the additional X-chromosome, while the spermatogonia expressed XIST despite having only one X-chromosome. XIST was expressed in Sertoli cells until puberty, where a gradual loss was observed. Our results suggest that a micro-mosaic loss of the additional X-chromosome is needed for Sertoli cells to mature and to allow focal spermatogenesis.
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Síndrome de Klinefelter , ARN Largo no Codificante , Células de Sertoli , Espermatogénesis , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patología , Síndrome de Klinefelter/metabolismo , Masculino , Células de Sertoli/metabolismo , Células de Sertoli/patología , Espermatogénesis/genética , Animales , Humanos , Ratones , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Cromosomas Humanos X/genética , Cromosoma X/genéticaRESUMEN
OBJECTIVE: To describe the natural history of inhibin B throughout life according to sex, age, and pubertal development. METHODS: Based on serum samples from 2707 healthy controls aged 0 to 80 years, sex- and age-specific reference ranges of inhibin B concentrations were constructed. Concentrations were evaluated according to pubertal development and use of oral contraceptives (OCs). Also, measurements from 42 patients with Klinefelter syndrome were included. RESULTS: In both sexes, inhibin B concentrations were high during minipuberty, decreased in childhood, and increased significantly from Tanner stages B1 to B3 (peak: B4) in females and from G1 to G3 (peak: G3) in males. Despite variations in menstruating females, inhibin B concentrations remained relatively constant after puberty, until becoming unmeasurable at menopause. Despite a modest decrease, the inhibin B concentration in males remained relatively high from puberty onwards. At any age, males had highest concentrations. Inhibin B standard deviation (SD) scores were lower in OC-users (median SD score = -0.88) than in non-users (SD score = 0.35), p < 0.001. In patients with Klinefelter syndrome, inhibin B concentrations spanned the reference range until around 15 years of age, where they decreased to subnormal or unmeasurable levels. CONCLUSION: Valuable sex- and age-specific reference data for inhibin B concentrations were provided. In OC-users, decreased concentrations of inhibin B underlined the ovaries as the only place of inhibin B production. In patients with Klinefelter syndrome, the decline in inhibin B concentrations at puberty underlined the shift in regulation of inhibin B production at pubertal onset.
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BACKGROUND: Endogenous sex steroids influence the pubertal growth spurt and adult height. However, the impact of puberty suppression and sex steroids on growth in transgender adolescents is sparsely studied. AIM: We investigated pubertal growth, serum IGF-I and IGFBP-3, and adult height of transgender adolescents receiving hormone therapy. METHODS: Observational study of a national cohort (2016-2023) comprising 219 transgender adolescents <18 years of age. Treatment consisted of gonadotropin-releasing hormone agonist (GnRHa) combined with estradiol or testosterone (adjusted to serum concentrations between 0 and +2 standard deviations (SDs) corresponding to the gender identity). RESULTS: Adult height was within ±2 SD for sex assigned at birth.Most trans girls reached adult height within references of girls. For trans girls (bone age ≤15 years before treatment), a growth spurt was observed during estradiol therapy. IGF-I and height SDS declined during oral estradiol administration (-0.13 SDS per month, p=0.059, and -0.02 SDS, p=0.001, respectively). We observed significantly lower adult height compared to target height for trans girls (-2.7 cm, p=0.01), and significant differences between height SDS before treatment and at adult height (-0.35 SDS, p<0.001).Half of the trans boys remained short (<-2 SD) compared to references for boys, and most completed growth spurt before initiation of treatment. IGFBP-3 declined following testosterone treatment. There was a significant difference between height SDS before treatment and at adult height (-0.17 SDS, p<0.001). DISCUSSION AND CONCLUSION: The minor reduction in adult height of trans girls after hormone treatment may be beneficial to some, whereas trans boys did not experience height gain.
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Microdisección , Semen , Humanos , Niño , Masculino , Testículo , Espermatozoides , Investigación , Estudios RetrospectivosRESUMEN
Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.
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Adult patients with Klinefelter syndrome (KS) are characterized by a highly variable phenotype, including tall stature, obesity, and hypergonadotropic hypogonadism, as well as an increased risk of developing insulin resistance, metabolic syndrome, and osteoporosis. Most adults need testosterone replacement therapy (TRT), whereas the use of TRT during puberty has been debated. In this retrospective, observational study, reproductive hormones and whole-body dual-energy x-ray absorptiometry-derived body composition and bone mineral content were standardized to age-related standard deviation scores in 62 patients with KS aged 5.9-20.6 years. Serum concentrations of total testosterone and inhibin B were low, whereas luteinizing hormone and follicle-stimulating hormone were high in patients before TRT. Despite normal body mass index, body fat percentage and the ratio between android fat percentage and gynoid fat percentage were significantly higher in the entire group irrespective of treatment status. In patients evaluated before and during TRT, a tendency toward a more beneficial body composition with a significant reduction in the ratio between android fat percentage and gynoid fat percentage during TRT was found. Bone mineral content (BMC) did not differ from the reference, but BMC corrected for bone area was significantly lower when compared to the reference. This study confirms that patients with KS have an unfavorable body composition and an impaired bone mineral status already during childhood and adolescence. Systematic studies are needed to evaluate whether TRT during puberty will improve these parameters.
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Objective: Klinefelter syndrome (KS) is the most common sex chromosome disorder and genetic cause of infertility in males. A highly variable phenotype contributes to the fact that a large proportion of cases are never diagnosed. Typical hallmarks in adults include small testes and azoospermia which may prompt biochemical evaluation that typically shows extremely high follicle-stimulating hormone and low/undetectable inhibin B serum concentrations. However, in prepubertal KS individuals, biochemical parameters are largely overlapping those of prepubertal controls. We aimed to characterize clinical profiles of prepubertal boys with KS in relation to controls and to develop a novel biochemical classification model to identify KS before puberty. Methods: Retrospective, longitudinal data from 15 prepubertal boys with KS and data from 1475 controls were used to calculate age- and sex-adjusted standard deviation scores (SDS) for height and serum concentrations of reproductive hormones and used to infer a decision tree classification model for KS. Results: Individual reproductive hormones were low but within reference ranges and did not discriminate KS from controls. Clinical and biochemical profiles including age- and sex-adjusted SDS from multiple reference curves provided input data to train a 'random forest' machine learning (ML) model for the detection of KS. Applied to unseen data, the ML model achieved a classification accuracy of 78% (95% CI, 61-94%). Conclusions: Supervised ML applied to clinically relevant variables enabled computational classification of control and KS profiles. The application of age- and sex-adjusted SDS provided robust predictions irrespective of age. Specialized ML models applied to combined reproductive hormone concentrations may be useful diagnostic tools to improve the identification of prepubertal boys with KS.
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INTRODUCTION: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. PATIENTS AND METHODS: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www. CLINICALTRIAL: gov (NCT02991209) and ended June 2019. RESULTS: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). CONCLUSION: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.
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Síndrome Metabólico , Neoplasias Testiculares , Método Doble Ciego , Glucosa/metabolismo , Humanos , Insulina , Células Intersticiales del Testículo/metabolismo , Hormona Luteinizante/metabolismo , Masculino , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Neoplasias de Células Germinales y Embrionarias , Sobrevivientes , Neoplasias Testiculares/terapia , TestosteronaRESUMEN
OBJECTIVE: To evaluate whether optimized and standardized diagnostic procedures would improve detection of germ cell neoplasia in situ (GCNIS) in the contralateral testis of patients with testicular germ cell tumour (TGCT) and decrease the rate of metachronous tumours, which in a nationwide Danish study was estimated to be 1.9%. PATIENTS AND METHODS: This was a retrospective analysis of outcomes in 655 patients with TGCT who underwent contralateral biopsies (1996-2007) compared with those in 459 non-biopsied TGCT controls (1984-1988). The biopsies were performed using a standardized procedure with immunohistochemical GCNIS markers and assessed by experienced evaluators. Initial histopathology reports were reviewed, and pathology and survival data were retrieved from national Danish registers. In 604/608 patients diagnosed as GCNIS-negative (four were lost to follow-up), the cumulative incidence of metachronous TGCT was estimated in a competing risk setting using the Grey method. All cases of metachronous TGCT were re-examined using immunohistochemistry. RESULTS: Germ cell neoplasia in situ was found in 47/655 biopsied patients (7.2%, 95% confidence interval [CI] 5.4-9.5%). During the follow-up period (median 17.3 years) five of the 604 GCNIS-negative patients developed a TGCT. In 1/5 false-negative biopsies, GCNIS was found on histological revision using immunohistochemistry and 2/5 biopsies were inadequate because of too small size. The estimated cumulative incidence rate of second tumour after 20 years of follow-up was 0.95% (95% CI 0.10%-1.8%) compared with 2.9% (95% CI 1.3%-4.4%) among the non-biopsied TGCT patients (P = 0.012). The estimates should be viewed with caution due to the small number of patients with metachronous TGCT. CONCLUSIONS: Optimized diagnostic procedures improved the detection rate of GCNIS in patients with TGCT and minimized their risk of developing metachronous bilateral cancer. Urologists should be aware of the importance of careful tissue excision (to avoid mechanical compression) and the need of adequate biopsy size. Performing contralateral biopsies is beneficial for patients' care and should be offered as a part of their management.
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Neoplasias de Células Germinales y Embrionarias , Neoplasias Primarias Secundarias , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/epidemiología , Testículo/patología , Estudios Retrospectivos , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Biopsia , Células Germinativas/patologíaRESUMEN
BACKGROUND: Surgical extraction of testicular spermatozoa is needed in men with nonobstructive azoospermia (NOA) who wish to become biological fathers. Based on available uncontrolled studies with unspecific patient selection, microdissection testicular sperm extraction (mTESE), having a sperm retrieval rate (SRR) of 50%, is considered the most efficient sperm retrieval procedure. However, no randomized clinical trials for comparison of different sperm retrieval procedures exist. Testicular sperm aspiration (TESA) is simple and commonly used, and we hypothesized that this technique using multiple needle passes would give similar SRRs to mTESE. OBJECTIVE: To compare mTESE and multiple needle-pass TESA in men with NOA. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial was performed between June 2017 and April 2021, with inclusion of 100 men with NOA from four centers in Denmark and Sweden. All participants received treatment at the same institution. INTERVENTION: Participants were randomized to mTESE (n = 49) or multiple needle-pass TESA (n = 51). Patients with failed multiple needle-pass TESA proceeded directly to salvage mTESE. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was SRR. Secondary outcomes included complications and changes in reproductive hormones after surgery. RESULTS AND LIMITATIONS: Spermatozoa were retrieved in 21/49 (43%) men after mTESE and in 11/51 (22%) men after multiple needle-pass TESA (rate difference -0.21; 95% confidence interval -0.39 to -0.03; p = 0.02). The combined SRR for multiple needle-pass TESA + salvage mTESE was 15/51 (29%). No complications occurred after multiple needle-pass TESA only, while 5/89 (6%) men having mTESE experienced a complication requiring surgical intervention. Overall, no statistically significant differences in reproductive hormones were observed between groups after 6 mo. Limitations include the low number of patients in secondary outcome data. CONCLUSIONS: In direct comparison, SRR was higher in mTESE than in multiple needle-pass TESA. PATIENT SUMMARY: Men with azoospermia need surgical extraction of spermatozoa to become biological fathers. In this randomized trial, we compared two surgeries (microdissection testicular sperm extraction [mTESE] and testicular sperm aspiration [TESA]) and found that mTESE gives a higher sperm retrieval rate than multiple needle-pass TESA.
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Azoospermia , Recuperación de la Esperma , Azoospermia/complicaciones , Azoospermia/cirugía , Femenino , Hormonas , Humanos , Masculino , Microdisección/métodos , Estudios Retrospectivos , Semen , Espermatozoides , Testículo/cirugíaRESUMEN
OBJECTIVES: 17ß-hydroxysteroid dehydrogenase 3 (17ß-HSD3) deficiency results in insufficient biosynthesis of testosterone and consequently dihydrotestosterone. This is important for the fetal development of male genitalia. Thus, most 46,XY patients with 17ß-HSD3 deficiency have a female appearance at birth and present with virilization at puberty. This study presents the differences in the clinical and hormonal data and analyses of gonadal characteristics in two siblings with 17ß-HSD3 deficiency. CASE PRESENTATION: Patient 1 presented with deepening of the voice and signs of virilization at puberty and increased serum levels of testosterone (T) of 10.9 nmol/L (2.9 SDS) and androstenedione (Δ4) of 27 nmol/L (3.3 SDS) were observed. The T/Δ4-ratio was 0.39. Patient 2 was clinically prepubertal at the time of diagnosis, but she also had increased levels of T at 1.97 nmol/L (2.9 SDS), Δ4 at 5 nmol/L (3.3 SDS), and the T/Δ4-ratio was 0.40, but without signs of virilization. Both siblings were diagnosed as homozygous for the splice-site mutation c.277+4A>T in intron 3 of HSD17B3. They were subsequently gonadectomized and treated with hormone replacement therapy. The gonadal histology was overall in accordance with pubertal status, although with a dysgenetic pattern in both patients, including Sertoli-cell-only tubules, few tubules containing germ cells, and presence of microliths. CONCLUSIONS: Two siblings with 17ß-HSD3 deficiency differed in pubertal development at the time of diagnosis and showed marked differences in their clinical presentation, hormonal profile, gonadal morphology and expression of cell lineage markers. Early diagnosis of 17ß-HSD3 deficiency appears beneficial to ameliorate long-term consequences.
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17-Hidroxiesteroide Deshidrogenasas , Hermanos , 17-Hidroxiesteroide Deshidrogenasas/genética , Linaje de la Célula , Femenino , Humanos , Recién Nacido , Masculino , Testosterona , VirilismoRESUMEN
BACKGROUND: Quarterly intramuscular injections with long-acting testosterone undecanoate (TU) provide stable serum testosterone concentrations over time and are therefore preferred by many testosterone-deficient patients. However, the use of long-acting TU in elderly patients is limited due to lack of safety and feasibility studies. OBJECTIVE: To investigate long-acting TU pharmacokinetics and assess differences in treatment regimens and risk of adverse outcomes in younger versus elderly testosterone-deficient patients. MATERIALS AND METHODS: Single-center longitudinal observational study. Patients who initiated long-acting TU treatment between 2005 and 2010 were included. Elderly patients were born before 1956 and younger patients between 1965 and 1985. TU dose was adjusted yearly through shortening or prolongation of time between injections. Treatment targets were as follows: (1) free testosterone between 0 and -1 SD from the age-adjusted mean, (2) no symptoms of testosterone deficiency, and (3) hematocrit within the normal range. RESULTS: The study population consisted of 63 elderly and 63 younger patients. Median follow-up time during testosterone replacement was 12.1 years. Increasing intervals between TU injections were performed 44% more often in the elderly compared to younger patients and time between TU injections were prolonged 4% more in the elderly patients. The hematocrit, as well as the hematocrit for a given serum testosterone (hematocrit: testosterone ratio), increased with treatment time but did not differ between age groups. During follow-up, 40% of patients-both elderly and younger-experienced polycythemia. Risk of polycythemia did not differ with age. DISCUSSION AND CONCLUSION: An increased number of adjustments of TU dose are necessary in elderly patients in order to reach treatment targets. TU treatment in elderly testosterone-deficient patients is not associated with an increased risk of polycythemia compared to younger patients if age-adjusted treatment targets are reached.
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Factores de Edad , Andrógenos/administración & dosificación , Terapia de Reemplazo de Hormonas/métodos , Testosterona/análogos & derivados , Testosterona/deficiencia , Anciano , Humanos , Inyecciones Intramusculares , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Testosterona/administración & dosificación , Testosterona/sangre , Resultado del TratamientoRESUMEN
Objective: Insulin-like factor 3 (INSL3) is produced in the testes and has been proposed as a circulating biomarker of Leydig cell capacity, but remains undescribed in 45,X/46,XY mosaicism. The aim was to examine serum concentrations and gonadal expression of INSL3 in 45,X/46,XY mosaicism. Methods: Retrospectively collected data from medical records, gonadal tissue samples, and prospectively analyzed serum samples from eighteen male patients with 45,X/46,XY mosaicism (one prepubertal, four testosterone-treated, 13 untreated) were included. Biochemical, clinical, and histological outcomes were evaluated according to serum INSL3 concentrations, quantified by LC-MS/MS methodology, and gonadal INSL3 immunohistochemical expression. Results: Serum INSL3 concentrations spanned from below to above the reference range. In untreated patients, the median serum INSL3 SD score was -0.80 (IQR: -1.65 to 0.55) and no significant difference was observed between INSL3 and testosterone. There was no clear association between serum INSL3 and External Genitalia Score at diagnosis, spontaneous puberty, or sperm concentration. INSL3 and CYP11A1 expression overlapped, except for less pronounced INSL3 expression in areas with severe Leydig cell hyperplasia. No other apparent links between INSL3 expression and histological outcomes were observed. Conclusions: In this pilot study, serum INSL3 concentrations ranged and seemed independent of other reproductive hormones and clinical features in males with 45,X/46,XY mosaicism. Discordant expression of INSL3 and CYP11A1 may explain low INSL3 and normal testosterone concentrations in some patients. Further studies are needed to elucidate the divergence between serum INSL3 and testosterone and the potential clinical use of INSL3.
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Disgenesia Gonadal 46 XY/diagnóstico , Insulina/sangre , Mosaicismo , Adolescente , Adulto , Niño , Estudios de Seguimiento , Disgenesia Gonadal 46 XY/sangre , Humanos , Insulina/genética , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Proteínas/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. OBJECTIVE: To create the first European Academy of Andrology (EAA) guidelines on KS. METHODS: An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. RESULTS: Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone-related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. CONCLUSION: These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.
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Síndrome de Klinefelter , Andrología , HumanosRESUMEN
STUDY QUESTION: What is the course of the LH/FSH ratio from infancy into adulthood in healthy individuals and in patients with Differences of Sex Development (DSD)? SUMMARY ANSWER: The LH/FSH ratio had a marked overlap between the sexes after infancy and onwards throughout adulthood in healthy individuals and it was not a marker of hypogonadism in DSD patients. WHAT IS KNOWN ALREADY: The LH/FSH ratio is a distinct marker of sex during minipuberty. No study has evaluated the LH/FSH ratio from infancy into adulthood. STUDY DESIGN, SIZE, DURATION: This was a combined study of prospective longitudinal and cross-sectional cohorts of healthy individuals totaling 6417 males and females aged 0-80 years. Retrospective data from a single, tertiary center on 125 patients with DSD was also included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the healthy males (n = 3144) and females (n = 3273) aged 0-80 years, reference ranges for LH, FSH and the LH/FSH ratio were established from infancy (after minipuberty) and onwards. LH, FSH, and the LH/FSH ratio in 125 patients with DSD not undergoing treatment were compared to the reference ranges. Included DSD diagnoses were: Klinefelter syndrome including mosaic variants (males: n = 14), Turner syndrome including mosaic variants without Y-chromosome material (females: n = 48), 45,X/46,XY mosaicism (males: n = 24 and females: n = 6), partial androgen insensitivity syndrome (males: n = 11), complete androgen insensitivity syndrome (females: n = 13) and anorchia (males: n = 9). MAIN RESULTS AND THE ROLE OF CHANCE: An overlap was observed in the LH/FSH ratio reference curves between males and females. However, when comparing the sexes at specific time points, the LH/FSH ratio was significantly higher in healthy males during childhood and adulthood and significantly higher in healthy females during puberty. When compared with healthy participants, male patients with anorchia and 45,X/46,XY mosaicism had significantly lower ratios, while patients with androgen insensitivity, regardless of sex, had significantly higher ratios. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study include that; (i) all healthy individuals were Caucasian, so conclusions may not apply to non-Caucasians; (ii) the calculated LH/FSH ratios were restricted to the specific analytical method used and may not be applicable to other laboratories; (iii) the samples from healthy individuals were stored for varying amounts of time up to 20 years which may affect the durability; and (iv) DSD diagnoses are heterogeneous thus making sturdy conclusions across diagnoses impossible. WIDER IMPLICATIONS OF THE FINDINGS: In this study of combined cohorts of healthy participants, the largest normative ranges of LH, FSH, and the LH/FSH ratio to date were created. These reference ranges provide the opportunity for clinical as well as research use for all three markers. However, the previously rather undescribed LH/FSH ratio was not a distinct marker of sex after infancy nor a new marker of hypogonadism. Although there were significant differences between subgroups of DSD patients compared to healthy controls, the clinical significance of the LH/FSH ratio after infancy lacked. However, it can be speculated whether there are other areas of clinical application not investigated in this article, for example as a marker of fertility in select patient groups. As gonadotropin assays are readily available and gonadotropin measurements are part of regular workups, the LH/FSH ratio can easily be explored in further research without additional costs. STUDY FUNDING/COMPETING INTEREST(S): M.L.L. was funded by the Absalon Foundation. Cohort 1 was funded by the European Commission, through the Biomed 2 Program (BMH4-CT96-0314), Environmental Reproductive Health (QLK4-CT1999-01422) and EXPORED (QLK4-2001-00269), by the Danish Council for Independent Research (9700833 and 9700909), and by the Svend Andersens Foundation. Cohort 2 was funded by the Danish Environmental Research Program (96.01.015.16.05). Cohort 3 was funded by Kirsten and Freddy Johansens Foundation. TRIAL REGISTRATION NUMBER: NA. DATE OF FIRST PATIENT'S ENROLMENT: June 1990 (the launch of the department from which this project stems).
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Hormona Folículo Estimulante , Hormona Luteinizante , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
Activation of the hypothalamic-pituitary-gonadal (HPG) axis happens in 3 phases during life. The first phase is during fetal life and is only separated from the second phase, called minipuberty, by the high concentration of placental hormones at birth. The third period of activation of the HPG axis is puberty and is well-described. Minipuberty consists of the neonatal activation of the HPG axis, mainly in the first 1-6 months, where the resulting high levels of gonadotropins and sex steroids induce the maturation of sexual organs in both sexes. With gonadal activation, testosterone levels rise in boys with peak levels after 1-3 months, which results in penile and testicular growth. In girls, gonadal activation leads to follicular maturation and a fluctuating increase in estrogen levels, with more controversy regarding the actual influence on the target tissue. The regulation of the HPG axis is complex, involving many biological and environmental factors. Only a few of these have known effects. Many details of this complex interaction of factors remain to be elucidated in order to understand the mechanisms underlying the first postnatal activation of the HPG axis as well as mechanisms shutting down the HPG axis, resulting in the hormonal quiescence observed between minipuberty and puberty. Minipuberty allows for the maturation of sexual organs and forms a platform for future fertility, but the long-term significance is still not absolutely clear. However, it provides a window of opportunity in the early detection of differences of sexual development, offering the possibility of initiating early medical treatment in some cases.
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Klinefelter syndrome is highly underdiagnosed and diagnosis is often delayed. With the introduction of non-invasive prenatal screening, the diagnostic pattern will require an updated description of the clinical and biochemical presentation of infants with Klinefelter syndrome. In the first months of life, the hypothalamic-pituitary-gonadal (HPG)-axis is transiently activated in healthy males during the so-called minipuberty. This period represents a "window of opportunity" for evaluation of the HPG-axis before puberty and without stimulation tests. Infants with Klinefelter syndrome present with a hormonal surge during the minipuberty. However, only a limited number of studies exist, and the results are contradictory. Further studies are needed to clarify whether infants with Klinefelter syndrome present with impaired testosterone production during the minipuberty. The aim of this review is to describe the clinical and biochemical characteristics of the neonate and infant with Klinefelter syndrome with special focus on the minipuberty and to update the clinical recommendations for Klinefelter syndrome during infancy.
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Sistema Hipotálamo-Hipofisario/metabolismo , Síndrome de Klinefelter/diagnóstico , Pruebas Prenatales no Invasivas , Pubertad/genética , Humanos , Sistema Hipotálamo-Hipofisario/diagnóstico por imagen , Recién Nacido , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patología , Masculino , Pubertad/fisiologíaRESUMEN
Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
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Envejecimiento/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Epigénesis Genética , Trastornos del Crecimiento/genética , Mutación , Anomalías Múltiples/genética , Adolescente , Adulto , Amish/genética , Niño , Metilación de ADN , ADN Metiltransferasa 3A , Cara/anomalías , Enfermedades Hematológicas/genética , Humanos , Discapacidad Intelectual/genética , Leucemia Mieloide Aguda/genética , Masculino , Metiltransferasas , Morfogénesis/genética , Síndrome , Enfermedades Vestibulares/genética , Adulto JovenRESUMEN
Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS.