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  • Abstract: fertility x
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  • Abstract: infertility x
  • Abstract: Kallmann x
  • Abstract: Klinefelter x
  • Abstract: menarche x
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  • Abstract: puberty x
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Marie Lindhardt Ljubicic Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Trine Holm Johannsen Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Margit Bistrup Fischer Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Emmie N Upners Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Alexander S Busch Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Katharina M Main Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Anna-Maria Andersson Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Casper P Hagen Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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The ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) has previously been described as an excellent marker of sex in healthy infants. However, LH/FSH remains not fully described in patients with differences of sex development (DSD). The aim was therefore to describe LH/FSH in infants with DSD. This was a retrospective study of DSD patients, all aged 0–1.2 years. In total, 87 infants with DSD and at least one serum sample per infant were included. Longitudinal samples from single patients were included whenever possible. Serum LH/FSH ratios in these patients were plotted against recently published age-related and sex-dimorphic cutoffs. Overall, LH/FSH sometimes corresponded to assigned sex without any obvious pattern in terms of diagnoses. LH/FSH corresponded to the biological sex in all patients with Turner or Klinefelter syndrome. In patients with 46,XX or 46,XY DSD (except congenital adrenal hyperplasia (CAH)), the ratios did not correspond to the assigned sex in all cases and were interchangeably within the male and female range. In patients with CAH, the ratio corresponded to biological sex (based on sex chromosomes) in some cases but also ranged across the cutoffs. In the 15 patients with 45,X/46,XY mosaicism, the LH/FSH ratios corresponded to the assigned sex in all cases (12 were raised as males, 3 as females) and at all time points in cases with multiple sampling. While this study describes LH/FSH in infants with DSD, the exact clinical role of the ratio in the management of these patients remains to be further elucidated.

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Isabelle Flechtner Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France

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Magali Viaud Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France

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Dulanjalee Kariyawasam Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France

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Marie Perrissin-Fabert Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France

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Maud Bidet Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France

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Anne Bachelot Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Endocrinology and Reproductive Medicine, AP-HPIE3M, Hôpital Pitié-Salpêtrière, ICAN, Paris, France

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Philippe Touraine Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Endocrinology and Reproductive Medicine, AP-HPIE3M, Hôpital Pitié-Salpêtrière, ICAN, Paris, France

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Philippe Labrune Department of Pediatrics, APHP, Centre de Référence des Maladies héréditaires du Métabolisme Hépatique, Hopital Antoine Béclère and Paris Sud University, Clamart, France

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Pascale de Lonlay Reference Center of Inherited Metabolic Diseases, Université de Paris, Necker Enfants Malades, University Hospital, Paris, France
Centre for Rare Gynecological Disorders, Hospital Universitaire Necker-Enfants Malades, Paediatric Endocrinology, Gynaecology and Diabetology, AP-HP, Université de Paris, Paris, France

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Michel Polak Center for Rare Gynecological Disorders, Centre des Pathologies Gynécologiques Rares, Paris, France
Department of Paediatric Endocrinology, Gynaecology, and Diabetology, AP-HP, Necker-Enfants Malades University Hospital, IMAGINE Institute affiliate, Paris, France
Centre for Rare Gynecological Disorders, Hospital Universitaire Necker-Enfants Malades, Paediatric Endocrinology, Gynaecology and Diabetology, AP-HP, Université de Paris, Paris, France

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Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000–60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelopmental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 females (median age, 19 years (3–52 years)) and 47 males (median age, 19 years (3–45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast development first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above reference range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, all have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche seems to be the best predictive factor for successful spontaneous pregnancy.

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Hans Valdemar López Krabbe Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Jørgen Holm Petersen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark

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Louise Laub Asserhøj Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Fertility, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

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Trine Holm Johannsen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Peter Christiansen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Rikke Beck Jensen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Line Hartvig Cleemann Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Casper P Hagen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Lærke Priskorn Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Niels Jørgensen Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Katharina M Main Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Lise Aksglaede Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
International Centre for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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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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Alan D Rogol Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA

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The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, and XXX, with special reference to the karyotype 45,X/47,XXX. Each has a ‘specific’ (but variable) phenotype but may be modified by mosaicism. Although the alterations in the hypothalamic–pituitary–gonadal axis are important (and discussed), the emphasis here is on potential fertility and if one might predict that at various epochs within an individual’s life span: fetal, ‘mini’-puberty, childhood, puberty, and adulthood. The reproductive axis is often affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5% of females with Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype, non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population but not nearly as severe as those with the 47,XXY karyotype. Assisted reproductive technology, especially micro-testicular sperm extraction, has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3D organoids in culture. Assisted reproductive technology is more complex for the female, but vitrification of oocytes has shown promising advances.

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Henrik Falhammar Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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Hedi Claahsen-van der Grinten Department of Pediatric Endocrine Disease, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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Nicole Reisch Medizinische Klinik and Poliklinik IV, Department of Endocrinology, University Hospital Munich, Munich, Germany

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Jolanta Slowikowska-Hilczer Department of Andrology and Reproductive Endocrinology, Medical University of Lodz, Lodz, Poland

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Anna Nordenström Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden

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Robert Roehle Coordinating Center for Clinical Studies, Charité Universitätsmedizin, Berlin, Germany

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Claire Bouvattier Paris-Sud University, Orsay, France
Department of Pediatric Endocrinology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France

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Baudewijntje P C Kreukels Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands

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Birgit Köhler Department of Paediatric Endocrinology and Diabetology, Charité Universitätsmedizin, Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

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on behalf of the dsd-LIFE group
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Objective

The knowledge about health status in adults with disorder of sex development (DSD) is scarce.

Design and methods

A cross-sectional observational study in 14 European tertiary centers recruited 1040 participants (717 females, 311 males, 12 others) with DSD. Mean age was 32.4 ± 13.6 year (range 16–75). The cohort was divided into: Turner (n = 301), Klinefelter (n = 224), XY-DSD (n = 222), XX-DSD (excluding congenital adrenal hyperplasia (CAH) and 46,XX males) (n = 21), 46,XX-CAH (n = 226) and 45,X/46,XY (n = 45). Perceived and objective health statuses were measured and compared to European control data.

Results

In DSD, fair to very good general health was reported by 91.4% and only 8.6% reported (very) bad general health (controls 94.0% and 6.0%, P < 0.0001). Longstanding health issues other than DSD and feeling limited in daily life were reported in 51.0% and 38.6%, respectively (controls 24.5% and 13.8%, P < 0.0001 both). Any disorder except DSD was present in 84.3% (controls 24.6%, P < 0.0001). Males reported worse health than females. In the subgroup analysis, Klinefelter and 46,XX-DSD patients reported bad general health in 15.7% and 16.7%, respectively (Turner 3.2% and CAH 7.4%). Comorbidities were prevalent in all DSD subgroups but Klinefelter and Turner were most affected. Early diagnosis of DSD and a healthy lifestyle were associated with less comorbidities.

Conclusions

Overall, general health appeared to be good but a number of medical problems were reported, especially in Klinefelter and Turner. Early diagnosis of DSD and a healthy lifestyle seemed to be important. Lifelong follow-up at specialized centers is necessary.

Open access
Anita Hokken-Koelega Erasmus University Medical Centre, Rotterdam, The Netherlands

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Aart-Jan van der Lely Erasmus University Medical Centre, Rotterdam, The Netherlands

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Berthold Hauffa University Children’s Hospital, Essen, Germany

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Gabriele Häusler Medical University and General Hospital of Vienna, Vienna, Austria

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Gudmundur Johannsson Sahlgrenska University Hospital, Göteborg, Sweden

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Mohamad Maghnie Istituto Giannina Gaslini, University of Genova, Genova, Italy

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Jesús Argente Hospital Infantil Universitario Niño Jesús, Madrid, Spain

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Jean DeSchepper University Hospital Brussels, Brussels, Belgium

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Helena Gleeson Queen Elizabeth Hospital, Birmingham, UK

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John W Gregory Cardiff University School of Medicine, Cardiff, UK

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Charlotte Höybye Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Endocrinology, Metabolism and Diabetology, Karolinska University Hospital, Stockholm, Sweden

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Fahrettin Keleştimur Department of Endocrinology, School of Medicine, Erciyes University, Kayseri, Turkey

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Anton Luger Sahlgrenska University Hospital, Göteborg, Sweden

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Hermann L Müller Department of Pediatrics, Klinikum Oldenburg, Medical Campus University Oldenburg, Oldenburg, Germany

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Sebastian Neggers University Children’s Hospital, Essen, Germany

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Vera Popovic-Brkic Belgrade University School of Medicine, Belgrade, Serbia

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Eleonora Porcu University of Bologna, Bologna, Italy

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Lars Sävendahl Department of Women’s and Children’s Health, Karolinska Institutet, and Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden

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Stephen Shalet The Christie Hospital, Manchester, UK

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Bessie Spiliotis University of Patras School of Medicine, Patras, Greece

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Maithé Tauber Hôpital des Enfants, Toulouse, France

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Objective

Seamless transition of endocrine patients from the paediatric to adult setting is still suboptimal, especially in patients with complex disorders, i.e., small for gestational age, Turner or Prader–Willi syndromes; Childhood Cancer Survivors, and those with childhood-onset growth hormone deficiency.

Methods

An expert panel meeting comprised of European paediatric and adult endocrinologists was convened to explore the current gaps in managing the healthcare of patients with endocrine diseases during transition from paediatric to adult care settings.

Results

While a consensus was reached that a team approach is best, discussions revealed that a ‘one size fits all’ model for transition is largely unsuccessful in these patients. They need more tailored care during adolescence to prevent complications like failure to achieve target adult height, reduced bone mineral density, morbid obesity, metabolic perturbations (obesity and body composition), inappropriate/inadequate puberty, compromised fertility, diminished quality of life and failure to adapt to the demands of adult life. Sometimes it is difficult for young people to detach emotionally from their paediatric endocrinologist and/or the abrupt change from an environment of parental responsibility to one of autonomy. Discussions about impending transition and healthcare autonomy should begin in early adolescence and continue throughout young adulthood to ensure seamless continuum of care and optimal treatment outcomes.

Conclusions

Even amongst a group of healthcare professionals with a great interest in improving transition services for patients with endocrine diseases, there is still much work to be done to improve the quality of healthcare for transition patients.

Open access
Andre Madsen Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

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Lise Aksglaede Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

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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.

Open access
Nicolás Crisosto Endocrinology and Metabolism Laboratory, West Division, School of Medicine, University of Chile, Santiago, Chile

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Bárbara Echiburú Endocrinology and Metabolism Laboratory, West Division, School of Medicine, University of Chile, Santiago, Chile

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Manuel Maliqueo Endocrinology and Metabolism Laboratory, West Division, School of Medicine, University of Chile, Santiago, Chile

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Marta Luchsinger Endocrinology and Metabolism Laboratory, West Division, School of Medicine, University of Chile, Santiago, Chile

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Pedro Rojas Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, University of Concepción, Chillán, Chile

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Sergio Recabarren Laboratory of Animal Physiology and Endocrinology, Faculty of Veterinary Sciences, University of Concepción, Chillán, Chile

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Teresa Sir-Petermann Endocrinology and Metabolism Laboratory, West Division, School of Medicine, University of Chile, Santiago, Chile

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Context

Intrauterine life may be implicated in the origin of polycystic ovary syndrome (PCOS) modifying the endocrine and metabolic functions of children born to PCOS mothers independently of the genetic inheritance and gender. The aim of the present study was to evaluate the reproductive and metabolic functions in sons of women with PCOS during puberty.

Methods

Sixty-nine PCOS sons (PCOSs) and 84 control sons of 7–18 years old matched by the Tanner stage score were studied. A complete physical examination was conducted including anthropometric measurements (weight, height, waist, hip and body mass index). An oral glucose tolerance test was performed and circulating concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), sex hormone-binding globulin, testosterone, androstenedione (A4), 17α-hydroxyprogesterone (17-OHP) and AMH were determined in the fasting sample.

Results

Waist-to-hip ratio, FSH and androstenedione levels were significantly higher in the PCOSs group compared to control boys during the Tanner stage II–III. In Tanner stages II–III and IV–V, PCOSs showed significantly higher total cholesterol and LDL levels. Propensity score analysis showed that higher LDL levels were attributable to the PCOSs condition and not to other metabolic factors. AMH levels were comparable during all stages. The rest of the parameters were comparable between both groups.

Conclusions

Sons of women with PCOS show increased total cholesterol and LDL levels during puberty, which may represent latent insulin resistance. Thus, this is a group that should be followed and studied looking for further features of insulin resistance and cardiovascular risk markers. Reproductive markers, on the other hand, are very similar to controls.

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E Kohva Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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P J Miettinen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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S Taskinen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Department of Pediatric Surgery, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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M Hero Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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A Tarkkanen Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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T Raivio Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Faculty of Medicine, Department of Physiology, University of Helsinki, Helsinki, Finland

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Background

We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center.

Methods

DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts.

Results

Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome (14.5%, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P < 0.001).

Conclusions

Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients’ adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.

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Rohit Barnabas Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Swati Jadhav Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, India

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Anurag Ranjan Lila Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Sirisha Kusuma Boddu Consultant Pediatric Endocrinology & Diabetes, Rainbow Children’s Hospital, Hyderabad, India

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Saba Samad Memon Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Sneha Arya Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Samiksha Chandrashekhar Hegishte Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Manjiri Karlekar Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Virendra A Patil Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Vijaya Sarathi Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, India

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Nalini S Shah Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Tushar Bandgar Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

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Background

The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series.

Methods

We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described.

Results

Three 46,XY patients (age 6–18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2–38).

Conclusion

In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.

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