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  • Abstract: fertility x
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  • Abstract: menopause x
  • Abstract: testes x
  • Abstract: transsexual x
  • Abstract: Turner x
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Antonina Khoruzhenko Institute of Interdisciplinary Research (IRIBHM), Université libre de Bruxelles, Brussels, Belgium
Institute of Molecular Biology and Genetics, NAS of Ukraine, Kiev, Ukraine

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Françoise Miot Institute of Interdisciplinary Research (IRIBHM), Université libre de Bruxelles, Brussels, Belgium

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Claude Massart Institute of Interdisciplinary Research (IRIBHM), Université libre de Bruxelles, Brussels, Belgium

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Jacqueline Van Sande Institute of Interdisciplinary Research (IRIBHM), Université libre de Bruxelles, Brussels, Belgium

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Jacques Emile Dumont Institute of Interdisciplinary Research (IRIBHM), Université libre de Bruxelles, Brussels, Belgium

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Renaud Beauwens Laboratory of Physiology and Pharmacology, Université libre de Bruxelles, Brussels, Belgium

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Alain Boom Laboratoire d’Histologie, de Neuroanatomie et de Neuropathologie, Université libre de Bruxelles, Brussels, Belgium

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Background

Long-term maintenance of functional activity of thyroid cells is an essential requirement for basic in vitro studies on the physiology and pathology of the thyroid. An important prerequisite of thyrocytes’ functional activity in vivo and in vitro is their follicle organization.

Aim

This study aimed at developing a method of cultivation of functionally active rat thyroid follicles in Matrigel under three-dimensional conditions.

Methods

Undamaged rat thyroid follicles were isolated by enzymatic digestion with collagenase/dispase, then embedded into Matrigel, and cultivated for 2 weeks. Thyroglobulin, thyroxine and zonula occludens-1 (ZO-1) localization were revealed by immunofluorescence analysis. Iodide organification was tested by protein-bound 125I (PBI) measurement.

Results

Integrity of the follicles was preserved during the whole period of cultivation and was confirmed by 3D reconstruction of ZO-1 localization. Thyroglobulin was detected in the thyrocyte cytoplasm, as well as in the intrafollicular lumen. Thyroxine was observed predominantly at the apical side of thyrocytes. Also, generated cultures were characterized by a high level of iodide organification: PB125I represented 39% of the total radioactivity in the Matrigel drop embedding the follicles; at the same time, methimazole almost totally inhibited this process (0.2% of total radioactivity).

Conclusion

The method of rat thyrocyte cultivation in Matrigel, as described here allows to maintain the structural integrity and the functional activity of thyroid follicles in vitro and could be used for wide ranges of basic and applied researches in thyroidology.

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Ladan Younesi Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran

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Zeinab Safarpour Lima Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran

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Azadeh Akbari Sene Department of Obstetrics and Gynecology, IVF Fellowship, Shahid Akbar-Abadi Hospital IVF Center, Iran University of Medical Sciences, Tehran, Iran

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Zahra Hosseini Jebelli Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran

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Ghazaleh Amjad Shahid Akbarabadi Clinical Research Development Unit (ShACRDU), Iran University of Medical Sciences (IUMS), Tehran, Iran

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Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders. The aim of this study was to find the correlation between color Doppler ultrasound and serum tests as auxiliary diagnostic criteria in areas where there is no possibility of some tests. A total of 108 patients were enrolled. They were divided into three groups including patients with PCOS, patients with PCOA ultrasound, patients with ovaries and normal hormone tests. Transvaginal sonography was performed from three groups and the results were evaluated in gray scale. The volume of the ovary, the number of follicles and the placement of follicles were recorded using using Doppler spectrum of uterine artery and ovarian stroma. Their arterial resistance index was also calculated. In the next step, serum samples were evaluated to determine the level of LH, FSH, free testosterone, DHEAS and 17-OHP hormones in the early follicular phase. Gray scale ultrasonographic findings (volume and number of ovarian follicles) as well as LH values were higher in patients with PCOS than those in the other two groups. These results proved the reliability of using these factors in the prediction of PCOS. In this study, Doppler indexes did not correlate with the size of the ovaries, the number of ovarian follicles and the measured hormone levels. The findings of transvaginal ultrasound and investigating the relationship with clinical and laboratory outcomes, a more suitable pattern could be chosen for more accurate patient selection and, leading to timely treatment and reducing the complications of the disease.

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Lian Hollander-Cohen Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, Rehovot, Israel

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Benjamin Böhm Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, Rehovot, Israel

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Krist Hausken Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, Rehovot, Israel

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Berta Levavi-Sivan Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, Rehovot, Israel

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The pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are the principle endocrine drivers of reproductive processes in the gonads of jawed vertebrates. Canonically, FSH recruits and maintains selected ovarian follicles for maturation and LH induces the stages of germinal vesicle breakdown and ovulation. In mammals, LH and FSH specifically activate cognate G-protein-coupled receptors that affect the proteins involved in steroidogenesis, protein hormone synthesis, and gametogenesis. This dual-gonadotropin model also exists in some fish species, but not in all. In fact, due to their diverse number of species, extended number of ecological niches, and remarkably flexible reproductive strategies, fish are appropriate as models to understand the co-evolution of gonadotropins and their receptors. In this study, we cloned and characterized the expression profile over the final stages of ovarian maturation of carp (Cyprinus carpio) LHCGR and FSHR. Expression of both gonadotropin receptors increased in the later stage of early vitellogenesis, suggesting that both LH and FSH play a role in the development of mature follicles. We additionally tested the activation of cLHCGR and cFSHR using homologous and heterologous recombinant gonadotropins in order to gain insight into an evolutionary model of permissive gonadotropin receptor function. These data suggest that carp (Cyprinus carpio) gonad development and maturation depends on a specific gonadotropin profile that does not reflect the temporally distinct dual-gonadotropin model observed in salmonids or mammals, and that permissive gonadotropin receptor activation is a specific feature of Ostariophysi, not all teleosts.

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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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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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Frederic Schrøder Arendrup Department of Neurology, Danish Headache Center, Rigshospitalet, University of Copenhagen, Denmark

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Severine Mazaud-Guittot Inserm (Institut National de la Santé et de la Recherche Médicale), Irset – Inserm, UMR 1085, Rennes, France

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Bernard Jégou Inserm (Institut National de la Santé et de la Recherche Médicale), Irset – Inserm, UMR 1085, Rennes, France
EHESP-School of Public Health, Rennes, France

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David Møbjerg Kristensen Department of Neurology, Danish Headache Center, Rigshospitalet, University of Copenhagen, Denmark
Inserm (Institut National de la Santé et de la Recherche Médicale), Irset – Inserm, UMR 1085, Rennes, France

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Concern has been raised over chemical-induced disruption of ovary development during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggests that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. Therefore, in this review, we discuss three recent reports that collectively indicate that prenatal exposure in a period of 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in the reduction of primordial follicles, irregular menstrual cycle, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could especially affect the Western parts of the world, where the age for childbirth is continuously being increased and acetaminophen is recommended during pregnancy for pain and fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.

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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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Mikkel Andreassen Department of Endocrinology, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Anders Juul Department of Growth and Reproduction, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Endocrinology, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Niels Jørgensen Department of Growth and Reproduction, Faculty of Health Science, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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Objective

Gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) are released from the pituitary gland and stimulate Leydig cells to produce testosterone and initiates spermatogenesis. Little is known about how and when the deterioration of semen quality occurs in patients with adult-onset gonadotropin insufficiency.

Design and methods

A retrospective study comprising 20 testosterone-deficient men (median age, 29 years) with acquired pituitary disease who delivered semen for cryopreservation before initiation of testosterone therapy. Semen variables and hormone concentrations were compared to those of young healthy men (n = 340).

Results

Thirteen of 20 patients (65%) and 82% of controls had total sperm counts above 39 million and progressive motile spermatozoa above 32% (P = 0.05). For the individual semen variables, there were no significant differences in semen volume (median (intraquartile range) 3.0 (1.3–6.8) vs 3.2 (2.3–4.3) mL, P = 0.47), sperm concentration 41 (11–71) vs 43 (22–73) mill/mL (P = 0.56) or total sperm counts (P = 0.66). One patient had azoospermia. Patients vs controls had lower serum testosterone 5.4 (2.2–7.6) vs 19.7 (15.5–24.5) nmol/L (P = 0.001), calculated free testosterone (cfT) 145 (56–183) vs 464 (359–574) pmol/L (P < 0.001), LH 1.5 (1.1–2.1) vs 3.1 (2.3–4.0) U/L (P = 0.002) and inhibin b (P < 0.001). Levels of FSH were similar (P = 0.63). Testosterone/LH ratio and cfT/LH ratio were reduced in patients (both P < 0.001).

Conclusions

Despite Leydig cell insufficiency in patients with acquired pituitary insufficiency, the majority presented with normal semen quality based on the determination of the number of progressively motile spermatozoa. In addition, the data suggest reduced LH bioactivity in patients with pituitary insufficiency.

Open access
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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Maki Igarashi Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan

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Tadayuki Ayabe Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan

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Kiwako Yamamoto-Hanada Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan

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Keiko Matsubara Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan

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Hatoko Sasaki Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan

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Mayako Saito-Abe Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan

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Miori Sato Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan

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Nathan Mise Department of Environmental and Preventive Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Akihiko Ikegami Department of Environmental and Preventive Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

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Masayuki Shimono Regional Center for Pilot Study of Japan Environment and Children’s Study, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan

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Reiko Suga Regional Center for Pilot Study of Japan Environment and Children’s Study, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan

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Shouichi Ohga Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
Research Center for Environment and Developmental Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

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Masafumi Sanefuji Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
Research Center for Environment and Developmental Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan

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Masako Oda Department of Public Health, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan

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Hiroshi Mitsubuchi Department of Neonatology, Kumamoto University Hospital, Chuo-ku, Kumamoto, Japan

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Takehiro Michikawa Japan Environment and Children’s Study Programme Office, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan

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Shin Yamazaki Japan Environment and Children’s Study Programme Office, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan

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Shoji Nakayama Japan Environment and Children’s Study Programme Office, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan

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Yukihiro Ohya Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan

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Maki Fukami Medical Support Center for Japan Environmental and Children’s Study, National Center for Child Health and Development, Setagaya, Tokyo, Japan
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan

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Objective

Ultra-sensitive hormone assays have detected slight sex differences in blood estradiol (E2) levels in young children before adrenarche. However, the origin of circulating E2 in these individuals remains unknown. This study aimed to clarify how E2 is produced in young girls before adrenarche.

Design

This is a satellite project of the Japan Environment and Children’s Study organized by the National Institute for Environmental Studies.

Methods

We collected blood samples from healthy 6-year-old Japanese children (79 boys and 71 girls). Hormone measurements and data analysis were performed in the National Institute for Environmental Studies and the Medical Support Center of the Japan Environment and Children’s Study, respectively.

Results

E2 and follicle stimulating hormone (FSH) levels were significantly higher in girls than in boys, while dehydroepiandrosterone sulfate (DHEA-S) and testosterone levels were comparable between the two groups. Girls showed significantly higher E2/testosterone ratios than boys. In children of both sexes, a correlation was observed between E2 and testosterone levels and between testosterone and DHEA-S levels. Moreover, E2 levels were correlated with FSH levels only in girls.

Conclusions

The results indicate that in 6-year-old girls, circulating E2 is produced primarily in the ovary from adrenal steroids through FSH-induced aromatase upregulation. This study provides evidence that female-dominant E2 production starts several months or years before adrenarche. The biological significance of E2 biosynthesis in these young children needs to be clarified in future studies.

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