Publications by authors named "Anders Juul"

385 Publications

Physical Fitness and Frailty in Males after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Long-Term Follow-Up Study.

Cancers (Basel) 2022 Jul 7;14(14). Epub 2022 Jul 7.

New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.

Purpose And Methods: To analyze physical fitness, physical activity and the prevalence of frailty in male long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We performed a Nordic two-center study of 98 male survivors (mean age 28.7 years, range 18.5-47.0) treated with pediatric allogeneic hematopoietic stem cell transplantation (HSCT) 1980-2010 in denmark or finland. physical fitness was evaluated by the dominant hand grip-strength, timed up-and-go, sit-to-stand, gait speed and two-minute walk tests.

Results: Survivors presented significantly lower muscle strength and muscle endurance in the dominant hand-grip strength (median Z-score -0.7, range -4.3-3.9) and sit-to-stand tests (median Z-score -1.5, range -3.5-2.5) compared to age and sex matched normative values of the tests. However, mobility and gait speed were not affected on a group level. The prevalence of frailty (pre-frail 20% or frail 10%) was high among the survivors. In multiple regression analysis, chronic graft-versus-host disease, shorter stature, higher body fat mass and hazardous drinking predicted prefrail/frail status. Common cardiovascular risk factors, such as increased levels of serum triglycerides, higher resting heart rate and diastolic blood pressure, were associated with lower physical fitness.

Conclusion: Low muscle strength and a high incidence of frailty were observed in survivors of pediatric HSCT. There is a predominant risk of cardiovascular and metabolic diseases in the long-term.
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http://dx.doi.org/10.3390/cancers14143310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9313275PMC
July 2022

Short-term oestrogen as a strategy to prevent postpartum depression in high-risk women: protocol for the double-blind, randomised, placebo-controlled MAMA clinical trial.

BMJ Open 2021 12 30;11(12):e052922. Epub 2021 Dec 30.

Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark

Introduction: Postpartum depression affects 10%-15% of women and has a recurrence rate of 40% in subsequent pregnancies. Women who develop postpartum depression are suspected to be more sensitive to the rapid and large fluctuations in sex steroid hormones, particularly estradiol, during pregnancy and postpartum. This trial aims to evaluate the preventive effect of 3 weeks transdermal estradiol treatment immediately postpartum on depressive episodes in women at high risk for developing postpartum depression.

Methods And Analysis: The Maternal Mental Health Trial is a double-blind, randomised and placebo-controlled clinical trial. The trial involves three departments of obstetrics organised under Copenhagen University Hospital in Denmark. Women who are singleton pregnant with a history of perinatal depression are eligible to participate. Participants will be randomised to receive either transdermal estradiol patches (200 µg/day) or placebo patches for 3 weeks immediately postpartum. The primary outcome is clinical depression, according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria of Major Depressive Disorder with onset at any time between 0 and 6 months postpartum. Secondary outcomes include, but are not limited to, symptoms of depression postpartum, exclusive breastfeeding, cortisol dynamics, maternal distress sensitivity and cognitive function. The primary statistical analysis will be performed based on the intention-to-treat principle. With the inclusion of 220 participants and a 20% expected dropout rate, we anticipate 80% power to detect a 50% reduction in postpartum depressive episodes while controlling the type 1 error at 5%.

Ethics And Dissemination: The study protocol is approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Centre for Data Protection Compliance in the Capital Region of Denmark. We will present results at scientific meetings and in peer-reviewed journals and in other formats to engage policymakers and the public.

Trial Registration Number: NCT04685148.
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http://dx.doi.org/10.1136/bmjopen-2021-052922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719185PMC
December 2021

Endocrine outcome and seminal parameters in young adult men born with hypospadias: A cross-sectional cohort study.

EBioMedicine 2022 Jul 24;81:104119. Epub 2022 Jun 24.

Department of Internal Medicine and Pediatrics, Ghent University and Pediatric Endocrinology Service, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium. Electronic address:

Background: Hypospadias affects around 1/200 newborn males. Intrauterine testicular dysfunction may underlie a subset of cases. The long-term endocrine and reproductive outcomes in these men remain largely unknown.

Methods: Cross-sectional study in Ghent and Vienna University Hospitals to assess the endocrine and seminal parameters of young adult men (16-21 years) born with non-syndromic hypospadias (NSH) (n = 193) compared to healthy typical males (n = 50). Assessments included physical exam, semen analysis, hormone assays and exome-based gene panel analysis (474 genes).

Findings: All participants had experienced a spontaneous puberty, in spite of higher LH and INSL3 levels than typical males. Oligo- or azoospermia was observed in 32/172 (18·6%; 99%-CI: 12·2-27·4%) of NSH men; but in 5/16 (31·3%; 99%-CI: 11·1;62·4%) of complex NSH men and in 13/22 (59·1%; 99%-CI: 33·2-80·7%) of those born small for gestational age (SGA). No (likely) pathogenic coding variants were found in the investigated genes. Suboptimal statural growth affected 8/23 (34·8%; 99%-CI: 15·4-61·0%) of men born SGA with NSH.

Interpretation: Spermatogenesis is significantly compromised in NSH men, especially in those born SGA or those with complex NSH. Long-term andrological follow-up is recommended, including end-pubertal semen analysis. No clear monogenic causes could be demonstrated in our cohort even in proximal or complex NSH. Being born SGA with NSH is frequently associated with poor catch-up growth, requiring growth hormone therapy in some.

Funding: Research grants from the European Society of Paediatric Endocrinology, the Belgian Society of Pediatrics, the Belgian Society of Pediatric Endocrinology and Diabetology and the Research Foundation Flanders (FWO).
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http://dx.doi.org/10.1016/j.ebiom.2022.104119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249999PMC
July 2022

Sex-dependent associations between maternal prenatal stressful life events, BMI trajectories and obesity risk in offspring: The Raine Study.

Compr Psychoneuroendocrinol 2021 Aug 12;7:100066. Epub 2021 Jun 12.

Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.

Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this.

Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events and gender-specific BMI score trajectories as well as risk of overweight/obesity at each age point. Mediation analyses were also conducted to model the indirect associations through maternal smoking during pregnancy and breastfeeding.

Results: Of the 2056-included offspring, 1322 (64.3%) were exposed to at least one maternal stressful life event during early gestation and 1203 (58.5%) were exposed in late gestation. In boys, exposure to stressful life events in early but not late gestation was significantly associated with ascending (accelerated) weight-gain (ages 3-14 years) (adjusted odds ratio (aOR): 1.25, 95% CI: 1.02, 1.52) and increased risk of overweight (aOR: 1.18, 95% CI: 1.00, 1.39) aged 10 years. No similar associations were observed in girls. We observed that 29.2% of the association between more maternal stressful life events and obesity in male offspring was mediated by breastfeeding for less than 6 months. Likewise, up to 35% of the association between more maternal stressful life events and obesity in male offspring was mediated by maternal smoking during the index pregnancy.

Conclusion: Prenatal stress in early gestation is directly associated with accelerated childhood weight gain (assessed by childhood BMI z-score trajectories) and risk of obesity in adolescent boys, but not girls and breastfeeding and maternal smoking significantly mediates this association.
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http://dx.doi.org/10.1016/j.cpnec.2021.100066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9216251PMC
August 2021

Effect of a single-dose denosumab on semen quality in infertile men (the FITMI study): study protocol for a randomized controlled trial.

Trials 2022 Jun 22;23(1):525. Epub 2022 Jun 22.

Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Background: Infertility is a common problem globally and impaired semen quality is responsible for up to 40% of all cases. Almost all infertile couples are treated with either insemination or assisted reproductive techniques (ARTs) independent of the etiology of infertility because no medical treatment exists. Denosumab is an antibody that blocks RANKL signaling and inhibition of testicular RANKL signaling has been suggested to improve semen quality in a pilot study. This RCT aims to assess whether treatment with denosumab can improve spermatogenesis in infertile men selected by serum AMH as a positive predictive biomarker. This paper describes the design of the study.

Methods/design: FITMI is a sponsor-investigator-initiated, double-blinded, placebo-controlled 1:1, single-center, randomized clinical trial. Subjects will be randomized to receive either a single-dose denosumab 60 mg subcutaneous injection or placebo. The study will be carried out at the Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen. The primary outcome of the study is defined as the difference in sperm concentration (millions pr. mL) one spermatogenesis (80 days) after inclusion.

Discussion: We describe a protocol for a planned RCT aimed at evaluating whether treatment with denosumab can improve the semen quality in infertile men selected by using serum AMH as a positive predictive biomarker. The results will provide evidence crucial for future treatment in a patient group where there is a huge unmet need.

Trial Registration: Clinical Trials.gov NCT05212337 . Registered on 14 January 2022. EudraCT 2021-003,451-42. Registered on 23 June 2021. Ethical committee H-21040145. Registered on 23 December 2021.
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http://dx.doi.org/10.1186/s13063-022-06478-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214471PMC
June 2022

The role of central serotonergic markers and estradiol changes in perinatal mental health.

Acta Psychiatr Scand 2022 Jun 21. Epub 2022 Jun 21.

Neurobiology Research Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Objective: Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum.

Methods: Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype.

Results: Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (β  = 0.73, p = 0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (β  = 0.002, p = 0.06).

Conclusion: In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.
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http://dx.doi.org/10.1111/acps.13461DOI Listing
June 2022

A Biphasic Pattern of Reproductive Hormones in Healthy Female Infants -The COPENHAGEN Minipuberty Study.

J Clin Endocrinol Metab 2022 Jun 15. Epub 2022 Jun 15.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Context: Minipuberty, a period of a transient activation of the hypothalamic-pituitary-gonadal (HPG) axis in both sexes, enables evaluation of gonadal function in infants suspected of hypogonadism. However, female minipuberty remains poorly elucidated.

Objective: We aimed to establish continuous reference ranges for the most commonly used reproductive hormones and to evaluate the dynamics of the HPG axis in females aged 0-1 year.

Design: The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), a longitudinal, prospective cohort study.

Setting: Healthy infants from Copenhagen.

Patients Or Other Participants: A total of 98 healthy, term female infants followed with six examinations including venipuncture during the first year of life.

Intervention(s): None.

Main Outcome Measure(s): Serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, anti-Müllerian hormone (AMH), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG) were quantified using highly sensitive methods in 266 serum samples.

Results: Reference ranges were established for LH, FSH, inhibin B, AMH, E1, E2, and SHBG. Two peaks were observed in normalized mean curves for all hormones. The first peaks were timed around postnatal days 15-27 followed by a general nadir for all hormones around days 58-92. The second peaks occurred around days 107-125 for inhibin B, AMH, E1, E2, and SHBG and day 164-165 for LH and FSH.

Conclusions: We present age-related, continuous reference ranges of the most commonly used reproductive hormones and present novel data revealing a biphasic and prolonged female minipuberty.
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http://dx.doi.org/10.1210/clinem/dgac363DOI Listing
June 2022

A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention).

Clin Genitourin Cancer 2022 May 2. Epub 2022 May 2.

Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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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http://dx.doi.org/10.1016/j.clgc.2022.04.017DOI Listing
May 2022

In reply.

Menopause 2022 Jun 1;29(6):756-758. Epub 2022 Jun 1.

Department of Growth and Reproduction Rigshospitalet, University of Copenhagen Copenhagen, Denmark.

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http://dx.doi.org/10.1097/GME.0000000000002009DOI Listing
June 2022

Male Gonadal Function After Pediatric Hematopoietic Stem Cell Transplantation: A Systematic Review.

Transplant Cell Ther 2022 Aug 26;28(8):503.e1-503.e15. Epub 2022 May 26.

Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT) that can lead to disturbances in pubertal development, sexual dysfunction, and infertility. However, no systematic review exists regarding prevalence and risk factors in relation to different treatment regimens. We aimed to systematically evaluate the current evidence regarding the prevalence of male gonadal dysfunction after pediatric HSCT, related risk factors, and the diagnostic value of surrogate markers of spermatogenesis in this patient group. We searched PubMed and Embase using a combination of text words and subject terms. The eligibility screening was conducted using predefined criteria. Data were extracted corresponding to the Leydig cell compartment involved in testosterone production and the germ cell compartment involved in spermatogenesis, respectively. Subsequently, data synthesis was performed. Of 2369 identified records, 25 studies were eligible. The studies were heterogeneous in terms of included diagnoses, gonadotoxic therapy, follow-up time, and definitions of gonadal dysfunction. The data synthesis revealed a preserved Leydig cell function in patients treated with non-total body irradiation (TBI) regimens, whereas the evidence regarding the impact of TBI conditioning on Leydig cell function was conflicting. Based on surrogate markers of spermatogenesis and only limited data on semen quality, the germ cell compartment was affected in half of the patients treated with non-TBI regimens and in nearly all patients treated with TBI conditioning. Testicular irradiation as part of front-line therapy before referral to HSCT led to complete Leydig cell failure and germ cell failure. Evidence regarding the impact of diagnosis, pubertal stage at HSCT, and chronic graft-versus-host disease is limited, as is the evidence of the diagnostic value of surrogate markers of spermatogenesis. Testicular irradiation as part of front-line therapy and TBI conditioning are the main risk factors associated with male gonadal dysfunction after pediatric HSCT; however, impaired spermatogenesis is also observed in half of the patients treated with non-TBI regimens. Methodological shortcomings limit existing evidence, and future studies should include semen quality analyses, follow-up into late adulthood, and evaluation of the cumulative exposure to gonadotoxic therapy.
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http://dx.doi.org/10.1016/j.jtct.2022.05.036DOI Listing
August 2022

Impact of Polymorphism in the β2-Receptor Gene on Metabolic Responses to Repeated Hypoglycemia in Healthy Humans.

J Clin Endocrinol Metab 2022 07;107(8):e3194-e3205

Endocrine Section, Department of Endocrinology and Nephrology, Copenhagen University Hospital, Nordsjællands Hospital, Hillerød, Denmark.

Context: The Arg16 variant in the β2-receptor gene is associated with increased risk of severe hypoglycemia in subjects with type 1 diabetes mellitus.

Objective: We hypothesized that the Arg16 variant is associated with decreased metabolic and symptomatic responses to recurrent hypoglycemia.

Methods: Twenty-five healthy male subjects selected according to ADRB2 genotype and being homozygous for either Arg16 (AA; n = 13) or Gly16 (GG; n = 12) participated in 2 consecutive trial days with 3 periods of hypoglycemia (H1-H3) induced by a hyperinsulinemic hypoglycemic clamp. The main outcome measure was mean glucose infusion rate (GIR) during H1-H3.

Results: During H1-H3, there was no difference between AA or GG subjects in GIR, counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone), or substrate levels of lactate, glycerol, and free fatty acids (FFAs), and no differences in symptom response score or cognitive performance (trail making test, Stroop test). At H3, lactate response was reduced in both genotype groups, but AA subjects had decreased response (mean ± standard error of the mean of area under the curve) of glycerol (-13.1 ± 3.8 μmol L-1 hours; P = .0052), FFA (-30.2 ± 11.1 μmol L-1 hours; P = .021), and β-hydroxybutyrate (-0.008 ± 0.003 mmol L-1 hour; P = .027), while in GG subjects alanine response was increased (negative response values) (-53.9 ± 20.6 μmol L-1 hour; P = .024).

Conclusion: There was no difference in GIR between genotype groups, but secondary outcomes suggest a downregulation of the lipolytic and β-hydroxybutyrate responses to recurrent hypoglycemia in AA subjects, in contrast to the responses in GG subjects.
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http://dx.doi.org/10.1210/clinem/dgac297DOI Listing
July 2022

Timing of Puberty, Pubertal Growth, and Adult Height in Short Children Born Small for Gestational Age Treated With Growth Hormone.

J Clin Endocrinol Metab 2022 07;107(8):2286-2295

Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Context: Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied.

Objective: To evaluate adult height and peak height velocity in short GH-treated SGA children.

Methods: Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (n = 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data.

Results: Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, P = .02) and boys (1.57 [1.13; 2.15] SDS, P < .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, P < .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, P = .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, P = .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, P = .18).

Conclusion: GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.
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http://dx.doi.org/10.1210/clinem/dgac282DOI Listing
July 2022

Dynamic changes in LH/FSH ratios in infants with normal sex development.

Eur J Endocrinol 2022 Jun 1;187(1):135-142. Epub 2022 Jun 1.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Objective: Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants.

Design: A prospective, longitudinal cohort study of healthy infants aged 0-1.2 years.

Methods: In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants.

Results: In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging from 93 to 100% with correspondingly narrow 95% CIs.

Conclusions: Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remain to be elucidated.
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http://dx.doi.org/10.1530/EJE-21-0999DOI Listing
June 2022

Effect of Testosterone Replacement Therapy on Quality of Life and Sexual Function in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency: Results From a Randomized Double-blind Trial.

Clin Genitourin Cancer 2022 08 1;20(4):334-343. Epub 2022 Apr 1.

Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address:

Background: Testicular cancer (TC) treatment leaves many patients with low levels of testosterone. While most TC patients with low testosterone (< - 2 SD) and hypogonadal symptoms will initiate testosterone replacement therapy (TRT), the role of TRT in patients with mild Leydig cell insufficiency, defined as elevated luteinizing hormone in combination with borderline low testosterone, is unknown. To clarify if TRT improves symptoms of depression and anxiety, sexual function, fatigue, and quality of life in TC survivors with mild Leydig cell insufficiency.

Materials And Methods: In total, 69 men aged between 18 and 65 years with mild Leydig cell insufficiency after TC treatment were randomized 1:1 to 12 months daily transdermal testosterone (maximum dose 40 mg/daily) vs. placebo. Patient reported anxiety, depression, sexual function, fatigue, and overall quality of life were assessed at baseline, after 6- and 12 months treatment, and 3 months post-treatment using validated questionnaires.

Results: After 12 months of treatment, median luteinizing hormone and median free testosterone were normalized in the testosterone group. Compared to placebo, TRT was not associated with statistically significant improvement of symptoms of anxiety and depression, sexual function, fatigue, and overall quality of life. Testosterone replacement therapy did not improve anxiety, depression, sexual function, fatigue, or overall quality of life in patients with mild Leydig cell insufficiency compared to placebo.

Conclusion: Routine TRT in TC survivors with mild Leydig cell insufficiency to improve sexual function and quality of life cannot be generally recommended. The findings should preferably be validated in a larger cohort.
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http://dx.doi.org/10.1016/j.clgc.2022.03.012DOI Listing
August 2022

The Danish High-Risk and Resilience Study-VIA 15 - A Study Protocol for the Third Clinical Assessment of a Cohort of 522 Children Born to Parents Diagnosed With Schizophrenia or Bipolar Disorder and Population-Based Controls.

Front Psychiatry 2022 4;13:809807. Epub 2022 Apr 4.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Amager and Hvidovre, Copenhagen, Denmark.

Background: Children born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene-environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important.

Methods: The Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021.

Discussion: We will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.
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http://dx.doi.org/10.3389/fpsyt.2022.809807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013818PMC
April 2022

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma.

Br J Cancer 2022 08 13;127(3):408-421. Epub 2022 Apr 13.

Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Background: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis.

Methods: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients.

Results: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value.

Conclusions: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.
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http://dx.doi.org/10.1038/s41416-022-01810-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345904PMC
August 2022

Neuroimaging in 205 consecutive Children Diagnosed with Central Precocious Puberty in Denmark.

Pediatr Res 2022 Apr 1. Epub 2022 Apr 1.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Introduction: A brain magnetic resonance image (MRI) is considered part of routine evaluation in children diagnosed with central precocious puberty (CPP) to rule out intracranial pathology. We evaluated the occurrence of pathological findings on neuroimaging among children diagnosed with CPP.

Methods: A retrospective study based on an evaluation of 1544 children referred with early signs of puberty from 2009-2019. Of these, 205 children (29 boys) with confirmed CPP had a brain MRI performed, and we report MRI results, pubertal stage, bone age, and hormonal analyses. All abnormal MRI results were re-evaluated by a trained neuroradiologist.

Results: A new intracranial pathology was found by brain MRI in 6 out of 205 patients aged 1.5 to 6.1 years. The occurrence of intracranial pathology was 3/162 (1.8%) and 3/24 (12.5 %) in girls and boys respectively.

Conclusion: Organic causes of precocious puberty are more frequent in boys with CPP than in girls. No cases of organic CPP were seen above age 6.1 years of age. The age cut off value for routine brain MRI could be lowered to seven or perhaps even six years of age for girls, except in rapidly progressing puberty or presence of neurological symptoms.

Impact: In our study of children with central precocious puberty (CPP), intracranial pathology is a rare cause and occurs only in younger children. It supports the general trend, that younger children are at higher risk of having organic causes to CPP and supports the clinical practice, that only high-risk patients with CPP should undergo routine brain MRI.
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http://dx.doi.org/10.1038/s41390-022-02047-2DOI Listing
April 2022

Serum Testosterone Levels in 3-Month-Old Boys Predict Their Semen Quality as Young Adults.

J Clin Endocrinol Metab 2022 06;107(7):1965-1975

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, DK-2100 Copenhagen, Denmark.

Context: It remains unknown how the postnatal activation of the hypothalamic-pituitary-gonadal axis in infancy, also known as "minipuberty", relates to adult testis function.

Objective: To investigate how markers of reproductive function in 3-month-old boys correlate with adult reproductive health parameters.

Methods: This population-based birth cohort study (the Copenhagen Mother-Child cohort), conducted at Copenhagen University Hospital, Denmark, included 259 boys examined once around 3 months of age and again at 18 to 20 years. Reproductive hormones, penile length, testis volume, and semen quality were analyzed. Minipubertal markers of testis function (by tertiles, T1-T3) were explored as predictors of adult semen quality using linear regression models. Associations between reproductive outcomes in infancy and young adulthood were estimated by intraclass correlation coefficients (ICCs), describing how well measurements in infancy correlate with those in adulthood.

Results: Serum testosterone concentration in infancy was positively associated with adult total sperm count. Median (IQR) total sperm count was 84 (54-138) million spermatozoa for boys in T1, 141 (81-286) million spermatozoa in T2, and 193 (56-287) million spermatozoa in T3. We found the highest ICC for FSH (0.41; 95% CI, 0.26-0.57), while ICCs for inhibin B, SHBG, penile length, and testis volume ranged between 0.24 and 0.27. ICCs for LH and for total and free testosterone were lower and statistically nonsignificant.

Conclusion: Serum testosterone in infancy was a predictor of adult total sperm count. Other reproductive hormones and genital measures showed good correlation between infancy and adulthood, suggesting that an individual's reproductive setpoint starts shortly after birth in boys and persists until adulthood.
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http://dx.doi.org/10.1210/clinem/dgac173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9202716PMC
June 2022

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe.

Eur J Endocrinol 2022 Mar 23;186(5):K17-K24. Epub 2022 Mar 23.

Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN' Université Lyon I, Lyon, France.

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design And Methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
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http://dx.doi.org/10.1530/EJE-21-0554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010809PMC
March 2022

Dynamic Changes of Reproductive Hormones in Male Minipuberty: Temporal Dissociation of Leydig and Sertoli Cell Activity.

J Clin Endocrinol Metab 2022 05;107(6):1560-1568

Department of Growth and Reproduction, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Context: The male hypothalamic-pituitary-gonadal (HPG) axis is transiently active during the first months of life with surging serum concentrations of reproductive hormones. This period, termed minipuberty, appears to be essential for priming testicular function. Despite the central role for male reproductive function, longitudinal data on HPG axis activation in infancy is sparse.

Objective: To explore the dynamics of HPG hormone activity in healthy male infants, to assess the association of HPG axis activity and testicular volume, and to establish reference curves for serum levels of reproductive hormones.

Design: Prospective, longitudinal birth cohort (the COPENHAGEN Minipuberty Study, 2016-2018, 1-year follow-up).

Setting: Population-based.

Patients Or Other Participants: Healthy, male, term, singleton newborns were followed from birth on with repeated clinical examinations including blood sampling during a 1-year follow-up. A total of 128 boys contributed to this study, while 119 participated in the postnatal follow-up.

Main Outcome Measures: Serum reproductive hormone concentrations and testicular volume.

Results: Reproductive hormone concentrations showed marked dynamics during the first 6 months of age. Gonadotropins, total testosterone, and insulin-like factor 3 peaked at around 1 month of age. Inhibin B, anti-Müllerian hormone, and testicular volume peaked at around 4 to 5 months. Correlations largely recapitulated typical HPG axis pathways but also differed significantly from adult men.

Conclusions: We demonstrate a temporal dissociation of Leydig and Sertoli cell activity during male minipuberty and provide reference curves for reproductive hormones.
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http://dx.doi.org/10.1210/clinem/dgac115DOI Listing
May 2022

The long-term association between bilateral oophorectomy and depression: a prospective cohort study.

Menopause 2022 01 24;29(3):276-283. Epub 2022 Jan 24.

Department of Obstetrics and Gynaecology, University of Melbourne and the Royal Women's Hospital, Melbourne, Victoria, Australia.

Objective: Depression is a leading cause of disability globally and affects more women than men. Ovarian sex steroids are thought to modify depression risk in women and interventions such as bilateral oophorectomy that permanently change the sex steroid milieu may increase the risk of depression. This study aimed to investigate the associations between unilateral and bilateral oophorectomy and depression over a 25-year period (1993-2018) and whether this varied by age at oophorectomy or use of menopausal hormone therapy.

Methods: Twenty-five thousand one hundred eighty-eight nurses aged ≥45 years from the Danish Nurse Cohort were included. Nurses with depression prior to baseline were excluded. Poisson regression models, with log-transformed person-years as offset, were used to assess the associations between oophorectomy and incident depression. Nurses who retained their ovaries were the reference group.

Results: Compared with nurses with retained ovaries, bilateral oophorectomy was associated with a slightly higher rate of depression (rate ratio [RR], 1.08; 95% confidence interval [CI], 0.95-1.23), but without statistical significance. However, when stratified by age at oophorectomy, compared with nurses with retained ovaries, bilateral oophorectomy at age ≥51 years was associated with higher rates of depression (RR 1.16; 95% CI, 1.00-1.34), but not bilateral oophorectomy at age <51 years (RR 0.86; 95% CI, 0.69-1.07); P value for difference in estimates = 0.02. No association between unilateral oophorectomy and depression was observed.

Conclusions: In this cohort of Danish female nurses, bilateral oophorectomy at age ≥51 years, but not at younger ages, was associated with a slightly higher rate of depression compared with those who retained their ovaries.
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http://dx.doi.org/10.1097/GME.0000000000001913DOI Listing
January 2022

Oophorectomy and rate of dementia: a prospective cohort study.

Menopause 2022 05 1;29(5):514-522. Epub 2022 May 1.

Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark.

Objective: Globally, dementia disproportionally affects women, which is not fully explained by higher female longevity. Oophorectomy at any age leads to the permanent loss of ovarian sex steroids, potentially increasing the risk of dementia. We aimed to investigate the association between oophorectomy and dementia and whether this was conditional on age at oophorectomy, hysterectomy or use of hormone therapy (HT).

Methods: A prospective study of 24,851 female nurses from the Danish Nurse Cohort. Nurses were followed from age 60 years or entry into the cohort, whichever came last, until date of dementia, death, emigration or end of follow-up (December 31, 2018), whichever came first. Poisson regression models with log-transformed person-years as offset were used to estimate the associations.

Results: During 334,420 person-years of follow-up, 1,238 (5.0%) nurses developed dementia and 1,969 (7.9%)/ 1,016 (4.1%) contributed person-time after bilateral-/unilateral oophorectomy. In adjusted analyses, an 18% higher rate of dementia was observed following bilateral oophorectomy (aRR 1.18: 95% CI, 0.89-1.56) and 13% lower rate (aRR 0.87: 95% CI, 0.59-1.23) following unilateral oophorectomy compared to nurses who retained their ovaries. Similar effects were detected after stratification according to age at oophorectomy. No statistically significant modifying effects of hysterectomy or HT were detected (Pinteraction≥0.60).

Conclusions: Bilateral, but not unilateral, oophorectomy was associated with an increased rate of incident dementia. We were unable to establish whether this association was conditional on hysterectomy or HT use. Although an increase in dementia after bilateral oophorectomy is biologically plausible, limited statistical power hampers the precision of the estimates.
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http://dx.doi.org/10.1097/GME.0000000000001943DOI Listing
May 2022

Exposure to 15 phthalates and two substitutes (DEHTP and DINCH) assessed in trios of infants and their parents as well as longitudinally in infants exclusively breastfed and after the introduction of a mixed diet.

Environ Int 2022 03 25;161:107107. Epub 2022 Jan 25.

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

Objective: Several phthalates have been restricted/banned due to their adverse endocrine disrupting properties. The use of other phthalates and substitutes has increased. Here we examine the current exposure to phthalates in family trios comprised of infants and their parents and in infants exclusive breastfed and following introduction to a mixed diet.

Methods: Metabolites of 15 phthalates and two substitutes, di(2-ethylhexyl)-teraphthalate (DEHTP) and diisononyl-cyclohexane-1,2-dicarboxylate (DINCH), were measured in urine samples collected from >100 infants and their parents and in paired urine samples collected from 67 infants, while they were exclusively breastfed and when they got mixed diet.

Results: Among infants and their parents, metabolites of nine out of 15 phthalates and both substitutes were detected in >74% of all samples. Estimated daily intake (DI) calculated as µg/kg/day, showed similar exposure levels among infants and their parents for several of the substances, and infants were more exposed to DEHTP than their mothers. Significantly higher estimated DIs were observed for some low-molecular phthalates in infants exclusively breastfed. In contrast, comparable estimated DIs were observed for many other phthalates and DEHTP regardless of feeding status. For most of the substances, the within-family variation, was lower than the between-family variation. Likewise, the within-infant variation on exclusively breast vs. mixed diet was lower than the between-infant variation. Independent of food status, some infants were concurrently exposed to almost all the measured phthalates and substitutes in higher amounts than others.

Conclusion: Surprisingly, irrespective of diet status infants were exposed to several phthalates and substitutes some of which have been regulated for years. Exposure patterns and levels were similar in infants and their parents. Importantly, risk assessment based on new refined reference doses (RfD-AA) exceeded the safety level for anti-androgenic effects in a number of infants and parents, which is of concern.
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http://dx.doi.org/10.1016/j.envint.2022.107107DOI Listing
March 2022

Clinical assessment of blood pressure in 60 girls with Turner syndrome compared to 1888 healthy Danish girls.

Clin Endocrinol (Oxf) 2022 03 7;96(3):428-438. Epub 2022 Jan 7.

Department of Growth and Reproduction and EDMaRC, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.

Objective: Hypertension contributes to increased risk of cardiovascular disease in patients with Turner syndrome (TS). Our objective was to evaluate blood pressure (BP) in girls with TS followed longitudinally through childhood and adolescence compared to a newly established BP reference material.

Design: Cohort study with data collected from 1991 to 2019 consisting of a population-based reference cohort and a group of girls with TS followed at a single tertiary centre.

Patients/participants: Reference population of 1888 healthy girls with 4890 BP recordings and 60 girls with TS with 365 BP recordings.

Measurements: Difference in diastolic BP (DBP) and systolic BP (SBP), expressed in standard deviation scores (SDS), between girls with TS and the reference population, unadjusted and adjusted for BMI. Difference in BP (SDS) between TS subgroups (karyotype, oestrogen treatment, cardiac diagnosis).

Results: The girls with TS had significantly higher DBP (mean ± SD, 0.72 SDS ± 0.95; p < .001) and SBP (0.53 SDS ± 1.11; p = .001) than the reference population. Adjusted for BMI, girls with TS had significantly higher DBP (mean ± SE, 0.71 SDS ± 0.12; p < .001) but not SBP (0.17 SDS ± 0.16; p = .29). There was no significant difference in DBP (median, IQR: 0.97 SDS, 0.30-1.58 vs. 0.76 SDS, 0.10-1.20; p = .31) or SBP (0.51 SDS, 0.15-1.30 vs. 0.57 SDS, -0.30 to 1.05; p = .67) between individuals with or without a cardiac diagnosis. In the TS population, 55% (31/56) had at least one BP recording above the hypertension threshold.

Conclusions: Our findings indicate that standardised longitudinal routine monitoring of BP in girls with TS already in childhood is of utmost importance.
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http://dx.doi.org/10.1111/cen.14669DOI Listing
March 2022

Environmental factors in declining human fertility.

Nat Rev Endocrinol 2022 03 15;18(3):139-157. Epub 2021 Dec 15.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.
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http://dx.doi.org/10.1038/s41574-021-00598-8DOI Listing
March 2022

Treatment options for hypercalcemia after cosmetic oil injections: Lessons from human tissue cultures and a pilot intervention study.

Bone 2022 01 29;154:116244. Epub 2021 Oct 29.

Group of Skeletal, Mineral, and Gonadal Endocrinology, Department of Growth and Reproduction, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Endocrinology, Copenhagen University Hospital, Herlev and Gentofte, Copenhagen, Denmark; Division of Bone and Mineral Research, HSDM/HMS, Harvard University, Boston, USA. Electronic address:

Objective: Granuloma formation following self-administered cosmetic oil injections can lead to severe hypercalcemia and renal calcifications due to extra-renal vitamin D activation. This translational study aims to identify Prednisolone sparing therapeutics for hypercalcemia after development of granulomatous disease secondary to paraffin oil injections.

Materials And Methods: Granuloma tissue isolated from five men were cultured ex vivo and treated with selected drugs to block generation of activated vitamin D (1,25(OH)D). In a retrospective study, we included data before and during different treatments of 21 men with paraffin oil induced granulomatous hypercalcemia (46 treatment courses) where serum calcium, parathyroid hormone, vitamin D metabolites, creatinine and inflammatory markers were measured.

Results: Addition of Ketoconazole or Ciclosporin to granuloma tissue ex vivo culture, significantly suppressed production of 1,25(OH)D after 48 h (both p < 0.05). Prednisolone was the first treatment option in most men and lowered serum levels of ionized calcium after 1, 2, 3 and 6 months compared with baseline (p < 0.05). Ketoconazole or Hydroxychloroquine had no significant effect on serum calcium levels and were unable to reduce the concomitant daily Prednisolone doses (p > 0.05). Azathioprine did not reduce calcium levels. However, addition of Tacrolimus to Prednisolone treatment enabled a reduction in Prednisolone dose after 3 months (p = 0.014), but with no additional effect on calcium homeostasis.

Conclusion: This study verifies that Prednisolone is an effective treatment and suggests that calcineurin inhibitors may be used as Prednisolone sparing treatment for paraffin oil-induced granulomatous hypercalcemia. Randomized clinical trials are needed to determine clinical efficacy.
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http://dx.doi.org/10.1016/j.bone.2021.116244DOI Listing
January 2022

Long-term testosterone undecanoate treatment in the elderly testosterone deficient male: An observational cohort study.

Andrology 2022 02 23;10(2):322-332. Epub 2021 Nov 23.

Department of Growth and Reproduction, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

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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http://dx.doi.org/10.1111/andr.13124DOI Listing
February 2022

Insulin-like growth factor-1 and insulin-like growth factor binding protein-3: impact on early haematopoietic reconstitution following allogeneic haematopoietic stem cell transplantation.

Eur J Haematol 2022 Mar 12;108(3):190-198. Epub 2021 Nov 12.

Department of Paediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objectives: The aim of the study was to investigate whether high endogenous levels of insulin-like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3) were related to a faster reconstitution of different blood cell populations in the early phase after allogeneic myeloablative haematopoietic stem cell transplantation (HSCT).

Methods: We measured IGF-1 and IGFBP-3 by chemiluminescence during the first three weeks after transplantation in 35 adult patients undergoing myeloablative HSCT and calculated area under the curve divided by time (AUC/t) for each patient.

Results: Circulating levels of IGF-1 and IGFBP-3 correlated with counts of reticulocytes (r = 0.44, p = .011 and r = 0.41, p = .017, respectively) and thrombocytes (r  = 0.38, p = .030 and r  = 0.56, p = .0008) three weeks post-transplant. Furthermore, high IGFBP-3 levels correlated with absolute lymphocyte counts 3 weeks post-HSCT (r  = 0.54, p = .012) and were associated with shorter time to neutrophil engraftment (r  = -0.35, p = .043). Both IGF-1 and IGFBP-3 levels were associated with the number of circulating natural killer cells one month after HSCT (r  = 0.42, p = .032 and r  = 0.57, p = .0026).

Conclusion: These data indicate that high levels of IGF-1 and IGFBP-3 relate to a faster haematopoietic reconstitution after HSCT and suggest a biological influence of these mediators in haematopoietic homeostasis in these patients.
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http://dx.doi.org/10.1111/ejh.13724DOI Listing
March 2022

Cardiovascular mortality after bilateral oophorectomy: a prospective cohort study.

Menopause 2021 11 1;29(1):28-34. Epub 2021 Nov 1.

Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Denmark.

Objectives: Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry.

Methods: A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset.

Results: A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed.

Conclusion: Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.
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http://dx.doi.org/10.1097/GME.0000000000001873DOI Listing
November 2021

Pubertal development in 46,XY patients with NR5A1 mutations.

Endocrine 2022 Feb 6;75(2):601-613. Epub 2021 Oct 6.

Division of Paediatric Endocrinology and Diabetes, Department of Paediatric and Adolescent Medicine, University of Lübeck, Lübeck, Germany.

Purpose: Mutations in the NR5A1 gene, encoding the transcription factor Steroidogenic Factor-1, are associated with a highly variable genital phenotype in patients with 46,XY differences of sex development (DSD). Our objective was to analyse the pubertal development in 46,XY patients with NR5A1 mutations by the evaluation of longitudinal clinical and hormonal data at pubertal age.

Methods: We retrospectively studied a cohort of 10 46,XY patients with a verified NR5A1 mutation and describe clinical features including the external and internal genitalia, testicular volumes, Tanner stages and serum concentrations of LH, FSH, testosterone, AMH, and inhibin B during pubertal transition.

Results: Patients who first presented in early infancy due to ambiguous genitalia showed spontaneous virilization at pubertal age accompanied by a significant testosterone production despite the decreased gonadal volume. Patients with apparently female external genitalia at birth presented later in life at pubertal age either with signs of virilization and/or absence of female puberty. Testosterone levels were highly variable in this group. In all patients, gonadotropins were constantly in the upper reference range or elevated. Neither the extent of virilization at birth nor the presence of Müllerian structures reliably correlated with the degree of virilization during puberty.

Conclusion: Patients with NR5A1 mutations regardless of phenotype at birth may demonstrate considerable virilization at puberty. Therefore, it is important to consider sex assignment carefully and avoid irreversible procedures during infancy.
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http://dx.doi.org/10.1007/s12020-021-02883-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8816419PMC
February 2022
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