The influence of body composition on the response to dynamic stimulation of the endocrine pituitary-testis axis.

BACKGROUND: Testosterone treatment is generally not recommended in men with obesity induced low serum testosterone. However, distinguishing this condition from overt testosterone deficiency in men with obesity where treatment should be initiated is a diagnostic challenge and tools to differentiate these conditions are scarce but could be of important clinical relevance. OBJECTIVES: To investigate the association between body composition and dynamic responses of the pituitary-testis axis in men. METHODS: Single-center cross-sectional study including 112 healthy men. Participants went through a full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of luteinizing hormone (LH) secretion (gonadotropin-releasing hormone (GnRH)-test) and testosterone secretion (choriogonadotropin (hCG)-test). A subset (N = 78) further had a DXA-scan performed. RESULTS: A higher body mass index (BMI) was associated with lower basal serum LH (BU = -0.44, 95% CI: -0.88--0.01, p = 0.04). The GnRH-stimulated LH increase was not significantly associated with BMI (BU = -0.10, 95% CI: -0.72-0.51, p = 0.74). Furthermore, a high BMI was associated with low basal testosterone (BU -0.02, 95% CI: -0.03--0.02, p < 0.001), and free testosterone (BU -15.0, 95% CI: -19.9--10.0, p < 0.001) and men with overweight and obesity had significantly lower testosterone (9%, p = 0.003 and 24%, p < 0.001) and free testosterone (25%, p = 0.006 and 50%, p < 0.001) concentrations compared to men with normal weight. The HCG-stimulated testosterone increase was significantly less dependent on BMI compared to the influence of BMI on basal testosterone concentrations (p = 0.04 for the interaction). CONCLUSIONS: Dynamic sex hormone responses following pituitary-testis axis stimulation were less dependent on BMI, compared to the influence of BMI on basal hormone concentrations and could potentially assist clinical decision making in patients with obesity suspected of testosterone deficiency.

The epidemiology of cryptorchidism and potential risk factors, including endocrine disrupting chemicals.

Congenital cryptorchidism, also known as undescended testis, is the condition where one or both testes are not in place in the scrotum at birth and is one of the most common birth defects in boys. Temporal trends and geographic variation in the prevalence of cryptorchidism from 1% to 9% have been reported in prospective cohort studies. The testes develop in the abdominal cavity and descend to the scrotum in two phases, which should be completed by gestational week 35. Thus, the risk of cryptorchidism is higher in preterm boys. In many cases a spontaneous descent occurs during the first months of life during the surge of gonadotropins and testosterone. If not, the testis is usually brought down to the scrotum, typically by surgery, to increase future fertility chances and facilitate cancer surveillance. The increasing frequency of impaired semen quality and testicular cancer, with which cryptorchidism is associated, represents a concern for male reproductive health in general and a need to understand its risk factors. The risk of cryptorchidism is closely related to gestational factors (preterm birth, low birth weight and intrauterine growth restriction), and especially maternal smoking seems to be a risk factor. Evidence is accumulating that the increasing prevalence of cryptorchidism is also related to prenatal exposure to environmental chemicals, including endocrine disrupting compounds. This association has been corroborated in rodents and supported by ecological studies. Conducting human studies to assess the effect of endocrine disrupting chemicals and their interactions is, however, challenged by the widespread concomitant exposure of all humans to a wide range of chemicals, the combined effect of which and their interactions are highly complex.

Low-serum antimüllerian hormone is linked with poor semen quality in infertile men screened for participation in a randomized controlled trial.

OBJECTIVE: To investigate possible associations between serum antimüllerian hormone (AMH) concentration and semen quality in infertile men. Studies investigating the associations between serum AMH concentration and semen quality in infertile men have shown conflicting results. DESIGN: Infertile men were included during screening for participation in the First in Treating Male Infertility Study, a double-blinded, placebo-controlled, 1:1, single-center randomized controlled trial. SETTING: Not applicable. PATIENTS: At the screening visit, 400 participants produced a semen sample and had their serum analyzed for AMH concentration. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Serum AMH concentration and semen quality. RESULTS: All men were stratified according to serum AMH concentrations in quartiles (Q1-Q4). Men in the lowest quartile had a lower sperm concentration (1 × 106/mL) (Q1: 8.0 vs. Q2: 10.4 vs. Q3: 11.0 vs. Q4: 13.0), total sperm count (1 × 106) (Q1: 29.1 vs. Q2: 38.2 vs. Q3: 44.4 vs. Q4: 55.7), sperm motility (%) (Q1: 41 vs. Q2: 57 vs. Q3: 50 vs. Q4: 53), and progressive sperm motility (%) (Q1: 31 vs. Q2: 44 vs. Q3: 35 vs. Q4: 40) compared with the other quartiles. Moreover, men with a sperm concentration <2 million/mL had a lower serum AMH concentration compared with men having 2-16 × 106 /mL and >16 × 106/mL (31 pmol/L vs. 38 pmol/L vs. 43 pmol/L, respectively). In accordance, men with sperm motility <20% had a lower serum AMH concentration compared with men with sperm motility 20%-42%, and >42% (31 pmol/L vs. 43 pmol/L. vs. 39 pmol/L, respectively). CONCLUSION: This study shows that low serum AMH concentration is associated with poor semen quality in infertile men, which implies that serum AMH concentration may have clinical value during the evaluation of male infertility. CLINICAL TRIAL REGISTRATION NUMBER: NCT05212337.

APHRODITE criteria: addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function.

RESEARCH QUESTION: Can a novel classification system of the infertile male - 'APHRODITE' (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) - stratify different subgroups of male infertility to help scientists to design clinical trials on the hormonal treatment of male infertility, and clinicians to counsel and treat the endocrinological imbalances in men and, ultimately, increase the chances of natural and assisted conception? DESIGN: A collaboration between andrologists, reproductive urologists and gynaecologists, with specialization in reproductive medicine and expertise in male infertility, led to the development of the APHRODITE criteria through an iterative consensus process based on clinical patient descriptions and the results of routine laboratory tests, including semen analysis and hormonal testing. RESULTS: Five patient groups were delineated according to the APHRODITE criteria; (1) Hypogonadotrophic hypogonadism (acquired and congenital); (2) Idiopathic male infertility with lowered semen analysis parameters, normal serum FSH and normal serum total testosterone concentrations; (3) A hypogonadal state with lowered semen analysis parameters, normal FSH and reduced total testosterone concentrations; (4) Lowered semen analysis parameters, elevated FSH concentrations and reduced or normal total testosterone concentrations; and (5) Unexplained male infertility in the context of unexplained couple infertility. CONCLUSION: The APHRODITE criteria offer a novel and standardized patient stratification system for male infertility independent of aetiology and/or altered spermatogenesis, facilitating communication among clinicians, researchers and patients to improve reproductive outcomes following hormonal therapy. APHRODITE is proposed as a basis for future trials of the hormonal treatment of male infertility.

High-dose vitamin D3 supplementation shows no beneficial effects on white blood cell counts, acute phase reactants, or frequency of respiratory infections.

BACKGROUND: Vitamin D has been suggested to influence the immune system, and vitamin D metabolites and the vitamin D receptor (VDR) are generated and expressed in white blood cells (WBC). Moreover, vitamin D status has been associated with incidence and prognosis of some respiratory tract infections (RTI). Therefore, we investigated the effect of vitamin D3 supplementation on WBC, acute phase reactants (APR), and the risk of developing RTIs. METHODS: A double-blinded, randomized, placebo-controlled clinical trial of 307 infertile men with multiple secondary immunological endpoints. The vitamin D3 group (n = 151) initially received 300,000 IU (7,500 µg) cholecalciferol once - followed by 1,400 IU (35 µg) daily for 150 days. The placebo group (n = 156) did not receive active ingredients. RESULTS: At baseline, stratification into clinically relevant groups of vitamin D status (< 25; 25-50; 50-75; >75 nmol/L), showed an inverse association with total leucocyte concentrations (7.0 vs. 6.0 vs. 6.0 vs. 5.5 (109/L); p = 0.007), lymphocytes (2.4 vs. 2.1 vs. 2.0 vs. 2.0 (109/L); p = 0.048), CRP (2.0 vs. 1.7 vs. 1.2 vs. 1.2 (mg/L); p = 0.037), and orosomucoid (0.82 vs. 0.77 vs. 0.76 vs. 0.70 (g/L); p = 0.015). After 150 days, no differences were detected in WBC counts or APRs between the vitamin D3 and the placebo group. However, vitamin D3 treated men had a higher prevalence of self-reported RTIs compared with the placebo group (55% vs. 39%; p = 0.005). CONCLUSIONS: High-dose vitamin D3 supplementation did not alter WBCs or APRs, but a higher prevalence of respiratory infections was observed in the vitamin D3 group. Serum 25(OH)D3 was negatively correlated with most WBCs, indicating that vitamin D status may be linked with inflammation and WBC turnover, but not an important determinant of developing RTIs. TRIAL REGISTRATION: NCT01304927 (ClinicalTrials.gov). Registered February 20, 2011.

Men treated with BEACOPP for Hodgkin lymphoma may be at increased risk of testosterone deficiency.

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors.

Effects of vitamin D on sex steroids, luteinizing hormone, and testosterone to luteinizing hormone ratio in 307 infertile men.

OBJECTIVE: Vitamin D status has been associated with sex steroid production. The question is whether vitamin D supplementation has an impact on sex steroid production in infertile men with vitamin D insufficiency? DESIGN: A single-center, double-blinded, randomized clinical trial. Differences in sex steroids and reproductive hormones were predefined secondary outcomes, vitamin D status at baseline was a predefined subgroup and the primary outcome was differences in semen quality. METHODS: A total of 307 infertile men were included and randomized 1:1 to active or placebo treatment for 150 days. Men in the active group initially received an oral bolus of 300,000 IU cholecalciferol, followed by daily supplementation with 1400 IU cholecalciferol and 500 mg calcium. RESULTS: After intervention, no differences were found in serum concentrations of sex steroids, luteinizing hormone, testosterone/luteinizing hormone ratio or SHBG between the vitamin D and placebo group. However, in a predefined subgroup analysis of men with serum 25OHD ≤ 50 nmol/L, men treated with vitamin D had a significantly higher testosterone/luteinizing hormone ratio [4.2 (3.8-4.4) vs. 3.7 (3.4-4.0); p = 0.033] compared with placebo treatment. In men with vitamin D deficiency, the difference between groups was larger but not significant due to few men with serum 25OHD < 25 nmol/L. CONCLUSION: Vitamin D + calcium supplementation did not alter sex steroid production in infertile men. However, vitamin D insufficient men treated with vitamin D supplementation had a significantly higher testosterone/LH ratio compared with placebo-treated men, suggesting that optimal Leydig cell function are dependent on adequate vitamin D status.

Insulin-like Factor 3, Basal and Human Chorionic Gonadotropin-Stimulated Testosterone as Biomarkers to Predict the Effect of Testosterone Replacement in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency.

INTRODUCTION: Mild Leydig cell insufficiency affects a substantial proportion of testicular cancer survivors. Previous studies have not shown a beneficial effect of testosterone replacement therapy, however, with a pronounced interindividual effect. Thus, biomarkers identifying the subgroups that might benefit are wanted. We aimed to determine if insulin-like factor 3 (INSL3), basal and human chorionic gonadotropin (hCG)-stimulated testosterone can predict the effect of testosterone replacement therapy in testicular cancer survivors with mild Leydig cell insufficiency. PATIENTS AND METHODS: We randomized adult testicular cancer survivors with mild Leydig cell insufficiency 1:1 to 12 months of transdermal testosterone replacement therapy (Tostran gel 2%) or placebo. INSL3, basal, and hCG-stimulated testosterone were measured at baseline. Outcomes (glucose, insulin, HbA1C, lipids, blood pressure, and body composition) were measured at baseline, 6 and 12 months. We applied a linear mixed-effect model comparing patients receiving testosterone with placebo in subgroups by biomarker. RESULTS: We included and randomized 69 patients between October 2016 and February 2018. Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had a -1.7 kg (95% CI: -3.1, -0.4) and -2.0 kg (95% CI: -3.5, -0.6) change in fat mass after 12 months of testosterone replacement therapy compared with placebo. This was not the case in patients with INSL3 and hCG-stimulated testosterone above the median. We did not find any effect of these biomarkers on glucose, insulin, HbA1c, or lipids. CONCLUSION: Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had decreased fat mass after 12 months of testosterone replacement therapy compared with placebo. It should be evaluated in larger trials if these biomarkers can be used as predictive markers identifying testicular cancer patients with mild Leydig cell insufficiency who might benefit from testosterone substitution.

The impact of acute SARS-CoV-2 on testicular function including insulin-like factor 3 (INSL3) in men with mild COVID-19: A longitudinal study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect the male reproductive system as it uses angiotensin-converting enzyme (ACE)2, which is expressed in testicular tissue, as an entry point into the cell. Few studies have evaluated the long-term effects of mild coronavirus disease 2019 (COVID-19) on testicular function, and insulin-like factor 3 (INSL3) levels have not previously been assessed during acute SARS-CoV-2 infection. OBJECTIVES: The aim of the study was to assess the impact of acute SARS-CoV-2 infection on testicular function including INSL3 and the presence of SARS-CoV-2 RNA in semen in non-hospitalised men with mild COVID-19. MATERIALS AND METHODS: This longitudinal study included 36 non-hospitalised SARS-CoV-2-positive men (median age 29 years). Inclusion was within seven days following a positive SARS-CoV-2 reverse-transcription polymerase chain reaction test. Reproductive hormone levels, semen parameters, and the presence of SARS-CoV-2 RNA in oropharyngeal and semen samples were assessed during acute SARS-CoV-2 infection (baseline) and at three- and six-month follow-up. Wilcoxon matched-pair signed-rank (two samples) test was used to assess time-related alterations in reproductive hormone levels and semen parameters. RESULTS: Lower plasma testosterone (T) (total and calculated free (c-fT)) and higher luteinising hormone (LH) concentrations were observed during acute SARS-CoV-2 infection (baseline) compared to three- and six-month follow-up. Consequently, ratios of c-fT/LH were lower at baseline compared to three- and six-month follow-up (p < 0.001 and p = 0.003, respectively). Concomitantly, lower INSL3 concentrations were observed at baseline compared to three-month follow-up (p = 0.01). The total number of motile spermatozoa was also lower at baseline compared to six-month follow-up (p = 0.02). The alterations were detected irrespective of whether the men had experienced SARS-CoV-2-related fever episodes or not. No SARS-CoV-2 RNA was detected in semen at any time point. DISCUSSION AND CONCLUSION: This study showed a reduction in testicular function, which was for the first time confirmed by INSL3, in men mildly affected by SARS-CoV-2 infection. The risk of transmission of SARS-CoV-2 RNA via semen seems to be low. Febrile episodes may impact testicular function, but a direct effect of SARS-CoV-2 cannot be excluded.

Frequency, morbidity and equity - the case for increased research on male fertility.

Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.

High-dose cholecalciferol supplementation to obese infertile men is sufficient to reach adequate vitamin D status.

Obesity is associated with low vitamin D status, and the optimal supplement and dosage of cholecalciferol (vitamin D3) or calcidiol (25OHD) for individuals with obesity have been debated. We aimed to determine the effect of high-dose vitamin D3 supplementation on achieving adequate vitamin D levels among infertile men with normal weight v. obesity. Here, we present secondary end points from a single-centre, double-blinded, randomised clinical trial, comprising 307 infertile men randomised to active or placebo treatment for 150 days. Men in the active group initially received an oral bolus of 300 000 mg of vitamin D3, followed by daily supplementation with 1400 mg of vitamin D3 and 500 mg of calcium. Baseline BMI was listed as a predefined subgroup. At baseline, serum 25OHD was significantly higher in men with normal weight (BMI < 25 kg/m2) compared with men with overweight (BMI 25-30 kg/m2) and obesity (BMI > 30 kg/m2) (48 nmol/l v. 45 nmol/l and 39 nmol/l, respectively; P = 0·024). After the intervention, men with normal weight, overweight and obesity treated with vitamin D3 had a significantly higher serum 25OHD compared with corresponding placebo-treated men (BMI < 25 kg/m2: 92 nmol/l v. 53 nmol/l, BMI = 25-30 kg/m2: 87 nmol/l v. 49 nmol/l and BMI > 30 kg/m2: 85 nmol/l v. 48 nmol/l; P < 0·001 for all, respectively). In conclusion, we show that high-dose vitamin D3 supplementation to infertile men with obesity and low vitamin D status is sufficient to achieve adequate serum 25OHD levels.

Results from the first autologous grafting of adult human testis tissue: a case report.

Fertility restoration using autologous testicular tissue transplantation is relevant for infertile men surviving from childhood cancer and, possibly, in men with absent or incomplete spermatogenesis resulting in the lack of spermatozoa in the ejaculate (non-obstructive azoospermia, NOA). Currently, testicular tissue from pre-pubertal boys extracted before treatment with gonadotoxic cancer therapy can be cryopreserved with good survival of spermatogonial stem cells. However, strategies for fertility restoration, after successful cancer treatment, are still experimental and no clinical methods have yet been developed. Similarly, no clinically available treatments can help men with NOA to become biological fathers after failed attempts of testicular surgical sperm retrieval. We present a case of a 31-year-old man with NOA who had three pieces of testis tissue (each ∼2 × 4 × 2 mm3) extracted and cryopreserved in relation to performing microdissection testicular sperm extraction (mTESE). Approximately 2 years after mTESE, the thawed tissue pieces were engrafted in surgically created pockets bilaterally under the scrotal skin. Follow-up was performed after 2, 4, and 6 months with assessment of reproductive hormones and ultrasound of the scrotum. After 6 months, all engrafted tissue was extracted and microscopically analyzed for the presence of spermatozoa. Furthermore, parts of the extracted tissue were analyzed histologically and by immunohistochemical analysis. Active blood flow in the engrafted tissue was demonstrated by doppler ultrasound after 6 months. No spermatozoa were found in the extracted tissue. Histological and immunohistochemical analysis demonstrated graft survival with intact clear tubules and normal cell organization. Sertoli cells and spermatocytes with normal morphology were located near the basement membrane. MAGE-A and VASA positive spermatogonia/spermatocytes were detected together with SOX9 positive Sertoli cells. Spermatocytes and/or Sertoli cells positive for γH2AX was also detected. In summary, following autologous grafting of frozen-thawed testis tissue under the scrotal skin in a man with NOA, we demonstrated graft survival after 6 months. No mature spermatozoa were detected; however, this is likely due to the pre-existing spermatogenic failure.

Characterization and finding the origin of off-flavor compounds in Nile tilapia cultured in net cages in hydroelectric reservoirs, São Paulo State, Brazil.

An increasing demand for fish products has led to an intensive aquaculture production in Brazil, and cultivation of fish constituted 860 × 103 tons in 2022, contributing to the 87% of total fish consumption. Nile tilapia constitutes almost half of the aquaculture production, and most tilapia farms use floating net cages. One of the major constraints of intensive fish production is production of off-flavors. Release of nutrients by the fish leads to deterioration of the water quality and stimulates growth of microorganisms, also including off-flavor producing species. The objective of this study was to determine levels of taste and odor compounds (geosmin, 2-MIB and a selection of volatile compounds) and their impact on the flavor quality of Nile tilapia produced in net cages in reservoirs in São Paulo State, Brazil. GC-MS analysis of fish and water from six different farms showed concentrations of geosmin in the water from 1 to 8 ng/L, while geosmin in fish flesh ranged from 40 to 750 ng/kg. The level of 2-MIB in water was 2 to 25 ng/L, and 0 to 800 ng/kg fish. The GC-MS analysis also revealed presence of more than 100 volatile organic compounds in the fish flesh, consisting of aldehydes, alcohols, benzene derivatives, hydrocarbons, ketones and few other compounds. Geosmin and 2-MIB related flavor notes were detected in all fish by a sensory panel, and a high correlation between the chemical and sensory analyses was found. The potential impact of the volatile organic compounds on the fish flavor is discussed. Analysis of the water quality in the reservoirs indicated that levels of geosmin and 2-MIB levels were highly influenced by the nutrient levels in the water.

Improving standard practices in studies using results from basic human semen examination.

The purpose of this article is to provide an explanation of the background behind a checklist that declares the laboratory methods used in a scientific study. It focuses primarily on implementing laboratory procedures to yield reliable results in basic semen examinations. While the World Health Organization (WHO) and international standards provide recommendations for basic semen examination, manuscripts submitted to Andrology frequently lack transparency regarding the specific techniques used. In addition, the terminology used for semen examination results often fails to provide a clear definition of the groups under study. Furthermore, the WHO's reference limits are often misinterpreted as strict boundaries between fertility and infertility. It is important to note that valid clinical andrological diagnoses and treatments cannot rely solely on semen examination results; they require proper laboratory procedures as a foundation for diagnosing and treating male patients. Therefore, scientific journals should promote the adoption of robust laboratory practices and an accurate definition of patient groups. A checklist can facilitate the design of high-quality studies and the creation of informative publications. Further, it can help journals assess submitted manuscripts and improve the overall quality of their publications.

Sexual dysfunction is highly prevalent in male survivors of malignant lymphoma.

Background: With improved survival in patients with lymphoma, long-term toxicity and quality of life (QoL), including sexual health, have become increasingly important. Aim: We aimed to (1) determine the prevalence of erectile dysfunction (ED) in adult male lymphoma survivors; (2) determine whether testosterone deficiency, comorbidities, or lifestyle factors were associated; and (3) evaluate their impact on QoL. Methods: A cross-sectional study including 172 male survivors of Hodgkin lymphoma or diffuse large B cell lymphoma diagnosed in adulthood between 2008 and 2018 was performed. Patients were in complete metabolic remission after first-line treatment and remained in remission at follow-up (3-13 years after diagnosis). Participants completed 3 questionnaires measuring sexual health and general QoL. Serum concentrations of total testosterone were measured and thorough medical history and sociodemographic factors were obtained. The Danish SEXUS Project, European Male Ageing Study, and European Organization of Research and Treatment of Cancer (EORTC) Reference Manual were used as reference values of the general population. Outcomes: Patient reported outcome measures including the 5-item International Index of Erectile Function, EORTC C30, and EORTC 22-item Sexual Health Questionnaire. Results: ED was reported by 55.2%, which was higher than in an age-matched Danish population cohort (17.5%). Erectile function score (5-item International Index of Erectile Function) was negatively associated with comorbidity, body mass index, smoking, and age and positively with the number of children conceived before treatment and serum concentration of total testosterone. Overt testosterone deficiency in combination with ED was detected in 10 (5.7%) of 176 survivors, including excluded survivors in hormonal treatment, which is higher than for the general population (0.1%-3.2% for men <70 years of age). Mean EORTC C30 global health score for survivors with ED was lower (67.7) than for survivors without ED (80.1) but was comparable to the general population (71.2). Furthermore, a positive association was seen between sexual function and both sexual and general QoL. Clinical implications: Sexual health is important for QoL and related to comorbidities. The focus on improving QoL requires that both sexual health and comorbidities are addressed in the follow-up of lymphoma patients. Strengths and limitations: Despite the relatively high number of included survivors, the cross-sectional design of this study warrants longitudinal studies to clarify the specific underlying causes of sexual dysfunction. Conclusion: ED was highly prevalent and associated with comorbidity in lymphoma survivors, and more focus on sexual health and treatment related comorbidity is needed to improve sexual and general QoL.

Reduced serum concentrations of biomarkers reflecting Leydig and Sertoli cell function in male patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a recessive condition that affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cell-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candidate biomarker to monitor Leydig cell function in patients with CAH.

Reproductive hormones, bone mineral content, body composition, and testosterone therapy in boys and adolescents with Klinefelter syndrome.

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.

A novel hepcidin mutation.

BACKGROUND: The bioactive peptide hormone hepcidin-25 regulates iron levels by inhibiting iron transport to plasma via ferroportin. Hepcidin-25 is synthesized in the liver where the 84 amino acids pro-hepcidin is cleaved into the bioactive hepcidin-25. A patient admitted to the hospital presented with infertility and fatigue. METHODS: Genomic DNA was purified from whole blood using the Maxwell 16 system (Promega). MLPA analysis was performed to detect large genomic rearrangements using the SALSA MLPA kit # P347, Hemochromatosis (MRC Holland, Holland). Plasma hepcidin measurements were performed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). RESULTS: A novel HAMP mutation (homozygous one base deletion in c.215delG, p.Cys72Serfs*?) was detected. The deletion in nucleotide 215 causes a frameshift altering the predicted protein sequence from cysteine13 in mature peptide. Whether this leads to nonsense mediated decay of the mRNA or synthesis of an aberrant peptide in unknown, but bioactive hepcidin-25 was undetectable in plasma. The patient had massive iron overload with ferritin up to 8360 µg/L. He was anaemic with a Hb at 7.0 mmol/L (11.3 g/dL) and suffered from hypogonadotropic hypogonadism with a total testosterone of 1.2 nmol/l. Continued treatment with venesection and gonadotropins led to reduced fatigue, reduction in iron overload, a normalized Hb and improvement of semen quality. CONCLUSION: A novel hepcidin mutation was detected in a patient with massive iron overload, fatigue and hypogonadotropic hypogonadism.

Exposure to Phthalates in European Children, Adolescents and Adults since 2005: A Harmonized Approach Based on Existing HBM Data in the HBM4EU Initiative.

Phthalates are mainly used as plasticizers and are associated inter alia with adverse effects on reproductive functions. While more and more national programs in Europe have started monitoring internal exposure to phthalates and its substitute 1,2-Cyclohexanedicarboxylic acid (DINCH), the comparability of results from such existing human biomonitoring (HBM) studies across Europe is challenging. They differ widely in time periods, study samples, degree of geographical coverage, design, analytical methodology, biomarker selection, and analytical quality assurance level. The HBM4EU initiative has gathered existing HBM data of 29 studies from participating countries, covering all European regions and Israel. The data were prepared and aggregated by a harmonized procedure with the aim to describe-as comparably as possible-the EU-wide general population's internal exposure to phthalates from the years 2005 to 2019. Most data were available from Northern (up to 6 studies and up to 13 time points), Western (11; 19), and Eastern Europe (9; 12), e.g., allowing for the investigation of time patterns. While the bandwidth of exposure was generally similar, we still observed regional differences for Butyl benzyl phthalate (BBzP), Di(2-ethylhexyl) phthalate (DEHP), Di-isononyl phthalate (DiNP), and Di-isobutyl phthalate (DiBP) with pronounced decreases over time in Northern and Western Europe, and to a lesser degree in Eastern Europe. Differences between age groups were visible for Di-n-butyl phthalate (DnBP), where children (3 to 5-year olds and 6 to 11-year olds) had lower urinary concentrations than adolescents (12 to 19-year-olds), who in turn had lower urinary concentrations than adults (20 to 39-year-olds). This study is a step towards making internal exposures to phthalates comparable across countries, although standardized data were not available, targeting European data sets harmonized with respect to data formatting and calculation of aggregated data (such as developed within HBM4EU), and highlights further suggestions for improved harmonization in future studies.