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CONTEXT: Klinefelter syndrome (KS) is associated with hypergonadotropic hypogonadism, which contributes to characteristic phenotypical manifestations including metabolic alterations. Extensive research has demonstrated important associations between androgens and liver function. OBJECTIVES: Investigation of the association between metabolic parameters, sex hormones and liver function in males with KS, both treated (T-KS) and untreated (U-KS) and healthy control males. METHODS: A total of 65 KS males were recruited, of which 32 received testosterone replacement therapy (TRT). Also, 69 healthy controls were recruited. We used alanine aminotransferase (ALAT), alkaline phosphatase and PP (prothrombin-proconvertin time ratio) as the main liver markers. Multivariable regression was performed within the three groups. All statistics were calculated using STATA. Principal component analysis was utilized to demonstrate the interconnected patterns among all measured biomarkers, and to elucidate how the different groups were linked to these patterns. RESULTS: Higher levels of main liver markers were observed in U-KS compared to controls, with no significant differences between U-KS and T-KS. T-KS had lower abdominal fat, total cholesterol, and LDL cholesterol than U-KS. Using multivariable models, variation in ALAT in U-KS was explained by HOMA2%S; in T-KS by BMI and SHBG; and in controls by hip circumference and estradiol. We found no multivariable models explaining variation in PP in U-KS; in T-KS, PP was explained by BMI and LDL cholesterol, and in controls by total cholesterol. Using principal component analysis U-KS was positively associated to D1 (an obese profile, which also included ALAT) and controls negatively associated with D1 (non-obese profile). CONCLUSION: KS males have mild liver dysfunction reflected by a significant increase in the main liver markers and decrease in albumin. The presented data underscore a primary role of metabolic conditions including obesity, insulin resistance and unfavourable lipid profile, in the elevated liver function markers seen in males with KS. Whether TRT can improve liver function in KS warrants further studies. Our findings, highlight that an evaluation of the liver function should be part of the clinical care in males with KS.
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STUDY QUESTION: Are transfer day, developmental stage and morphology of the competent blastocyst in pregnancies leading to live birth associated with preterm birth, birthweight, length at birth and sex of the child? SUMMARY ANSWER: A high score in blastocyst developmental stage and in trophectoderm (TE) showed a significant association with the sex of the child, while no other associations with obstetric outcomes were observed. WHAT IS KNOWN ALREADY: The association between blastocyst assessment scores and obstetric outcomes have been reported in small single-center studies and the results are conflicting. STUDY DESIGN, SIZE, DURATION: Multicenter historical cohort study based on exposure data (transfer day (blastocyst developmental stage reached by Day 5 or Day 6)) blastocyst developmental stage (1-6) and morphology (TE and inner cell mass (ICM): A, B, C)) and outcome data (preterm birth, birthweight, length at birth, and sex of the child) from women undergoing single blastocyst transfer resulting in a singleton pregnancy and live birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 16 private and university-based facilities for clinical services and research were used. A total of 7246 women, who in 2014-2018 underwent fresh-embryo transfer with a single blastocyst or frozen-thawed embryo transfer (FET) with a single blastocyst resulting in a singleton pregnancy were identified. Linking to the Danish Medical Birth Registry resulted in a total of 4842 women with a live birth being included. Cycles with pre-implantation genetic testing and donated gametes were excluded. The analyses were adjusted for female age (n = 4842), female BMI (n = 4302), female smoking (n = 4290), parity (n = 4365), infertility diagnosis (n = 4765), type of treatment (n = 4842) and center (n = 4842); some analyses additionally included gestational age (n = 4368) and sex of the child (n = 4833). MAIN RESULTS AND THE ROLE OF CHANCE: No statistically significant associations between blastocyst assessment scores (transfer day, developmental stage, TE, ICM) and preterm birth (8.3%) or birthweight (mean 3461.7 g) were found. The adjusted association between blastocysts with a TE score of C and a TE score of A and length at birth (mean 51.6 cm) were statistically significant (adjusted mean difference 0.4 cm (95% CI: 0.02; 0.77)). Blastocysts transferred with developmental stage score 5 compared to blastocysts transferred with score 3 had a 34% increased probability of being a boy (odds ratio (OR) 1.34 (95% CI: 1.09; 1.64). Further, TE score B blastocysts compared to TE score A blastocysts had a 31% reduced probability of being a boy (OR 0.69 (95% CI: 0.60; 0.80)). LIMITATIONS, REASONS FOR CAUTION: It is possible that some residual confounding remains. WIDER IMPLICATIONS OF THE FINDINGS: Blastocyst selection during ART does not appear to introduce any negative effects on obstetric outcome. Therefore, clinicians and patients can be reassured that the assessment scores of the selected blastocyst will not in themselves pose a risk of preterm birth or affect birthweight and the length at birth. STUDY FUNDING/COMPETING INTEREST(S): Unrestricted grant from Gedeon Richter Nordics AB, Sweden. None of the authors have any competing interest to declare. TRIAL REGISTRATION NUMBER: N/A.
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Nascimento Prematuro , Blastocisto , Estudos de Coortes , Transferência Embrionária/métodos , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Estudos RetrospectivosRESUMO
BACKGROUND: Men with inflammatory bowel disease (IBD) may have decreased sexual function due to factors related to the underlying disease, medication, and/or surgery. We aimed to examine the use of erectile dysfunction (ED) medications in men with IBD. METHODS: This is a nationwide cohort study based on the Danish registries, comprising all men >18 years old with IBD during 1 January 1995 through December 2016. The cohorts included 31,498 men with IBD and 314,980 age-matched men without IBD. Our main outcome was a first prescription of an ED medication. Cox regression analyses were used to estimate the hazard rate (HR) for use of ED medications, controlled for multiple time-varying covariates. RESULTS: Overall, 21,966 (69.7%) men had ulcerative colitis (UC) while 9532 (30.3%) had Crohn's disease (CD). Men with a first ED prescription numbered 3749 (11.9%) (men with IBD) and 30,635 (9.7%) (men without IBD). Adjusting for central nervous system and intestinal anti-inflammatory medications, systemic corticosteroids and co-morbidities, the HR was 1.19 (95% CI: 1.13-1.26) (IBD and no prior IBD operation), and 1.31 (95% CI: 1.20-1.43) (IBD and prior IBD operation). The adjusted HR for UC was 1.17 (95% CI: 1.10-1.24) (no operation) and 1.43 (95% CI: 1.27-1.61) (prior operation), and for CD 1.26 (95% CI: 1.15-1.38) (no operation) and 1.20 (95% CI: 1.06-1.35) (prior operation). DISCUSSION: Men with IBD are more likely to fill an ED prescription than men without IBD. This result is significant regardless of a history of IBD surgery.
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Colite Ulcerativa/complicações , Doença de Crohn/complicações , Prescrições de Medicamentos/estatística & dados numéricos , Disfunção Erétil/tratamento farmacológico , Agentes Urológicos/uso terapêutico , Adulto , Anti-Inflamatórios/efeitos adversos , Estudos de Casos e Controles , Fármacos do Sistema Nervoso Central/efeitos adversos , Estudos de Coortes , Colectomia/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/cirurgia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/cirurgia , Dinamarca , Disfunção Erétil/etiologia , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros/estatística & dados numéricosRESUMO
STUDY QUESTION: Does phthalate exposure from prescription drugs affect semen quality? SUMMARY ANSWER: Exposure to phthalate-containing drugs is associated with poor semen quality. WHAT IS KNOWN ALREADY: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans. STUDY DESIGN, SIZE, DURATION: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality. LIMITATIONS, REASONS FOR CAUTION: The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest.
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Exposição Ambiental , Fertilização in vitro , Ácidos Ftálicos/toxicidade , Medicamentos sob Prescrição/química , Espermatozoides/efeitos dos fármacos , Adulto , Dinamarca , Humanos , Masculino , Ácidos Ftálicos/análise , Sistema de Registros , Análise do Sêmen , Contagem de EspermatozoidesRESUMO
STUDY QUESTION: Is there an association between the need for medical puberty induction and the diagnosis or treatment received in girls who have undergone cryopreservation of ovarian tissue for fertility preservation? SUMMARY ANSWER: There was a clear association between the intensity of treatment received and requirement for medical puberty induction but no association with the diagnosis. WHAT IS KNOWN ALREADY: Although it cannot be predicted which girls will become infertile or develop premature ovarian insufficiency (POI) following intensive chemotherapy or irradiation, patients who are at high risk of POI should be offered ovarian tissue cryopreservation (OTC). This includes girls who are planned to receive either high doses of alkylating agents, conditioning regimen before stem cell transplantation (SCT), total body irradiation (TBI) or high radiation doses to the craniospinal, abdominal or pelvic area. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study. In total, 176 Danish girls under 18 years of age have had OTC performed over a period of 15 years. An overview of the girls' diagnoses and mean age at OTC as well as the number of deceased is presented. Of the 176 girls, 38 had died and 46 girls were still younger than 12 years so their pubertal development cannot be evaluated yet. For the 60 girls who had OTC performed after 12 years of age, the incidence of POI was evaluated and in the group of 32 girls who were younger than 12 years at OTC, the association between the diagnosis and received treatment and the requirement for medical puberty induction was examined. PARTICIPANTS/MATERIALS, SETTING, METHODS: The need for medical puberty induction was assessed in 32 girls who were prepubertal at the time of OTC. MAIN RESULTS AND THE ROLE OF CHANCE: Indications for OTC were allogeneic SCT for leukaemia, myelodysplastic syndrome or benign haematological disorders, autologous SCT for lymphoma or sarcoma, and irradiation to the pelvis or to the spinal axis. The mean age at OTC of the 176 girls were 11.3 years. The two most prevalent diagnoses of the 176 girls were malignant tumours and malignant haematological diseases. Among the 32 prepubertal girls, 12 received high dose chemotherapy and either TBI prior to SCT or irradiation to the pelvis, abdomen or the spinal axis, 13 received high dose alkylating agents but no irradiation prior to SCT, six received alkylating agents as part of conventional chemotherapy and one patient had a genetic metabolic disorder and did not receive gonadotoxic treatment. Among these 32 girls, 23 did not undergo puberty spontaneously and thus received medical puberty induction. Among the nine girls, who went through spontaneous puberty, four had received high dose alkylating agents and five had received conventional chemotherapy. LIMITATIONS REASONS FOR CAUTION: All information was retrieved retrospectively from patient records, and thus some information was not available. WIDER IMPLICATIONS OF THE FINDINGS: OTC should be recommended to all young girls, who present a high risk of developing ovarian insufficiency and/or infertility following high dose chemotherapy and/or irradiation. STUDY FUNDING/COMPETING INTERESTS: The Childhood Cancer Foundation (2012-2016) and the EU interregional project ReproHigh are thanked for having funded this study. They had no role in the study design, collection and analysis of the data or writing of the report. The authors have no conflict of interest to disclose.
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Criopreservação/métodos , Preservação da Fertilidade/métodos , Ovário/patologia , Insuficiência Ovariana Primária/patologia , Puberdade/fisiologia , Adolescente , Criança , Dinamarca , Feminino , Humanos , Estudos RetrospectivosRESUMO
STUDY QUESTION: What is the epidemiology and trajectory of health and socioeconomic status in males with 46,XX disorders of sex development (DSD)? SUMMARY ANSWER: 46,XX DSD males had an increased overall morbidity compared to male background population controls, and the socioeconomic status was inferior on outcome parameters such as education and long-term income. WHAT IS KNOWN ALREADY: 46,XX DSD males are rare and estimates of prevalence and incidence are limited. An increased morbidity and mortality as well as a negatively affected socioeconomic status are described in males with Klinefelter Syndrome. However, this has never been systematically studied in 46,XX DSD males. STUDY DESIGN, SIZE, DURATION: In this nationwide registry study including 44 males with a verified diagnosis of 46,XX DSD we aimed to estimate incidence, prevalence and diagnostic delay. Further, we aimed to study morbidity, mortality and socioeconomic outcome parameters using the Danish registries. The socioeconomic outcome parameters were education, income, retirement, parenthood and cohabitation. 46,XX DSD males were born during 1908-2012 and follow-up started at birth or at start of registration and ended in 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Potential cases (n = 69) were identified in the Danish Cytogenetic Central Registry and the diagnosis was verified by medical record evaluation (n = 44). A randomly selected age-matched control group of 100 males and 100 females per case was identified by Statistics Denmark. MAIN RESULTS AND THE ROLE OF CHANCE: Among newborn males the prevalence of diagnosed 46,XX DSD males was 3.5-4.7 per 100 000. Median age at diagnosis was 17.0 years (range: 0.0-62.8). Overall morbidity was increased compared to male controls (hazard ratio [HR] = 2.4, 95% CI: 1.8-3.3) but not when excluding endocrine and urogenital diseases as well as congenital malformations (HR = 1.2, 95% CI: 0.8-1.6). Mortality was not increased (HR = 0.6, 95% CI: 0.2-2.5) compared to male controls. 46,XX DSD males had poorer education (HR = 0.1, 95% CI: 0.0-0.9) and fewer fatherhoods (HR = 0.4, 95% CI: 0.2-0.7) than male controls, and their income was reduced for the following age groups; 45-49 years: odds ratio [OR] = 0.4 (95% CI: 0.2-0.7); 50-54 years: OR = 0.1 (95% CI: 0.0-0.6). LIMITATIONS, REASONS FOR CAUTION: The study cohort is rather small, although it is large in comparison to other studies on 46,XX DSD males. Some 46,XX DSD males may have been excluded from the study owing to lack of data in medical records, making the diagnosis impossible to verify. As in all epidemiologic studies a risk of misclassification must be considered when interpreting the study results, and as the study included diagnosed 46,XX DSD males only, conclusions cannot be extended to non-diagnosed 46,XX DSD males. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a new insight into trajectory of health and socioeconomic status of 46,XX DSD males. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by research grants from the Health Research Fund of Central Denmark Region, the A.P. Møller Foundation 'Fonden til Laegevidenskabens Fremme', the Lundbeck Foundation and the Novo Nordisk Foundation (NNF13OC0003234 and NNF15OC0016474). The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.
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Transtornos 46, XX do Desenvolvimento Sexual/epidemiologia , Transtornos 46, XX do Desenvolvimento Sexual/diagnóstico , Transtornos 46, XX do Desenvolvimento Sexual/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Diagnóstico Tardio , Dinamarca/epidemiologia , Nível de Saúde , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Classe Social , Fatores Socioeconômicos , Adulto JovemRESUMO
OBJECTIVE: To examine the chance of live births and adverse birth outcomes in women with ulcerative colitis (UC) and Crohn's disease (CD) compared with women without inflammatory bowel disease (IBD) who have undergone assisted reproductive technology (ART) treatments. METHODS: This was a nationwide cohort study based on Danish health registries, comprising all women with an embryo transfer during 1 January 1994 through 2013. The cohorts comprised 1360 ART treatments in 432 women with UC, 554 ART treatments in 182 women with CD and 148,540 treatments in 52,489 women without IBD. Our primary outcome was live births per ART treatment cycle. We controlled for multiple covariates in the analyses. Our secondary outcomes were adverse birth outcomes. RESULTS: The chance of a live birth for each embryo transfer was significantly reduced in ART treatments in women with UC (OR=0.73, 95% CI 0.58 to 0.92), but not significantly reduced in the full model of ART treatments in women with CD (OR=0.77, 95% CI 0.52 to 1.14). Surgery for CD before ART treatment significantly reduced the chance of live birth for each embryo transfer (OR=0.51, 95% CI 0.29 to 0.91). In children conceived through ART treatment by women with UC, the OR of preterm birth was 5.29 (95% CI 2.41 to 11.63) in analyses including singletons and multiple births; restricted to singletons the OR was 1.80, 95% CI 0.49 to 6.62. CONCLUSIONS: Our results suggest that women with UC and CD receiving ART treatments cannot expect the same success for each embryo transfer as other infertile women. Women with CD may seek to initiate ART treatment before needing CD surgery. Increased prenatal observation in UC pregnancies after ART should be considered.
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Colite Ulcerativa , Doença de Crohn , Resultado da Gravidez , Técnicas de Reprodução Assistida/efeitos adversos , Adulto , Estudos de Coortes , Dinamarca , Feminino , Humanos , Nascido Vivo , Gravidez , Fatores de TempoRESUMO
STUDY QUESTION: What are the results of transplanting cryopreserved ovarian tissue? SUMMARY ANSWER: The transplanted ovarian tissue can last up to 10 years, with no relapses following the 53 transplantations, and the chance of a successful pregnancy is currently around one in three for those with a pregnancy-wish. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue is now gaining ground as a valid method for fertility preservation. More than 36 children worldwide have now been born following this procedure. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study of 41 women who had thawed ovarian tissue transplanted 53 times over a period of 10 years, including 1 patient who was lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 41 Danish women, who had in total 53 transplantations, were followed for ovarian function and fertility outcome. Safety was assessed by monitoring relapse in cancer survivors. MAIN RESULTS, AND THE ROLE OF CHANCE: Among 32 women with a pregnancy-wish, 10 (31%) had a child/children (14 children in total); this included 1 woman with a third trimester on-going pregnancy. In addition, two legal abortions and one second trimester miscarriage occurred. A total of 24 clinical pregnancies were established in the 32 women with a pregnancy-wish. The tissue remained functional for close to 10 years in some cases and lasted only a short period in others. Three relapses occurred but were unlikely to be due to the transplanted tissue. LIMITATIONS, REASONS FOR CAUTION: Self-report through questionnaires with only in-one hospital formalised follow-up of transplanted patients could result in unreported miscarriages. The longevity of the tissue may vary by few months compared with those reported because some patients simply could not remember the date when the tissue became non-functional. WIDER IMPLICATIONS OF THE FINDINGS: Cryopreservation of ovarian tissue is likely to become integrated into the treatment of young women, with cancer, who run a risk of losing their fertility. The full functional lifespan of grafts is still being evaluated, because many of the transplanted women have continued to maintain ovarian activity. Some of our first cases have had tissue functioning for â¼ 10 years.
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Criopreservação/métodos , Preservação da Fertilidade/métodos , Fertilidade/fisiologia , Ovário/transplante , Adulto , Dinamarca , Feminino , Humanos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Resultado do TratamentoRESUMO
STUDY QUESTION: Does neonatal outcome including congenital malformations in children born after ICSI with epididymal and testicular sperm [testicular sperm extraction (TESE)/percutaneous epididymal sperm aspiration (PESA)/testicular sperm aspiration (TESA) (TPT)] differ from neonatal outcome in children born after ICSI with ejaculated sperm, IVF and natural conception (NC)? SUMMARY ANSWER: Children born after TPT have similar neonatal outcome, including total malformation rates, as have children born after ICSI and IVF with ejaculated sperm. Testing for variance over the four groups may indicate smaller differences in specific malformation rates with TPT as the highest risk group. WHAT IS KNOWN ALREADY: Regarding neonatal outcome as well as congenital malformations in children born after TPT, studies are few, with limited sample size, heterogeneous and often performed without relevant control groups. STUDY DESIGN, SIZE, DURATION: Population-based cohort study including all Danish children born after TPT and fresh embryo transfer in Denmark from 1995 to 2009. Children born after transfer of frozen-thawed embryos were excluded. Control groups of children conceived by ICSI with ejaculated sperm, IVF and NC were identified by cross-linkage of the Danish IVF Register, Medical Birth Register (MBR) and National Hospital Discharge Register (HDR). PARTICIPANTS/MATERIALS, SETTING: The study group consisted of 466 children born after TPT, while the control groups consisted of 8967 (ICSI with ejaculated sperm), 17 592 (IVF) and 63 854 (NC) children. Neonatal outcomes and congenital malformations were analysed for singletons and twins separately. Risk estimates for low birthweight (LBW, <2500 g) and preterm birth (PTB, <37 gestational weeks) were adjusted for maternal age, parity, child gender and year of childbirth. The study group was identified from the Danish national database on children born after TPT. Control groups were obtained from the IVF register and the MBR. All information included in the study was retrieved from the national registers. MAIN RESULTS AND THE ROLE OF CHANCE: Considering singletons and twins as one group, the sex ratio (â/â) was significantly lower for children born after TPT (0.89) compared with conventional IVF (1.11; P = 0.017) but did not differ significantly when compared with ICSI with ejaculated sperm (0.94) and NC (1.05). The mean birthweight (BW) for singletons did not differ significantly between groups when including only first-born children. The mean gestational age (GA) in the TPT singletons (279 ± 12 days) was significantly higher compared with IVF (276 ± 18 days; P = 0.02), but similar to ICSI with ejaculated sperm and NC singletons when including only first-born children (277 ± 16 days and 279 ± 14 days, respectively). Rate of stillbirths, perinatal and neonatal mortality in the group of TPT singletons did not differ significantly from any of the control groups. Comparable results were found for the TPT twin group, except for perinatal mortality, which was significantly lower in the TPT group compared with naturally conceived twins. The adjusted risk of LBW was significantly higher for TPT versus NC singletons [adjusted odds ratio (AOR) = 0.67 (0.48-0.93)]; however AOR for PTB was similar in the two groups. Regarding twins, similar adjusted risks were observed for PTB and LBW between the TPT and all three control groups. Significantly more Caesarean sections were performed after IVF (27.3% for singletons) and ICSI (25.1% for singletons) with ejaculated sperm compared with the TPT group (16.4% for singletons). The total rate of congenital malformations in the TPT group was 7.7% and did not differ significantly from any of the control groups. However, singleton TPT boys showed an increased rate of cardiac malformations (3.6%) compared with singleton boys after IVF (1.4%; P = 0.04) and NC (1.1%; P = 0.02). Considering the level of male infertility as a continuum over the four groups, tests for variance in the rate of cardiac malformations in singleton boys, and undescended testicles for singleton as well as twin boys were each significantly increased from NC to IVF to ICSI to TPT (P < 0.001). The rate of hypospadias showed the same pattern, but the TPT group did not differ significantly compared with the control groups. LIMITATIONS, REASONS FOR CAUTION: One of the limitations is that the TPT group could not be classified according to testicular or epididymal sperm, as these data were not available in the IVF register. Another limitation is that registry-based studies are encumbered with the risk of reporting or coding errors or missing data due to insufficient coding. However, the quality of data on congenital malformations in HDR has, in other studies, been validated and found acceptable for epidemiological research, and furthermore, recordings on study and control groups are performed similarly. WIDER IMPLICATIONS OF THE FINDINGS: Accumulating data show that TPT treatment is equally safe as conventional ICSI and IVF treatment and as NC with regard to neonatal outcome including congenital malformation. STUDY FUNDING/POTENTIAL COMPETING INTERESTS: This study is supported by Laboratory of Reproductive Biology, Scientific Unit, Horsens Hospital. No competing interests declared.
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Anormalidades Congênitas/etiologia , Epididimo/patologia , Doenças Fetais/etiologia , Doenças do Recém-Nascido/etiologia , Injeções de Esperma Intracitoplásmicas/efeitos adversos , Recuperação Espermática/efeitos adversos , Testículo/patologia , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/mortalidade , Dinamarca/epidemiologia , Transferência Embrionária/efeitos adversos , Epididimo/citologia , Feminino , Fertilização in vitro/efeitos adversos , Doenças Fetais/epidemiologia , Doenças Fetais/mortalidade , Humanos , Recém-Nascido , Doenças do Recém-Nascido/epidemiologia , Doenças do Recém-Nascido/mortalidade , Infertilidade Masculina/patologia , Masculino , Gravidez , Resultado da Gravidez , Gravidez de Gêmeos , Sistema de Registros , Risco , Testículo/citologiaAssuntos
Colite Ulcerativa , Nascido Vivo , Doença de Crohn , Feminino , Humanos , Gravidez , Resultado da GravidezRESUMO
BACKGROUND: Structural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men. RESULTS: Eleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line. CONCLUSIONS: In men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.
RéSUMé: CONTEXTE: Des anomalies structurelles ainsi que des variations mineures du chromosome Y peuvent provoquer des troubles de la différenciation sexuelle ou, plus fréquemment, une azoospermie. Cette étude visait à déterminer la prévalence de la perte de matériel chromosomique Y dans le spectre allant de petites microdélétions dans la région du facteur d'azoospermie (AZF) à la perte complète du chromosome Y chez les hommes azoospermiques. RéSULTATS: Onze des 865 hommes azoospermiques (1,3 %), collectés entre 1997 et 2022, présentaient un caryotype comprenant une lignée cellulaire 45,X. Deux avaient un caryotype pur 45,X et neuf avaient un caryotype mosaïque 45,X/46,XY. La région AZF, ou une partie de celle-ci, était absente chez huit des neuf hommes présentant un chromosome Y anormal sur le plan structurel. Sept hommes présentaient un caryotype avec un chromosome Y structurellement anormal sous une forme non mosaïque. De plus, des microdélétions du chromosome Y ont été trouvées chez 34 hommes présentant un chromosome Y de structure normale. Aucune malformation congénitale n'a été détectée par échocardiographie et échographie des reins des 11 hommes porteurs d'une lignée cellulaire 45,X mosaïque ou non mosaïque. CONCLUSIONS: Chez les hommes qui ont une azoospermie, une perte du chromosome Y, allant de petites microdélétions à une perte complète du chromosome Y, a été observée chez 6,1 % (53/865). Les microdélétions partielles de la région AZFb peuvent donner un phénotype testiculaire plus doux que les microdélétions complètes de l'AZFb.
RESUMO
OBJECTIVE: Epidemiological data suggest there is an increased risk of dying from heart disease among patients with Klinefelter syndrome (KS). Due to high prevalence of hypogonadism and metabolic syndrome, we speculated that patients with KS may have subclinical changes in the left ventricular function. Therefore, the aim was to assess left ventricular long axis function by tissue Doppler echocardiography in patients with KS and relate these findings to the metabolic status and testosterone levels. DESIGN: Cross-sectional study. Out-patient clinic. PATIENTS: We investigated 25 unselected patients with KS, recruited from endocrine and fertility clinics. Twenty-five age-matched males served as controls. MEASUREMENTS: Left ventricular systolic long axis function (velocities and strain rate) assessed by tissue Doppler echocardiography related to free testosterone, fasting values of plasma glucose, insulin, homeostasis model assessment (HOMA)-index, cholesterol and triglycerides in addition to dual energy X-ray absorptiometry (DEXA) scan derived assessment of truncal body fat. RESULTS: The long axis function was significantly reduced in patients with KS (peak systolic velocities 4.4 +/- 1.3 vs. 5.3 +/- 1.0 cm/s, P < 0.01 and strain rate -1.3 +/- 0.3 vs.-1.6 +/- 0.3 s(-1), P < 0.01). However, the ventricular dysfunction was mainly attributed KS patients with metabolic syndrome. The peak systolic velocities were significantly correlated to truncal body fat (r = -0.72, P < 0.01) and free testosterone (r = 0.63, P < 0.01), but uncorrelated to plasma glucose, insulin and HOMA-index. CONCLUSION: Systolic long axis function is decreased in patients with KS and metabolic syndrome. The decrease in myocardial systolic function was significantly related to truncal body fat and hypogonadism, but not correlated to insulin sensitivity.
Assuntos
Gordura Abdominal/patologia , Adiposidade/fisiologia , Hipogonadismo/complicações , Resistência à Insulina , Síndrome de Klinefelter/complicações , Disfunção Ventricular Esquerda/complicações , Gordura Abdominal/metabolismo , Adulto , Estudos de Casos e Controles , Estudos Transversais , Humanos , Hipogonadismo/epidemiologia , Hipogonadismo/metabolismo , Hipogonadismo/fisiopatologia , Resistência à Insulina/fisiologia , Síndrome de Klinefelter/epidemiologia , Síndrome de Klinefelter/metabolismo , Síndrome de Klinefelter/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Testosterona/sangue , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/fisiologia , Adulto JovemRESUMO
Testicular hyperechogenic foci (THF) are associated with Klinefelter's syndrome, cryptorchidism, infertility, and testicular germ cell neoplasia. The aims of the study were to evaluate THF in relation to etiology of azoospermia and to Sertoli cell dysfunction. The structures inside the scrotum of consecutive non-vasectomized, azoospermic were examined by ultrasonography, and hormone (FSH, LH, testosterone, and prolactin), and genetic analyses (karyotype, Y microdeletions, and CFTR mutations) were performed. At testicular ultrasonography, patients were graduated into: pronounced THF (>7 THF per transducer field), distributed universally (uTHF) or collected in plaques (pTHF), borderline THF (bTHF; 3-7 THF per transducer field), or no THF (<3 THF per transducer field). Diagnostic testicular biopsy was taken open or with TruCut needle (14G). THF status was sufficiently described in 382 of 449 potential participants, and testicular histology was available in 300 cases. Presence of ultrasonographically detectable THF was compared to presence of testicular microlithiasis (TM) detected histologically. Sertoli cell dysfunction was investigated in a subgroup using a three-stage immunoperoxidase technique for detection of cytokeratin-18 (CK-18). The prevalence of THF was 13.4%. uTHF was found in 11 men (2.9%), the pattern was bilateral in four while other four had bTHF in the other testis. pTHF was detected in eight cases (2.1%), and except for one case with Klinefelter's syndrome, pTHF was in all cases occurring unilaterally. bTHF was detected in 32 cases (8.4%), bilaterally in 17 (53%). Pronounced THF was significantly associated with testicular malignancy. CK-18 was detected in more azoospermic men with sperm production in ≤50% seminiferous tubules than in azoospermic men with spermatogenesis in ≥90% of seminiferous tubules and normal controls (p < 0.05). Unfortunately, TM detected histologically was not detected in any patient expressing THF, and neither THF nor TM was detected in any of the patients examined for CK-18. Sertoli cell dysfunction was not associated with testicular microlithiasis or hyperechogenic foci.
Assuntos
Azoospermia/diagnóstico por imagem , Testículo/diagnóstico por imagem , Ultrassonografia , Adulto , Azoospermia/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Estudos Retrospectivos , Testosterona/sangueRESUMO
Sperm DNA Fragmentation has been extensively studied for more than a decade. In the 1940s the uniqueness of the spermatozoa protein complex which stabilizes the DNA was discovered. In the fifties and sixties, the association between unstable chromatin structure and subfertility was investigated. In the seventies, the impact of induced DNA damage was investigated. In the 1980s the concept of sperm DNA fragmentation as related to infertility was introduced as well as the first DNA fragmentation test: the Sperm Chromatin Structure Assay (SCSA). The terminal deoxynucleotidyl transferase nick end labelling (TUNEL) test followed by others was introduced in the nineties. The association between DNA fragmentation in spermatozoa and pregnancy loss has been extensively investigated spurring the need for a therapeutic tool for these patients. This gave rise to an increased interest in the aetiology of DNA damage. The present decade continues within this research area. Some of the more novel methods recently submerging are sorting of cells with increased DNA fragmentation and hyaluronic acid (HA) binding techniques. The clinical value of these tests remains to be elucidated. In spite of half a century of research within the area, this analysis is not routinely implemented into the fertility clinics. The underlying causes are multiple. The abundance of methods has impeded the need for a clinical significant threshold. One of the most promising methods was commercialized in 2005 and has been reserved for larger licensed laboratories. Myriads of reviews and meta-analyses on studies using different assays for analysis of DNA fragmentation, different clinical Artificial Reproductive Treatments (ART), different definitions of successful ART outcome and small patient cohorts have been published. Although the area of DNA fragmentation in spermatozoa is highly relevant in the fertility clinics, the need for further studies focusing on standardization of the methods and clinical implementation persists.
Assuntos
Dano ao DNA , Infertilidade Masculina/diagnóstico , Análise do Sêmen/história , Espermatozoides/patologia , Aborto Espontâneo/etiologia , Aborto Espontâneo/patologia , Animais , Consenso , Fertilidade , História do Século XX , História do Século XXI , Humanos , Infertilidade Masculina/patologia , Infertilidade Masculina/fisiopatologia , Masculino , Valor Preditivo dos Testes , Fatores de Risco , Análise do Sêmen/métodos , Análise do Sêmen/normasRESUMO
Clinical review of the present data on the effects of selective serotonin reuptake inhibitors (SSRIs) on male fertility was the objective of the study. PubMed and Scopus were searched for publications in English or Danish and reviewed. Human trials, animal studies and in vitro studies were included. Use of SSRIs negatively affects semen parameters in most studies. In some studies, SSRIs are also shown to reduce DNA integrity. SSRIs can also delay ejaculation. Depression and anxiety can cause reduced libido, erectile dysfunction and delayed ejaculation as well. The use of SSRIs seems to reduce male fertility by affecting semen parameters, although most studies have a degree of confounding by indication caused by the underlying depression.
Assuntos
Disfunção Erétil/induzido quimicamente , Infertilidade Masculina/induzido quimicamente , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Ejaculação/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Humanos , Libido/efeitos dos fármacos , Masculino , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
The presence of Y chromosome material in patients with Turner syndrome is a risk factor for the development of gonadoblastoma. However, no cases with gonadoblastoma or other ovarian malignancies have been found in epidemiological studies of cancer, morbidity, or mortality in Turner syndrome. We examined 114 females with Turner syndrome for the presence of Y chromosome material by PCR. Initially, five different primer sets were used. Y Chromosome-positive individuals were further examined with an additional four primer sets. We found 14 (12.2%; 95% confidence interval, 6.9-19.7%) patients who had Y chromosome material. The karyotype in 7 of these patients did not suggest the presence of Y chromosome material. Seven of the patients had been ovariectomized before entering the study due to verified Y chromosome material, whereas three patients were operated upon after the DNA analysis. The histopathological evaluations showed that 1 of the 10 ovariectomized patients actually had a gonadoblastoma. The rest of the patients did not have gonadoblastoma or carcinoma in situ on histopathological evaluation. Three patients (age, >50 yr) positive for Y chromosome material chose not to have ovariectomy performed, and detailed ultrasonographies did not suggest the presence of gonadoblastoma. The frequency of Y chromosome material is high in Turner syndrome (12.2%), but the occurrence of gonadoblastoma among Y-positive patients seems to be low (7-10%), and the risk may have been overestimated in previous studies, perhaps due to problems with selection bias. This study emphasizes the need for prospective unbiased studies.
Assuntos
Gonadoblastoma/complicações , Gonadoblastoma/genética , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/genética , Síndrome de Turner/complicações , Síndrome de Turner/genética , Cromossomo Y/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Dinamarca/epidemiologia , Feminino , Frequência do Gene , Gonadoblastoma/diagnóstico por imagem , Humanos , Imuno-Histoquímica , Lactente , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico por imagem , População , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome de Turner/diagnóstico por imagem , Ultrassonografia , Vagina/diagnóstico por imagemRESUMO
Azoospermia can be due to a genetic defect (abnormal karyotype, Y chromosome micro-deletion or cystic fibroses carrier), genital tract infection or trauma. Examination of azoospermic men includes ultrasound examination of the scrotal contents, prostate and seminal vesicles, hormone analysis, genetic examinations and testis biopsy. Some patients with obstructive azoospermia can be cured surgically. If passage can not be established through the genital tract, sperm can be obtained from the epididymis or testis for micro-insemination of oocytes from the female partner. No increased occurrence of malformations among children born after micro-insemination has been found, but an increased occurrence of severe reduced semen quality may be expected, when the "ICSI boys" grow up. Freezing of additional sperm or testis tissue is recommended.
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Infertilidade Masculina/etiologia , Oligospermia/complicações , Epididimo/patologia , Epididimo/fisiopatologia , Feminino , Fertilização in vitro , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/terapia , Masculino , Microinjeções , Oligospermia/diagnóstico , Oligospermia/genética , Oligospermia/terapia , Gravidez , Resultado da Gravidez , Próstata/patologia , Próstata/fisiopatologia , Espermatogênese , Testículo/patologia , Testículo/fisiopatologiaRESUMO
A phenotypical girl aged 16 years with primary amenorrhoea had an XY-karyotype and reacted positively to serologically demonstrable H-Y antigen. The left gonad was an immature testis while the right was a streak gonad with a gonadoblastoma. The value of H-Y antigen determinations in the diagnosis and choice of treatment is discussed.
Assuntos
Disgenesia Gonadal 46 XY/diagnóstico , Disgenesia Gonadal/diagnóstico , Adolescente , Feminino , Disgenesia Gonadal 46 XY/imunologia , Antígeno H-Y/análise , HumanosRESUMO
Klinefelter syndrome (KS, 47,XXY) is associated with increased psychiatric morbidity and cognitive disabilities, although the neuropsychological phenotype shows great variability. Androgen receptor polymorphism (CAG repeat length), skewed X-chromosome inactivation and parent-of-origin of the extra X-chromosome have been suggested to influence cognitive function and psychological traits. These issues have not been clarified for KS patients. We studied X-chromosome inactivation pattern, CAG repeat length and parent-of-origin in relation to educational and cohabitation status, personality and autism traits, psychological distress, cognitive function and brain volumes in 73 KS patients and 73 controls. Grey matter (GM) volume of left insula was significantly decreased in KS patients with skewed X-inactivation (z = 5.78) and we observed a borderline significant difference in global brain matter volume where KS patients with skewed X-chromosome inactivation tended to have smaller brains. Skewed X-inactivation, CAG repeat length and parent-of-origin were not correlated with educational and marital status, personality traits, autism traits, and psychological distress, prevalence of depression and anxiety or cognitive function. Interestingly our results regarding brain volumes indicate that X-inactivation has an influence on GM volume in left insula and might also be related to global GM volume, indicating a possible effect of X-linked genes on the development of GM volume in KS patient. Skewed X-inactivation, CAG repeat length and parent-of-origin have no impact on the neuropsychological phenotype in KS (http://www.clinicaltrials.gov (Clinical trial NCT00999310)).