A. Nordenström - Academia.edu (original) (raw)

Papers by A. Nordenström

Endocrine Connections

Objective The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize... more Objective The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42–59) for patients with acromegaly, 68% (95% CI: 60–75) for Cushing’s disease, and 53% (95% CI: 39–66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37–61%) of patients and visu...

The goal of this update regarding the diagnosis and care of persons with disorders of sex develop... more The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possib...

Frontiers in Endocrinology, 2021

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of ad... more Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 7...

Prostaglandins, 1986

The metabolism of thromboxane B2 was studied in the rabbit. The aim of the study was to identify ... more The metabolism of thromboxane B2 was studied in the rabbit. The aim of the study was to identify metabolites in blood and urine that might serve as parameters for monitoring thromboxane production in vivo. [5,6,8,9,11,12,14,15-3H8]-Thromboxane B2 was administered by i.v. injection to rabbits, and blood samples and urine were collected with brief intervals. The metabolic profiles were visualized by two-dimensional thin layer chromatography and autoradiography, and the structures of five major metabolites were determined using chromatographic and mass spectrometric methods. In urine the major metabolites were identified as 11-dehydro-TXB2 and 2,3,4,5-tetranor-TXB1, and other prominent products were 11-dehydro-2,3,4,5-tetranor-TXB1, 2,3-dinor-TXB1 and 2,3-dinor-TXB2. In the circulation, TXB2 was found to disappear rapidly. The first major metabolite to appear was 11-dehydro-TXB2, which also remained a prominent product in blood for the remainder of the experiment (90 min). With time, the profile of circulating products became closely similar to that in urine. TXB2 was not converted into 11-dehydro-TXB2 by blood cells or plasma. The dehydrogenase catalyzing its formation was tissue bound and was found to have a widespread occurrence: the highest conversion was found in lung, kidney, stomach and liver. The results of the present study suggest that 11-dehydro-TXB2 may be a suitable parameter for monitoring thromboxane production in vivo in the rabbit in blood as well as urinary samples, and possibly also several tissues. This was also demonstrated in comparative studies using radioimmunoassays for TXB2 and 11-dehydro-TXB2.

Advances in prostaglandin, thromboxane, and leukotriene research, 1985

Journal of Pediatric Urology, 2012

Existing outcomes for DSD individuals are inadequate because reports are based upon information c... more Existing outcomes for DSD individuals are inadequate because reports are based upon information collected retrospectively. This paper is presented to review existing data emphasizing information needed to lead to better future care, is based on presentations and discussions at a multi-disciplinary meeting on DSD held in Annecy in 2012, and is not intended to define the present status of management of each of the various DSD diagnoses. Rather it is intended to provide information needed to do studies regarding outcome data from the treatment of children with DSD by providing a summary of recommendations of 'patient-centered' topics that need investigation. The hope is that by being concerned with what is not known, new protocols will be developed for improving both early management and transition to adult life.

Journal of Pediatric Urology, 2012

This paper is a review of some of the recent publications regarding outcome of DSD patients, with... more This paper is a review of some of the recent publications regarding outcome of DSD patients, with an emphasis upon surgical and sexual outcomes. Currently available outcome studies of patients with DSDs have limitations because of multiple factors, including lack of representative patient sampling, and lack of adequate information concerning both medical and surgical care, and psychological, social and family support. The most frequent reports involve females with 21-α-hydroxylase deficiency congenital adrenal hyperplasia (CAH). This most common form of DSD, if one excludes hypospadias and cryptorchidism, is an excellent example of a form of DSD in which all aspects of outcome, regarding surgery, sexual functionality and sensitivity, psychological input and endocrine hormonal therapy, carry a major role. The goals of therapy include a surgical outcome with a good cosmetic appearance and functionality with potential for sexual intercourse with sufficient sensitivity for satisfactory responsiveness. Endocrine replacement therapy should provide a normal adrenal hormonal milieu, while sex steroid therapy may be indicated. Psychological care should be provided from birth with gradual transition primarily to the patient, including basic counseling with full disclosure, although adjustment depends upon the patient's personality and parents' abilities and acceptance. Among forms of DSD involving gonadal insufficiency, hormonal replacement therapy should provide physiologic levels. Among females, estrogen therapy enhances healing after feminizing surgery and is required from puberty throughout adult life to maintain femininity, sexual organs and bone health, and enhance gender and sexuality. Among males, appropriate testosterone therapy maintains stamina, muscle tone, bone health, libido, sexual potency and general well-being, while benefit for healing after genital surgery is unclear. Further, outcome is clearly related to predominant cultural factors. Outcome studies should include evaluation of all of these factors.

Journal of Inherited Metabolic Disease, 2007

N-acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder. An effective treatmen... more N-acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder. An effective treatment, N-carbamoyl-L-glutamic acid (NCGA), is now available, increasing the importance of identifying and treating these patients early. We describe a case with genetically verified NAGS deficiency and neonatal onset of severe hyperammonaemia. The ammonia levels increased above 1400 micromol/L. The patient did not respond to NCGA treatment during the first 15 h, indicating that a delayed response or no response cannot be used as a safe indicator for excluding NAGS deficiency in the acute situation. Hence, conventional treatment should not be delayed by a diagnostic procedure, such as a loading test. Furthermore, at 3 years of age this patient has normal psychomotor development, underlining the possibility of a favourable outcome despite markedly elevated ammonia levels, coma, and seizures in the neonatal period. Including NCGA early in the treatment of patients with hyperammonaemia may be of clinical importance. In order to detect patients with NAGS deficiency and neonatal onset and to optimize care, it is important to use the available treatment strategies to reduce plasma ammonia concentrations without delay. We propose the use of combined symptomatic treatment, i.e. glucose infusion, sodium benzoate, arginine or citrulline, and when indicated haemodialysis, as well as NCGA treatment in all neonates presenting with severe hyperammonaemia. The treatment should be continued until laboratory investigations are complete or indicate another disorder.

Hormone Research in Paediatrics, 2005

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ran... more Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children’s Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone t...

The Journal of Clinical Endocrinology & Metabolism, 2010

Context: Females with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency are expose... more Context: Females with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency are exposed to androgens during fetal development, resulting in virilization of the external genitalia. Little is known about how these women feel that the disease has affected their lives regarding surgery and psychosexual adaptation. Objective: Our objective was to investigate the correlation between the surgical results, the selfperceived severity of the disease, and satisfaction with sexual life and relate the results to the CYP21A2 genotype. Design and Participants: Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire, and a composite score for sexual function was constructed. The surgical outcome, including genital appearance and clitoral sensitivity, was evaluated by clinical examination. The patients were divided into four CYP21A2 genotype groups. Results: The sexual function score, but not for genital appearance, was higher in the patients satisfied with their sexual life. This was also true of the patients who were satisfied with the surgical result. There were discrepancies between the patients' perception of the impact of the condition on their sexual life and what health professionals would assume from clinical examination. The patients in the null genotype group scored lower on sexual function and satisfaction with their sexual life and had more surgical complications, also compared with the slightly less severe I2-splice genotype group. Conclusion: Our data show that the null genotype group was considerably more affected by the condition than the other groups and should be regarded as a subgroup, both psychologically and from a surgical perspective. Genotyping adds clinically valuable information.

European Journal of Endocrinology

An Endo-European Reference Network guideline initiative was launched including 16 clinicians expe... more An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are revi...

European Journal of Endocrinology, 2018

Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly l... more Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. Objective To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort. Design Cross-sectional clinical outcome study, including retrospective data from medical records. Methods Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. Results At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased t...

Hormone and Metabolic Research, 2015

Disorders or differences in sex development (DSD) comprise a wide spectrum of severity. The overa... more Disorders or differences in sex development (DSD) comprise a wide spectrum of severity. The overall goal for the treatment and care is good quality of life but current knowledge concerning the psychosocial situation and health related quality of life for patients with different forms of DSD is limited. Follow-up studies have often focused on surgical results, sexual function, and psychosexual outcome and indicated unsatisfactory results in many cases. Epidemiological studies show less than optimal psychosocial situation for some of the diagnostic groups. Studies indicate that access to psychological support and understandable information is important for the outcome. Hormonal and surgical treatments are improving and new and better ways to strengthen the patient's ability to cope with the situation are needed. In a well-functioning multidisciplinary team, the patient's and family's needs should be identified. Tools to accomplish this can be developed. The care and our knowledge about disorders of sex development have developed considerably during the last decade. These are small patient groups with rare conditions that require specialized, highly qualified care in all aspects: medical, surgical, and psychological. It is important that changes in treatment practice are continuously evaluated.

Andrology, 2016

The aim of this study was to investigate sexual function and fertility in adult men born with hyp... more The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias.

Clinical Endocrinology, 2016

Background Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal rec... more Background Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of 1 in 15 000. About 1 in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic-pituitary-adrenal axis. We investigated vulnerability to psychological stress in obligate carriers. Method The Swedish CAH Registry encompasses more than 600 patients. Parents, i.e., obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias, and (iii) parents of children with diabetes mellitus type 1 (T1DM). Results Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0.6), an affective disorder (OR, 0.5) or substance misuse (OR, 0.5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0.6, 0.4 and 0.2, respectively) and parents of a child with T1DM (OR 0•7, 0•6 and 0•2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child. Conclusion Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage.

Journal of Pediatric Urology, 2017

Journal of Neurology, 2016

Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repea... more Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis, it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.

Hormone research in paediatrics, Jan 28, 2016

The goal of this update regarding the diagnosis and care of persons with disorders of sex develop... more The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possib...

JIMD Reports, 2015

Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) a... more Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are scarce. We present results from neuropsychological assessments of eight patients diagnosed with LCHADD prior to newborn screening with regard to clinical disease severity. Intellectual ability and adaptive and executive functions were assessed using age-appropriate Wechsler Scales, Adaptive Behavior Assessment Scales (ABAS), and Behavior Rating Inventory of Executive Function (BRIEF). Five patients performed in the normal range on IQ tests but with lower scores on verbal working memory. In addition, they had lower parent-rated adaptive and executive functions.Three patients had intellectual disabilities with IQs below normal and/or autism spectrum disorders. In addition, they had low results on parent-rated adaptive functions. (Two of these patients had epilepsy.) Conclusions: Patients with LCHADD seem to have a specific cognitive pattern, with presentation as intellectual disability and specific autistic deficiencies or a normal IQ with weaknesses in auditive verbal memory and adaptive and executive functions. Future studies are warranted to investigate whether newborn screening programs and early treatment may promote improved neuropsychological development and outcomes.

The Journal of clinical endocrinology and metabolism, Jan 30, 2015

Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with gluco... more Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. To study cardiovascular and metabolic morbidity in CAH. Patients with CAH due to 21-hydroxylase deficiency (n=588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n=58,800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt-wasting, simple virilising, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age-groups, and non-obesity. Cardiovascular and metabolic morbidity. In CAH, both any cardiovascular and metabolic disorders (OR 3.9, 95%CI 3.1-5.0), and cardiovascular disease (OR 2.7, 95%CI 1.9 -3.9) were increased. Separate analyses of the individual diseases showed higher...

Endocrine Connections

Objective The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize... more Objective The European Reference Network on Rare Endocrine Conditions (Endo-ERN) aims to organize high-quality healthcare throughout Europe, including care for pituitary adenoma patients. As surgery is the mainstay of treatment, we aimed to describe the current surgical practice and published surgical outcomes of pituitary adenoma within Endo-ERN. Design and Methods Systematic review and meta-analysis of studies reporting surgical outcomes of pituitary adenoma patients within Endo-ERN MTG6 pituitary reference centers between 2010 and 2019. A survey was completed by reference centers on their current surgical practice. Results A total of 18 out of 43 (42%) reference centers located in 7 of the 20 (35%) MTG6-represented countries published 48 articles. Remission rates were 50% (95% CI: 42–59) for patients with acromegaly, 68% (95% CI: 60–75) for Cushing’s disease, and 53% (95% CI: 39–66%) for prolactinoma. Gross total resection was achieved in 49% (95% CI: 37–61%) of patients and visu...

The goal of this update regarding the diagnosis and care of persons with disorders of sex develop... more The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possib...

Frontiers in Endocrinology, 2021

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of ad... more Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 7...

Prostaglandins, 1986

The metabolism of thromboxane B2 was studied in the rabbit. The aim of the study was to identify ... more The metabolism of thromboxane B2 was studied in the rabbit. The aim of the study was to identify metabolites in blood and urine that might serve as parameters for monitoring thromboxane production in vivo. [5,6,8,9,11,12,14,15-3H8]-Thromboxane B2 was administered by i.v. injection to rabbits, and blood samples and urine were collected with brief intervals. The metabolic profiles were visualized by two-dimensional thin layer chromatography and autoradiography, and the structures of five major metabolites were determined using chromatographic and mass spectrometric methods. In urine the major metabolites were identified as 11-dehydro-TXB2 and 2,3,4,5-tetranor-TXB1, and other prominent products were 11-dehydro-2,3,4,5-tetranor-TXB1, 2,3-dinor-TXB1 and 2,3-dinor-TXB2. In the circulation, TXB2 was found to disappear rapidly. The first major metabolite to appear was 11-dehydro-TXB2, which also remained a prominent product in blood for the remainder of the experiment (90 min). With time, the profile of circulating products became closely similar to that in urine. TXB2 was not converted into 11-dehydro-TXB2 by blood cells or plasma. The dehydrogenase catalyzing its formation was tissue bound and was found to have a widespread occurrence: the highest conversion was found in lung, kidney, stomach and liver. The results of the present study suggest that 11-dehydro-TXB2 may be a suitable parameter for monitoring thromboxane production in vivo in the rabbit in blood as well as urinary samples, and possibly also several tissues. This was also demonstrated in comparative studies using radioimmunoassays for TXB2 and 11-dehydro-TXB2.

Advances in prostaglandin, thromboxane, and leukotriene research, 1985

Journal of Pediatric Urology, 2012

Existing outcomes for DSD individuals are inadequate because reports are based upon information c... more Existing outcomes for DSD individuals are inadequate because reports are based upon information collected retrospectively. This paper is presented to review existing data emphasizing information needed to lead to better future care, is based on presentations and discussions at a multi-disciplinary meeting on DSD held in Annecy in 2012, and is not intended to define the present status of management of each of the various DSD diagnoses. Rather it is intended to provide information needed to do studies regarding outcome data from the treatment of children with DSD by providing a summary of recommendations of 'patient-centered' topics that need investigation. The hope is that by being concerned with what is not known, new protocols will be developed for improving both early management and transition to adult life.

Journal of Pediatric Urology, 2012

This paper is a review of some of the recent publications regarding outcome of DSD patients, with... more This paper is a review of some of the recent publications regarding outcome of DSD patients, with an emphasis upon surgical and sexual outcomes. Currently available outcome studies of patients with DSDs have limitations because of multiple factors, including lack of representative patient sampling, and lack of adequate information concerning both medical and surgical care, and psychological, social and family support. The most frequent reports involve females with 21-α-hydroxylase deficiency congenital adrenal hyperplasia (CAH). This most common form of DSD, if one excludes hypospadias and cryptorchidism, is an excellent example of a form of DSD in which all aspects of outcome, regarding surgery, sexual functionality and sensitivity, psychological input and endocrine hormonal therapy, carry a major role. The goals of therapy include a surgical outcome with a good cosmetic appearance and functionality with potential for sexual intercourse with sufficient sensitivity for satisfactory responsiveness. Endocrine replacement therapy should provide a normal adrenal hormonal milieu, while sex steroid therapy may be indicated. Psychological care should be provided from birth with gradual transition primarily to the patient, including basic counseling with full disclosure, although adjustment depends upon the patient's personality and parents' abilities and acceptance. Among forms of DSD involving gonadal insufficiency, hormonal replacement therapy should provide physiologic levels. Among females, estrogen therapy enhances healing after feminizing surgery and is required from puberty throughout adult life to maintain femininity, sexual organs and bone health, and enhance gender and sexuality. Among males, appropriate testosterone therapy maintains stamina, muscle tone, bone health, libido, sexual potency and general well-being, while benefit for healing after genital surgery is unclear. Further, outcome is clearly related to predominant cultural factors. Outcome studies should include evaluation of all of these factors.

Journal of Inherited Metabolic Disease, 2007

N-acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder. An effective treatmen... more N-acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder. An effective treatment, N-carbamoyl-L-glutamic acid (NCGA), is now available, increasing the importance of identifying and treating these patients early. We describe a case with genetically verified NAGS deficiency and neonatal onset of severe hyperammonaemia. The ammonia levels increased above 1400 micromol/L. The patient did not respond to NCGA treatment during the first 15 h, indicating that a delayed response or no response cannot be used as a safe indicator for excluding NAGS deficiency in the acute situation. Hence, conventional treatment should not be delayed by a diagnostic procedure, such as a loading test. Furthermore, at 3 years of age this patient has normal psychomotor development, underlining the possibility of a favourable outcome despite markedly elevated ammonia levels, coma, and seizures in the neonatal period. Including NCGA early in the treatment of patients with hyperammonaemia may be of clinical importance. In order to detect patients with NAGS deficiency and neonatal onset and to optimize care, it is important to use the available treatment strategies to reduce plasma ammonia concentrations without delay. We propose the use of combined symptomatic treatment, i.e. glucose infusion, sodium benzoate, arginine or citrulline, and when indicated haemodialysis, as well as NCGA treatment in all neonates presenting with severe hyperammonaemia. The treatment should be continued until laboratory investigations are complete or indicate another disorder.

Hormone Research in Paediatrics, 2005

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ran... more Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children’s Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone t...

The Journal of Clinical Endocrinology & Metabolism, 2010

Context: Females with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency are expose... more Context: Females with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency are exposed to androgens during fetal development, resulting in virilization of the external genitalia. Little is known about how these women feel that the disease has affected their lives regarding surgery and psychosexual adaptation. Objective: Our objective was to investigate the correlation between the surgical results, the selfperceived severity of the disease, and satisfaction with sexual life and relate the results to the CYP21A2 genotype. Design and Participants: Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire, and a composite score for sexual function was constructed. The surgical outcome, including genital appearance and clitoral sensitivity, was evaluated by clinical examination. The patients were divided into four CYP21A2 genotype groups. Results: The sexual function score, but not for genital appearance, was higher in the patients satisfied with their sexual life. This was also true of the patients who were satisfied with the surgical result. There were discrepancies between the patients' perception of the impact of the condition on their sexual life and what health professionals would assume from clinical examination. The patients in the null genotype group scored lower on sexual function and satisfaction with their sexual life and had more surgical complications, also compared with the slightly less severe I2-splice genotype group. Conclusion: Our data show that the null genotype group was considerably more affected by the condition than the other groups and should be regarded as a subgroup, both psychologically and from a surgical perspective. Genotyping adds clinically valuable information.

European Journal of Endocrinology

An Endo-European Reference Network guideline initiative was launched including 16 clinicians expe... more An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are revi...

European Journal of Endocrinology, 2018

Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly l... more Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. Objective To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort. Design Cross-sectional clinical outcome study, including retrospective data from medical records. Methods Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. Results At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased t...

Hormone and Metabolic Research, 2015

Disorders or differences in sex development (DSD) comprise a wide spectrum of severity. The overa... more Disorders or differences in sex development (DSD) comprise a wide spectrum of severity. The overall goal for the treatment and care is good quality of life but current knowledge concerning the psychosocial situation and health related quality of life for patients with different forms of DSD is limited. Follow-up studies have often focused on surgical results, sexual function, and psychosexual outcome and indicated unsatisfactory results in many cases. Epidemiological studies show less than optimal psychosocial situation for some of the diagnostic groups. Studies indicate that access to psychological support and understandable information is important for the outcome. Hormonal and surgical treatments are improving and new and better ways to strengthen the patient's ability to cope with the situation are needed. In a well-functioning multidisciplinary team, the patient's and family's needs should be identified. Tools to accomplish this can be developed. The care and our knowledge about disorders of sex development have developed considerably during the last decade. These are small patient groups with rare conditions that require specialized, highly qualified care in all aspects: medical, surgical, and psychological. It is important that changes in treatment practice are continuously evaluated.

Andrology, 2016

The aim of this study was to investigate sexual function and fertility in adult men born with hyp... more The aim of this study was to investigate sexual function and fertility in adult men born with hypospadias. Patients born with hypospadias, age-matched controls, and a group of circumcised men completed a questionnaire constructed to reflect their psychosexual situation and fertility. Core gender identity, sexual orientation, and gender role behavior was also assessed. 167 patients [63% distal, 24% mid shaft and 13% proximal, mean age 34 (19-54) years], 169 controls from the general population [mean age 33 (19-48) years] and 47 controls circumcised because of phimosis (mean age 26 [19-44]) participated and completed the questionnaire. There were no differences in having a partner, reported fertility, age at sexarche (mean age 17.8), number of sex partners or sexual interest between the patients and controls. More patients than controls reported anejaculation. Reported glanular sensitivity was lower in hypospadias patients and circumcised controls compared with non-circumcised controls. The odds of being satisfied with their sexual life increased with a higher penile perception score in patients (OR = 1.54, p = 0.01). There was no association with penile length. Sexual orientation, core gender identity and gender role behavior were sex-typical in both patients and controls. Patients with proximal hypospadias had a lower reported fertility, experienced anejaculation more often, and were less satisfied with their sexual life. Men born with hypospadias have a good long-term outcome concerning sexual function and fertility. Men born with proximal hypospadias have a more impaired outcome concerning both sexual function and fertility. As satisfaction with genital appearance is important for sexual life satisfaction, clinical, and psychological follow-up into adulthood is especially important in boys born with proximal hypospadias.

Clinical Endocrinology, 2016

Background Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal rec... more Background Congenital adrenal hyperplasia (CAH) is one of the most common monogenic autosomal recessive disorders with an incidence of 1 in 15 000. About 1 in 70 individuals in the general population are carriers of a severe CYP21A2 mutation. It has been suggested that this confers a survival advantage, perhaps as a result of increased activity in the hypothalamic-pituitary-adrenal axis. We investigated vulnerability to psychological stress in obligate carriers. Method The Swedish CAH Registry encompasses more than 600 patients. Parents, i.e., obligate carriers of the CYP21A2 mutation, were identified through the Multigeneration Register. The diagnosis of the child was used as the psychological stressor. Psychiatric diagnoses before and after the birth of a child with CAH were compared to those of controls derived from (i) the general population, (ii) parents of children with hypospadias, and (iii) parents of children with diabetes mellitus type 1 (T1DM). Results Parents of children with CAH had less risk of being diagnosed with any psychiatric disorder (OR, 0.6), an affective disorder (OR, 0.5) or substance misuse (OR, 0.5) after the diagnosis of the child, compared to the general population. Their risk was also decreased compared to parents of a child with hypospadias (OR, 0.6, 0.4 and 0.2, respectively) and parents of a child with T1DM (OR 0•7, 0•6 and 0•2, respectively). The CYP21A2 carriers had a lower risk of developing mood and stress-related disorders after the diagnosis of the child. Conclusion Obligate CYP21A2 carriers had a reduced risk of a psychiatric diagnosis and were less vulnerable to a psychologically stressful situation, at least with respect to receiving a psychiatric diagnosis. This indicates a better ability to cope with psychological stress among heterozygous carriers of severe CYP21A2 mutations, which may contribute to the apparent survival advantage.

Journal of Pediatric Urology, 2017

Journal of Neurology, 2016

Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repea... more Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis, it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.

Hormone research in paediatrics, Jan 28, 2016

The goal of this update regarding the diagnosis and care of persons with disorders of sex develop... more The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possib...

JIMD Reports, 2015

Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) a... more Reports on cognitive outcomes in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) are scarce. We present results from neuropsychological assessments of eight patients diagnosed with LCHADD prior to newborn screening with regard to clinical disease severity. Intellectual ability and adaptive and executive functions were assessed using age-appropriate Wechsler Scales, Adaptive Behavior Assessment Scales (ABAS), and Behavior Rating Inventory of Executive Function (BRIEF). Five patients performed in the normal range on IQ tests but with lower scores on verbal working memory. In addition, they had lower parent-rated adaptive and executive functions.Three patients had intellectual disabilities with IQs below normal and/or autism spectrum disorders. In addition, they had low results on parent-rated adaptive functions. (Two of these patients had epilepsy.) Conclusions: Patients with LCHADD seem to have a specific cognitive pattern, with presentation as intellectual disability and specific autistic deficiencies or a normal IQ with weaknesses in auditive verbal memory and adaptive and executive functions. Future studies are warranted to investigate whether newborn screening programs and early treatment may promote improved neuropsychological development and outcomes.

The Journal of clinical endocrinology and metabolism, Jan 30, 2015

Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with gluco... more Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. To study cardiovascular and metabolic morbidity in CAH. Patients with CAH due to 21-hydroxylase deficiency (n=588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n=58,800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt-wasting, simple virilising, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age-groups, and non-obesity. Cardiovascular and metabolic morbidity. In CAH, both any cardiovascular and metabolic disorders (OR 3.9, 95%CI 3.1-5.0), and cardiovascular disease (OR 2.7, 95%CI 1.9 -3.9) were increased. Separate analyses of the individual diseases showed higher...