Helena Filipsson

Gender Role Behavior, Sexuality, and Psychosocial Adaptation in Women with Congenital Adrenal Hyperplasia due to CYP21A2 Deficiency

CONTEXTnGender-atypical behavior has been described in young girls as well as in women with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency.nnnOBJECTIVEnThe aim of the study was to assess health-related, psychosexual, and psychosocial parameters and correlate the results to CYP21A2 genotype.nnnDESIGN AND PARTICIPANTSnSixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire and a validated quality of life instrument [psychological general well-being (PGWB) formula] to identify psychosexual and psychosocial parameters. The patients were divided into four CYP21A2 genotype groups.nnnRESULTSnThe women with CAH held more male-dominant occupations (30%) compared to controls (13%) (P = 0.04), especially those in the null genotype group (55%) (P = 0.006). They also reported a greater interest in rough sports (74%) compared to controls (50%) (P = 0.007). Eight women with CAH (14%) reported a prime interest in motor vehicles, compared to none of the controls (P = 0.002). Non-heterosexual orientation was reported by 19% of women with CAH (P = 0.005), 50% in the null genotype group (P = 0.0001), 30% in I2 splice (NS), and 5% in I172N (NS). PGWB total score did not differ between patients and controls.nnnCONCLUSIONnWe identified increased gender-atypical behavior in women with CAH that could be correlated to the CYP21A2 genotype. This speaks in favor of dose-dependent effects of prenatal androgens on the development of higher brain functions. The impact of the disease on upbringing and interpersonal relationships did not correlate with disease severity, indicating that other factors, such as coping strategies, are important for psychosocial adaptation. This illustrates the need for psychological support to parents and patients.

Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

BACKGROUNDnLow pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known.nnnMETHODSnIn a Swedish study, 62 adult women with CAH, aged 18-63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children.nnnRESULTSnPregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause.nnnCONCLUSIONSnPregnancy and delivery rates are reduced in women with CAH mainly due to psychosocial reasons. The outcome of children did not differ from controls. The unexpected sex ratio in children born to mothers with CAH warrants further research.

Sexual Function and Surgical Outcome in Women with Congenital Adrenal Hyperplasia Due to CYP21A2 Deficiency: Clinical Perspective and the Patients’ Perception

CONTEXTnFemales 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.nnnOBJECTIVEnOur objective was to investigate the correlation between the surgical results, the self-perceived severity of the disease, and satisfaction with sexual life and relate the results to the CYP21A2 genotype.nnnDESIGN AND PARTICIPANTSnSixty-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.nnnRESULTSnThe 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.nnnCONCLUSIONnOur 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.

Influence of the Exon 3-Deleted/Full-Length Growth Hormone (GH) Receptor Polymorphism on the Response to GH Replacement Therapy in Adults with Severe GH Deficiency

CONTEXTnThere is considerable individual variation in the clinical response to GH replacement therapy in GH deficient (GHD) adults. Useful predictors of treatment response are lacking.nnnOBJECTIVEnThe aim of the study was to assess the influence of the exon 3-deleted (d3-GHR) and full-length (fl-GHR) GH receptor isoforms on the response to GH replacement therapy in adults with severe GHD.nnnDESIGN AND PATIENTSnA total of 124 adult GHD patients (79 men; median age, 50 yr) were studied before and after 12 months of GH therapy. GHD patients were divided into those bearing fl/fl alleles (group 1) and those bearing at least one d3-GHR allele (group 2), and the genotype was related to the effects of GH therapy on IGF-I levels and total body fat (BF).nnnINTERVENTIONnGH dose was individually titrated to obtain normal serum IGF-I levels.nnnMAIN OUTCOME MEASURESnGHR genotype was determined by PCR amplification, IGF-I levels by immunoassay, and BF by a four-compartment model.nnnRESULTSnSeventy-two (58%) patients had fl/fl genotype and were classified as group 1, whereas 52 (42%) had at least one d3-GHR allele and were classified as group 2 (40 were heterozygous and 12 were homozygous). At baseline, there were no significant differences in the study groups. Changes in IGF-I and BF after 12 months of GH treatment did not differ significantly between the two genotype groups.nnnCONCLUSIONnThe presence of d3-GHR allele did not influence the response to GH replacement therapy in our cohort of adults with severe GHD.

Adequate iodine nutrition in Sweden: a cross-sectional national study of urinary iodine concentration in school-age children

Background/Objectives:Sweden has a long-standing salt iodization program; however, its effects on iodine intake have never been monitored on a national level. The objective of this study was to evaluate iodine nutrition in the Swedish population by measuring the urinary iodine concentration (UIC) in a national sample of Swedish school-age (6–12 years of age) children.Subjects/Methods:A stratified probability proportionate to size cluster sampling method was used to obtain a representative national sample of school-age children from 30 clusters. Spot urine samples were collected for UIC analysis using a modified Sandell–Kolthoff method.Results:The median UIC of the children (n=857) was 125u2009μg/l (range 11–757u2009μg/l). The proportion of children with a UIC <100u2009μg/l was 30.0% and the proportion of children with a UIC <50 and >300u2009μg/l was 5.5 and 3.0%, respectively.Conclusions:The iodine nutritional status of the Swedish population is adequate. Iodized table salt remains the main dietary source of iodine in Swedish diet. Recommendations to reduce total salt intake in the population urge increased use of iodized salt in the production of processed foods. Pregnant and lactating women with high iodine requirements may still be at risk for low iodine intake. This study will serve as the basis for future monitoring of iodine nutritional status in Sweden.

Long-Acting Hydrocortisone for Glucocorticoid Replacement Therapy

Background: Glucocorticoid (GC) deficiency is a consequence of various disorders that are by themselves rare. Because of this low prevalence, the low cost of GC replacement therapy and the belief that existing outcomes are good, there has been little interest in development of new and improved pharmaceutical products for treatment of GC deficiency. However, GC replacement therapy is complex: diurnal variation of endogenous cortisol must be replicated, GC needs may change during times of physical and psychological stress and there is no biomarker of its action that can be used to monitor individual dose response. Current Limitations: Recent data suggest that the outcome of established long-term GC replacement therapy may not be as good as previously believed. Short-acting GCs such as hydrocortisone (HC) and cortisone acetate for replacement therapy require 2 to 3 administrations per day. Developing Alternatives: Drug delivery system technologies are now available that could permit design and manufacture of a formulation that could accommodate once-daily administration of HC. Such a formulation would enable more physiological serum cortisol-time profiles than are possible with currently available formulations. This short review provides some background on GC replacement therapy, along with recent data on the outcome of patient groups with GC insufficiency, and briefly discusses some general principles for a controlled-release (‘long-acting’) HC formulation.

Exploring the use of recombinant human TSH in the diagnosis of central hypothyroidism

CONTEXTnThe diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased.nnnOBJECTIVEnTo explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH.nnnDESIGNnRandomized single-blind clinical trial.nnnSETTINGnOutpatient clinic of a tertiary care referral center.nnnINTERVENTIONnA single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval.nnnPARTICIPANTSnEighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T(3)) for 4 weeks. One week before stimulation, treatment was withdrawn.nnnMAIN OUTCOME MEASURESnThyroid hormones and thyroglobulin (Tg) before and 2, 3(1/2), 7, 24, 48, and 72 h after each injection.nnnRESULTSnIn the newCH group, basal free thyroxine (FT(4)) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT(4) and reverse T(3) (rT(3)) were less marked in the newCH group than in controls (FT(4)+/-s.e.m. 9.2+/-0.5 to 19.7+/-1.2 vs 11.3+/-0.5 to 27.8.2+/-2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT(4) compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection.nnnCONCLUSIONnIn this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT(4) and rT(3) than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.

Role of iodine-containing multivitamins during pregnancy for children’s brain function: protocol of an ongoing randomised controlled trial: the SWIDDICH study

Introduction Iodine is essential for normal brain development. Moderate and severe fetal iodine deficiency results in substantial to serious developmental delay in children. Mild iodine deficiency in pregnancy is associated with neurodevelopmental deficits in the offspring, but evidence from randomised trials is lacking. The aim of the Swedish Iodine in Pregnancy and Development in Children study is to determine the effect of daily supplementation with 150u2009µg iodine during pregnancy on the offspring’s neuropsychological development up to 14 years of age. Methods and analysis Thyroid healthy pregnant women (n=1275: age range 18–40 years) at ≤12 weeks gestation will be randomly assigned to receive multivitamin supplements containing 150u2009µg iodine or non-iodine-containing multivitamin daily throughout pregnancy. As a primary outcome, IQ will be measured in the offspring at 7 years (Wechsler Intelligence Scale for Children-V). As secondary outcomes, IQ will be measured at 3.5 and 14 years, psychomotor development at 18 months and 7 years, and behaviour at 3.5, 7 and 14 years. Iodine status (urinary iodine concentration) will be measured during pregnancy and in the offspring at 3.5, 7 and 14 years. Thyroid function (thyroid hormones, thyroglobulin), and deiodinase type 2 polymorphisms will be measured during pregnancy and in the offspring at 7 and 14 years. Structural MRI or other relevant structural or functional brain imaging procedures will be performed in a subgroup of children at 7 and 14 years. Background and socioeconomic information will be collected at all follow-up times. Ethics and dissemination This study is approved by the Ethics Committee in Göteborg, Sweden (Diary numbers: 431-12 approved 18 June 2012 (pregnancy part) and 1089-16 approved 8 February 2017 (children follow-up)). According to Swedish regulations, dietary supplements are governed by the National Food Agency and not by the Medical Product Agency. Therefore, there is no requirement for a monitoring committee and the National Food Agency does not perform any audits of trial conduct. The trial will be conducted in accordance with the Declaration of Helsinki. The participating sites will be contacted regarding important protocol changes, both orally and in writing, and the trial registry database will be updated accordingly. Study results will be presented at relevant conferences, and submitted to peer-reviewed journals with open access in the fields of endocrinology, paediatrics and nutrition. After the appropriate embargo period, the results will be communicated to participants, healthcare professionals at the maternal healthcare centres, the public and other relevant groups, such as the national guideline group for thyroid and pregnancy and the National Food Agency. Trial registration number NCT02378246; Pre-results.