Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria.

INTRODUCTION: Gender-affirming hormone treatment is known to affect adrenal androgen levels in adult individuals with gender dysphoria (GD). This may be clinically relevant because the adrenal gland plays a critical role in many different metabolic processes. AIM: This study aims to assess the effects of gonadotropin-releasing hormone analogs (GnRHa) treatment and gender-affirming hormone treatment on adrenal androgen levels in adolescents with GD. METHODS: In this prospective study, dehydroepiandrosterone-sulfate (DHEAS) and androstenedione values were measured every 6 months during 2 years of GnRHa treatment only, and 2 years of GnRHa combined with gender-affirming hormone treatment (estradiol or testosterone) in 73 transgirls and 54 transboys. To determine trends in adrenal androgen levels a linear mixed model was used to approximate androgen levels. MAIN OUTCOME MEASURES: DHEAS and androstenedione levels were the main outcome measures. RESULTS: DHEAS levels rose in transboys during GnRHa treatment, which may represent the normal increase during adolescence. In transgirls no change in DHEAS levels during GnRHa treatment was found. Gender-affirming hormone treatment did not affect DHEAS levels in either sex. In transboys androstenedione levels decreased during the first year of GnRHa treatment, which may reflect reduced ovarian androstenedione synthesis, and rose during the first year of gender-affirming hormone treatment, possibly due to conversion of administered testosterone. In transgirls androstenedione levels did not change during either GnRHa or gender-affirming hormone treatment. CLINICAL IMPLICATIONS: No deleterious effects of treatment on adrenal androgen levels were found during approximately 4 years of follow-up. STRENGTHS & LIMITATIONS: This is one of the largest cohort of adolescents with GD, treated using a uniform protocol, with standardized follow-up. The lack of a control group is a limitation. CONCLUSION: The changes in androstenedione levels during GnRHa and gender-affirming hormone treatment in transboys may not be of adrenal origin. The absence of changes in androstenedione levels in transgirls or DHEAS levels in either sex during gender-affirming hormone treatment suggests that gender-affirming hormone treatment does not significantly affect adrenal androgen production. Schagen SEE, Lustenhouwer P, Cohen-Kettenis PT, et al. Changes in Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender Dysphoria. J Sex Med 2018;15:1357-1363.

Efficacy and Safety of Pubertal Induction Using 17ß-Estradiol in Transgirls.

Context: Puberty suppression using gonadotropin-releasing hormone agonists, followed by induction of the desired sex characteristics using sex steroids, has been recommended by the current guidelines as the treatment of choice for gender dysphoric adolescents, although little evidence is available. Aim: To evaluate the efficacy and safety of estrogen treatment for pubertal induction in transgirls (female-identifying adolescents assigned male at birth). Methods: Twenty-eight adolescents treated with oral estrogen for ≥1 year were included. The Tanner stage, anthropometry, laboratory parameters, bone age, and body composition were evaluated. Results: Breast development started within 3 months in 83% of adolescents, and after 3 years, 86% had Tanner breast stage 4 to 5. The hip circumference increased and the waist/hip ratio decreased. The median serum estradiol was 100 pmol/L (range, 24 to 380) at the standard adult dose of 2 mg of 17ß-estradiol. The adult height standard deviation score was +1.9 (for females). The body mass index standard deviation score, lean body mass percentage, fat percentage, and blood pressure did not change. No abnormalities of creatinine or liver enzymes were detected, and the hematocrit and hemoglobin A1c did not change. One individual developed hyperprolactinemia during high-dose ethinylestradiol treatment to limit growth. Conclusions: Pubertal induction using estradiol is effective; however, an adult dose of 2 mg does not always result in appropriate serum estradiol levels. Monitoring renal function, liver enzymes, hematocrit, and hemoglobin A1c during pubertal induction with estradiol is not necessary. Further studies are needed to establish effective and safe methods to limit growth.

Efficacy and Safety of Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric Adolescents.

INTRODUCTION: Puberty suppression using gonadotropin-releasing hormone agonists (GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric adolescents. Although GnRHas have long been used to treat precocious puberty, there are few data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal and liver function. AIM: To evaluate the efficacy and safety of GnRHa treatment to suppress puberty in gender dysphoric adolescents. METHODS: Forty-nine male-to-female and 67 female-to-male gender dysphoric adolescents treated with triptorelin were included in the analysis. MAIN OUTCOME MEASURES: Physical examination, including assessment of Tanner stage, took place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6 months. Body composition was evaluated using dual energy x-ray absorptiometry. RESULTS: GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In one of four female-to-male subjects who presented at Tanner breast stage 2, breast development completely regressed. Gonadotropins and sex steroid levels were suppressed within 3 months. Treatment did not have to be adjusted because of insufficient suppression in any subject. No sustained abnormalities of liver enzymes or creatinine were encountered. Alkaline phosphatase decreased, probably related to a slower growth velocity, because height SD score decreased in boys and girls. Lean body mass percentage significantly decreased during the first year of treatment in girls and boys, whereas fat percentage significantly increased. CONCLUSION: Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is not necessary during treatment with triptorelin. Further studies should evaluate the extent to which changes in height SD score and body composition that occur during GnRHa treatment can be reversed during subsequent cross-sex hormone treatment.

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

The relationship between moderate-to-vigorous intensity physical activity and insulin resistance, insulin-like growth factor (IGF-1)-system 1, leptin and weight change in healthy women during pregnancy and after delivery.

CONTEXT: Childbearing is considered to be a significant risk factor for developing overweight and obesity. Physical activity might influence weight change via hormonal changes. OBJECTIVE: To test the hypothesis that higher levels of moderate-to-vigorous intensity physical activity (MVPA) are positively associated with maternal insulin sensitivity and reduce IGF-1, IGFBP-3, leptin levels, bodyweight gain/retention and birth weight. METHODS: In healthy nulliparous women, weight measurements were carried out and blood was collected during pregnancy in the 15th, 25th and 35th week, and after delivery at 6, 26 and 52 weeks. At 15 and 35 weeks of pregnancy and 26 weeks postpartum, MVPA was measured using accelerometers. In linear regression models, the relationship between MVPA below or above the median with metabolic and weight outcomes was assessed, adjusted for maternal BMI, age and smoking. RESULTS: Moderate-to-vigorous intensity physical activity (MVPA) decreased significantly during pregnancy, but was very low already in early pregnancy. Insulin resistance and leptin levels increased during pregnancy and decreased significantly after delivery (all P < 0·05). After adjustment, insulin, IGFBP-3 and BMI were significantly lower at 15 weeks of pregnancy in women with MVPA above the median compared to those with MVPA below the median. After 15 weeks of pregnancy, no significant associations were observed between hormonal levels and MVPA. MVPA was neither related to weight retention, nor to birth weight. CONCLUSION: Except in early pregnancy, MPVA was not related to metabolic outcomes. In addition, MVPA during pregnancy was not related to weight retention or birth weight.

Estrogen receptor-alpha gene polymorphisms and body composition in children and adolescents.

BACKGROUND/AIMS: Gender differences in body composition are largely explained by differences in sex hormones, such as estrogens. Associations between 2 polymorphisms in the estrogen receptor-α gene (ESR1) and body composition in children and adolescents were investigated. METHODS: Two comparable Dutch cohorts with a generational difference of about 20 years were investigated. The first consisted of 350 subjects (184 girls) and the second of 316 subjects (155 girls). Associations between height, weight, BMI, fat mass (FM) and fat-free mass and two polymorphisms in the ESR1 gene were investigated. RESULTS: In girls in the recent cohort, the PvuII-XbaI haplotype 2 polymorphism in the ESR1 gene was associated with a lower body weight, BMI, and FM. These associations were not observed in the older cohort. The younger cohort had a significantly higher total FM, body weight and BMI compared to the older cohort. CONCLUSION: Because the associations between the PvuII-XbaI haplotype 2 polymorphism and body FM in girls were only found in the recent cohort, but not in a comparable, generally leaner cohort from an older generation, it is suggested that non-carriers of this polymorphism are likely to be more vulnerable to fat accumulation in today's obesity promoting environment, than carriers.

Puberty suppression in a gender-dysphoric adolescent: a 22-year follow-up.

Puberty suppression by means of gonadotropin releasing hormone (GnRH) analogs is considered a diagnostic aid in gender dysphoric adolescents. However, there are also concerns about potential risks, such as poor outcome or post-surgical regret, adverse effects on metabolic and endocrine status, impaired increment of bone mass, and interference with brain development. This case report is on a 22-year follow-up of a female-to-male transsexual, treated with GnRH analogs at 13 years of age and considered eligible for androgen treatment at age 17, and who had gender reassignment surgery at 20 and 22 years of age. At follow-up, he indicated no regrets about his treatment. He was functioning well psychologically, intellectually, and socially; however, he experienced some feelings of sadness about choices he had made in a long-lasting intimate relationship. There were no clinical signs of a negative impact on brain development. He was physically in good health, and metabolic and endocrine parameters were within reference ranges. Bone mineral density was within the normal range for both sexes. His final height was short as compared to Dutch males; however, his body proportions were within normal range. This first report on long-term effects of puberty suppression suggests that negative side effects are limited and that it can be a useful additional tool in the diagnosis and treatment of gender dysphoric adolescents.

DNA methylation of IGF2, GNASAS, INSIGF and LEP and being born small for gestational age.

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (< 32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10 (-13) ) and head circumference at birth (P=4.1x10 (-13) ). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline.

OBJECTIVE: The aim was to formulate practice guidelines for endocrine treatment of transsexual persons. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence, which was low or very low. CONSENSUS PROCESS: Committees and members of The Endocrine Society, European Society of Endocrinology, European Society for Paediatric Endocrinology, Lawson Wilkins Pediatric Endocrine Society, and World Professional Association for Transgender Health commented on preliminary drafts of these guidelines. CONCLUSIONS: Transsexual persons seeking to develop the physical characteristics of the desired gender require a safe, effective hormone regimen that will 1) suppress endogenous hormone secretion determined by the person's genetic/biologic sex and 2) maintain sex hormone levels within the normal range for the person's desired gender. A mental health professional (MHP) must recommend endocrine treatment and participate in ongoing care throughout the endocrine transition and decision for surgical sex reassignment. The endocrinologist must confirm the diagnostic criteria the MHP used to make these recommendations. Because a diagnosis of transsexualism in a prepubertal child cannot be made with certainty, we do not recommend endocrine treatment of prepubertal children. We recommend treating transsexual adolescents (Tanner stage 2) by suppressing puberty with GnRH analogues until age 16 years old, after which cross-sex hormones may be given. We suggest suppressing endogenous sex hormones, maintaining physiologic levels of gender-appropriate sex hormones and monitoring for known risks in adult transsexual persons.

Sex steroids and brain structure in pubertal boys and girls.

Sex steroids exert important organizational effects on brain structure. Early in life, they are involved in brain sexual differentiation. During puberty, sex steroid levels increase considerably. However, to which extent sex steroid production is involved in structural brain development during human puberty remains unknown. The relationship between pubertal rises in testosterone and estradiol levels and brain structure was assessed in 37 boys and 41 girls (10-15 years). Global brain volumes were measured using volumetric-MRI. Regional gray and white matter were quantified with voxel-based morphometry (VBM), a technique which measures relative concentrations ('density') of gray and white matter after individual global differences in size and shape of brains have been removed. Results showed that, corrected for age, global gray matter volume was negatively associated with estradiol levels in girls, and positively with testosterone levels in boys. Regionally, a higher estradiol level in girls was associated with decreases within prefrontal, parietal and middle temporal areas (corrected for age), and with increases in middle frontal-, inferior temporal- and middle occipital gyri. In boys, estradiol and testosterone levels were not related to regional brain structures, nor were testosterone levels in girls. Pubertal sex steroid levels could not explain regional sex differences in regional gray matter density. Boys were significantly younger than girls, which may explain part of the results. In conclusion, in girls, with the progression of puberty, gray matter development is at least in part directly associated with increased levels of estradiol, whereas in boys, who are in a less advanced pubertal stage, such steroid-related development could not (yet) be found. We suggest that in pubertal girls, estradiol may be implicated in neuronal changes in the cerebral cortex during this important period of brain development.

Inducing puberty.

Puberty is the result of increasing pulsatile secretion of the hypothalamic gonadotropin releasing hormone (GnRH), which stimulates the release of gonadotropins and in turn gonadal activity. In general in females, development of secondary sex characteristics due to the activity of the gonadal axis, i.e., the growth of breasts, is the result of exposure to estrogens, while in boys testicular growth is dependent on gonadotropins and virilization on androgens. Hypogonadotropic hypogonadism is a rare disease. More common is the clinical picture of delayed puberty, often associated with a delay of growth and more often familial occurring. Especially, boys are referred because of the delay of growth and puberty. A short course (3-6 months) of androgens may help these boys to overcome the psychosocial repercussions, and during this period an increase in the velocity of height growth and some virilization will occur. Hypogonadotropic hypogonadism may present in a congenital form caused by developmental disorders, some of which are related to a genetic disorder, or secondary to hypothalamic-pituitary dysfunction due to, among others, a cerebral tumor. In hypogonadotropic hypogonadism puberty can be initiated by the use of pulsatile GnRH, gonadotropins, and sex steroids. Sex steroids will induce development of the secondary sex characteristics alone, while combined administration of gonadotropins and GnRH may induce gonadal development including fertility.

The treatment of adolescent transsexuals: changing insights.

INTRODUCTION: Treatment of individuals with gender identity disorder (GID) has in medicine nearly always met with a great deal of skepticism. Professionals largely follow the Standards of Care of the World Professional Association for Transgender Health. For adolescents, specific guidelines have also been issued by the British Royal College of Psychiatrists. AIM: To describe the stepwise changes in treatment policy which, in recent years, have been made by the team of the Gender Identity Clinic at the VU University Medical Center in Amsterdam, The Netherlands. METHODS: The first step taken to treat adolescents was that, after careful evaluation, (cross-sex hormone) treatment could start between the ages of 16 and 18 years. A further step was the suppression of puberty by means of gonadotropin-releasing hormone analogs in 12-16 year olds; the latter serves also as a diagnostic tool. Very recently, other clinics in Europe and North America have followed this policy. Results. The first results from the Amsterdam clinic show that this policy is promising. CONCLUSIONS: Professionals who take responsibility for these youth and are willing to help should yet be fully aware of the impact of their interventions. In this article, the pros and cons of the various approaches to youngsters with GID are presented, hopefully inciting a sound scientific discussion of the issue.

The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an open-label study.

BACKGROUND: To reduce the risk of brain damage children with acute lymphoblastic leukaemia (ALL) are nowadays mainly treated with intrathecal chemotherapy (ITC) instead of central nervous system (CNS) radiation therapy (CRT) to prevent CNS relapse. However, chemotherapy may also lead to cognitive deficits. As growth hormone deficiency (GHD) or impaired growth hormone secretion are frequently found in ALL patients treated with cranial radiation therapy and/or chemotherapy, we hypothesized that GH therapy may reduce cognitive deficits in these patients. METHODS: Twenty young adult survivors of childhood ALL with reduced bone mineral density (<-1 SD) and/or low IGF-I SD-scores (<-1 SD) were included in the study. A final group of 13 patients (9 males and 4 females), mean age 23.7 +/- 2.9 years (range 20 - 29.7) completed a 2-year treatment with GH.IQ and neuropsychological performance were assessed at pre-treatment (T1) and after one (T2) and two (T3) years. ANOVA was performed with assessment at T1, T2 and T3 as repeated measurements factor. Relations between test score changes and changes of IGF-I levels were determined by calculating the Pearson correlation coefficient. RESULTS: Scores on the cognitive tests were in the normal range. Verbal short- and long-term memory performance decreased between T1 and T2, and increased between T2 and T3. Performance at T3 was not significantly different from that at T1. Performance for sustained attention improved from T1 to T2 and from T1 to T3. Visual-spatial memory was improved after one year of GH treatment. A significant positive correlation was found for Delta IGF-I (T2-T1) with difference scores of visual-spatial memory (T2-T1 and T3-T1), indicating that IGF-I increase after one year of GH treatment is associated with increase in cognitive-perceptual performance at month 12 and 24. CONCLUSION: Since the level of intellectual functioning of our patient cohort was in the normal range the present finding that GH treatment has negative effects on verbal memory and positive on attention and visual-spatial memory warrants similar studies in other groups of ALL survivors. Also, a lower dose of GH should be determined inducing as much IGF as needed to improve verbal as well as visual cognitive functions. The present findings indicate that more knowledge is needed before GH treatment may be recommended to enhance cognitive functions in ALL survivors.

Hypertension and microalbuminuria in children with congenital solitary kidneys.

AIM: According to the hyperfiltration hypothesis, a low nephron endowment will lead to hyperfiltration in the remaining glomeruli and is associated with systemic hypertension, proteinuria and glomerulosclerosis. Being born with one functioning kidney instead of two, for instance because of unilateral renal agenesis or multicystic dysplastic kidney, is a cause of congenital renal mass reduction. METHODS: In order to study the effect of congenital renal mass reduction on renal function and blood pressure, a retrospective chart review of 66 patients at the Pediatric Renal Center of the VU University Medical Center was performed. As intrauterine growth restriction is associated with a low nephron endowment, the additional effect of birthweight was also studied. RESULTS: A total of 50% of patients with congenital renal mass reduction is found to be hypertensive, using anti-hypertensive drugs, and/or having microalbuminuria (>20 mug/min). Patients born small for gestational age have significantly smaller kidneys and lower estimated glomerular filtration rate than patients with a normal birthweight. CONCLUSIONS: We conclude that microalbuminuria and/or hypertension is present in 50% of patients with congenital solitary kidneys, which warrants a systematic follow-up of blood pressure, proteinuria and renal function in all patients with congenital solitary functioning kidneys, especially in patients with a low birthweight.

Growth and development of children born after in vitro fertilization.

OBJECTIVE: To evaluate growth and development of children born after IVF treatment. DESIGN: Literature review. CONCLUSION(S): At present there is substantial evidence that children born after IVF are at increased risk for adverse perinatal outcome, congenital malformations, and rare epigenetic defects. It is still unclear whether observed health problems originate from the IVF procedure itself or the underlying subfertility problems of the parents. Current follow-up studies regarding postnatal growth and morbidity rates are scarce with conflicting results and other areas of long-term research in children born after IVF are still in its infancy. The importance of the worldwide continuing monitoring of children born after IVF to investigate potential long-term consequences including the development of cardiovascular diseases is therefore highlighted.

Final height outcome after three years of growth hormone and gonadotropin-releasing hormone agonist treatment in short adolescents with relatively early puberty.

OBJECTIVE: Our objective was to assess final height (FH) and adverse effects of combined GH and GnRH agonist (GnRHa) treatment in short adolescents born small for gestational age or with normal birth size (idiopathic short stature). DESIGN AND PATIENTS: Thirty-two adolescents with Tanner stage 2-3, age and bone age (BA) less than 12 yr for girls or less than 13 yr for boys, height sd score (SDS) less than -2.0 SDS or between -1.0 and -2.0 SDS plus a predicted adult height (PAH0) less than -2.0 SDS were randomly allocated to receive GH plus GnRHa (n=17) or no treatment (n=15) for 3 yr. FH was assessed at the age of 18 yr or older in girls or 19 yr or older in boys. RESULTS: FH was not different between treatment and control groups. Treated children had a larger height gain (FH-PAH0) than controls: 4.4 (4.9) and -0.5 (6.4) cm, respectively (P<0.05). FH was higher than PAH0 in 76 and 60% of treated and control subjects, respectively. During follow-up, 50% of the predicted height gain at treatment withdrawal was lost, resulting in a mean gain of 4.9 cm (range, -4.0 to 12.3 cm) compared with controls. Treatment did not affect body mass index or hip bone mineral density. Mean lumbar spine bone mineral density and bone mineral apparent density tended to be lower in treated boys, albeit statistically not significant. CONCLUSION: Given the expensive and intensive treatment regimen, its modest height gain results, and the possible adverse effect on peak bone mineralization in males, GH plus GnRHa cannot be considered routine treatment for children with idiopathic short stature or persistent short stature after being born small for gestational age.

Early assessment of hypothalamic-pituitary-gonadal function in patients with congenital hypothyroidism of central origin.

CONTEXT: Early recognition of gonadotropic dysfunction could enable well-timed growth and maturation and prevent damage to gonads and external genitalia. The adaptation of the Dutch neonatal screening program for congenital hypothyroidism in the mid 1990s resulted in enhanced detection of congenital hypothyroidism of central origin (CH-C), with high likelihood of multiple pituitary hormone deficiency, including gonadotropin (Gn) deficiency. OBJECTIVE: We analyzed GnRH test results and baseline Gn and sex hormone measurements in 15 infants with CH-C to examine these diagnostic tools for assessment of the integrity of the hypothalamus-pituitary-gonad axis in young infants. DESIGN: In a nationwide prospective study (1994-1996), patients were referred to our department if neonatal CH screening results were indicative of CH-C. When CH-C was confirmed, GnRH tests and baseline Gn and sex hormone measurements took place at the age of 3 months, when euthyroid status had been accomplished by T4 supplementation, and if necessary, cortisol supplementation was installed. SETTING: The study took place at the Department of Pediatric Endocrinology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam (referral center). PATIENTS: The study included 15 neonates (five girls and 10 boys) with CH-C, detected by neonatal screening, in whom investigation of the hypothalamus-pituitary-gonad axis could be performed at 3 months of age. MAIN OUTCOME MEASURES: Results of GnRH tests and baseline Gn and sex hormone measurements were assessed. RESULTS: GnRH tests at 3 months of age showed a pattern indicative of endogenous GnRH stimulation in nine infants and a blunted response in six. Baseline Gn and sex hormone concentrations except estradiol (P = 0.053) were significantly different between responders and nonresponders. CONCLUSIONS: The GnRH test and baseline measurements of Gn and sex hormone serum concentrations at 3 months of age are promising options in the assessment of hypothalamic-pituitary-gonadal function in infants with CH-C of both sexes.

TNF-alpha levels are associated with skin capillary recruitment in humans: a potential explanation for the relationship between TNF-alpha and insulin resistance.

The mechanism by which TNF-alpha (tumour necrosis factor-alpha) may cause insulin resistance is not clear. On the basis of experiments in rats, TNF-alpha has been suggested to cause defects in capillary function, with a decreased access of insulin and glucose to tissues. To test this hypothesis in humans, we assessed serum TNF-alpha concentrations, skin capillary recruitment and insulin sensitivity in a group of 37 healthy adults. In addition, we measured these variables in 21 of their prepubertal children. Serum TNF-alpha levels were measured by sandwich enzyme immunoassay, and insulin sensitivity was assessed with the hyperinsulinaemic euglycaemic clamp technique. Capillary recruitment during post-occlusive reactive hyperaemia was evaluated by videomicroscopy. In the adults, serum TNF-alpha levels were associated with both capillary recruitment (r=-0.40, P=0.02) and insulin sensitivity (r=-0.33, P=0.05). In addition, capillary recruitment was associated with insulin sensitivity (r=0.34, P=0.04). Regression analysis showed that the association between TNF-alpha and insulin sensitivity [-0.527 mg.kg(-1) of body weight.min(-1) per pmol/l per pg/ml TNF-alpha (95% confidence interval, -1.066 to 0.011); P=0.05] decreased by 30% after adjustment for capillary recruitment. In the children, neither capillary recruitment (r=0.33, P=0.2) nor insulin sensitivity (r=-0.24, P=0.4) was significantly associated with TNF-alpha. In conclusion, in adults, but not in children, serum TNF-alpha levels are associated with capillary recruitment during post-occlusive hyperaemia, which, in part, can explain the relationship between TNF-alpha and insulin resistance. Our data suggest that these relationships are initiated during growth from childhood to adulthood.

Application of gonadotropin releasing hormone in hypogonadotropic hypogonadism--diagnostic and therapeutic aspects.

BACKGROUND: Puberty is the result of reactivation of the gonadotropin releasing hormone (GnRH) pulse generator resulting in an increasing release of GnRH by the hypothalamus, which stimulates the gonadotropic cells of the pituitary to synthesize and secrete LH and FSH. Hypogonadotropic hypogonadism (HH) is often the result of GnRH deficiency. The clinical picture is characterized by the absence of pubertal development and infertility. It is difficult to differentiate HH from delayed puberty since low gonadotropin and low testosterone levels are found in both conditions. We hypothesized that long-term GnRH administration may differentiate between the two conditions by a difference in the increase of gonadotropins, the idea being that in normal delayed puberty the pituitary of the patient has been primed with GnRH during the fetal and early postnatal period. PATIENTS: Seventeen adolescents suspected of having hypogonadotropic hypogonadism were treated with pulsatile GnRH for 7 days. At the present time, the diagnosis of these patients is known and the results of the long-term GnRH stimulation have been evaluated according to the present diagnosis. RESULTS: The results show that the increase in gonadotropins following GnRH treatment is similar in both conditions. Therefore, at a prepubertal age a normal delayed puberty cannot be distinguished from hypogonadotropic hypogonadism using long-term GnRH stimulation. Long-term pulsatile GnRH treatment is a physiological therapy for the induction of puberty. Unlike testosterone it has the advantage of stimulation of testicular growth and fertility, as well as virilization, in males. We have treated 68 male patients with HH with pulsatile GnRH. The results show testicular growth and virilization in all the patients and spermatogenesis in 58 patients. Wearing a portable pump is cumbersome. However, the patients were very motivated and adapted very easily to this inconvenience. When spermatogenesis had developed, GnRH treatment was changed to human chorionic gonadotropin (hCG) administration 1-2 times per week intramuscularly or subcutaneously. During hCG therapy spermatogenesis was maintained or even improved. At least ten patients fathered children. CONCLUSION: Pulsatile GnRH cannot distinguish between a normal delayed puberty and a hypothalamic defect in still prepubertal patients. Pulsatile GnRH offers an appropriate way to initiate testicular growth including virilization and fertility in males with hypogonadotropic hypogonadism.