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Henriette A. Delemarre-van de Waal and J. Schoemaker


Pubertal maturation was induced in a 17.7 year old hypogonadotrophic boy by pulsatile LRH treatment. LRH was administered in three periods. During period one 20 μg LRH pulses were given iv 16 times per day for 10 weeks; during period two 2 μg LRH pulses iv 16 times per day for 12 weeks. During period three 2 μg LRH pulses 16 times per day were given sc for 13 weeks. Treatment was interrupted for 6 weeks between period one and two.

Rapid initiation of pubertal maturation was evidenced by an increase of penile length and testicular volume as well as by growth of pubic hair. After 21 weeks of treatment spermatozoa were observed in the ejaculate. Gonadotrophin levels increased from prepubertal values into the supranormal range in the beginning of period one, spontaneously declining to normal adult levels. A rapid increment of testicular volume during period one was also evidence for overstimulation.

During period two gonadotrophin levels were in the normal range.

Testosterone levels were normal during period one and two albeit higher during period one. We conclude that 1) pulsatile LRH treatment with 2 μg per pulse iv 16 times per day is an adequate and feasible way to induce puberty in hypogonadotrophic males with an intact pituitary. 2) Under pulsatile LRH treatment spermatogenesis takes place more rapidly than during normal puberty. 3) Testicular hormones exert a negative feedback action at the pituitary in the LRH treated hypogonadotrophic male. 4) The supranormal levels of LH and FSH during the first weeks of treatment may be caused by a delayed reaction of the testicles to gonadotrophin stimulation rather than to an overdose of LRH. 5) No evidence was found of a direct inhibitory action of LRH on testicular function.

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Henriette A Delemarre-van de Waal and Peggy T Cohen-Kettenis

Treatment outcome in transsexuals is expected to be more favourable when puberty is suppressed than when treatment is started after Tanner stage 4 or 5. In the Dutch protocol for the treatment of transsexual adolescents, candidates are considered eligible for the suppression of endogenous puberty when they fulfil the Diagnostic and Statistic Manual of Mental Disorders-IV-RT criteria for gender disorder, have suffered from lifelong extreme gender dysphoria, are psychologically stable and live in a supportive environment. Suppression of puberty should be considered as supporting the diagnostic procedure, but not as the ultimate treatment. If the patient, after extensive exploring of his/her sex reassignment (SR) wish, no longer pursues SR, pubertal suppression can be discontinued. Otherwise, cross-sex hormone treatment can be given at 16 years, if there are no contraindications. Treatment consists of a GnRH analogue (GnRHa) to suppress endogenous gonadal stimulation from B2-3 and G3-4, and prevents development of irreversible sex characteristics of the unwanted sex. From the age of 16 years, cross-sex steroid hormones are added to the GnRHa medication.

Preliminary findings suggest that a decrease in height velocity and bone maturation occurs. Body proportions, as measured by sitting height and sitting-height/height ratio, remains in the normal range. Total bone density remains in the same range during the years of puberty suppression, whereas it significantly increases on cross-sex steroid hormone treatment. GnRHa treatment appears to be an important contribution to the clinical management of gender identity disorder in transsexual adolescents.

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Jantine JG Hoorweg-Nijman, Henriette A Delemarre-van de Waal, Frans C de Waal and Henk Behrendt

Gonadal function was evaluated in 23 men (aged 14.8–28.8 years) treated in childhood with cytotoxic drugs for a solid tumour. Group 1 (N = 14) had been treated with non-alkylating drugs only, while group 2 (N=9) received the alkylating drug cyclophosphamide in addition (range 3.8–19.5 g/m2). Median age at the start of treatment was 4.6 years (range 0.6–16.1) in group 1 and 13.9 years (range 3.7–16.9) in group 2. Data of the patients were compared with a reference group consisting of 14 normal men. Almost all patients of both groups showed normal development of puberty; 13 of the 14 men in group 1 showed normal hormonal values. In group 2, basal LH and FSH as well as the LH and FSH responses to GnRH showed higher levels compared to those of a reference group (p<0.001). Correlation analysis showed an evident correlation between the total dose of received cyclophosphamide and the basal FSH level (r=0.78; p=0.002), the FSH response to GnRH (r=0.73; p=0.002) and the LH response to GnRH (r=0.67; p=0.002). There was no correlation between the hormonal parameters and the doses of the other cytotoxic drugs. Semen analysis showed azoospermia in four boys of group 2 and in none of group 1. Two patients in group 2 had an elevated FSH response to GnRH while their semen analysis was normal. Conclusions: (1) There is a dose-response relationship between the basal FSH. the LH and FSH responses to GnRH and the dose of cyclophosphamide. In all cyclophosphamide-treated patients the FSH response to GnRH increased. (2) Increased gonadotropin secretion can be found while semen analysis is normal; an increased FSH response to GnRH can be the first manifestation of testicular damage. (3) Evaluation of gonadotropins, both basal and stimulated LH and FSH values, is an easy and useful method for following up gonadal function in cyclophosphamide-treated men, especially for detecting early and subtle testicular damage.

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Eveline M Delemarre, Bram Felius and Henriette A Delemarre-van de Waal

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.

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Henriette A. Delemarre-van de Waal, J. L. Van den Brande, H. van Kessel and J. Schoemaker


A nine year old prepubertal patient with 45,X gonadal dysgenesis received pulsatile LRH administration for 3 weeks, every 90 min 10 μg iv. In the first week LH and FSH levels increased from prepubertal levels into the castrate range. Under 2.5 μg ethinyloestradiol (EE) LH levelled off for 3 days, followed by an LH surge. FSH showed an ethinyloestradiol dose-dependent decrease. These data suggest that: 1) pulsatile LRH administration may help to distinguish prepubertally those Turner patients with potential ovarian function from those without; 2) oestrogens exert both a negative and positive feedback action at the pituitary level in the LRH treated human; 3) the pituitary does not need 'pubertal maturation' for developing positive feedback to oestrogens. This supports the notion that pubertal maturation is confined to suprapituitary changes.

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Jantine JG Hoorweg-Nijman, Hester M Havers and Henriette A Delemarre-van de Waal

Hoorweg-Nijman JJG, Havers HM, Delemarre-van de Waal HA. Effect of human chorionic gonadotrophin (hCG)/follicle-stimulating hormone treatment versus hCG treatment alone on testicular descent: a double-blind placebo-controlled study. Eur J Endocrinol 1994;1 30:60–4. ISSN 0804–4643

The medical treatment of retentio testis remains controversial because of ineffectiveness and/or adverse events. Follicle-stimulating hormone (FSH) seems to influence the spontaneous descent of the testis; furthermore, it induces luteinizing hormone (LH) receptors. Therefore, we performed a double-blind placebo-controlled study to investigate the effect of FSH with human chorionic gonadotrophin (hCG) versus hCG alone in retentio testis patients. Twenty-two boys with retentio testis were investigated, excluding retractile testis. Group A (N= 14: four with bilateral and 10 with unilateral retentio testis; mean age 3.1 5 years) was treated with 150 IU of FSH twice a week for 2 weeks followed by 1 50 IU of FSH and 250 IU of hCG (half the recommended World Health Organization dose) twice a week for another 4 weeks. Group B (N = 8: two with bilateral and six with unilateral retentio testis: mean age 3.3 years) was treated with 250 IU of hCG twice a week for 6 weeks. Testicular position, volume and consistency as well as the appearance of the scrotum and the penile length were determined at the start of the treatment as well as at weeks 2.4.6 and 12 by two independent investigators. Blood investigation consisted of measurements of LH, FSH, testosterone and sex hormone-binding globulin. Successful descent was considered when the testis reached a mid- or low scrotal position. In group A, 6/18 testes descended successfully. In group B, 6/10 testes descended. Of the unsuccessfully treated patients, six of group A and three of group B underwent surgery. Of these patients, 6/8 testes of group A and all testes of group B showed anatomical abnormalities, which could explain the lack of hormonal response. There were no significant differences in hormonal parameters between the two groups. In both groups no serious adverse events were mentioned or observed. In conclusion, half the recommended WHO dose of hCG is sufficient to reach successful descent in 43% of treated patients, with no serious adverse events; this response rate is in agreement with the literature. Follicle-stimulating hormone does not seem to have an additional effect on the success rate, and most of the unsuccessfully treated patients showed anatomical abnormalities at operation.

JJG Hoorweg-Nijman, Department of Paediatrics, Free University Hospital. PO Box 7057, 1007 MB Amsterdam, The Netherlands

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Johanna M.B. Wennink, Henriette A. Delemarre-van de Waal, Rik Schoemaker, Gert Blaauw, Caro van den Braken and Joop Schoemaker


Pulsatile growth hormone secretion patterns were studied in relation to luteinizing hormone and estradiol release in 33 healthy (pre)pubertal girls. Plasma GH was determined every 10 min, plasma LH and E2 every hour. Night-time GH release was always higher than daytime GH release. During daytime, all GH secretion parameters, except for the basal GH level, increased significantly from the prepubertal stage to stage B4 before (m−) the menarche (p=0.05) and decreased thereafter (p=0.05). During night-time, mean GH level and the fraction of GH in pulses also tended to increase from stage B1 to stage B4m−. The number of high pulses (>8 μg/l) during day and night together tended to increase until stage B4m− and decreased after the menarche (p=0.05). Height velocity did not correlate with the number of high pulses (Kendall τ=0.14, p=0.14). From stage B1 to B4m− high correlations were observed between E2 levels and GH secretion parameters, particularly during the day (τ=0.59-0.71, p≤0.01). The correlations between LH levels and GH secretion were high as well (τ=0.50-0.81, p≤0.01), but equal during day and night. It is concluded that during puberty 1. spontaneous GH release in girls increases 2-3 fold until the menarche and decreases thereafter, primarily as the result of an increasing and decreasing GH pulse amplitude; 2. diurnally increasing estradiol levels correlated with increasing GH secretion.

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Johanna M. B. Wennink, Henriette A. Delemarre-van de Waal, Rik Schoemaker, Gert Blaauw, Caro van den Braken and Joop Schoemaker


Pulsatile growth hormone secretion patterns were studied in relation to LH and testosterone release in 30 healthy prepubertal boys and 2 adult men. Plasma GH was measured every 10 min, plasma LH and testosterone every hour. Night-time GH secretion parameters were 2-3 times higher than daytime values. During daytime, mean GH level and the fraction of GH in pulses increased from Tanner stage G2 to G4 (p=0.01); during night-time these parameters increased as well (p≤0. 1) and decreased from stage G5 to adulthood (p=0.05). GH pulse number did not increase; the number of high-amplitude (>8 μg/l pulses, however, increased from stage G2 to G4 (p=0.05) during the day. Height velocity correlated with the number of high pulses during day and night (τ=0.39, p<0.003). From stage G2 to G4 significant correlations were observed between nocturnal testosterone levels and GH secretion parameters (τ=0.53-0.57), in contrast to nocturnal LH levels. It is concluded that during puberty 1. GH secretion increases as a result of an increased pulse amplitude; 2. there is no consistent correlation between GH and LH levels; 3. increasing nocturnal testosterone levels are correlated with the increasing GH secretion; therefore GnRH does not seem to influence GH secretion directly, but an indirect effect via testosterone is more conceivable, and 4. height velocity is correlated with the number of high GH pulses.

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Joost Rotteveel, Eline J Belksma, Carry M Renders, Remy A Hirasing and Henriette A Delemarre-Van de Waal

Objective: The worldwide trend towards obesity in childhood is also observed in the Netherlands and one of the consequences may be type 2 diabetes. In this study, we assessed the number of children with type 2 diabetes, diagnosed by paediatricians, in the Netherlands.

Methods: In 2003 and 2004 the Dutch Paediatric Surveillance Unit, a nationwide paediatric register, was used to assess new cases of diabetes mellitus. Data on socio-demographic and clinical characteristics were collected by means of a questionnaire. A second questionnaire was sent to the reporting paediatrician if the diagnosis was inconclusive or if the diagnosis was type 1 diabetes in combination with overweight or obesity, according to international criteria.

Results: During the 24 months of registration, the paediatricians reported 1142 new cases of diabetes, 943 of which were eligible for analysis. Initially, 14 patients (1.5%) were reported with type 2 diabetes. Only seven of these patients were classified as type 2 diabetes according to the ADA criteria, as information on C-peptides or antibodies was often missing. Based on clinical characteristics, the other seven patients were very likely to have type 2 diabetes. After the second questionnaire, six more patients met the ADA criteria and two were very likely to have type 2 diabetes. Most of the patients were female (95%), 14% were of Turkish and 18% of Moroccan origin.

Conclusion: This study shows a discrepancy between the number of patients with type 2 diabetes diagnosed by paediatricians in daily practice and diagnosed according to the ADA criteria. Moreover, a considerable amount of reported patients were misclassified. Finally, 2.4% patients were classified as (very likely) type 2 diabetes. The development of programmes and protocols for prevention, diagnosis and classification applicable in daily practice is warranted.

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Richard G Ijzerman, Coen D A Stehouwer, Erik H Serné, Jasper J Voordouw, Yvo M Smulders, Henriette A Delemarre-van de Waal and Mirjam M van Weissenbruch


Based on fasting insulin and glucose, several indices of insulin sensitivity have been developed in adults. Recently, it has been demonstrated that incorporation of the fasting free fatty acid (FFA) concentration improves the association with insulin sensitivity in adults. We investigated the association of clamp-derived insulin sensitivity with indices of insulin sensitivity derived from fasting blood in prepubertal children and adults, with and without incorporation of FFAs.

Design and methods

We studied 59 healthy adults and 29 of them are prepubertal children. We measured insulin sensitivity with the euglycemic–hyperinsulinemic clamp. Based on fasting insulin and glucose, we estimated insulin sensitivity with the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and the revised QUICKI after the incorporation of FFAs.


The associations of HOMA and QUICKI with clamp-derived insulin sensitivity in children (r=−0.55 and 0.54 respectively; P<0.01) were similar to those in adults (r=−0.54 and 0.53 respectively; P<0.01). However, incorporation of FFAs into the QUICKI model resulted in an increase in the association in adults, but not in children (r=0.68 and 0.48 respectively; P<0.01). Adding FFA levels to a regression model with glucose and insulin as independent variables resulted in an increase in the explained variance in clamp-derived insulin sensitivity in adults, but not in children (P value 0.004 in adults and 0.3 in children).


HOMA and QUICKI are associated with clamp-derived insulin sensitivity in both children and adults. Incorporating fasting levels of FFAs into the QUICKI model improves the association with clamp-derived insulin sensitivity in adults, but not in children.