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A 13 year old male with mild mental retardation, obesity, and poor secondary sexual differentiation was found to have a 46,X,+,mar karyotype. In situ hybridisation with X and Y specific probes proved the marker to be composed of Y centromeric and short arm material.
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We present a prepubertal male cystic fibrosis patient with high circulating oestrogen levels (as a consequence of sever cystic-fibrosis-related hepatobiliary disease) who subsequently developed a large pelvic arteriovenous malformation. This has not previously been described in patients with cystic fibrosis, despite the association between high oestrogen levels and arteriovenous malformations. The aetiology and treatment options of arteriovenous malformations are discussed.
Vitamin D and parathyroid hormone concentrations were assessed in 31 adults with cystic fibrosis (mean age 24, range 17-52 years), in 28 of whom the bone mineral index in the forearm was also determined. Serum 25-hydroxyvitamin D was subnormal in eight patients, of whom five were receiving vitamin D supplements in standard doses. 1,25-dihydroxyvitamin D and parathyroid hormone concentrations showed no consistent abnormalities. The bone mineral index was lower in patients with cystic fibrosis (p less than 0.02) than in controls. Five patients with unequivocally reduced bone mineral index had a subnormal mean serum 25-hydroxyvitamin D and significantly worse lung function than the other patients. There was a positive correlation between age and bone mineral index (r = 0.68, p less than 0.001). Thus a significant proportion of patients with cystic fibrosis living in a temperate climate are at risk of vitamin D deficiency. Osteopenia is common and is probably related to a combination of hypovitaminosis D, delay in puberty, hypo-oestrogenism in women, and reduced physical activity, rather than to secondary hyperparathyroidism. Since most patients with deficiency of 25-hydroxyvitamin D were receiving oral supplements, parenteral vitamin D supplementation may be appropriate for selected patients who are unable to maintain adequate 25-hydroxyvitamin D concentrations despite oral vitamin D supplements.
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Studies were conducted to investigate the effect of reduced food intake on pituitary gonadotropin-releasing hormone (GnRH) sensitivity as a possible link in the delay of puberty by underfeeding. Immature female rats (30-32 days old at the start of each experiment) were used throughout the study. Rats on reduced food intake (R) received 60% of normal food intake beginning at the age of 21 days, whereas control (C) animals were fed ad libitum. In ovariectomized (OVX), estradiol benzoate-progesterone-treated R rats, low doses (less than 5 ng/100 g body wt) of GnRH injected intravenously produced higher serum luteinizing hormone (LH) concentration than in comparable C rats. No difference was found at 5 ng GnRH but response to high doses (15 and 45 ng/100 g body wt) was sharply reduced in R rats. No difference in serum follicle-stimulating hormone concentrations was found. In contrast to the OVX-steroid treated animals, in intact R rats, GnRH evoked higher serum LH concentrations at both low and high doses. These studies indicate that reduced caloric intake can affect pituitary GnRH sensitivity and that the effect depends on both the dose of GnRH and the internal, gonadal steroid hormone milieu.
Cushing's disease (CD) in adolescence and childhood is a rare pathology and has some different clinical and therapeutic characteristics than in adults. We report 3 cases treated surgically, with the diagnosis of CD. Their common complaints were short stature and obesity. Endocrinological investigations and radiological evaluation pointed out the diagnosis of CD for all children. They were operated on by the transsphenoidal route, and adenoma resection was performed. Histopathologic and immunohistochemical examination of the tissue specimens confirmed the diagnosis of CD. Long-term follow-up demonstrated weight loss and increase in height.
The major biologically active circulating estrogen in both males and females is estradiol (E(2)). Circulating E(2) is a product of the ovarian granulosa cell and the testicular Leydig cell. Its gonadal formation is dependent on A-ring aromatization of its immediate precursor, testosterone, by a particular isoform of the enzyme aromatase, which also catalyses the conversion of the much weaker androgen, androstenedione, to the weak estrogen, estrone. E(2) is also formed in non-gonadal tissues, such as adipose tissue, liver, muscle and brain. Only adipose tissue makes significant extra-gonadal contributions to circulating estrogen. Loss of ovarian function during reproductive life, as a result of loss of gonadotropin secretion (secondary hypogonadism) or as a result of premature ovarian failure (generally defined as cessation of ovarian function prior to age 40), results in loss of the majority of circulating E(2) and of luteal progesterone. Loss of ovarian function at the menopause likewise results in a 90% loss of circulating E(2). The consequences of loss of ovarian function during reproductive life may be severe. Symptoms include hot flushes, night sweats, vaginal dryness and dyspareunia, loss of libido, loss of bone mass with subsequent osteoporosis and abnormalities of cardiovascular function, including a substantial increase in the risk of ischemic heart disease. Various regimens of estrogen replacement have been employed, aiming to eliminate symptoms, restore well-being and avert the consequences of estrogen depletion. The commonly adopted form of replacement is with the low-dose oral contraceptive pill for reasons of convenience, cost, efficacy, general freedom from side effects and the psychological advantage that many of the patient's peer group are also "taking the pill". An often neglected aspect of hormone therapy in the reproductive age group is the therapeutic use of testosterone. The application of such principles to the postmenopausal period is more problematic, as there is a common perception that the menopause is a normal physiological occurrence and that it is therefore not physiological to offer hormone therapy at that time. The pragmatic approach is to recommend standard therapy with estrogen and progestogen for the management of menopausal symptoms and to recommend longer term hormone replacement in the light of the individual's needs and current data with regard to efficacy for protection from osteoporosis and cardiovascular disease.
The management of children and adolescents with hypogonadism and in particular the induction of puberty in the hypogonadal girl is subject to controversy. Therefore, under the auspices and through organization of the Drugs and Therapeutics Committee of the European Society of Paediatric Endocrinology (ESPE), an interactive voting session and workshop was held at the 39th ESPE Annual Meeting in Brussels to discuss these topics. Common practice in Europe and attitudes of pediatric endocrinologists in Europe were questioned and recorded in the 1.5-hour program. We now report on some of the results of the questionnaires and discussions of that session to further the discussion on and knowledge of current concepts of induction of puberty in the hypogonadal girl in Europe. It became clear from the data accumulated here that the start of treatment, the aims of therapy and the modalities of how to treat the hypogonadal girl vary amongst pediatric endocrinologists in Europe. For example, a chronological age > or =11 years was considered appropriate for the start of estrogen therapy by 40.4% (out of 188 answers), while 47.8 and 7.5% felt that a chronological age > or =13 and > or =15 years respectively was appropriate. In respect to the form and route of estrogen administration, the audience was asked for their common estrogen replacement practice: 31.9% used oral 17beta-estradiol treatment, while 10% would prescribe 17beta-estradiol transdermal patches. Another 12.2% would recommend conjugated estrogens (e.g. Premarin) orally, 4.8% use oral estradiol valerate and 39.3% ethinylestradiol orally. Only 1.8% out of 229 physicians answering were undecided. In addition, counseling of patients and their families is quite variable and perceptions for example regarding potential pregnancies in affected women are also not uniform. In this report the authors do not want to provide their own personal views but rather reflect current practice in Europe. It is hoped that a more uniform picture will emerge once European and international guidelines on how to treat the girl with hypogonadism will be available and even more discussions amongst doctors from different countries have been led.
BACKGROUND: The present survey among members of the ESPE on current practice in diagnosis and treatment of growth hormone (GH) deficiency (GHD) is of great clinical relevance and importance in the light of the recently published guidelines for diagnosis and treatment of GHD by the Growth Hormone Research Society. We have found much conformity but also numerous discrepancies between the recommendations of the Growth Hormone Research Society and the current practice in Europe. RESULTS: We found that 80% of the pediatric endocrinologists included insulin-like growth factor I (IGF-I) in their initial evaluation of a short child suspected of having GHD, whereas only 22% used GH provocative testing alone in the initial evaluation of a short child. Sixty-eight percent confirmed the diagnosis of GHD using two separate provocative tests. In the present survey cutoff values for GH provocative testing clustered around two values; 10 ng/ml and 20 mU/l. Interestingly, these two values, differing by a factor of 2, were also the most prevalent cutoff values among those who reported their assay to be calibrated against the WHO International Reference Preparation 80/505 where the conversion factor between milligrams and milliunits is 2.6. This suggests that the selection of cutoff values is based on tradition rather than on specific GH assay characteristics. In addition, only 63% of the respondents actually knew what GH assay they were using, and only 57% knew how their GH assay was calibrated. Dosing of GH at the start of treatment was reported according to body surface by 39%, whereas 59% were dosing according to body weight. GH dose adjustment was primarily based on growth response and height during auxological assessment every 3-4 months (height velocity, change in height velocity or change in height standard deviation scores) as indicated by almost 70% of the respondents. However, dose adjustment according to body surface (38%) and body weight (44%) was also quite common. Sixty-five percent measures IGF-I regularly (at least once a year) during GH therapy in children, and to our surprise 17% reported that they adjust the GH dose according to the IGF-I levels. SUMMARY: In summary, we have found large heterogeneity in the current practice of diagnosis and treatment of childhood GHD among European pediatric endocrinologists. Especially standardizations of GH assays and cutoff values are urgently required to ensure a uniform and correct diagnosis and therapy of GHD in the future.
The induction of puberty by the administration of subcutaneous 15-micrograms pulses of gonadotrophin-releasing hormone (GnRH) every 90 min during day and night is described in two patients. Too rapid an induction of puberty occurred in one patient while initial progress in the other ceased after the development of pituitary desensitisation. We have attributed these results to the use of GnRH pulses in too high amplitude, and we suggest a more appropriate dose regimen.
In order to evaluate the onset of puberty and the presence of menstrual disorders in Finnish sportswomen with different training programs, 53 long-distance runners, 39 skiers and their 93 controls, and 63 volleyball players with 64 controls were interviewed. All the sportswomen had trained intensively for several years and were in the top category of their sport in Finland. Menarche and thelarche in all the sportswomen and also pubarche in the volleyball players developed significantly later than in their controls. The runners and skiers (43%) suffered significantly more often from menstrual irregularities than their controls (27%), whereas volleyball players (19%) did not differ from their controls (13%) in this respect. Among runners and skiers, but not among volleyball players, premenarchal start of sports activity had an aggravating effect on these endocrine disorders. Dysmenorrhea was found to occur more seldom in sportswomen than in the control subjects, and physical exercise often alleviated menstrual distress. Because the runners and skiers trained as often and used as much time for their sport as the volleyball players, the more common occurrence of their menstrual disorders may be due to the nature of training and competition activity which is characterized by endurance physical exercise.
Turner's Syndrome and its associated problems are discussed. The developmental/adaptational difficulties surrounding Turner's Syndrome necessitate a comprehensive treatment approach, with a special emphasis on psychological assessment of "space-form blindness." A case history of assessment and treatment is presented to illustrate this approach.
We report a child with craniosynostosis, partial absence of the corpus callosum, developmental delay, precocious puberty, and deletion of chromosome 9(p12p13,3). A review of the literature did not reveal any previous combination of the same kind. Craniosynostosis and partial absence of the corpus callosum, separately or in conjunction, may be part of the spectrum of malformations in the chromosome 9p deletion syndrome, and its presence, in combination with other known features, should prompt a search for this particular deletion as part of the differential diagnosis.
Polyamines, putrescine (PUT), spermidine (SPD), spermine (SPM), and agmatine (AGM), are polycationic amines related to multiple cell functions found in high concentrations during the development of hypothalamus and pituitary. In previous works, we demonstrated that alpha-difluoromethylornithine (DFMO), an inhibitor of polyamines biosynthesis, induced a delay in puberty of female rats, accompanied by high, sustained follicle-stimulating hormone (FSH) levels during the infantile period. Also, DFMO treatment induced changes in polyamine concentration both in hypothalamus and pituitary of rats, mainly a decrease of PUT and SPD, an increase in SPM, and no change in AGM. In the present work, we investigated the direct effects of polyamines on the secretion of hypothalamic GnRH and pituitary gonadotropins in 6- and 15-day-old female rats. In 6-day-old animals, in vitro incubations with PUT, SPD, and AGM of hypothalami or anterior pituitaries were able to inhibit GnRH, FSH, and leutinizing hormone (LH) secretion, respectively. SPM showed a nonspecific transient inhibitory effect on FSH. When challenged with either high K(+) (hypothami) or GnRH (pituitaries), the tissues incubated in the presence of polyamines showed no differences when compared with their controls. No effects of polyamines in 15-day-old rats in either tissue were observed. Pituitary cell cultures of 6-day-old animals incubated with DFMO for 4 days showed a significant increase in FSH, but not in LH. We conclude that high PUT, SPD, and AGM levels during the first 10 days of life are important for the development of the hypothalamic-hypophyseal unit, probably related to an inhibitory effect on GnRH and gonadotropins. Therefore, polyamine participation, especially PUT and SPD, is of importance in the regulation of GnRH and gonadotropin secretion in the neonatal and infantile periods, critical stages in the establishment of sexual differentiation.
The pervasiveness of low bone mass (LBM) in beta-thalassemia (Thal) patients (pts) is escalating as the average life expectancy of these pts increases. Adolescence is a period of substantial bone accrual, which is crucial for future bone strength. Studies of LBM are prevalent among adults with Thal. However, limited information exists about bone accrual and LBM in adolescents with the disease. Thirty-one pts with beta-Thal (26 Thal major [TM], 5 Thal intermedia [TI]), aged 9-20 years (mean: 15.3 years), 14 males and 17 females, underwent measurement of spinal bone mineral density (BMD) by DEXA (Lunar, Prodigy). Height, weight, body mass index, and Tanner stage were assessed at the time of the BMD measurement. A total of 16.1% of the patients had normal bone mass (Z > or = -1), 22.6% had reduced bone mass (Z = -1 to -2), and 61.3% had low bone mass (Z < or = -2). BMD Z correlated with height and weight Z scores. Some 53.9% of subjects had normal gonadal function and 46.1% had induced puberty with gonadal steroids. BMD Z significantly worsened with age (P < .0001). However, there was no difference in the LBM prevalence between subjects with normal versus those with induced puberty: BMD Z was -2 or less in 71.4% of subjects with normal puberty versus 66.7% in those with induced puberty. Our results indicate a high prevalence of LBM among adolescents with Thal regardless of adequate transfusion and chelation regimens. Bone accrual was found to be suboptimal in adolescents with normal or induced puberty. Thus, calcium and vitamin D supplementation with antiresorptive therapies should be evaluated in the adolescent Thal pt with close monitoring of growth and sexual development.
GnRH agonists are the established treatment of precocious puberty caused by premature stimulation of gonadotropin secretion. It has been reported that after an initial stimulation ("flare-up") they reduce LH secretion by desensitization of pituitary GnRH receptors. Little has been published about the use of GnRH antagonists such as cetrorelix to control the onset of puberty and whether they are potentially advantageous compared with GnRH agonists. We conducted two multigroup experiments (12 and 10 d, respectively) treating prepubertal/peripubertal female rats with either the GnRH agonist triptorelin or buserelin and compared them with rats treated with the GnRH antagonist cetrorelix and controls to assess the effects on pubertal progress and serum hormones. In the second experiment, the effects of buserelin and cetrorelix on gene expression of the GnRH receptor, LH-beta, FSH-beta, and the alpha subunit genes in the pituitary were also investigated. Cetrorelix, triptorelin, and buserelin retarded the onset of puberty as determined by delayed vaginal opening, lower ovarian weights, and lower serum estradiol levels. However, although LH and FSH levels were stimulated by both agonists, they were inhibited by cetrorelix. In the cetrorelix versus buserelin experiment, pituitary gene expression of the GnRH receptor and LH-beta subunit were significantly lower in cetrorelix treated rats compared with controls whereas buserelin had little effect. Expression of FSH-beta and alpha subunit were stimulated by buserelin but not by cetrorelix. Even though all three of these GnRH analogues inhibited gonadal development and delayed the onset of puberty, the GnRH agonists had stimulating and inhibiting effects on the pituitary-gonadal axis whereas cetrorelix exerted only inhibiting effects. We conclude from this female rat model that cetrorelix may offer advantages for a more controlled medical treatment of precocious puberty compared with GnRH agonist treatment.