Delay In Pubertal Development Research Articles

Ultrasound findings of pubertal development in girls with cystic fibrosis and their association with clinical outcomes and Tanner staging.

Patients with cystic fibrosis (CF) have a high incidence of pubertal and growth delay. In girls with CF, pubertal delay has an important psychological impact. Still, only a few studies have explored the occurrence of pubertal delay in girls with CF. The aims of this study were to compare the pubertal development of girls with CF compared with healthy controls regarding Tanner staging and pelvic ultrasound and, in girls with CF, correlate the findings with those of spirometry, body mass index, Shwachman-Kulczycki score (SKS), and genotyping. This was a cross-sectional, case-control study including 35 girls with CF aged 6-17 years and following up at the Pediatric Pulmonology Outpatient Clinic of a tertiary hospital. These patients were compared with 59 healthy controls who had undergone pelvic ultrasound as part of another study conducted by the same group. Girls with CF were consecutively enrolled in the study during their annual routine check-up visit. Data collected in the CF group included spirometry and anthropometric results, SKS values, bone age, occurrence of current cystic fibrosis-related diabetes (CFRD) and Pseudomonas aeruginosa colonization, history of meconium ileus, genotype, ultrasound parameters, and Tanner stage. Pelvic ultrasound findings and Tanner stage reflected less pubertal development in girls with CF compared with healthy controls. Pubertal stage in patients with CF who presented CFRD (3.17 ± 1.16), had chronic colonization by Pseudomonas aeruginosa (3.10 ± 1.10), or were homozygous for the F508del mutation (1.91 ± 1.30) was more delayed than in controls (3.41 ± 1.41). Tanner stage correlated with age at menarche, bone age, and anthropometric and ultrasound data. Girls with CF presented a delay in pubertal development evaluated by Tanner stage and ultrasound parameters, which was more evident in the presence of comorbidities.

The Quality of Life of Thalassemic Patients: The Role of Endocrine Defect Compensation.

The improvement of beta thalassaemia treatments has led to an increase in life expectancy. This implies the emergence of new comorbidities. Amongst others, endocrine glands are extremely sensitive to iron overload. We aimed to understand the impact of the endocrine conditions on the patient's quality of life (QOL). Hypogonadism may present with lack or delay of pubertal development, sexual dysfunctions and impaired fertility, which impact QOL in both sexes. Early recognition and treatment, as well as choosing the most appropriate therapy, according to patient's needs (fertility, pubertal development, psychological concerns, comorbidities), are advisable. Osteoporosis affects QOL irrespective of symptoms. Growth hormone deficiency may occur both in childhood and in adulthood, and it affects different aspects of QOL. In adults, it could be difficult to examine if the symptoms are due to GHD, and a trial of GH replacement could be useful to identify benefits and needs. Glucose metabolism impairment is common in thalassaemic patients and early recognition is mandatory because long-term complications can have a detrimental impact on QOL (as blindness or dialysis). Although the incidence of adrenal insufficiency seems to be rare in thalassaemic patients, when it occurs, it has a severe impact on QOL. Limited data is available on QOL in thalassaemic patients, and is even less related to endocrinopathies. We can speculate that endocrinopathies have an impact on everyday life. More studies are needed to allow our patients to achieve not just a longer life but also a better quality of life.

Biological maturation of Portuguese rhythmic gymnasts in different competition levels of performance

The aims of the present study were: (1) identify and compare the biological maturity in Portuguese gymnasts across competitive levels; (2) investigate how morphological variables and training volume behave in the different status and indicators of maturity and (3) determinate if the maturity status influences the competitive performance. The sample (n=164) consisted of three competition levels (Base, 1st division and Elite) from Portugal. Anthropometric measurements and body composition were performed. For analysis of biological maturation, the sexual and somatic maturation were evaluated. For the statistical analysis, Mann-Whitney and Kruskal-Wallis tests, Pearson correlation and Linear Regression were used. In total, 63.4% of gymnasts had not yet reached menarche and the higher competition level, lower the number of gymnasts with menarche. On mean, all groups had reached the age at peak height velocity. The higher the competition level, higher the chronological age and age at peak height velocity. Thus, the maturation indicators showed a delay in pubertal development in all competition levels and the elite gymnasts seem present a later pubertal development. The chronological age, the values of body mass, height, BMI and body fat increased with the maturity status according all maturity indicators. However, gymnasts with different maturity status revealed similar training volume. Finally, the maturational status explained 11.5% of competition success with higher advantage in the competitive performance to prepubertal gymnasts. Thus, the premenarcheal status and a higher age at peak height velocity contribute to performance in Rhythmic Gymnastics.

Elite athletes and pubertal delay.

Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes' pubertal development. On the other hand, pubertal timing, early or late, may impact on an athlete selection for a particular sport. Genetic predisposition, training load, nutritional status and psychological stress determine athletes' pubertal timing. Athletes that practice esthetic sports, especially gymnasts, are predisposed to a delay in pubertal development. The growing evidence indicates that energy deficiency, not a systemic training per se, plays a crucial role in the pathogenesis of functional hypothalamic hypogonadism in female athletes. Metabolic and psychologic stress activate hypothalamic-pituitary-adrenal axis and suppress hypothalamic-pituitary-ovarian axis. Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and a targeted treatment. Somatic growth and sexual maturation of elite female athletes are largely sport-specific since each sport favors a particular somatotype and requires a specific training. Chronic negative energy balance resulting from a systemic physical training and inadequate energy intake may delay pubertal development in elite athletes. Youth athletes, especially those engaged in competitive sports that emphasize prepubertal or lean appearance, are at risk of developing relative energy deficiency in sport associated with disordered eating or eating disorders. Management strategies should address the complex conditions underlying functional hypothalamic hypogonadism.

Anthropometric Measurements, Serum Reproductive Hormonal Levels and Sexual Development among Boys in the Rural Western Cape, South Africa.

Data on growth and sexual maturation among boys from the rural Western Cape in South Africa is limited. A cross-sectional study of 269 school boys was conducted testing for serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, sex hormone binding globulin (SHBG) and estradiol (E2); height, weight and body mass index (BMI); sexual maturity (using Tanner Stages) and a questionnaire (demographic and medical history). The median age at pubertal onset (Tanner Stage 2) and Tanner Stage 5 was 11.6 and 14.7 years, respectively. The median testicular volume was 5.5 mL at Tanner Stage 2 increasing from 2.5 mL at Tanner Stage 1 to 14.7 mL at Tanner Stage 5. Height and weight measurements were <25th & 50th percentile references at Tanner Stages 1–3. Controlling for confounders, serum FSH and LH increased (p < 0.05) from Tanner Stage 1 to 4 (by 4.1 and 3 mL respectively), and serum testosterone and estradiol increased after Tanner Stage 2 (by 12.7 nmol/L and 59.5 pmol/L respectively). These results indicate some delays in pubertal development of boys in the rural Western Cape when compared to boys from other settings possibly due to nutritional, socio-economic and environmental exposures. Changes in serum hormone levels were consistent with other populations. Initiatives to improve nutrition amongst Western Cape rural communities are recommended.

Nutritional and Pubertal Disorders.

Caloric-protein malnutrition can slow growth and cause pubertal delay. This chapter focuses on endocrine abnormalities and pubertal alterations in patients with eating disorders, childhood obesity, the female athlete triad and children cancer survivors. Patients with anorexia nervosa (AN) exhibit multiple endocrine abnormalities, including isolated hypogonadotropic hypogonadism. The delay in pubertal development and reduction in growth seen in AN patients may be a direct result of malnutrition. Appropriate psychiatric, nutritional and hormonal therapy is necessary. It is suggested that obesity during childhood can accelerate pubertal onset and these children usually exhibit accelerated linear growth during puberty. In girls the relationship between childhood obesity and early pubertal onset could be related to their insulin resistance and/or hyperinsulinemia. The female athlete triad is often observed in physically active girls and women in whom low energy availability with or without disordered eating, menstrual dysfunction and low bone mineral density can be present. In prepubertal girls excess exercise can cause delayed menarche with no effects on adult height, while in postpubertal females it results in menstrual cycle irregularities. The consequences of childhood cancer depend on the type of cancer, its location, the age at which the disease was diagnosed, the dose of radiotherapy, and the type and dose of chemotherapy.

Anti-androgenicity can only be evaluated using a weight of evidence approach

Preputial separation (PPS) is a commonly used external marker for the onset of male puberty in experimental animal studies. While treatment-related delays in PPS may be indicative of specific anti-androgenic activity, impaired general growth also alters the onset of puberty. To differentiate between specific and non-specific effects on the age at PPS – and thereby evaluate the validity of the endpoint PPS-two-generation toxicity studies of 23 substances were evaluated. The 23 substances were assessed regarding anti-androgenicity using all available data and external assessments in a weight-of-evidence evaluation (WoE).Correlation of individual pup body weight with age at PPS revealed that delays in pubertal development coincided with reduced pup body weight. After comparison with the WoE assessment, we concluded that inclusion of body weight analysis into the PPS evaluation of each study was able to correctly identify three compounds which specifically induced delayed PPS and 16 which only showed unspecific changes. A further two compounds which might be categorized as anti-androgens based on delayed PPS, were correctly regrouped using our refined methodology. Based on this analysis and in comparison to the WoE evaluation, it was found, that caution should be exercised when using the endpoint PPS in hazard assessment.

The gonadal effects of diabetes

The functional reproductive alterations seen in women with type 1 diabetes (T1D) have changed as therapy has improved. Historically, patients with T1D and insufficient metabolic control exhibited a high prevalence of amenorrhea, hypogonadism, and infertility. Recent publications have shown that in spite of intensive insulin therapy, some delay in the age of thelarche, pubarche and menarche is still observed in girls with T1D. In addition, ovarian hyperandrogenism may be observed during late adolescence and an increased prevalence of hirsutism and polycystic ovarian syndrome (PCOS) has been described in adult women with T1D. These endocrine abnormalities may be related to non-physiologic insulin replacement therapy and to hyperglycemia. Insulin is well known for its effects on carbohydrate metabolism, but this hormone also plays an important role in regulating ovarian function. Granulosa, theca and stromal ovarian cells may be affected by insulin deficiency or excess, which may be present in women with type 1 diabetes mellitus (T1D)[1]. Diabetes disrupts hypothalamic-pituitary-ovarian function, as documented by animal model studies which have helped to decipher the underlying basis of these conditions and have highlighted the variable contributions of defective leptin, insulin and kisspeptin signalling to the mechanisms of perturbed reproduction in T1D[2]. Effects of diabetes on gonadal function vary according to the age of the patient. Young girls during adrenarche exhibit an elevation of DHEAS, androstenedione, inhibin B and anti-mullerian hormone[3], an endocrine profile that is similar to the one observed in young girls in risk of developing polycystic ovarian syndrome later in life. During puberty a delay in pubertal development has been described which is followed by menstrual irregularities and hyperandrogenism during adolescence [1,4,5]. Despite these abnormalities in ovarian function, ovulatory functions is preserved in adolescents with type 1 diabetes[6]. Later in life, adult women with type 1 diabetes exhibit PCOS, polycystic ovaries at the ultrasonographic exam, menstrual irregularities and early decline in ovarian reserve[7-9]. Clearly, despite improvements in insulin therapy, T1D patients still suffer several significant clinical problems, such as pubertal delay, menstrual disturbances and hyperandrogenism which may ultimately lead to the development of PCOS in adulthood. (Fondecyt 1100123 y 1050452)

Treatment of children and adolescents with idiopathic short stature

Idiopathic short stature (ISS) is defined as shortness in childhood without a specific cause. ISS may be familial or nonfamilial and may be associated with or without delay of pubertal development. Treatment can be considered in an attempt to reduce the psychological burden caused by short stature in childhood and adult life. If counselling alone is not sufficient, medical modifications of the growth process can be attempted. In cases with pubertal delay, sex steroids, such as testosterone and oxandrolone, can favourably influence height velocity and growth tempo, although adult height is not affected. Medications that prolong the process of growth--for example, gonadotropin-releasing hormone agonists or aromatase inhibitors--might increase adult height, but findings to date are still experimental. Growth hormone therapy is approved for the treatment of very short children with reduced adult height expectation, as evidence has accumulated that this therapy can increase height in childhood and in adult life. Sensitivity to growth hormone is impaired in patients with ISS; therefore, doses higher than a replacement dose have to be applied. This treatment still needs to be optimized in terms of efficacy, cost-effectiveness and long-term safety. A debate is ongoing concerning the psychological benefit of height increase, with clinicians warning against the medicalization of a deviation in height.

Pubertal Development Moderates the Importance of Environmental Influences on Depressive Symptoms in Adolescent Girls and Boys

Prevalence differences in depressive symptoms between the sexes typically emerge in adolescence, with symptoms more prevalent among girls. Some evidence suggests that variation in onset and progression of puberty might contribute to these differences. This study used a genetically informative, longitudinal (assessed at ages 12, 14, and 17) sample of Finnish adolescent twins (N = 1214, 51.6% female) to test whether etiological influences on depressive symptoms differ as a function of pubertal status. These tests were conducted separately by sex, and explored longitudinal relationships. Results indicated that pubertal development moderates environmental influences on depressive symptoms. These factors are more important on age 14 depressive symptoms among more developed girls relative to their less developed peers, but decrease in influence on age 17 depressive symptoms. The same effects are observed in boys, but are delayed, paralleling the delay in pubertal development in boys compared to girls. Thus, the importance of environmental influences on depressive symptoms during adolescence changes as a function of pubertal development, and the timing of this effect differs across the sexes.

Delayed pubertal development by hypothalamic suppression causes an increase in periosteal modeling but a reduction in bone strength in growing female rats

The timing of the pubertal growth is a critical event in skeletal development. A delay in the onset of puberty has been correlated with increased stress fracture incidence in young women and as a result, suboptimal skeletal development may affect long-term bone strength. Gonadotropin releasing hormone antagonist (GnRH-a) injections were used to delay the onset of puberty in growing female rats. 23-day-old female rats were injected with a GnRH-antagonist at 2 dosage levels ( n = 15/group). The Low Dose group (1.25 mg/kg/dose) received daily injections for 27 days (sacrifice 49 days). The High Dose group received (5.0 mg/kg/dose) only 5 days per week over a 26 day period (sacrifice 48 days). Calcein injections measured bone formation activity on the periosteal and endocortical surfaces. Standard histomorphometric and biomechanical analyses were performed on the femora and ash content was measured on the tibiae of all animals. Serum estradiol and insulin-like growth factor (IGF)-1 levels were assayed. Significant delays in pubertal development occurred in the two GnRH-a groups as evidenced by delayed vaginal openings, decreased uterine and ovarian weights and suppressed estradiol levels compared to control. Femoral lengths were significantly shorter in the experimental groups and serum IGF-1 levels were higher than control. Bone strength and stiffness were significantly lower in the GnRH-a groups. Cortical bone area was decreased and total area was not different between groups. There was a significant decrease in % Ct.Ar/T.Ar. The decreased bone strength may have resulted from a decrease in the amount and distribution of bone, however, stress and Young's modulus were also decreased. There was a different response between endocortical formation indices and periosteal formation indices to the GnRH-a protocol. Endocortical bone formation rates decreased and there was an increase in periosteal labeled surface. A dose response between bone strength and GnRH-a dosage was found. The data suggest that hypothalamic suppression during pubertal development resulted in decreased bone strength which may result in fracture development.

Artistic Versus Rhythmic Gymnastics: Effects on Bone and Muscle Mass in Young Girls

We compared 35 prepubertal girls, 9 artistic gymnasts and 13 rhythmic gymnasts with 13 nonphysically active controls to study the effect of gymnastics on bone and muscle mass. Lean mass, bone mineral content and areal density were measured by dual energy X-ray absorptiometry, and physical fitness was also assessed. The artistic gymnasts showed a delay in pubertal development compared to the other groups (p<0.05). The artistic gymnasts had a 16 and 17 % higher aerobic power and anaerobic capacity, while the rhythmic group had a 14 % higher anaerobic capacity than the controls, respectively (all p<0.05). The artistic gymnasts had higher lean mass (p<0.05) in the whole body and the extremities than both the rhythmic gymnasts and the controls. Body fat mass was 87.5 and 61.5 % higher in the controls than in the artistic and the rhythmic gymnasts (p<0.05). The upper extremity BMD was higher (p<0.05) in the artistic group compared to the other groups. Lean mass strongly correlated with bone mineral content (r=0.84, p<0.001), and multiple regression analysis showed that total lean mass explained 64 % of the variability in whole body bone mineral content, but only 20 % in whole body bone mineral density. Therefore, recreational artistic gymnastic participation is associated with delayed pubertal development, enhanced physical fitness, muscle mass, and bone density in prepubertal girls, eliciting a higher osteogenic stimulus than rhythmic gymnastic.

Lead and growth.

Lead is highly toxic to the human body and children are much more vulnerable to lead toxicity than adults. Many studies have revealed that relatively low levels of blood lead can adversely affect human health, especially childhood growth and development. Blood lead levels (BLL) of children and adults have been decreasing recently almost all over the world, but a safety level for blood lead does not exist, and lead exposure is still a serious health problem especially for fetuses and children. Maternal lead burden causes fetal lead exposure and increases the risk of abortions, prematurity, low birth weight, and some minor anomalies. Infant BLL are inversely associated with weight gain. A negative relationship between somatic growth and BLL in children has been revealed. It has been suggested that lead exposure causes decrease of gonadotropin secretion of adolescents and delay of pubertal development. Several studies have revealed that children who are exposed to cigarette smoke have higher BLL than children who are not. Children should be protected from cigarette smoke for the purpose of avoiding the risk of increased BLL which might adversely affect their intellectual development and physical growth.

Pituitary adenomas in childhood.

Pituitary adenomas are common tumors composed of adenohypophysial cells. Although they usually arise in the sella turcica, they may occasionally be ectopic. Pituitary adenomas are rarely diagnosed in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. Many signs or symptoms of pituitary adenoma, complained of in adulthood, not became evident during adolescence, suggesting true prevalence of this tumor in teenagers is higher than expected. Pititury adenoma occuring during adolescence are associated with features or therapeutic needs sometimes different from those occuring in adulthood. At the onset of disease, delay in growth was rarely observed in teenagers with pituitary adenomas. Many girls complain of oligoamenorrhoea and galactorrhoea, while headache and delay in pubertal development are the most commons features in boys. Hypopituitarism is occasionally encountered in adolescence. Early diagnosis and appropriate choice of therapy are necessary to avoid permanent endocrine complications of disease and its treatment.

Delayed Menarche Causes A Transient Reduction In Cancellous Bone Area In Female Rats

Optimizing peak bone mass during late adolescence may help reduce the effects of osteoporosis. Multiple factors affect the structural development of the skeleton; including estrogen levels during growth which are an important factor in the pathogenesis of bone fragility. The delay of menarche decreases estrogen levels during adolescence and subsequent peak bone mass. Therefore, low estrogen levels during bone development decrease peak bone mass accrual in young adults and may lead to an increased risk of fracture later in life. PURPOSE The investigative hypothesis predicts that administration of a GnRH antagonist initiated prior to the onset of the first estrus cycle will reduce estrogen levels and impede the development of cancellous bone area in the proximal tibial metaphysis of female rats (6 weeks) and the peak bone area at maturity (6 months). METHODS Twenty-five day old female Sprague Dawley rats were randomly assigned into short-term control (C-ST) (n = 12), long-term control (C-LT) (n = 12), short-term GnRH antagonist (GnRH-a ST) (n = 12) and long-term GnRH antagonist groups (GnRH-a LT) (n = 12). Injections (0.2 ml) were given intraperitoneally for 18 days of either saline or GnRH antagonist (100 ug/day) and animals were monitored daily for vaginal opening. Both short-term and long-term groups received the GnRH antagonist for 18 days. However, the short-term groups were sacrificed after the last injection (day 42) and the long-term groups were sacrificed at 6 months of age. Uterine weights were measured. Serum Estradiol levels were assayed. Bone area (%) was measured at the proximal tibial metaphysis. Differences were detected using Students t-test. The Institutional Animal Care and Use Committee at Brooklyn College approved the study. RESULTS Day of vaginal opening was delayed 22% in the short term GnRH-a group and 30% in the long-term group. The delay in pubertal development was also confirmed by decreased uterine weights (74 %) in the GnRH-a ST group, uterine weights were normal in the GnRH-a LT group. GnRH-a ST estrogen levels were suppressed after the injection period (38.1 (13.6) pg/mL v 26.8 (16.6) pg/mL). Bone area was decreased 16.5% (p = 0.05) in the short-term groups but was not significantly different at 6 months of age. CONCLUSION GnRH antagonist given to animals prior to the first estrus cycle significantly decreased the bone area in the proximal tibial metaphysis at 6 weeks but not at 6 months of age. Delayed vaginal openings and decreased uterine weights in the GnRH-a ST group resulted in a reduction in the level of available estrogen. Supported by NIH R15 AG19654-01A1and PSC-CUNY 64293-00 33

SERUM DIOXIN CONCENTRATIONS AND AGE AT MENARCHE

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is associated with delays in pubertal development in animal studies. On 10 July 1976, as a result of a chemical e...

Serum dioxin concentrations and age at menarche.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a widespread environmental contaminant, is associated with delays in pubertal development in animal studies. On 10 July 1976, as a result of a chemical explosion, residents of Seveso, Italy, experienced the highest levels of TCDD exposure experienced by a human population. Twenty years later, we initiated the Seveso Women’s Health Study (SWHS), a retrospective cohort study of female residents of the most contaminated areas, to determine whether the women were at higher risk for reproductive disease. We examined the association of TCDD serum levels, based on measurements in serum collected soon after the explosion, with reported age at menarche among the 282 SWHS women who were premenarcheal at the time of the explosion. We found no change in risk of onset of menarche with a 10-fold increase in TCDD (e.g., 10–100 ppt; hazard ratio = 0.95; 95% confidence interval, 0.83–1.09; p-value for trend = 0.46). When TCDD levels were categorized, there was also no evidence of a dose–response trend (p = 0.65). In summary, we found that individual serum TCDD measurements are not significantly related to age at menarche among women in the SWHS cohort. The women in this study experienced substantial TCDD exposure during the postnatal but prepubertal developmental period. Given that animal evidence suggests in utero exposure has the most significant effect on onset of puberty, continued follow-up of the offspring of the SWHS cohort is important.

Pubertal development in female Wistar rats following exposure to propazine and atrazine biotransformation by-products, diamino-S-chlorotriazine and hydroxyatrazine.

We showed previously that the chlorotriazine herbicide, atrazine (ATR), delays the onset of pubertal development in female rats. ATR and its biotransformation by-products are present in soil and groundwater. Since current maximum contaminant levels are set only for ATR, it is important to determine whether these by-products can also alter pubertal development and possibly pose a cumulative exposure hazard. We evaluated the effects of two ATR by-products, diamino-s-chlorotriazine (DACT) and hydroxyatrazine (OH-ATR), and a structurally similar chlorotriazine, propazine (PRO), on female pubertal development. Rats were gavaged from postnatal days (PNDs) 22 through PND 41 with DACT (16.7, 33.8, 67.5, 135 mg/kg), OH-ATR (22.8, 45.7, 91.5, 183 mg/kg), or PRO (13, 26.7, 53, 106.7, 213 mg/kg). The dose range for each chemical was selected as the molar equivalent of ATR (12.5, 25, 50, 100, 200 mg/kg). The females were monitored daily for vaginal opening (VO) and killed on PND 41. DACT, a by-product of ATR that occurs in the environment and is also the primary chlorinated metabolite of ATR in animal tissue, delayed VO by 3.2, 4.8, and 7.6 days compared to the controls (33.1 +/- 0.4 (SE) days of age) following exposure to 33.8, 67.5, and 135 mg/kg, respectively. The no effect level (NOEL) for DACT (16.7 mg/kg) was identical to the equimolar NOEL for ATR (25 mg/kg). Although the body weight (BW) on PND 41 was reduced by the high dose of DACT (8.4% reduction), this reduction did not exceed the criteria for selecting the maximum tolerated dose (e.g., a dose that causes >10% decrease in BW at necropsy). None of the lower doses of DACT caused a significant difference in BW gain. Additionally, 33.8, 67.5, and 135 mg/kg of DACT significantly increased the BW on the day of VO. PRO (107 or 213 mg/kg) delayed VO by 4 days but did not alter the BW on PND 41. While no significant delays in pubertal development were observed in two separate dose-response studies with doses ranging up to 183 mg/kg (OH-ATR), a minor but statistically significant delay in the onset of puberty in a pilot study using OH-ATR raises the possibility that an effect might occur following exposure to higher doses. However, it is clear from these data that OH-ATR has a much lower potency when compared with equimolar doses of DACT and PRO. Together, these data demonstrate that PRO and DACT can delay the onset of puberty in the female rat at doses equimolar to ATR and provide the scientific basis for the use of additivity in the upcoming risk assessments.

Clinical presentation and outcome of pituitary adenomas in teenagers.

Pituitary adenomas rarely occur in childhood and adolescence, but their mass effect and endocrine abnormalities can compromise both quality and length of life. In this study we evaluated the symptoms at onset and the long-term consequences induced in teenagers by functioning or nonfunctioning pituitary adenomas. Clinical, biochemical and neuroradiological data of 44 young patients (12 males and 32 females, aged 16.3 +/- 1.9 years at diagnosis) with pituitary adenomas were evaluated retrospectively at baseline and after therapy. Patients underwent surgery, radiotherapy and/or medical treatment depending on clinical history and endocrine secretion of the tumour. Follow-up ranged from 8 to 252 months (median 55 months). Baseline and dynamic pituitary function were evaluated in all cases at diagnosis and after treatments. Magnetic resonance imaging (MRI) or computed tomography (CT) scan were performed before therapy and during follow-up. Hormone levels were measured using commercial radioimmunologic or immunoradiometric methods. Pituitary macroadenomas (group 1) or microadenomas (group 2) were found in 61% and 39% of cases, respectively. Overall, 68% were PRL-secreting, 7% GH-secreting, 5% ACTH-secreting and 20% nonfunctioning. The most frequent symptoms at onset were oligoamenorrhoea (62%) and galactorrhoea (59%) in the girls, and headache (58%) in the boys. Pubertal development was delayed in 12/27 (44%) cases with macroadenoma. Growth failure was observed in 4/44 (9%) patients (3 in group 1 and 1 in group 2). At diagnosis, hypopituitarism was detected in 10/27 (37%) patients with macroadenoma. Surgery alone cured 4/18 (22%) and 4/9 (44%) patients in group 1 and group 2, respectively. Adjuvant therapies (second surgery and/or radiotherapy and/or medical treatment) cured the disease in 2/13 (15%) patients with macroadenoma and allowed a persistent normalization in other 4/13 (31%) and 2/4 (50%) cases in group 1 and group 2, respectively. Medical treatment alone cured 2/9 (22%) patients with PRL-secreting macroadenoma and normalized PRL levels in another six (66%) with macroprolactinoma and in 2/7 (28%) patients with microprolactinoma. Delay of growth was rarely observed in teenagers with pituitary adenomas. At the onset of the disease, many girls complained of oligoamenorrhoea and galactorrhoea, while headache and delay of pubertal development were the symptoms more frequently referred by boys. Surgery alone was effective in a minority of patients and adjuvant therapies were helpful to obtain the remission of the disease in many cases. In patients with PRL-secreting pituitary adenoma, medical treatment, both as first choice or as adjuvant therapy, normalizes serum PRL levels in 14/27 (52%) cases.

The role of mutations affecting gonadotrophin secretion and action in disorders of pubertal development.

A number of mutations that disturb the development and function of the hypothalamic-pituitary-gonadal (HPG) axis and cause disturbances in pubertal development are known today. These mutations have effects at all levels of the HPG axis, from the migration of gonadotrophin releasing hormone (GnRH) neurones from the nasal cavity to the hypothalamus, GnRH secretion, GnRH action, pituitary gonadotroph differentiation, gonadotrophin synthesis and secretion, right through to gonadotrophin action. Most of the mutations are inactivating, thus causing hypogonadism and arrest or delay of pubertal development. One exception is the activating mutations of the LH receptor, which causes the male-limited gonadotrophin-independent precocious puberty. The human mutations and animal models with disrupted function of orthologous genes have clarified the molecular pathogenesis of hypogonadism and disturbances of pubertal development. The correct diagnosis of these disorders using molecular biological techniques is now possible. This allows the selection of specific treatments and correct counselling of the patients and their families.