Aspartame Intake Delayed Puberty Onset in Female Offspring Rats and Girls.

SCOPE: The disturbance of the hypothalamic-pituitary-gonadal (HPG) axis, gut microbiota (GM) community, and short-chain fatty acids (SCFAs) is a triggering factor for pubertal onset. The study investigates the effects of the long-term intake of aspartame on puberty and GM in animals and humans. METHODS AND RESULTS: Aspartame-fed female offspring rats result in vaginal opening time prolongation, serum estrogen reduction, and serum luteinizing hormone elevation. , 60 mg kg-1 aspartame treatment decreases the mRNA levels of gonadotropin-releasing hormone (GnRH), Kiss1, and G protein-coupled receptor 54 (GPR54), increases the mRNA level of RFamide-related peptide-3 (RFRP-3), and decreases the expression of GnRH neurons in the hypothalamus. Significant differences in relative bacterial abundance at the genus levels and decreased fecal SCFA levels are noted by 60 mg kg-1 aspartame treatment. Among which, Escherichia-Shigella is negatively correlated with several SCFAs. In girls, high-dose aspartame consumption decreases the risk of precocious puberty. CONCLUSIONS: Aspartame reduces the chance of puberty occurring earlier than usual in female offspring and girls. Particularly, 60 mg kg-1 aspartame-fed female offspring delays pubertal onset through the dysregulation of HPG axis and GM composition by inhibiting the Kiss1/GPR54 system and inducing the RFRP-3. An acceptable dose of aspartame should be recommended during childhood.

Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with ß-thalassemia major.

Iron overload in ß-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.

Delayed puberty in spontaneously hypertensive rats involves a primary ovarian failure independent of the hypothalamic KiSS-1/GPR54/GnRH system.

Spontaneously hypertensive (SH) rats, extensively used as experimental models of essential human hypertension, display important alterations in the neuroendocrine reproductive axis, which manifest as markedly delayed puberty onset in females but whose basis remains largely unknown. We analyze herein in female SH rats: 1) possible alterations in the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems, 2) the integrity of feedback mechanisms governing the hypothalamic-pituitary-ovarian axis, and 3) the control of ovarian function by gonadotropins. Our data demonstrate that, despite overtly delayed puberty, no significant decrease in hypothalamic KiSS-1, GPR54, or GnRH mRNA levels was detected in this strain. Likewise, in vivo gonadotropin responses to ovariectomy and systemic kisspeptin-10 or GnRH administration, as well as in vitro gonadotropin responses to GnRH, were fully preserved in SH rats. Moreover, circulating LH levels were grossly conserved during prepubertal maturation, whereas FSH levels were even enhanced from d 20 postpartum onwards. In striking contrast, ovarian weight and hormone (progesterone and testosterone) responses to human chorionic gonadotropin (CG) in vitro were profoundly decreased in SH rats, with impaired follicular development and delayed ovulation at puberty. Such reduced hormonal responses to human CG could not be attributed to changes in LH/CG or FSH-receptor mRNA expression but might be linked to blunted P450scc, 3beta-hydroxy steroid dehydrogenase, and aromatase mRNA levels in ovaries from SH rats. In conclusion, our results indicate that the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems is normal in SH rats, whereas ovarian development, steroidogenesis, and responsiveness to gonadotropins are strongly compromised.

Augmentation of growth hormone secretion after testosterone treatment in boys with constitutional delay of growth and adolescence: evidence against an increase in hypothalamic secretion of growth hormone-releasing hormone.

The increase in pituitary GH secretion that occurs during mid-late puberty in boys follows an increase in circulating testosterone (T) concentration; the direct mechanism by which this occurs is unknown. We hypothesized that T increases GH secretion during puberty by augmenting hypothalamic output of GHRH. Using constant infusions of a GHRH antagonist, we tested this hypothesis in six early pubertal boys with constitutional delay of growth and adolescence who had a mean chronological age of 14.0 +/- 0.3 yr and mean bone age of 11.4 +/- 0.2 yr. Blood samples were obtained from subjects every 15 min for 24 h during the overnight infusion of normal saline (2000-0600 h) and again during the overnight infusion of GHRH antagonist (0.33 microg/kg/h) the following night. Subjects then received transdermal T (5-mg patch) for 12 h nightly and were studied again after 4 wk of treatment. Serum samples were assayed for GH and total ghrelin; the percent suppression of GH during GHRH antagonist infusion was calculated. Morning serum T rose from 0.44 +/- 0.09 to 4.43 +/- 0.74 microg/liter (P = 0.005). T treatment was associated with a 92.6% increase in mean nocturnal GH secretion area under the curve (830 +/- 177 to 1599 +/- 340 microg/24 h.liter). Infusion of GHRH-antagonist suppressed mean nocturnal GH area under the curve by 29.1% before T treatment (830 +/- 177 to 621 +/- 168 microg/24 h.liter), and by 29.4% after T treatment (1599 +/- 340 to 1182 +/- 249 microg/24 h.liter; P = 0.99). Somatotroph sensitivity to GHRH was tested with 0.1- and 1.0-microg/kg doses of GHRH-44 iv; GH response did not change with regard to T treatment. The mean 24-h concentration of total ghrelin was unchanged with regard to T treatment. In summary, nightly transdermal T administration in six boys with constitutional delay of growth and adolescence increased GH output almost 2-fold, whereas the degree of GH suppressibility by GHRH antagonist remained unchanged. We conclude that the T-associated augmentation of GH secretion during early puberty in boys is unlikely to involve an absolute increase in hypothalamic GHRH output.

[Evaluation of bone mineral density and selected metabolic markers of bone in boys with constitutional delay of growth and puberty]. / Ocena gestosci mineralnej koscca i wybranych wskazników metabolizmu kostnego u chlopców z konstytucjonalnie wolnym przebiegiem wzrastania i rozwoju.

The aim of this study was to evaluate bone mineral density and some markers of bone metabolism (alkaline phosphatase activity, osteocalcin concentration, deoxypirydinoline excretion), as well as the influence of physical activity and dietary calcium supplementation on bone density and bone metabolism in boys with a constitutional delay of growth and puberty (CDGP), in relation to calendar age, bone age and pubertal stage. The study was done in 41 boys aged 8-18 years with CDGP diagnosed on the basis of family history and typical pattern of growth, with prior exclusion of hormonal and non-hormonal causes of height deficiency. According to Tanner's criteria, boys were assigned to 4 groups corresponding to 4 stages of puberty (Tab. 1). Total body (total BMD) and lumbar spine (L2L4 BMD) bone mineral density were obtained using DEXA densitometry. The activity of alkaline phosphatase (AP) and serum osteocalcin (OC) concentration served as markers of bone formation. 24-h urinary deoxypirydinoline (DPD) excretion was a marker of bone resorption. Using a questionnaire, daily dietary calcium intake and physical activity were established. A positive correlation between calendar age, total BMD and L2L4 BMD was found (R = 0.70 and R2 = 0.49; R = 0.72 and R2 = 0.51; p < 0.001, respectively). Bone age was positively correlated with total BMD and L2L4 BMD (for both correlations R = 0.68, R2 = 0.47; p < 0.001). Total BMD adjusted for calendar age revealed osteoporosis in 4 cases (9.7%), osteopenia in 19 cases (46.3%) and normal bone density in 18 cases (43.9%). After adjustment of BMD to bone age, 2 boys (4.9%) were diagnosed with osteoporosis, 9 (21.9%) with osteopenia, and 30 (73.2%) with normal bone density. L2L4 BMD adjusted for calendar age showed osteoporosis in 6 cases (14.6%), osteopenia in 21 cases (51.2%) and normal density in 14 cases (34.2%). After adjustment of BMD to bone age, 3 boys (7.3%) were diagnosed with osteoporosis, 10 (24.4%) with osteopenia, and 28 (68.3%) with normal bone density. A significant correlation between stage of puberty, total BMD (p < 0.045) and L2L4 BMD (p < 0.001) was found. Values for total BMD and L2L4 BMD in boys with CDGP in relation to pubertal stage are presented in Table 2. Mean AP activity, serum OC concentration, DPD excretion, dietary calcium intake and physical activity in boys at consecutive stages of puberty are presented in Table 3. No significant correlation between pubertal stage, markers of bone metabolism, daily dietary calcium intake or physical activity was found. The boys were next grouped according to level of physical activity: low (< 10 h/week) or high (> 10 h/week). Table 4 summarizes the results for both groups. No significant differences between the groups were found concerning the parameters studied. Two groups with a low (< 1.2 g) and high (> 1.2 g) dietary calcium intake were also formed. The results for both groups are presented in Table 5. A significant correlation between dietary calcium intake and total BMD (R = 0.34 and R2 = 0.11; p < 0.03) was revealed. On the basis of these results it can be concluded that BMD values in boys with CDGP should be adjusted for bone age, thus significantly limiting the diagnosis of osteoporosis and osteopenia. BMD values for these boys increase with consecutive pubertal stage, while markers of bone metabolism do not reveal significant abnormalities (markers of bone formation increase until stage IV, markers of bone resorption show fluctuating values).