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PubMed2006

Evidence for hypermetabolism in boys with constitutional delay of growth and maturation.

CONTEXT: Children with constitutional delay of growth and maturation (CDGM) tend to be thin and have a growth pattern reminiscent of nutritional insufficiency. OBJECTIVE: Our objective was to compare differences in nutrition, body composition, bone mineral density, and resting and total energy expenditure (REE/TEE) in boys with CDGM and controls. We hypothesized that an imbalance between energy intake and expenditure may contribute to the pathogenesis of CDGM. DESIGN AND SETTING: We conducted an observational, cross-sectional study at an outpatient clinical research center. PATIENTS: Patients included 36 boys (8-17 yr): 12 with CDGM (short stature, delayed bone age and puberty, and no other pathology) and 12 height-matched (pre- or early-pubertal) and 12 age-matched (pubertal) healthy controls. MAIN OUTCOME MEASURES: Outcome measures included doubly labeled water studies (TEE), serum nutritional/hormonal markers, dual-energy x-ray absorptiometry, dietary analysis, and indirect calorimetry (REE). RESULTS: Nutritional markers were comparable among the groups. CDGM subjects had bone mineral density lower than age-matched controls (P < 0.01) but comparable with height-matched controls. Even though REE did not differ between groups, CDGM subjects had 25% higher caloric intake adjusted for fat-free mass (FFM) than height-matched controls (P < 0.05) and 78% higher caloric intake per kilogram FFM compared with age-matched controls (P < 0.00001). CDGM subjects had 46% (P < 0.05) and 91% (P < 0.001) higher TEE per kilogram FFM than height- and age-matched controls, respectively. CDGM subjects had lower IGF-I and testosterone than age-matched controls (P < 0.001) but levels were comparable with height-matched controls. CONCLUSIONS: Boys with CDGM have higher rates of overall energy expenditure compared with age- and size-matched controls. This increased metabolism may result in impaired tempo of growth. Additional studies are needed to determine whether augmenting nutrition to match their energy needs (with or without hormonal therapy) can improve linear and ponderal growth in patients with CDGM.

Adolescent↗
PubMed2005

Pubertal androgen therapy in boys.

Anabolic-androgenic steroids (AAS) are necessary for normal male sexual differentiation and development and pubertal development. Androgen therapy is appropriate for boys with delayed development (constitutional delay of growth and puberty, CDGP) as well as those with primary or secondary hypogonadism. The principal goal is to restore the serum testosterone (T) level to the normal range at each stage of adolescent development and then to the normal adult range if the hypogonadism is permanent. In addition the levels of dihydrotestosterone and estradiol should also be within the normal range. One should be able to do that with a wide variety of androgen preparations-injectable, implantable, and cutaneous patches or gels. However, during the transition from prepubertal to adult it is difficult to reliably deliver the relatively small doses of T necessary for adolescent development using any of the cutaneous preparations. Androgen therapy should permit normal linear growth (including the adolescent growth spurt), adolescent sexual development, and the attainment of normal body composition including lean body mass, bone and the appropriate regional distribution of body fat as well as the psychological development appropriate for the stage of adolescent development.

Adolescent↗
PubMed1992

Is testosterone therapy for boys with constitutional delay of growth and puberty associated with impaired final height and suppression of the hypothalamo-pituitary-gonadal axis?

We report the treatment of 44 boys with constitutional delay of growth and puberty (CDGP) at a mean chronological age of 14.3 years (range, 12.4-17.1) and bone age of 12.1 years (range, 9.1-15.0). All were below the 3rd height percentile for chronological age. They received monthly intramuscular injections of depot testosterone esters (50 mg) for a mean period of 0.35 years (range, 0.25-0.5). Means (SD) height velocity was 4.5 (1.5) cm/year during a pretreatment period of 0.5 years. During a period of 0.9 years which included the period of treatment with depot testosterone, mean growth velocity increased to 8.8 (1.9) cm/year (P less than 0.001). In the initial 1.8 years following the cessation of treatment growth velocity was sustained at 7.0 (1.7) cm/year. Pretreatment height standard deviation score (SDS) for bone age was -0.89 and this gradually reduced over the next 1.5 years to a minimum of -1.48. Thereafter, height SDS for bone age gradually increased to attain a value of -1.2, 3 years after the commencement of therapy (P less than 0.02). The same pattern of an initial decrease, followed by an increase, in height prediction was also observed when TW2 height prediction was analysed. Sexual maturation progressed during treatment, with mean testicular volume increasing both during and after treatment, confirming the diagnosis of CDGP. The time interval for progress through puberty was shorter in boys with testosterone therapy than in the normal population. The mean duration of puberty was 2.2 years compared to 3.3 years in normal boys. We conclude that low-dose depot testosterone treatment is safe and effective for boys with CDGP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Decrease in plasma high-density lipoprotein cholesterol levels at puberty in boys with delayed adolescence. Correlation with plasma testosterone levels.

A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate (100, 200, and 200 mg/mo, respectively, for three months). Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels (-12.0 mg/dL [-0.30 mmol/L]) during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant (not necessarily directly causal) of plasma HDL-C levels during pubertal development.

Adolescent↗
PubMed2004

Vitamin A and iron supplementation is as efficient as hormonal therapy in constitutionally delayed children.

OBJECTIVE: To assess the effect of nutritional supplementation on growth and puberty in constitutionally delayed children. PATIENTS: One hundred and two boys, 13.6-15.5 years of age, who were referred because of short stature and delayed puberty. METHODS: The boys were randomly allocated to one of the following treatment groups: oxandrolone therapy, 5 mg/day for 6 months (n = 15), testosterone depot, 100 mg monthly for 3 months (n = 15) or for 6 months (n = 20), nutritional programme (n = 17), oxandrolone and nutritional programme (n = 15) or passive observation (n = 20). Boys in the nutritional programmes received 12 mg/day iron and 6000 IU/week of vitamin A. Outcome measurements were of height, weight, pubertal signs, dietary intake, serum vitamin A, iron, GH and IGF-1. RESULTS: Six months of vitamin A supplementation induced growth acceleration similar to that seen in the oxandrolone- and testosterone-treated children, and significantly greater than in the observation group (9.3 +/- 2.9 vs. 4.0 +/- 0.9 crn/yr, P < 0.001). Whereas in the vitamin A-supplemented group, puberty (increase in testicular volume >/= 12 ml) was induced within 12 months. In all testosterone-treated patients, pubic hair was noted within 3 months and a testicular volume of >/= 12 ml was observed 9-12 months after the initiation of therapy. No pubertal signs were noted in the observation group during this time. CONCLUSIONS: Subnormal vitamin A intake is one of the aetiological factors in delayed pubertal maturation. Supplementation of both vitamin A and iron to normal constitutionally delayed children with subnormal vitamin A intake is as efficacious as hormonal therapy in the induction of growth and puberty.

Adolescent↗
PubMed1990

Adult height in boys and girls with untreated short stature and constitutional delay of growth and puberty: accuracy of five different methods of height prediction.

To determine how accurately several methods of height prediction estimate adult height, we compared height predictions calculated by the Bayley-Pinneau, Roche-Wainer-Thissen (RWT), target height, and Tanner-Whitehouse Mark I (TW-MI), and Mark II (TW-MII) methods with final adult height in 37 boys and 32 girls with short stature and constitutional delay of growth and puberty. They were first seen at a chronologic age (mean +/- SD) of 14.80 +/- 1.70 years (boys) and 12.87 +/- 2.56 years (girls). Adult height at 23.14 +/- 1.95 years and 21.05 +/- 2.02 years was 170.4 +/- 5.4 cm (boys) and 157.8 +/- 4.2 cm (girls), respectively, and thus within the lower range of normal. Height predictions were calculated for the total group and for patients with parents of normal (group 1) as well as short stature (group 2). For boys, the RWT method gave very accurate results, underestimating adult height by -0.6 cm for the total group. The prediction errors for the other methods were -7.3 cm (TW-MI), -4.2 cm (TW-MII), and +3.1 cm (Bayley-Pinneau method) or +1.7 cm (target height). For girls, no method was superior in estimating adult height. The mean prediction error was -0.8 cm, -2.1 cm, and -1.8 cm with the Bayley-Pinneau, TW-MI, and TW-MII methods, respectively. In contrast, adult height was overpredicted by +2.3 cm and +1.2 cm with the RWT and target height methods. We conclude that patients with short stature and constitutional delay of growth and puberty reach an adult height in the lower range of normal. Height prediction methods differ with respect to their accuracy and their tendency to overestimate or underestimate adult height.

Adolescent↗
PubMed2005

Pubertal upregulation of erythropoiesis in boys is determined primarily by androgen.

OBJECTIVES: To study the relative roles of androgens and the growth hormone-insulin-like growth factor I (GH-IGF-I) system in the regulation of erythropoiesis in boys during puberty. STUDY DESIGN: We treated 23 boys with constitutional delay of puberty with low-dose testosterone (T), in combination with either a potent aromatase inhibitor, letrozole (Lz; 2.5 mg/d), or placebo (P). The study design was randomized, double-blinded, and placebo-controlled between the treated groups. Treatment with T + Lz was associated with high T and low IGF-I concentrations, whereas treatment with T + P resulted in moderately increased T and high IGF-I concentrations. RESULTS: The blood hemoglobin concentration increased by 1.6 g/dL in T + Lz-treated boys, despite their low IGF-I concentrations. The estimated red blood cell volume increased more in T + Lz-treated than in T + P-treated boys (349 vs 174 mL, respectively, P = .01). Serum T concentrations during the treatment period correlated with the 12-month increments in hemoglobin and red blood cell volume. The changes in blood hemoglobin concentration and RBC in T + Lz-treated boys were similar to those we observed in a population of normal adolescent boys in the late stages of puberty. CONCLUSIONS: The pubertal increase in hemoglobin concentration in boys is related to direct androgen effects.

Adolescent↗
PubMed2002

The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor.

OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We treated boys with constitutional delay of puberty either with testosterone plus placebo or with testosterone plus an aromatase inhibitor, letrozole, which inhibits the conversion of androgens to oestrogens. We demonstrated previously that during treatment with testosterone plus letrozole the increase in testosterone concentration was more than 5-fold higher than during treatment with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I and IGF-binding protein-3 increased during testosterone-plus-placebo treatment, but during testosterone-plus-letrozole treatment the concentrations remained unchanged. These divergent changes in the two groups enabled us to study the effects of sex steroids and GH on insulin sensitivity and lipid concentrations. RESULTS: The insulin concentration in the testosterone-plus-placebo-treated group did not change. In contrast, in the testosterone-plus-letrozole-treated group, the concentration decreased during letrozole treatment, indicating improved insulin sensitivity. Changes in insulin and IGF-I concentrations within 12 and 18 months were correlated. In the testosterone-plus-placebo-treated group, the high-density lipoprotein cholesterol concentration did not change but in the testosterone-plus-letrozole-treated group the concentration decreased. The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides did not change in either of the groups. CONCLUSIONS: The findings indicate that androgens do not directly alter insulin sensitivity in boys during puberty. In contrast, the observations suggest tight regulation of glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our findings indicate that sex steroids do not significantly participate in the regulation of serum concentrations of LDL-cholesterol or triglycerides in boys during early and mid-puberty.

Adolescent↗
PubMedDate not supplied

Diversity of pubertal testosterone changes in boys with constitutional delay in growth and/or adolescence.

In a group of 22 boys with constitutional delay in growth and/or adolescence, intermittent testosterone enanthate treatment was employed in a randomized clinical trial at multiple doses ranging from 25-100 mg every two weeks for three month periods extending over 15-21 months. Twelve of the patients displayed a prompt increase in endogenous testosterone levels during the study period, reaching levels in the adult male range (> 250 ng/dl). The remaining 10 boys showed sluggish changes in endogenous testosterone during the investigation, ranging from 35-177 ng/dl. The bone ages and testicular sizes of the two groups at study initiation did not differ though urine LH was significantly less at study entry in the slowly maturing group. The data reveal a great diversity in the pace and pattern of endogenous testosterone changes in the study population. The results also suggest that exogenous sex steroid treatment of such patients does not speed up the central nervous system processes controlling the onset and progression of puberty. Boys with delayed puberty should be followed until endogenous testosterone levels reach the adult male range in order to rule out mild gonadotropin deficits.

Adolescent↗
PubMed1999

A synthetic peptide corresponding to amino acid residues 90 to 95 of human follicle-stimulating hormone beta-subunit delays the onset of puberty in female Swiss Webster mice.

We have recently reported that a synthetic peptide corresponding to amino acid residues 81-95, a receptor-binding region of the human FSH-beta-subunit, and a subdomain within this region, hFSH-beta-(90-95) (DSTDCT), prolonged vaginal estrus when administered intraperitoneally (ip) to normally cycling Swiss Webster mice. These results were similar to those we reported for a synthetic peptide corresponding to hFSH-beta-(34-37) [TRDL, a subdomain within receptor-binding region hFSH-beta-(33-53)] in the same model system. TRDL also accelerated the onset of puberty in immature mice. We now report the effects of hFSH-beta-(90-95) in prepubertal female mice. In two separate experiments, a single ip injection of 200 microg/g body weight (BW) hFSH-beta-(90-95) in phosphate buffered saline (PBS, vehicle) administered to mice on day 28 delayed first vaginal estrus by 3 days in 50% (4/8) and 62.5% (6/8) when compared to mice given vehicle alone on day 28. Vaginal opening was also delayed in mice receiving hFSH-beta-(90-95) when compared to mice injected with vehicle alone. Serum estradiol levels of vehicle-injected control mice in first vaginal estrus were three-fold higher than in mice treated with hFSH-beta-(90-95), whose vaginal smears showed no evidence of first estrus. No significant differences in ovarian or uterine weights, or serum progesterone levels, were observed between vehicle-injected control mice achieving first vaginal estrus and mice receiving hFSH-beta-(90-95) in whom first estrus was delayed. The contrasting effects on the onset of puberty of hFSH-beta-(90-95) (delay) and hFSH-beta-(34-37) (acceleration) may reflect synthetic peptide binding to different domains of the FSH receptor, resulting in variable post-binding effects. These results are consistent with our earlier study suggesting that FSH-beta-subunit-related synthetic peptides can induce significant in vivo effects on the onset of puberty in female mice.

Animals↗
PubMed2006

[Pubertal growth and final height in 40 patients with type 1 diabetes mellitus].

OBJECTIVE: Type 1 diabetes mellitus (DM1), the most important chronic endocrine-metabolic disease in children and adolescents, may lead to delayed growth and puberty. In this study we analyzed the influence of DM1 on growth spurt and puberty of patients whose onset of the disease was before or at the beginning of this phase. PATIENTS AND METHODS: Data from 40 patients, 25 females, who had attained final height were retrospectively obtained, including duration of disease, patient's height and weight SDS at each consultation, parental target height, yearly growth velocities (GV), peak of growth spurt, duration of puberty, magnitude of growth spurt and glycated hemoglobin (HbA1C) levels. RESULTS: 37 patients had an adequate final height to parental target height, and only 3 were below the lower limit. There was no significant association among the variables and the appropriate final height to the target height, except for GV on growth spurt, when it was lower than or equal to 6 cm/year. The age of onset of DM1 and the age of peak of growth spurt was similar to previously data reported; regarding the age of the onset of puberty, there was no delay. However, the magnitude of the growth spurt and the peak of GV were lower. According to HbA1C levels, all patients exhibited a bad chronic control of DM1. CONCLUSIONS: In this group of inadequately controlled patients, the final height was lower than expected when compared to the height at onset of DM1, probably due to a slow GV during puberty, which however had no influence on the final height to parental target height.

Adolescent↗
PubMed1992

Endocrine events prior to puberty in heifers: role of somatotropin, insulin-like growth factor-I and insulin-like growth factor binding proteins.

We have utilized active immunization against growth hormone releasing factor (GRF) to investigate relationships among somatotropin (ST), insulin-like growth factor-I (IGF-I), IGF binding proteins (IGFBP) and ovarian function in heifers. Active immunization against GRF (GRFi) has been demonstrated to abolish episodic release of ST and decrease serum concentrations of IGF-I. In initial experiments investigating onset of puberty, breeds of heifers differing in growth rate and reproductive traits (Angus, Charolais and Simmental) were immunized against GRF or served as controls (immunized against carrier protein, human serum albumin, HSAi). GRFi decreased rate of muscle and skeletal growth, but increased deposition of adipose tissue. In Angus and Charolais, but not Simmental heifers, GRFi at 6 mo of age significantly delayed onset of puberty beyond 18 mo of age. Retrospective analyses of serum IGF-I revealed that GRFi heifers reaching puberty at a normal age had greater pre-treatment (6 mo of age) IGF-I than GRFi heifers in which puberty was delayed. Collectively, these results strongly indicate that the bovine hypothalamic-hypophyseal-ovarian axis is particularly sensitive to changes in metabolism at or near 6 mo of age. Another series of experiments tested the hypothesis that lowering serum IGF-I via GRFi initially at 3 mo of age would increase the percentage of Angus and Simmental heifers not reaching puberty. Three mo old Angus and Simmental heifers were assigned to GRFi (n = 18), HSAi (n = 14) or received no treatment (controls, n = 16). HSAi and GRFi heifers were unilaterally ovariectomized (ULO) at 6 mo of age. As anticipated, GRFi at a younger age increased percentage of heifers not reaching puberty; over 75% of control and HSAi heifers reached puberty by 14 mo of age compared to 22% of GRFi heifers. Serum and follicular fluid (FFL; follicles < or = 4 mm) concentrations of IGF-I were suppressed by GRFi. Serum, but not FFL concentrations of IGF binding protein-2 (IGFBP-2) were greater in GRFi than in HSAi heifers. GRFi delayed puberty apparently by suppressing follicular growth because number of follicles < or = 7 mm was significantly lower in GRFi than in HSAi heifers. In conclusion, active immunization against GRF at 3 or 6 months of age delays puberty in beef heifers. Delayed puberty was preceded by suppression of follicular growth, and decreased concentrations of IGF-I in serum and follicular fluid.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed2004

Reduced growth hormone secretion prolongs puberty but does not delay the developmental increase in luteinizing hormone in the absence of gonadal negative feedback.

Previous studies have shown that the growth hormone (GH) axis is important for timing the later stages of puberty in female monkeys. However, it is not clear whether these growth-related signals are important for the initiation of puberty and early pubertal events. The present study, using female rhesus monkeys, used two approaches to answer this question. Experiment 1 tested the hypothesis that reduced GH secretion would blunt the rise in nocturnal LH secretion in young (17 mo; n = 7) but not older adolescent ovariectomized females (29 mo; n = 6). Reduced GH secretion was induced by treating females with the sustained release somatostatin analogue formulation, Sandostatin LAR (625 microg/kg). Morning (0900-0930 h) and evening (2200-2230 h) concentrations of bioactive LH were higher in older adolescent compared to young adolescent females. However, diurnal concentrations were not affected by the inhibition of GH secretion in either age group when compared to the placebo-treated, control condition. Experiment 2 tested the hypothesis that reduced GH secretion induced in young juvenile females would delay the initial increase in nocturnal LH secretion and subsequent early signs of puberty. In order to examine this hypothesis, puberty in control females (n = 7) was compared to those in which puberty had been experimentally arrested until a late adolescent age (29 mo) by the use of a depot GnRH analogue, Lupron (750 microg kg(-1) mo(-1); n = 7). Once the analogue treatment was discontinued, the progression of puberty was compared to a group treated in a similar fashion but made GH deficient by continuous treatment with Sandostatin LAR (n = 6). Puberty occurred as expected in control females with the initial rise in evening LH at 21 mo, menarche at 22 mo, and first ovulation at 30 mo. As expected, Lupron arrested reproductive maturation, but elevations in morning and evening LH and menarche occurred within 2 mo of the cessation of Lupron in both Lupron and Lupron-GH-suppressed females. In contrast, first ovulation was delayed significantly in the Lupron-GH-suppressed females (41 mo) compared to the Lupron-only females (36 mo). These data indicate that within this experimental model, reduced GH secretion does not perturb the early stages of puberty but supports previous observations that the GH axis is important for timing the later stages of puberty and attainment of fertility. Taken together, the data indicate that factors that reduce GH secretion may have a deleterious effect on the completion of puberty.

Animals↗
PubMed1993

Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma.

BACKGROUND: Growth in stature in asthmatic adolescents may be delayed compared to normals as a result of treatment with inhaled corticosteroids (CS) or because of a delay in puberty. However, growth rates in asthmatic children have never been studied when treatment with CS was randomized and when growth was compared with that of matched healthy control subjects. OBJECTIVE: To assess the long-term effect of CS treatment on growth rates in asthmatic adolescents. METHODS: Participants were 40 asthmatic teenagers (mean age 12.8 years) who received randomized treatment with 0.2 mg of albuterol (salbutamol) with either placebo three times a day (BA + PL) or 0.2 mg of budesonide three times a day (BA + CS) for a median period of 22 months in a double-blind controlled study. Growth rates were compared with those of 80 control subjects who were matched for sex, age, height, and duration of follow-up. RESULTS: Growth rates in male patients, but not in female patients, were significantly less than in control subjects (P < .05), a finding consistent with a delay of puberty due to asthma. The mean difference (95% confidence interval) in growth rates between patients treated with BA+PL and their controls was -0.70 (-1.62, 0.22) cm/y; that between patients treated with BA + CS and their controls was -0.44 (-1.25, 0.37) cm/y. The observed mean (SEM) case-control difference between treatment groups was +0.27 (0.58) cm/y in favor of BA + CS. CONCLUSION: Growth retardation observed in adolescents with asthma may be due to a delay in puberty but not to the prescription of 0.6 mg of budesonide daily.

Administration, Inhalation↗
PubMed1992

Growth and sexual maturation of Brazilian patients with sickle cell diseases.

Growth and sexual maturation was studied of 125 Brazilian patients with sickle cell disease whose ages ranged from 7 months to 42 years. Height and weight were significantly lower when compared with the unaffected population. The height and weight deficit increased in the age range of 11-19 years as compared with patients less than 11 years of age. Age of menarche, breast and pubic hair staging in girls, and genitalia staging and testicular volume measurements in boys indicated a delayed sexual maturation for both sexes. The comparison of adult and young patients, however, demonstrated that although puberty is delayed, a normal sexual maturation is attained later in life by most patients.

Adolescent↗
PubMed2005

Fetal nutrition and timing of puberty.

Over the last decade growing evidence has been documented on the relationship between intrauterine growth retardation (IUGR) and pubertal development indicating changes in timing and progression of puberty. These changes in pubertal development are part of a growing list of IUGR-related diseases, which includes type 2 diabetes mellitus, cardiovascular disease, short stature and polycystic ovary syndrome. The influence of IUGR on the mechanisms behind the onset of puberty is still elusive. In the absence of prospective studies on gonadotropin-releasing hormone pulse patterns in IUGR children, other markers of pubertal development such as age at menarche in girls and progression of puberty have been employed. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) after third trimester growth retardation and children born appropriate for gestational age (AGA). A faster progression of puberty was found in girls but not in boys. DHEAS levels tended to be higher in SGA children than in AGA children. In animal studies using two rat models, growth and onset of puberty based on perinatal undernutrition were also investigated. In one model intrauterine growth retardation was induced by ligation of the uterine arteries (IUGR) at day 17 of gestation and in the other model postnatal food restriction (FR) was induced by increasing litter size after birth until weaning. In both models, the rats showed a persistent growth failure. Onset of puberty was defined by vaginal opening (VO) in female rats and by balanopreputial separation (BPS) in male rats. At onset of puberty IUGR and FR rats had a lower body weight compared to controls, indicating that no threshold for body weight is needed for the onset of puberty. In the IUGR female rats, the onset of puberty was delayed and in the FR female rats the onset of puberty was in time. In both IUGR and FR female rats VO and first cycle were uncoupled. In IUGR female rats, at VO, at first cycle and at the age of 6 months the ovaries showed a decline in number of follicles indicating that intrauterine malnutrition in the female rat has a permanent influence on the growth and development of follicles. In the FR female rats, at VO, the ovaries showed a normal number of follicles but an abnormal maturation pattern. At the time of first cycle and at the age of 6 months normalization in follicle growth pattern was observed. These findings suggest that postnatal undernutrition has a transient influence on follicle growth and development. In male rats, both models showed delayed onset of puberty and impaired testicular function, as shown by decreased testosterone levels. These data indicate that early malnutrition during different critical developmental time windows may result in different long-lasting effects on pubertal development in both humans and rats.

Animals↗
PubMed2006

Early influences on the tempo of puberty.

Fetal growth retardation appears to be associated with an increased risk of premature adrenarche, early puberty, polycystic ovary syndrome and associated fertility problems. In a rat model of intrauterine growth retardation, based on ligation of the uterine arteries, the onset of puberty was delayed in female pups, with anovulation during the first cycle. The ovaries showed a lower number of follicles. The onset of puberty was also delayed in male pups. Testosterone production was lower in these growth-retarded rats compared with controls. The relationship between birth weight and the onset of puberty and pubertal progression in different cohorts of healthy children has been examined. In girls, no differences were observed in timing and progression of puberty, including age of menarche, between groups of different birth weights. In boys, a relatively delayed onset of puberty was observed in those with low birth weight, with a normally timed progression. In children with low birth weight, particularly boys, higher dehydroepiandrosterone levels were found compared with children with a normal birth weight, indicating an overactive adrenal gland in children with low birth weight. These data indicate that impaired fetal growth may have long-lasting effects on pubertal development. The fact that results of human studies on the relationship between fetal growth and the onset of puberty are often controversial may be explained by the heterogeneity of children born small for gestational age with respect to the intrauterine insult that they experience. From rat studies, it is clear that a serious intrauterine insult associated with growth failure can lead to dysregulation of puberty and gonadal function.

Adolescent↗