Factors affecting onset of puberty

In humans, foetal and early postnatal growth failure may have persistent consequences for growth and pubertal development in later life. During this period, the developing organs are still plastic to change their function, which may have long-lasting effects. At the time of onset of puberty, acute factors may also interfere with pubertal development. Malnutrition, as seen in anorexic patients, and chronic diseases with malabsorption or diseases with systemic effects result in a delayed onset of puberty. We have observed an earlier onset of puberty in girls with low birth weight; menarcheal age also tended to be earlier. In boys, a low birth weight tended to be associated with a later development. Two rat models with growth failure based on perinatal malnutrition have been examined, one with intrauterine growth retardation (IUGR) by ligation of the uterine arteries and one with postnatal food restriction (FR) by increasing the litter size postnatally. In both models, the rats had a persistent postnatal growth failure. The onset of puberty in female rats, defined by vaginal opening, was delayed only in the IUGR group. Despite a significantly lower weight, there was no difference in the timing of puberty onset in the FR group. In IUGR rats, the ovaries had fewer follicles, while FR rats had a normal number of follicles but an abnormal maturation pattern. In male rats, both models showed a delayed onset of puberty, defined by the balano-preputial separation, as well as impaired testicular function, shown by decreased testosterone levels. These data indicate that early malnutrition during a critical developmental time window may have long-lasting effects on pubertal development, including gonadal maturation in both humans and rats.     

Neuroendocrine dysfunction in polycystic ovary syndrome

Polycystic ovarian syndrome (PCOS) is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Neuroendocrine abnormalities including increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased luteinizing hormone (LH) pulsatility, and relatively decreased follicle stimulating hormone contribute to its pathogenesis. HA reduces inhibition of GnRH pulse frequency by progesterone, causing rapid LH pulse secretion and increasing ovarian androgen production. The origins of persistently rapid GnRH secretion are unknown but appear to evolve during puberty. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. However, even early pubertal girls with HA have increased LH pulsatility and enhanced daytime LH pulse secretion, indicating the abnormalities may begin early in puberty. Decreasing sensitivity to progesterone may regulate normal maturation of LH secretion, potentially related to normally increasing levels of testosterone during puberty. This change in sensitivity may become exaggerated in girls with HA. Many girls with HA-especially those with hyperinsulinemia-do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA and the development of PCOS.     

Ascertainment and treatment of delayed puberty

The majority of patients with pubertal delay, can be classified as having primary pubertal delay (constitutional delay of growth and puberty, CDGP), although any child with a chronic disease could present with delayed puberty. In contrast, children with hypogonadism, either hyper- or hypogonadotropic, exhibit a total absence of pubertal development. Hence, early evaluation of these patients should be performed. Delay of puberty leads to psychological problems, secondary to short stature and/or delay in the acquisition of secondary sex characteristics and the reduction of bone mass. Although the final height in patients with CDGP is usually normal, some of these patients do not reach the third percentile or remain in the lowest part of the growth chart according to familial height. The most common reason for treating CDGP patients, usually with sex steroids, is for psychological difficulties and for loss of bone mineralization. Treatment must be individualized. Therapeutic options and new drugs will be discussed. Appropriate treatment and adequate nutritional intake are indicated in patients with delayed puberty due to chronic illness. In patients with hypo- or hypergonadotropic hypogonadism, puberty must be induced or completed. Different treatments (GnRH analogues, gonadotropins and sex steroids), and the main objectives are discussed.     

Forty years trends in timing of pubertal growth spurt in 157,000 Danish school children

Background

Entering puberty is an important milestone in reproductive life and secular changes in the timing of puberty may be an important indicator of the general reproductive health in a population. Too early puberty is associated with several psychosocial and health problems. The aim of our study was to determine if the age at onset of pubertal growth spurt (OGS) and at peak height velocity (PHV) during puberty show secular trends during four decades in a large cohort of school children.

Methods and Findings

Annual measurements of height were available in all children born from 1930 to 1969 who attended primary school in the Copenhagen Municipality. 135,223 girls and 21,612 boys fulfilled the criteria for determining age at OGS and age at PHV. These physiological events were used as markers of pubertal development in our computerized method in order to evaluate any secular trends in pubertal maturation during the study period (year of birth 1930 to 1969). In this period, age at OGS declined statistically significantly by 0.2 and 0.4 years in girls and boys, respectively, whereas age at PHV declined statistically significantly by 0.5 and 0.3 years in girls and boys, respectively. The decline was non-linear with a levelling off in the children born between 1940 and 1955. The duration of puberty, as defined by the difference between age at OGS and age at PHV, increased slightly in boys, whereas it decreased in girls.

Conclusion

Our finding of declining age at OGS and at PHV indicates a secular trend towards earlier sexual maturation of Danish children born between 1930 and 1969. Only minor changes were observed in duration of puberty assessed by the difference in ages at OGS and PHV.     

Puberty in chronically diseased patients

Delayed onset of puberty and a reduced pubertal growth spurt are often reported in patients suffering from chronic diseases. The basis of abnormal puberty in these patients is multifactorial. Nutritional deficiency may contribute to growth disorders and delayed puberty. Insufficient food supply and/or eating disorders and/or malabsorption of nutrients can be observed in these patients. Moreover, increased energy supplies are often needed in patients with chronic lung disease, infection or inflammation. More specific factors due to the disease itself may be involved in growth and puberty disorders. Abnormalities of the growth hormone (GH)-insulin-like growth factor (IGF)1 axis and gonadotrophin secretion have been described in patients with chronic renal failure, cystic fibrosis and Crohn's disease. More recently, it has been shown that cytokines produced during chronic diseases such as juvenile idiopathic arthritis may affect the GH-IGF1 axis. Finally, concomitant medication, namely corticosteroids, which are often given to these patients, may contribute to delayed puberty and poor pubertal growth.     

Pubertal growth of the short normal girl

OBJECTIVES: To determine the timing, magnitude and duration of the pubertal spurt for short normal and average height girls, to compare these with Tanner's standard and to investigate predictors of pubertal growth. METHODS: The growth of 46 short normal and 55 control girls, identified at school entry, was monitored throughout puberty. Height and weight were measured at 6-month intervals from which body mass index (BMI) was derived. Annual velocities were calculated and used to estimate the age and magnitude of peak height velocity (PHV). Age of menarche was recorded to the nearest month. Parents provided information on the child's medical and social history. RESULTS: The mean age at PHV, the magnitude of PHV and age at menarche were similar for both groups and close to Tanner's 50th centile values. Pre-pubertal BMI predicted age at menarche for short and control girls, accounting for 17% of the variance. There was a tendency for early maturing girls of average stature to have greater PHV. However, this relationship was not observed in short girls, nor did any other variable, genetic or environmental, predict the timing or magnitude of their pubertal spurt. CONCLUSIONS: Delayed puberty in short normal girls is unlikely and their growth during puberty is comparable to girls of average height. The pubertal variables measured remain close to Tanner's original standards for both groups, suggesting the lack of a secular trend towards earlier puberty in girls. The onset of menstruation is influenced by pre-pubertal BMI. However, the clinician should be aware that short normal girls have normal pubertal growth and that no genetic or environmental variable can predict the timing or magnitude of their growth spurt.     

Timing of puberty and synchronization of seasonal rhythms by simulated natural photoperiods in female Siberian hamsters

The timing of puberty is a critical life history trait of short-lived species; spring-born individuals mature rapidly and breed in the season of birth, whereas young born in mid- to late summer delay puberty until the next spring. The cues that govern the transition from rapid to delayed maturation in natural populations remain unknown. To identify ecologically relevant photoperiod cues that control timing of puberty, we monitored nine cohorts of female Siberian hamsters (Phodopus sungorus) born every 2 wk from 4 wk before to 12 wk after the summer solstice in a simulated natural photoperiod (SNP). Hamsters born by the summer solstice underwent rapid somatic growth and achieved puberty that summer; among females born 2-4 wk after the solstice, some delayed puberty by many weeks, whereas others manifested early puberty. Hamsters born 6 or more weeks after the solstice generally delayed puberty until the following spring. The transition from accelerated to delayed pubertal development in the SNP occurred at day lengths that induce early puberty when presented as static photoperiods. Despite differences in timing of birth and timing of puberty, fall and subsequent spring seasonal events occurred at similar calendar dates in all cohorts. We found no evidence that prenatal photoperiod history influenced postnatal development of female hamsters. Considered together with a parallel study on males, the present findings point to sex differences in responsiveness to natural photoperiod variations. In both sexes, incrementally changing photoperiods exert a strong organizing effect on seasonal rhythms.     

Gene-environment interactions, not neonatal growth hormone deficiency, time puberty in female rhesus monkeys

The factors that influence the timing of puberty and the onset of adult fertility are poorly understood. While focus on the juvenile period has provided insights into how growth-related cues affect pubertal timing, growth velocity during infancy that is sustained into the juvenile period may be important. On the other hand, social factors, specifically exposure to psychosocial stressors, can delay sexual maturation, possibly by altering growth velocities during development. Using female rhesus monkeys, the present study used a prospective analysis to determine how neonatal growth hormone (GH) inhibition with a sandostatin analog or suppression of the pituitary-gonadal axis with a GnRH analog affected growth and sexual maturation. A separate retrospective analysis was done assessing the effects of social dominance status during development on pubertal timing. Because a specific polymorphism in the gene encoding the serotonin (5HT) reuptake transporter increases vulnerability to psychosocial stressors, females were also genotyped and were then classified as socially dominant, having both alleles for the long promoter variant or having at least one allele for the short promoter variant, or as socially subordinate, having the long variant or having the short variant. Neonatal treatments were not balanced for social status or genotype, so analyses were performed separately. Although the neonatal treatments reduced GH secretion postnatally and through the juvenile period, neither growth nor sexual maturation was affected. In contrast, the retrospective analysis showed sexual maturation was delayed significantly in subordinate females carrying at least one allele of the short promoter variant in the gene encoding the 5HT reuptake transporter, and this delay was associated with reduced GH and leptin secretion during the juvenile phase but not with differences in growth velocities from birth. These data suggest that decreased neonatal GH secretion does not adversely affect sexual maturation, but that polymorphisms in the gene encoding the 5HT transporter modulate the adverse consequences of social subordination on the timing of puberty in female rhesus monkeys.     

The role of estrogen in bone growth and maturation during childhood and adolescence

Twenty years ago it was believed that pubertal growth was stimulated by testicular androgen in boys and by adrenal androgen in girls. Estrogen, which was used to inhibit growth in excessively tall girls, was not thought to have growth-promoting effects. We hypothesized that estrogen has a biphasic effect on epiphyseal growth, with maximal stimulation at low levels. We showed that the administration of low doses of estrogen, corresponding to a serum estradiol level of about 4 pg/ml (15 pmol/l) caused more than a 60% increase over the prepubertal growth rate in both boys and girls. To test the hypothesis that estrogen is the principal mediator of the pubertal growth spurt in boys, we administered the aromatase inhibitor, testolactone, to boys with familial male-limited precocious puberty. Testolactone produced near normalization of both growth velocity and bone maturation, despite levels of serum testosterone that remained within the adult male range. The observation that low levels of estrogen stimulate growth and bone maturation suggested that estrogen might explain the more rapid epiphyseal maturation of prepubertal girls compared to boys. To determine whether prepubertal girls have higher estrogen levels than prepubertal boys, we developed an ultrasensitive recombinant cell bioassay for estrogen with a sensitivity of 0.02 pg/ml (0.07 pmol/l) estradiol equivalents. Prepubertal girls had approximately eight-fold higher levels of serum estradiol than did prepubertal boys (0.6 ± 0.6 pg/ml (SD) (2.2 ± 2.2 pmol/l) vs 0.08 ± 0.2 pg/ml (0.29 ± 0.73 pmol/l), P < 0.05). We concluded that the pubertal growth spurt of both sexes is driven primarily by estrogen, and that the more rapid epiphyseal maturation of prepubertal girls (vs boys) may be explained by their higher estradiol levels.     

Diagnostic utility of a low-dose gonadotropin-releasing hormone test in the context of puberty disorders

OBJECTIVES: The 10-microg gonadotropin-releasing hormone (GnRH) test assesses pituitary gonadotroph responsiveness, whereas the 100-microg dose assesses maximal secretory capacity. Our aims were to establish normative data for the low-dose test in children and to evaluate the test in diagnosing common pubertal disorders. METHODS: We retrospectively classified 107 children who underwent 10-microg GnRH tests into normal prepubertal (20 boys, 10 girls), normal early pubertal (10 boys, 16 girls), constitutional delay of puberty (CDP, 13 prepubertal boys >12 years), hypogonadotropic hypogonadism (HH, 5 prepubertal boys >12 years), central precocious puberty (CPP, 19 girls) or premature thelarche/variant (13 girls). RESULTS: Peak LH response was higher in prepubertal boys >12 years compared with younger boys (p < 0.01) but showed no further change in early puberty. CDP boys had LH responses similar to prepubertal boys >12 years. HH boys showed an absent LH response which diagnosed HH with 100% sensitivity and 96% specificity. Thelarche girls had LH:FSH peak ratios lower than normal prepubertal (p = 0.001), pubertal (p < 0.05) or CPP (p = 0.001) girls. CONCLUSIONS: We have established normative values for the low-dose GnRH test in children. The test successfully differentiated HH from CDP in boys, and contributed to the differential diagnosis of CPP and premature thelarche in girls.     

Diurnal and Seasonal Cortisol,Testosterone, and DHEA Rhythms in Boys and Girls during Puberty

Diurnal and seasonal rhythms of cortisol, testosterone, and DHEA were examined, as little is known about the relationship between these rhythmicities and pubertal development. Salivary samples were obtained from 60 boys and 60 girls at approximately 07∶45, 08∶00, 08∶30, 12∶00, 16∶50, and 21∶00 h. The participants' ages ranged from 8–14 yrs, and each participant was tested three times at six‐month intervals. The study was conducted at a General Clinical Research Center (GCRC) and at the homes of the participants. All hormones showed diurnal fluctuations. The acrophase (peak time) of cortisol occurred earlier than for testosterone or DHEA and showed a seasonal effect, with the acrophase occurring earlier in spring than in summer. The cortisol acrophase also occurred later in the day for boys than for girls during later puberty. Seasonal effects were found only for cortisol with higher concentrations in the spring and summer. Cortisol concentrations were relatively stable across pubertal maturation, but significantly lower concentrations were observed at pubertal stage 3 compared to the other stages. Morning cortisol levels were also higher in boys at pubertal stage 2. Testosterone concentrations were higher in boys at pubertal stages 3 and 4, and DHEA was lower at pubertal stage 1 than 3 and 4 for both boys and girls. For the total sample, there was a positive correlation between DHEA and testosterone during early puberty (stages 1–3) but not later puberty (stages 4–5). Awakening secretory activity correlated with daytime secretory activity for testosterone and DHEA, but not for cortisol. These data provide novel chronobiological information on cortisol, testosterone, and DHEA as it relates to sexual maturation and encourage further study on both normal and abnormal endocrine rhythms.     

Diurnal and seasonal cortisol, testosterone, and DHEA rhythms in boys and girls during puberty

Diurnal and seasonal rhythms of cortisol, testosterone, and DHEA were examined, as little is known about the relationship between these rhythmicities and pubertal development. Salivary samples were obtained from 60 boys and 60 girls at approximately 07:45, 08:00, 08:30, 12:00, 16:50, and 21:00 h. The participants' ages ranged from 8-14 yrs, and each participant was tested three times at six-month intervals. The study was conducted at a General Clinical Research Center (GCRC) and at the homes of the participants. All hormones showed diurnal fluctuations. The acrophase (peak time) of cortisol occurred earlier than for testosterone or DHEA and showed a seasonal effect, with the acrophase occurring earlier in spring than in summer. The cortisol acrophase also occurred later in the day for boys than for girls during later puberty. Seasonal effects were found only for cortisol with higher concentrations in the spring and summer. Cortisol concentrations were relatively stable across pubertal maturation, but significantly lower concentrations were observed at pubertal stage 3 compared to the other stages. Morning cortisol levels were also higher in boys at pubertal stage 2. Testosterone concentrations were higher in boys at pubertal stages 3 and 4, and DHEA was lower at pubertal stage 1 than 3 and 4 for both boys and girls. For the total sample, there was a positive correlation between DHEA and testosterone during early puberty (stages 1-3) but not later puberty (stages 4-5). Awakening secretory activity correlated with daytime secretory activity for testosterone and DHEA, but not for cortisol. These data provide novel chronobiological information on cortisol, testosterone, and DHEA as it relates to sexual maturation and encourage further study on both normal and abnormal endocrine rhythms.     

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.     

Treatment of late puberty

The induction of puberty is physically and emotionally disturbing. For that reason, low doses of medication need to be introduced and increased slowly, regardless of the age at which treatment is started. In boys with growth delay, the growth spurt may be induced earlier in the sequence of pubertal developmental by using oxandrolone, but puberty itself is induced by slowly increasing doses of testosterone. For girls with ovarian failure, oestradiol should be introduced from the age of 8 or 9 years, but doses should be very cautiously increased in order to allow time for cosmetic development of breasts and growth of the uterus.     

Different patterns of puberty effect in neural oscillation to negative stimuli: sex differences

The present study investigated the impact of puberty on sex differences in neural sensitivity to negative stimuli. Event-related oscillation technique was used. Because girls are more vulnerable to affective disturbances than boys during adolescence, it was hypothesized that puberty exerts different influences on neural sensitivity to negative stimuli in boys and girls. EEGs were recorded for highly negative (HN), mildly negative (MN) and neutral pictures, when boys and girls distinct in pubertal status performed a non-emotional distracting task. No emotion effect and its interaction with sex and puberty were observed in response latencies. However, puberty influenced the gamma-band oscillation effect for negative stimuli differently for boys and girls: Pre-pubertal boys showed a significant emotion effect for HN stimuli, whose size was decreased in pubertal boys. By contrast, there was a significant emotion effect for HN stimuli in pubertal girls but not in pre-pubertal girls. On the other hand, the size of the emotion effect for HN stimuli was similar for pre-pubertal boys and girls; while this effect was significantly more pronounced in pubertal girls compared to pubertal boys. Additionally, the size of the emotion effect in gamma oscillations decreased as a function of pubertal development during both HN and MN stimulation in boys. For girls, the emotion effect in gamma oscillations increased with pubertal development during HN stimulation. Thus, puberty is associated with reduced neural sensitivity in boys but increased sensitivity in girls, in reaction to negative stimuli. The implications of these results for the psychopathology during adolescence were discussed.     

Sex‐Specific Fat Distribution Is Not Linear Across Pubertal Groups in a Multiethnic Study

Objective: To investigate sexual dimorphism and race differences in fat distribution (android/gynoid) before and during puberty. Research Methods and Procedures: Fat distribution was measured by skinfold thickness and DXA in healthy African‐American, Asian, and white subjects (n = 920), divided into pre‐, early, and late pubertal groups. Results: Gynoid fat masses adjusted for covariates were lower in late pubertal compared with prepubertal boys, but were not consistently greater in late pubertal compared with prepubertal girls. Progression of sex‐specific fat distribution with increasing maturation was present in Asians only. Among African‐American and white subjects, early pubertal boys had greater gynoid fat mass compared with the prepubertal group, whereas early pubertal girls had less gynoid fat mass compared with the prepubertal group. Sexual dimorphism in fat distribution was present in all pubertal groups, except among whites at early puberty. Among girls, Asians had lower gynoid fat than whites and African Americans in all pubertal groups. Among boys, Asians had less gynoid fat by DXA in early puberty and late puberty. Discussion: Comparison among races demonstrated differences in sexual dimorphism and sex‐specific fat distribution with progression in pubertal group. However, in all race groups, the fat distribution of late pubertal boys was more “male” or “android” than prepubertal boys, but late pubertal girls did not differ consistently from prepubertal girls. These findings suggested that the greater sexual dimorphism of fat distribution in late puberty compared with prepuberty may be attributable to larger changes in boys with smaller changes in girls.     

Low serum allopregnanolone levels in girls with precocious pubarche

Allopregnanolone, a neuroactive steroid, increases during pubertal development and high concentrations are present in subjects with precocious puberty. The aim of the present study was to evaluate serum allopregnanolone levels in girls with precocious pubarche (PP). Basal gonadotropins and steroid hormones were assessed in 17 girls with PP, 22 girls with central precocious puberty (CPP), 25 girls with normal puberty at the same pubertal stage of CPP ones, and 17 prepubertal girls. Adrenocorticotropin hormone (ACTH) and gonadotropin-releasing hormone (GnRH) stimulation tests were performed in all subjects with PP, and in 12 out of 22 with CPP. All girls with normal puberty underwent to GnRH test, while ACTH test was performed in 17 out of 25. Basal dehydroepiandrosterone sulfate (DHEAS) concentrations resulted significantly higher in PP and normal pubertal girls than in prepubertal ones. Allopregnanolone, gonadotropins and estradiol levels were significantly lower in PP group with respect to CPP (P<0.05), while they were comparable among PP, normal pubertal and prepubertal groups. After ACTH administration, allopregnanolone concentrations significantly increased in all groups (P<0.05). After GnRH stimulation, its levels significantly increased in CPP and normal pubertal controls (P<0.05), while no incremental rise was found in PP girls. In conclusion, our study shows that in girls with PP basal and GnRH-stimulated levels of allopregnanolone are significantly lower than in CPP girls. These data suggest that this neurosteroid may be considered a new marker of pubertal development.     

Age at Puberty and the Emerging Obesity Epidemic

Background

Recent studies have shown that puberty starts at younger ages than previously. It has been hypothesized that the increasing prevalence of childhood obesity is contributing to this trend. The purpose of this study was to analyze the association between prepubertal body mass index (BMI) and pubertal timing, as assessed by age at onset of pubertal growth spurt (OGS) and at peak height velocity (PHV), and the secular trend of pubertal timing given the prepubertal BMI.

Methodology/Principal Findings

Annual measurements of height and weight were available in all children born from 1930 to 1969 who attended primary school in the Copenhagen municipality; 156,835 children fulfilled the criteria for determining age at OGS and PHV. The effect of prepubertal BMI at age seven on these markers of pubertal development within and between birth cohorts was analyzed. BMI at seven years was significantly inversely associated with age at OGS and PHV. Dividing the children into five levels of prepubertal BMI, we found a similar secular trend toward earlier maturation in all BMI groups.

Conclusion/Significance

The heavier both boys and girls were at age seven, the earlier they entered puberty. Irrespective of level of BMI at age seven, there was a downward trend in the age at attaining puberty in both boys and girls, which suggests that the obesity epidemic is not solely responsible for the trend.     

Growth curves of children with Down syndrome.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight. These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.