Leptin levels during estrogenization phases in pubertal girls

OBJECTIVE: We searched for associations between leptin levels, basic body composition, primary, secondary and tertiary sex features during pre-menarche without signs of estrogenization, estrogenic crisis and full estrogenization. MATERIAL AND METHODS: The study group consisted of 45 healthy girls over the age of 8 years. Height, body mass, BMI, basic body composition and plasma concentration of leptin were determined every three months. In addition, ultrasound of the ovaries, uterus and breasts was done. RESULTS: The highest levels of leptin were observed in girls without signs of estrogenization. The ratio of leptin/fat (ng/ml/kg) was higher in pubertal girls, particularly those without signs of estrogenization, than in adult women. CONCLUSIONS: The estrogenic crisis was accompanied by a reduction in body mass, followed by the pubertal acceleration of growth and increase in fatty, lean and total body mass. The correspondence of tertiary sex features with pre-menarche, estrogenic crisis and full estrogenization phases did not exceed 55%. Enlargement of the uterine body was followed by a dynamic growth of ovaries. Individual variation in ovarian size was significant. Changes in leptin levels occurring during estrogenization point to the importance of this protein in metabolic signaling.     

Inhibin B in pubertal development and pubertal disorders

The inhibin B pubertal surge is a prominent signal of gonadal maturation in females as well as in males. In boys, it denotes the final functional maturation of Sertoli cells, which is accompanied by a progressive suppression of antimüllerian hormone production. In girls it reflects the initial recruitment of preantral follicles and their evolution to the antral stage. In both the prepubertal quiescent phase and the active peripubertal phase there is a striking sexual dimorphism, inhibin B levels being significantly higher in boys than in girls, in contrast to follicle-stimulating hormone (FSH) levels. Determining inhibin B levels together with FSH levels is of considerable help for diagnosing disorders of pubertal development. In girls with central precocious precocity, inhibin B levels are in accordance with the clinical stage of maturation, by contrast to normal or low levels in the McCune-Albright syndrome. In boys with delayed puberty, inhibin B levels are very low in congenital defects of the gonadotropin-releasing hormone-FSH-testis axis, but they are normal or intermediate in constitutional delayed puberty. Together with antimüllerian hormone, inhibin B is a useful marker of the presence of Sertoli cells in bilateral cryptorchidism and in the androgen insensitivity syndrome. In addition, inhibin B measurement, together with that of inhibin A, is helpful for the diagnosis and follow-up of inhibin-secreting tumors: granulosa cell tumors in girls and Sertoli cell tumors of the Peutz-Jeghers syndrome in boys. In conclusion, inhibin determination is an essential tool in the assessment of physiological development as well as in the management of pubertal disorders.     

Disorders of pubertal development

Puberty is the period of life during which reproductive capability is acquired. It is characterized clinically by the acquisition of secondary sexual characteristics associated with a growth spurt, and on average takes 3-4 years. Early maturation is defined as the development of sexual characteristics before the age of 8 years in girls and 9 years in boys. Delayed puberty is defined when there are no signs of puberty at the age of 13.4 years in girls and 14 years in boys (2 SD above the mean of chronological age for the onset of puberty). There are many forms of premature sexual maturation: gonadotrophin-dependent (central, or 'idiopathic' or 'true' precocious puberty) and gonadotrophin-independent precocious puberty (McCune-Albright syndrome in girls, testotoxicosis in boys); isolated premature thelarche (in the forms of classical, atypical and variant); premature adrenarche (characterized by the production of significant quantities of androgens between 5 and 8 years of age); premature menarche. The differential diagnosis of delayed puberty is between constitutional delay of growth and puberty, pubertal delay secondary to chronic disease and hypogonadotrophic hypogonadism.     

Update on female pubertal development

PURPOSE OF REVIEW: To elucidate recent findings regarding female puberty. The successful completion of puberty is a prerequisite for reproduction. Many later disorders of fertility and metabolism may develop during puberty. New more sensitive and specific assays provided us with possibilities for a better understanding of the process of puberty, and the discovery of new factors such as leptin evoked the hope of finding key regulators of the onset of puberty. RECENT FINDINGS: The secular trend towards earlier menarche appears now to have come to an end, but discussions about changes in the age of pubertal onset still continue. In a few detected cases of leptin mutations puberty has not occurred spontaneously. The intact secretion of leptin seems to be a necessary prerequisite for the onset of puberty. Apart from that, recent research has indicated that leptin levels mainly reflect body composition. Leptin as well as gonadotropins, steroids and growth hormone shows specific circadian patterns. The 24 h pattern of leptin is similar before and after puberty, but the 24 h pattern of the other hormones changes. The serum concentration of inhibin B increases in the years preceding puberty and in early puberty, whereas inhibin A increases in mid to late puberty. SUMMARY: The biological significance of the changing circadian patterns remains to be determined. Inhibin B serum concentrations together with follicle-stimulating hormone may indicate remaining potential ovarian activity during childhood in, for example, patients with Turner syndrome, but more information and other possible markers are needed.     

Update on pubertal development.

This review provides updated information relating to the timing of pubertal onset from a large study of girls seen in pediatric practices. In addition, new studies investigating the relationship of the hormone leptin to the onset of puberty are discussed, as well as new information on the neuroendocrine control of pubertal regulation. A provocative study documenting poor mental health, more behavior problems, and lower IQ in children with premature adrenarche when compared with controls raises the question of whether psychological stress triggers premature adrenarche or whether the early increase in adrenal hormone secretion causes psychosocial problems. Finally, significant advances in the management of central precocious puberty in girls have been made over the past year.     

Disorders of pubertal development: precocious puberty

Puberty is a complex developmental process culminating in sexual maturity. This transitional period begins in late childhood and is characterized by maturation of the hypothalamic-pituitary-gonadal axis, the appearance of secondary sexual characteristics, acceleration of growth, and, ultimately, the capacity for fertility. Significant endocrinologic changes accompany these developmental events. Disorders of pubertal development may occur at any of the steps of the maturational process leading to either precocious or delayed puberty. A thorough understanding of the normal pubertal process is important to the accurate diagnosis and treatment of pubertal disorders.     

Clinical expression of precocious pubertal development in girls

The paediatric endocrinologist is frequently asked whether pubertal development in a girl is normal, early or too early (precocious). This review will cover all clinical expression of premature development of puberty: central precocious puberty (neurogenic, secondary, and idiopathic) where treatment with GnRHa is considered, early puberty, partial puberty or pubertal variants and peripheral or pseudo precocious puberty related to an antonomous hypersecretion of estrogens by the ovaries. A special attention should be paid also to the role of environmental disruptors in the development of peripheral precocious puberty. GnRHa treatment should be considered only when evidence of central activation of the gonadotropic axis is proved by the LHRH-test.     

Relationship of age and pubertal development to ovulation in adolescent girls

A random sample of adolescent girls, 13 to 16 years of age, were surveyed with multiple serum progesterone determinations. The presence of ovulation was correlated with various indexes of pubertal development, including a pubertal developmental index that was devised using a summation of developmental factors. There was a significant correlation of ovulation with breast development, pubic hair development, and with the developmental index.     

Evaluation and management of the child with delayed pubertal development.

The physical and hormonal changes of puberty are presented and the wide range of ages at which the pubertal process may begin is emphasized. The great variability in the timing of onset of adolescence, its rate of progression, and the age of completion are detailed. The causes of delayed adolescence in males and females are considered. The most common form of delayed adolescent development is termed constitutional delay in growth and development, which may occur sporadically, or may be the familial pattern of growth and development or may reflect a suboptimal nutritional environment. The evaluation of such children, including appropriate historical review, physical examination, and laboratory assessment, is outlined. In most patients with constitutional delay in growth and development, strong reassurance is sufficient therapy. In other subjects, treatment with androgens (boys) or estrogens (girls) may be indicated. In patients with primary systemic diseases accociated with delayed maturation, specific treatment which eradicates the illness will often be followed by resumption of growth and development. In subjects with primary disorders of the hypothalamus, pituitary, or gonads, replacement therapy with androgens or estrogens is indicated. If gonadal function is intact, these patients may eventually become fertile with appropriate use of hypothalamic and/or pituitary hormones.     

Hormonal therapy and pubertal development in boys with selective hypogonadotropic hypogonadism

The authors have compared the effects of treatment with weekly injections of human chorionic gonadotropin (hCG) with those of monthly testosterone (T) injections in males with hypogonadotropic hypogonadism. There was no significant difference in pubertal development as measured by progression through the Tanner stages, final height, or bone age, with the two treatment regimens. The final testicular volume in patients treated with 5,000 U/week of hCG (14.0 +/- 2.0 ml) was significantly greater than that in patients treated with 250-mg monthly T injections (4.3 +/- 1.8 ml) (P less than 0.01). This study shows that weekly injections of hCG are effective in achieving virilization in hypogonadotropic hypogonadic males, leading to a greater testicular growth than T preparations. Therefore, hCG treatment may have an advantageous effect on the eventual induction of fertility with human menopausal gonadotropin.     

Neuroendocrine features of pubertal development in females with mental retardation

In order to evaluate the hypothalamic–pituitary effects of mental retardation during pubertal development ,follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to gonadotropin-releasing hormone (GnRH) administration were evaluated at various pubertal stages in a female population with mental retardation (MR) compared to a healthy control group of adolescents. Fifty-six girls aged 8–16 years with MR and 146 normal females of the same age participated in the study. The analyzed subjects were divided into different pubertal stages ,ranging from P2 to P5 ,in line with their degree of sexual maturation. Each patient underwent a GnRH test (100 μg); blood samples were collected basally and 15 ,30 ,60 ,90 minutes after the GnRH injection. FSH and LH were assayed in each sample; the gonadotropin response to GnRH administration was evaluated as incremental area. No differences were found at any pubertal stage between the two studied groups with regard to the age ,body mass index ,or age at menarche. Patients with mental retardation during stages P2 and P3 showed lower FSH secretion in response to GnRH bolus compared with control subjects (P2 ,p < 0.05; P3 ,p < 0.01). In conclusion, our data show that MR is related to an impaired response of the FSH-secreting pituitary cells to their appropriate stimulus; this feature is present only in the initial pubertal stages ,whereas it disappears during sexual development.     

Serum activin A levels in males and females during pubertal development.

Activin A is a dimeric protein composed of two beta A-subunits protein of the transforming growth factor-beta (TGF-beta) family. This protein is synthesized by a variety of organs. A sensitive and specific assay for bioactive dimeric activin A has recently been developed, to measure circulating levels in adult women and men, giving a new insights into the possible physiological role of this protein in the reproductive axis and/or in other functions. The aim of the present study was to evaluate serum dimeric activin A levels in boys and girls during pubertal development. The study was performed on a group of children (n = 54) aged between 6 and 18 years at different Tanner stages. Serum levels of activin A were measured using a specific and sensitive two-site ELISA. Serum activin A levels were not significantly different at various Tanner stages (Tanner I, 0.36 +/- 0.02 ng/ml; Tanner II, 0.33 +/- 0.02 ng/ml; Tanner III, 0.35 +/- 0.03 ng/ml; Tanner IV, 0.41 +/- 0.04 ng/ml; Tanner V, 0.35 +/- 0.05 ng/ml; p > 0.01). No difference between male and female children was observed. In conclusion, the lack of significant differences in activin A serum levels according to the Tanner stages or to gender demonstrates that this protein is not involved in the endocrine modifications during pubertal development and that its measurement may not provide a sensitive new tool for determining gonadal maturity at puberty.     

Menarcheal and pubertal development and determining factors among schoolgirls in Kumasi, Ghana

To determine menarcheal and pubertal ages and possible factors responsible for current pubertal trends in Kumasi, Ghana, a cross-sectional study was conducted among 720 urban and rural Kumasi 7-17-year-old schoolgirls and their mothers in 2008. Heights and weights were measured and additional information obtained by survey. Mantel-Haenzsel, χ(2), ordered logistic regression and probit analyses were used to analyse the data collected. With 40.42% menarcheal prevalence, median menarcheal ages were significantly different: 12.37 ± 1.48 years urban and 13.41 ± 2.25 years rural; 12.89 ± 1.93 years, overall. Obesity (OR = 2.57; p = 0.033) and high socioeconomic status (OR = 2.12; p = 0.008) were predictors of early menarche, while a younger mother was protective against early menarche (OR = 0.32; p = 0.039). Age at menarche among Kumasi schoolgirls has dropped 0.76 years since it was last determined among similarly aged girls in 1986, declining at a rate of about 0.32 years/decade. The predicting factors provide an important opportunity for intervention through school curricula and targeted education of adolescents.     

Neuroendocrine features of pubertal development in females with mental retardation.

In order to evaluate the hypothalamic-pituitary effects of mental retardation during pubertal development, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to gonadotropin-releasing hormone (GnRH) administration were evaluated at various pubertal stages in a female population with mental retardation (MR) compared to a healthy control group of adolescents. Fifty-six girls aged 8-16 years with MR and 146 normal females of the same age participated in the study. The analyzed subjects were divided into different pubertal stages, ranging from P2 to P5, in line with their degree of sexual maturation. Each patient underwent a GnRH test (100 micrograms); blood samples were collected basally and 15, 30, 60, 90 minutes after the GnRH injection. FSH and LH were assayed in each sample; the gonadotropin response to GnRH administration was evaluated as incremental area. No differences were found at any pubertal stage between the two studied groups with regard to the age, body mass index, or age at menarche. Patients with mental retardation during stages P2 and P3 showed lower FSH secretion in response to GnRH bolus compared with control subjects (P2, p < 0.05; P3, p < 0.01). In conclusion, our data show that MR is related to an impaired response of the FSH-secreting pituitary cells to their appropriate stimulus; this feature is present only in the initial pubertal stages, whereas it disappears during sexual development.     

Leptin and Soluble Leptin Receptor in Follicular Fluid

PURPOSE: Previous studies suggest that follicular fluid leptin levels predict successful assisted reproduction. The relationship between intrafollicular leptin and the soluble leptin receptor, ovarian hormones, and oocyte quality was examined to determine potential factors contributing to this finding. METHODS: Follicular fluid leptin, soluble leptin receptor, hormones, and oocyte quality were examined in 84 individual follicles from 30 women undergoing in vitro fertilization. RESULTS: Follicular fluid leptin and soluble leptin receptor levels correlated inversely with each other (r = -0.354; p = 0.001). Follicular fluid leptin levels correlated with intrafollicular estradiol (r = 0.42; p < 0.001), progesterone (r = 0.48; p < 0.001), and androstenedione (r = 0.49; p < 0.001), whereas soluble leptin receptor levels correlated with activin (r = 0.38; p < 0.001) and follistatin (r = 0.35; p < 0.002). There was no relationship between follicular fluid leptin or soluble leptin receptor levels and pretreatment serum hormone levels, stimulated serum estradiol, follicle number, oocyte quality, fertilization, or embryo grade. CONCLUSION: The data demonstrate that leptin and the soluble leptin receptor are highly interrelated with each other and with other intrafollicular hormones, but not with markers of oocyte quality, fertilization, or embryo grade.     

Leptin and reproduction

In the few years since leptin was identified as a satiety factor in rodents, it has been implicated in the regulation of various physiological processes. Leptin has been shown to promote sexual maturation in rodent species and a role in reproduction has been investigated at various sites within the hypothalamo-pituitary-gonadal axis. This review considers the evidence that leptin (or alteration in amount of body fat) can affect reproduction. There is evidence that leptin plays a permissive role in the onset of puberty, probably through action on the hypothalamus, where leptin receptors are found in cells that express appetite-regulating peptides. There is little evidence that leptin has a positive effect on the pituitary gonadotrophs and the gonads. There is also very little indication that leptin acts in an acute manner to regulate reproduction in the short term. It seems more likely that leptin is a 'barometer' of body condition that sends signals to the brain. Studies in vitro have shown negative effects on ovarian steroid production and there are no reports of effects on testicular function. Leptin concentrations in plasma increase in women during pregnancy, owing to production by the placenta but the functional significance of this is unknown. A number of factors that affect the production and action of leptin have yet to be studied in detail.