DEFINITION AND INTRODUCTION
Precocious puberty is the development of sexual maturation in boys and girls occurring at an unusually early age, that is 2.5 standard deviations below the mean age at onset of puberty in the population.
Many studies have indicated that internationally adopted children (especially girls) are at risk of developing precocious puberty. Children adopted from developing countries may arrive at their new homes in a chronically undernourished state, with deficiency of both height and weight. In the following months, the improved living, nutritional and psychological conditions determine a catch up in linear and weight growth, that may trigger the onset of puberty.
STUDIES' SUMMARY
The first study to analyze the characteristics of a large population of adopted girls was made in Sweden in 1991 by Proos et al. They studied 107 girls from India, that were stunted on arrival and subsequently underwent catch up growth. This continued until the start of the pubertal growth spurt, which occurred about 1.5 years earlier than either the indigenous population or their upper class Indian peers growing up in India. The menarche’s age was at 11 years, instead of 13 in Swedish girls and 11.8-12 years in upper class indian girls, with a high percentage of girls with menarche before the 10 year. (Menarcheal age and growth pattern of Indian girls adopted in Sweden. II. Catch-up growth and final height, 1991 )
In a large population-based study in Denmark, Teilmann et al. reported that internationally adopted girls run a 10-20 times increased risk of developing precocious puberty. The comparison between the adopted girls and the reference group of girls of Danish origin showed that on average, breast development and menarche started 1.3 years earlier in adopted girls.
The puberty related rise in LH, FSH and estradiol was detected at early stages in adopted girls, confirming the early activation of pituitary-gonadal axis. They also showed that 5-8 years old adopted girls had increased levels of gonadotropins without any clinical signs of puberty, which lead to the conclusion of a central origin of the early onset of puberty. (Early puberty in internationally adopted girls: hormonal and clinical markers of puberty in 276 girls examined biannually over two years, 2009)
In Italy Virdis et al. conducted a study on 19 adopted girls, that were referred because of signs of precocious puberty. Those adopted at a later age (> 5 years) had a greater weight deficit and a greater delay in bone age than the children who were adopted earlier (< 4 years of age), while height at adoption was less affected. Bone maturation in these girls shows very rapid progression and puberty is completed faster, compromising final height and aggravating the psychological problems associated with adoption. This is also true, but to a lesser extent, in girls adopted at a younger age (< 4 years). (Precocious puberty in girls adopted from developing countries, 1998)
DIAGNOSIS
The diagnosis is simple and often would not be necessary use exams. However it’s recommended to perform a GnRH test to prove the real onset of puberty. In addition may be useful a brain RMN to exclude organic forms of central precocious puberty, due to neoplasia, trauma, bacterial and parasitic infections, especially if the anamnestic history isn’t complete.
PHYSIOPATHOGENETICS BASES
An important role is played from the diet, directly or indirectly through the metabolic and somatic changes that implies. Before adoption these girls were mostly on a low protein, low energy, vegetarian diet, which changed to a balanced enriched diet after adoption, with consequent production of endogenous substances and important somatic changes for the onset of puberty. The following fatting underline the role of the adipose tissue, especially in girls adopted after the 5 years, in which there is a significant increase in fat mass in a short time.
Fat cells are able to convert adrenal androgens (already present in the body and further stimulated by the re-feeding) to estrogens. In fact they have the aromatase, that catalyzes the aromatization of the androgens’ A ring transforming them into estrogens.
The increased in circulating levels of active estrogens could prime the hypothalamic centers and cause precocious stimulation of the hypothalamic-pituitary-gonadal axis.
Adipose cells synthetize and secrete the leptin, that functions as a peripheral satiety signal to the hypothalamus. Leptin deficiency in the human and rodent is associated with hypogonadotropic hypogonadism leading to infertility. The leptin acts on the neuroendocrine reproductive axis via interneurons projecting to GnRH-expressing cells. In this respect, neuropeptide Y(NPY)-expressing neurons as well as Kisspeptin-expressing neurons represent likely candidates, since both subtypes of neurons have been demonstrated to express functional leptin receptors.
NPY is an important hypothalamic integrator of the leptin signal, for feeding/metabolic regulations as well as neuroendocrine modulation of reproductive function. When infused chronically, NPY consistently induces a profound inhibition of the gonadotrope axis suggesting that the increased expression of hypothalamic NPY observed in fasting or unfavorable metabolic conditions may account for the tonic inhibition of pulsatile GnRH release.
NPY activates at least five different receptor subtypes, among which Y1 and Y5 have been implicated in the control of food intake and in the regulation of the neuroendrocrine reproductive axis. The sensitivity of the neuroendocrine reproductive axis to the accelerating effects of leptin on puberty was markedly enhanced in the absence of Y1. In fact in the absence of Y1, hypothalamic GnRH neurons become essentially insensitive to the negative regulation exerted by NPY. (Insulin and NPY pathways and the control of GnRH function and puberty onset, 2010)
The leptin also works in the hypothalamus, promoting the expression of KISS1 gene; this gene controls the synthesis of Kisspeptin, a neuropeptide with a receptor GPR54 in the areas of the synthesis of GnRH. The peptidergic leptin-Kisspeptin GnRH pathway would just convey informations from the adipose tissue, stock of available energy, to the SNC. In men the administration of kisspeptin causes a powerful release of gonadotropins, that ceases in the course of prolonged administration for the effect of desensitization. FSH, LH and Testosterone significantly increases already after 3h after the infusion for 90 'of a solution of kisspeptin (4 pmol / kg / m ').
Improved nutritional conditions increase IGF1, which would stimulate both the maturation of ovarian follicles and their estrogen production, and also the hypothalamic secretion of GnRH. The locally produced IGF1, rather than the circulatory, is responsible for IGF1 action in the ovary. It has been established that the granulosa cells are the sole somatic ovarian cells concerned with IGF1 gene expression and translation. FSH has been reported to increase IGF1 expression and production in granulosa cells of several species. Therefore, this has raised the possibility that the follicle-stimulating action of FSH is mediated by IGF1, which will be acting in a paracrine or autocrine manner. It is also been shown that IGF1 is capable of augmenting FSH-supported progesterone and estrogen biosynthesis as well as the FSH-mediated acquisition of LH receptors.
For these reasons IGF1 is considered important for the promotion of juvenile and early pubertal FSH levels and may be a bearing on the puberty-promoting effect of GH. In fact the ability of GH to accelerate pubertal maturation may be due to the promotion of ovarian IGF1 production and reception with the consequent local potentiation of gonadotropin action. (Insulin-like growth factor I as an intraovarian regulator: basic and clinical implications, 1991)
Ethnic factors must be also taken into account, especially in Indian girls. In India, age at menarche in upper class is quite low and in particularly the mean height and weight are lower at the onset of puberty than in children from developing countries. Also the importance of psychological factors is underlined by the timeliness of the onset of puberty immediately after the adoption.
TREATMENT
Gonadotrophin inhibitory treatment, which reduces and hopefully blocks bone maturation, is indicated when the initial height prediction is low or when it worsens rapidly and progressively. The treatment with GnRH analogue therapy, usually includes a monthly injection of a medication, such as leuprolide. When used regularly, GnRH agonists cause a decreased release of FSH and LH.
Another possible treatment is with anastrozole, that is an aromatase-inhibiting drug.
