Prematurity is the onset of puberty before the age of 8 years for girls or 9 years for boys. It is diagnosed based on comparisons with population standards, an x-ray of the left arm and wrist to assess skeletal maturation, test for accelerated bone growth, measurements of serum gonadotropins, as well as gonadal and adrenal steroids. Treatment depends on the disease etiology.
In girls, the first stage of puberty is usually the development of the breasts (thelarche), followed by the appearance of pubic hair (pubarche) and axillary hair, and then the first menstruation (menarche), which usually occurs 2-3 years after thelarche (Puberty period – the period of development of female sexual characteristics.).
In boys, the first stage of puberty is, as a rule, the growth of the testicles, accompanied by the growth of the penis and the appearance of pubic and axillary hair (Puberty – when male secondary sexual characteristics develop.).
In both sexes, the appearance of pubic and axillary hair is called puberty. Adrenarche can begin before the gonadarche in about 10% of children (premature maturation). Although the gonadarche and adrenarche may have the same symptoms. They are regulated independently of each other.
The definition of prematurity depends on the reliability of standards for puberty (i.e., when puberty occurs). Since maturity seems to be earlier in the US, especially for girls, these traditional standards are currently overrated. Breast development with increasing frequency occurs at an earlier age. This trend reflects an obesity epidemic, with a higher body mass index (> 85th percentile) associated with the early appearance of thelarche.
Nearly 8–10% of white girls, 20–30% of black girls and an intermediate percentage of Hispanic women reach early puberty at the age of 8 years. The lower limit of normal puberty can be 7 years for white girls and 6 for black. The average age for early breast development is about 9.5 to 10 years for white girls and 8.5 to 9 for black girls (8 to 13 years old). However, the age of menarche has not decreased, so sharply, with an average decrease of only 3 months, over the past 30 years (average age of 11.5 years for black girls and 12.5 years for white girls). The average age of hair growth is from 9 years to 10.5 for both groups. These data indicate that the main principles for assessing disorders that cause premature puberty can be interpreted more gently if the children are healthy and are projected to reach the full potential of an adult.
Prematurity can be divided into 2 types:
- Gonadotropin-releasing hormone (GnRH) -dependent (central precocious puberty);
- GnRH-independent (effects of peripheral sex hormones);
- GnRH-dependent prematurity as a whole is more common, usually 5 to 10 times more common in girls.
With GnRH-dependent premature puberty, the hypothalamic-pituitary system is activated, which results in an increase and maturation of the gonads, the development of secondary sexual characteristics, oogenesis or spermatogenesis.
GnRH-independent premature puberty is much less common. Secondary sexual characteristics develop as a result of a high level of circulating estrogens or androgens without activation of the hypothalamic-pituitary system.
Prematurity can also be classified with the development of the gonadarche or adrenarche. In girls, gonadarche includes breast development, physique changes, uterus growth, and menstruation onset. In boys, gonadarche includes enlarged testicles, penis, the first appearance of pubic hair, face and armpits, the appearance of an adult body odor, the appearance of oily or acne on face skin. Puberty for girls and boys involves the development of body hair, the appearance of body odor and acne.
Incomplete or irregular sexual development is most common in the form of an isolated premature appearance of thelarche or adrenarche. In girls with the premature appearance of thelarche. Breast development usually occurs during the first 2 years of life, but this change is not accompanied by an increase in the level of sex hormones, menarche, x-ray anticipation of bone age, androgen effects, or growth acceleration. Isolated premature adrenarche is also not associated with accelerated sexual development.
Children with premature adrenarche may have signs of adrenal androgen production (e.g., pubic hair, acne, sweat smell) that progress slowly, without accelerating linear growth. Premature adrenarche may be associated with the further development of polycystic ovary syndrome in adolescent girls.
Girls develop breasts and pubic hair, axillary hair, or both. Girls may begin to menstruate. In boys, hair appears on the face, pubis and armpits, the penis grows with or without testicular enlargement, depending on the etiology. The smell of sweat, acne, and changes in behavior can develop in both sexes.
A puberty jump in growth is observed in individuals of both sexes (at the beginning to mid-puberty in girls, and in the mid-to-late puberty in boys), but premature closure of the pineal glands leads to short stature in adulthood. Enlarged ovaries or testicles occur with premature puberty, but are absent with premature adrenarche.
- X-ray to determine bone age;
- Serum hormone measurements;
- Perhaps pelvic ultrasound and MRI of the brain;
- The diagnosis of prematurity is clinical.
X-rays of the left hand and wrist are made to determine accelerated skeletal maturation as a result of the sex hormones’ influence. In the case when the anamnesis and examination do not suggest a pathology, further evaluation is not required for children with puberty milestones that are within 1 year of population standards. Girls and boys with isolated premature adrenarche, as well as girls with premature thelarche, do not require additional evaluation until an x-ray confirms the accelerated skeleton maturation.
When the additional examination is necessary, blood tests should be selected in accordance with the available features. For patients with predominantly androgenic manifestations, the most useful initial tests include measuring total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone and luteinizing hormone (LH); all studies should be performed using high sensitivity tests intended for pediatric patients. For patients with exclusively estrogenic manifestations, the most useful tests include:
- for girls, hypersensitive tests for LH and follicle-stimulating hormone (FSH), as well as estradiol;
- for boys – LH, FSH, human beta-chorionic gonadotropin and estradiol.
Ultrasound of the pelvic organs and adrenal glands can be useful if the level of any of the steroid hormones is elevated, brain MRI can be performed to exclude intracranial abnormality in young patients or in boys with central precocious puberty.
A test with GnRH stimulation can be considered to confirm GnRH-dependent premature puberty if the initial examination does not give convincing results. Previously, a 1-hour test was used to stimulate GnRH agonists with gonadorelin, but since this drug is no longer available, other GnRH agonists, such as leuprorelin, are now used. Leuprolide acetate 10–20 µg/kg is administered subcutaneously, and levels of LH, FSH, testosterone (in boys), and estradiol (in girls) are measured at 0, 1, and 2 hours. 24 hours after the leuprolide administration, estradiol and testosterone can be measured to increase the test sensitivity. With GnRH-dependent premature puberty, puberty gonadotropin responses are obtained. With GnRH-independent premature puberty, a prepubertal response of gonadotropin to leuprolide is obtained.
- GnRH agonist therapy (GnRH-dependent premature puberty);
- Therapy with androgen or estrogen antagonists (GnRH-independent premature puberty);
- Tumor excision as needed.
If signs of sexual development meet population standards within 1 year, confirmation and regular re-examinations are sufficient. With premature puberty or thelarche, treatment is not required, but regular repeated examinations are warranted to check the further development of premature puberty. With GnRH-dependent premature puberty, the secretion of LH and FSH by the pituitary gland can be suppressed using GnRH agonists, including leuprolide – 7.5 to 15 mg intramuscularly every 4 weeks or 11.25 mg or 30 mg intramuscularly every 12 weeks, or histrelin implants (require annual replacement). Responses to treatment should be monitored, drug doses adjusted according to these responses. Treatment can be continued until the age of 11 years for girls and the age of 12 years for boys.
In girls with McCune-Albright syndrome, aromatase inhibitors such as letrozole and anastrozole have been used to reduce estradiol levels with varying degrees of success.
If GnRH-independent premature puberty in boys is associated with family male GnRH-independent premature sexual development or McCune-Albright syndrome, androgen antagonists (e.g., spironolactone) mitigate the effects of androgen excess. The antifungal drug ketoconazole lowers testosterone in boys with male gonadotropin-independent premature development.
If GnRH-independent prematurity occurs due to hormone-producing tumors (e.g., granulosa-thelarche cell tumor in girls, testicular tumor in boys), the tumor must be removed. However, girls need further extended follow-up to control relapse in the contralateral ovary.