Disorders of sexual development and puberty

Question 1

Precocious Puberty

Answer 1

Precocious puberty is onset of sexual maturation before age 8 in girls or age 9 in boys.
Diagnosis is by comparison with population standards, x-rays of the left hand and wrist to assess skeletal maturation and check for accelerated bone growth, and measurement of serum levels of gonadotropins and gonadal and adrenal steroids.
Treatment depends on the cause.

Question 2

Puberty in girls

Answer 2

In girls, the first pubertal milestone is typically breast development (thelarche), followed soon after by appearance of pubic hair (pubarche) and axillary hair and later by the first menstrual period (menarche), which traditionally occurs 2 to 3 yr after thelarche

Question 3

Puberty in boys

Answer 3

In boys, the first pubertal milestone is typically testicular growth, followed by penile growth and appearance of pubic and axillary hair

Question 4

In both sexes

Answer 4

In both sexes, appearance of pubic and axillary hair is called adrenarche. Adrenarche may occur before gonadarche in about 10% of children (premature adrenarche). Although gonadarche and adrenarche may have overlapping signs, they are regulated independently.

Question 5

Defining precocious puberty

Answer 5

Depends on reliable population standards for onset of puberty (ie, when pubertal milestones occur); because onset seems to be occurring earlier in the US, especially in females, these traditional standards are being reevaluated. Breast development is increasingly occurring at younger ages and this trend is mirroring the obesity epidemic, with a higher body mass index (> 85th percentile) associated with earlier thelarche.

Question 6

Classification

Answer 6

Gonadotropin-releasing hormone (GnRH)–dependent (central precocious puberty) - more common overall and 5 to 10 times more frequent in girls.

GnRH-independent (peripheral sex hormone effects) - much less common. Secondary sexual characteristics result from high circulating levels of estrogens or androgens, without activation of the hypothalamic-pituitary axis.

Question 7

GnRH-dependent precocious puberty aetiology

Answer 7

In GnRH-dependent precocious puberty, the hypothalamic-pituitary axis is activated, resulting in enlargement and maturation of the gonads, development of secondary sexual characteristics, and oogenesis or spermatogenesis.

Physical changes are typically those of normal puberty for a child of that sex, with the exception of age of onset.

Question 8

GnRH-independent precocious puberty

Answer 8

The etiology of GnRH-independent precocious puberty depends on the predominant sex hormone effect (estrogenic or androgenic). Estrogenic effects are most commonly caused by follicular ovarian cysts, granulosa-theca cell tumors and McCune-Albright syndrome. Adrenal enzyme defects, specifically congenital adrenal hyperplasia, are the most common pathologic form of androgen excess in children of either sex. Additional causes in boys include familial male gonadotropin-independent precocity (due to an activating mutation of the gene for luteinizing hormone [LH] receptors), testosterone-producing testicular tumors, and occasionally McCune-Albright syndrome.

Question 9

Symptoms and Signs

Answer 9

In girls, breasts develop, and pubic hair, axillary hair, or both appear. Girls may begin to menstruate. In boys, facial, axillary, and pubic hair appears and the penis grows, with or without enlargement of testes, depending on the etiology. Body odor, acne, and behavior changes may develop in either sex.

Pubertal growth spurt is seen in both sexes (with early-mid puberty in females, mid-late puberty in males), but premature closure of the epiphyses results in short adult stature. Ovarian or testicular enlargement occurs in precocious puberty but is absent in isolated precocious adrenarche.

Question 10

Dx 1

Answer 10

Bone age x-rays
X-rays of the left hand and wrist are done to check for accelerated skeletal maturation as a result of sex hormone effect.

Question 11

Dx 2

Answer 11

Serum hormone measurement -
For patients who have mainly androgen effects, the most useful initial tests include measurements of total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, and luteinizing hormone (LH); all should be measured using high-sensitivity assays designed for pediatric patients. For patients who have only estrogen effects, the most useful screens for girls include ultrasensitive LH and follicle-stimulating hormone (FSH), and estradiol, and, for boys, LH, FSH, beta-human chorionic gonadotropin, and estradiol.

Question 12

Dx 3

Answer 12

Possibly pelvic ultrasonography and brain MRI -
May be useful if any of the steroid levels are elevated, and MRI of the brain may be done to rule out intracranial anomalies in younger patients or in males with central precocious puberty

Question 13

Dx 4

Answer 13

A GnRH stimulation test -
only when initial tests are inconclusive. Previously, with agonist gonadorelin was used, but gonadorelin is no longer available. Leuprolide acetate 10 to 20 mcg/kg sc is given and LH, FSH, testosterone (in boys), and estradiol (in girls) are measured at 0, 1, and 2 h. At 24 h post-leuprolide, estradiol and testosterone may be measured to improve sensitivity of the test.

In GnRH-dependent, gonadotropin responses are pubertal.
In GnRH-independent, gonadotropin responses to leuprolide are prepubertal.

Question 14

Treatment

Answer 14

GnRH agonist therapy (GnRH-dependant precocious puberty)

Androgen or estrogen antagonist therapy (GnRH-independent precocious puberty)

Tumor excision as needed

Question 15

Treatment in details

Answer 15

If pubertal milestones are within 1 yr of population standards, reassurance and regular reexamination are sufficient. Treatment is not needed for premature adrenarche or thelarche, but regular reexamination is warranted to check for later development of precocious puberty.

Question 16

GnRH-dependent Tx

Answer 16

Pituitary LH and FSH secretion can be suppressed with GnRH agonists, including leuprolide acetate 7.5 to 15 mg IM q 4 wk or 11.25 mg or 30 mg IM q 12 wk, or histrelin implants (changed annually). Responses to treatment must be monitored, and drug dosages modified accordingly. Treatment may be continued until age 11 yr in girls and age 12 yr in boys.

Question 17

GnRH-independent Tx

Answer 17

If due to familial male gonadotropin-independent precocity or McCune-Albright syndrome, androgen antagonists (eg, spironolactone) ameliorate the effects of excess androgen. The antifungal drug ketoconazole reduces testosterone in boys with familial male gonadotropin-independent precocity.

Question 18

Girls with McCune-Albright syndrome Tx

Answer 18

aromatase inhibitors, including older drugs such as testolactone and newer drugs such as letrozole and anastrozole, have been used with varying success to reduce estradiol; alternatively, tamoxifen, an estrogen antagonist, may be beneficial.

Question 19

GnRH-independent precocious puberty is due to a hormone-producing tumor (eg, granulosa-theca cell tumors in girls, testicular tumors in boys) Treatment

Answer 19

The tumor should be excised. However, girls require extended follow-up to check for recurrence in the contralateral ovary.

Question 20

Tx Key point

Answer 20

Treat GnRH-dependent precocious puberty with the GnRH agonists leuprolide or histrelin.

Treat GnRH-independent precocious puberty based on the cause, including giving androgen or estrogen antagonists and removing tumors.

Question 21

Aetiology Key point

Answer 21

Most commonly, secondary sexual characteristics develop prematurely because the hypothalamic-pituitary axis is activated (GnRH-dependent precocious puberty); often the cause is idiopathic, but some children have a CNS tumor.

Less commonly, the cause is high circulating levels of estrogens or androgens (GnRH-independent precocious puberty) caused by congenital adrenal hyperplasia or various gonadal tumors.