Disorders of Puberty

Question 1

What is gonadarche?

Answer 1

Gonadarche is the onset of puberty. Pubertal onset is heralded by re-emergence of hypothalamic GnRH secretion which stimulates gonadotropes to secrete FSH and LH which in turn bind to receptors in ovaries and testes causing gonadal maturation and the production of sex steroids (testosterone, estradiol).

Question 2

What is the adrenal component of puberty called and what occurs at this time?

Answer 2

The adrenal component of puberty is called adrenarche. It involves maturation of the adrenal gland and production of the adrenal androgens, primarily DHEA-S and androstenedione.

Question 3

What is the normal age of onset of puberty in boys and girls, and what are the first signs?

Answer 3

The first physical sign of puberty is testicular enlargement >3 ml (or >2.2 cm) in boys and breast bud development in girls. Normal onset of puberty in boys is age 9-14 years, and normal onset of puberty in Caucasian girls is age 8-13
years. African-American and Hispanic girls start puberty on average 1 year earlier.

Question 4

What is the definition of delayed puberty, including ages?

Answer 4

Delayed puberty is defined as the lack of onset or lack of normal progression of puberty. Boys with delayed puberty have no testicular enlargement by age 14 years. Girls with delayed puberty have no breast development by age 13 years or no menses 4 years after pubertal onset or by age 16 years.

Question 5

What are the two primary causes of delayed puberty and how are they distinguished?

Answer 5

Delayed puberty results from a lack of pubertal maturation of the hypothalamic-pituitary axis or from gonadal dysfunction. The approach to delayed puberty is to categorize based on gonadotropin status. Elevated gonadotropins (hypergonadotropic hypogonadism) indicate primary gonadal failure, and low gonadotropins (hypogonadotropic hypogonadism) indicate hypothalamic or pituitary immaturity or dysfunction.

Question 6

What is the most common cause of delayed puberty in cases with low gonadotropins and what bone-age is associated?

Answer 6

The most common cause of delayed puberty associated with low gonadotropins is constitutional delay of growth and puberty. It occurs both in boys and girls. Although the onset of puberty is delayed, puberty follows a normal
pattern of progression. Prior to the onset of puberty, children grow at a normal prepubertal rate although are following a height percentile shorter than expected for
family. The timing and progression of puberty is commensurate with the bone age (which is delayed in this growth pattern). Growth continues after peers stop growing, and genetic height potential is usually achieved. Often, there is a family history of “late bloomers”.

Question 7

What conditions may lead to a reversible hypogonadotropic hypogonadism?

Answer 7

Gonadotropin levels can be suppressed in situations such as chronic illness, malnutrition, stress, excessive exercise, anorexia nervosa, hyperprolactinemia, and hypothyroidism.
When the underlying problem is adequately treated, normal gonadotropin secretion is expected to follow.

Question 8

What conditions may lead to permanent hypogonadotropic hypogonadism?

Answer 8

Permanent forms of hypogonadotropic hypogonadism may be the result of congenital disorders such as isolated gonadotropin deficiency, Kallmann syndrome (GnRH deficiency associated with anosmia), congenital hypopituitarism, midline CNS defects, or Prader-Willi syndrome. Hypogonadotropic hypogonadism may also be due to acquired CNS lesions such as a pituitary or hypothalamic tumor, trauma, irradiation, infection, infiltrative diseases, or autoimmune hypophysitis.

Question 9

What is the fundamental disorder in hypergonadotropic hypogonadism, and what are the congenital and acquired causes?

Answer 9

In primary gonadal failure, there is decreased negative feedback of sex steroids to the brain which results in elevated gonadotropin levels, hence the term hypergonadotropic hypogonadism.
Congenital causes:
Klinefelter’s Syndrome (47 XXY), Turner syndrome (45X0 or 46X/abnormal X), 46 XX or 46 XY gonadal dysgenesis, vanishing testes syndrome, and Noonan syndrome. Acquired causes:
chemotherapy (especially alkylating agents), irradiation (to pelvic region), galactosemia, autoimmune oophoritis, testicular torsion or trauma, mumps orchitis, and cryptorchidism.

Question 10

What is complete precocious puberty and what are its associated risks?

Answer 10

“Complete” precocious puberty is defined by early
onset AND progression of pubertal development with evidence of linear growth acceleration and bone age advancement. Consequently, children with complete
precocious puberty may have early closure of growth plates and compromised final height.

Question 11

What is incomplete precocious puberty and what two types are there?

Answer 11

When signs of puberty are not progressive, a child is considered to have “incomplete” puberty which includes the diagnoses of benign premature thelarche and benign premature adrenarche.

Question 12

What are the two classes of precocious puberty?

Answer 12

Precocious puberty is classified as either central (gonadotropin-dependent) or peripheral (gonadotropin-independent).

Question 13

What is the cause of central precocious puberty and what condition does it resemble?

Answer 13

Central precocious puberty is due to premature activation of the hypothalamic-pituitary-gonadal axis. Consequently, the sequence of hormonal and physical events is identical but earlier in onset compared to normal puberty. Central precocious puberty may result from CNS abnormalities that
disrupt the balance between the inhibitory and stimulatory factors that regulate pubertal onset. Precocious puberty occurs more commonly in girls but the majority of affected girls will have no identifiable abnormality (idiopathic). The prevalence of precocious puberty in boys is significantly lower, but 50% of affected boys will have a CNS lesion.

Question 14

What occurs in peripheral precocious puberty, and what may cause it?

Answer 14

In peripheral precocious puberty, puberty occurs independent of GnRH and gonadotropin stimulation. In boys with peripheral precocious puberty, excess androgen production may be caused by: 
congenital adrenal hyperplasia, 
adrenal tumor, 
Leydig cell tumor, 
hCG secreting tumor, 
testotoxicosis,
exogenous androgens. 

In girls with peripheral precocious puberty, excess estrogens may be caused by:
ovarian cyst,
ovarian granulosa cell tumor,
exogenous estrogens.

Other causes of peripheral precocious puberty in both sexes include hypothyroidism and severe primary hypothyroidism and McCune-Albright Syndrome (triad of precocious puberty, café au lait spots, and polyostotic fibrous dysplasia caused by an activating
mutation in the α subunit of the G-protein in the FSH receptor).

Question 15

What are three testicular size abnormalities and what may cause each?

Answer 15

Bilaterally enlarged, unilaterally enlarged, prepubertal sized
Bilaterally testicular enlargement may be due to:
central precocious puberty
activation of the LH receptor by a hCG producing tumor
testotoxicosis
McCune-Albright Syndrome.

Unilateral testicular enlargement is usually associated with a testicular tumor.

Prepubertal sized testes are seen in
adrenal disorder (CAH, adrenal tumor)
exogenous androgen exposure.

Question 16

What clinical test may be performed to distinguish central and peripheral precocious puberty?

Answer 16

A GnRH stimulation test may distinguish between
central and peripheral precocious puberty. A PUBERTAL LH response to GnRH is seen in CENTRAL precocious puberty whereas a PREpubertal LH response is seen in
PERIPHERAL precocious puberty.

Question 17

How are LH and FSH levels changed in peripheral versus central precocious puberty?

Answer 17

In peripheral precocious puberty, LH and FSH levels are suppressed. In central precocious puberty, random LH and FSH levels may or may not be in the pubertal range

Question 18

What is the rationale for treating precocious puberty?

Answer 18

Treatment of precocious puberty is aimed to arrest or cause regression of the signs of puberty, alleviate the psychosocial stress of early puberty, and slow bone age
advancement to preserve final adult height.

Question 19

What is the treatment, including drug name, for central precocious puberty?

Answer 19

For central precocious puberty, GnRH analogues such as intramuscular leuprolide acetate or histrelin implant can be
used which down regulate pituitary GnRH receptors and thus decrease gonadotropin secretion. These are given continuously, not fluctuating, in order to suppress the HPT/HPO axis.

Question 20

How is McCune-Albright syndrome treated in girls? In boys?

Answer 20

Girls with McCune-Albright Syndrome can be treated with an aromatase inhibitor to block conversion of androgens to estrogens. Boys with this syndrome and familial testotoxicosis can be treated either with ketoconazole or a combination of an androgen blocker and aromatase inhibitor.

Question 21

How are adrenal tumors, CAH, and ovarian cysts treated?

Answer 21

Tumors of the adrenal gland and testis require surgery. Congenital adrenal hyperplasia = glucocorticoids.
Girls with ovarian cysts = Watchful waiting is usually sufficient

Question 22

What is benign premature thelarche?

Answer 22

Benign thelarche is onset of breast development without other signs of puberty, and the absence of linear growth acceleration and bone age advancement. Benign thelarche typically occurs in girls under 2 years of age but may also occur in older girls. This is a variant of normal development and does not require intervention except for monitoring

Question 23

What is benign premature adrenarche?

Answer 23

Benign premature adrenarche is characterized by pubic hair and/or axillary hair prior to age 8 years in girls and 9 years in boys. It is due to premature activation of adrenal androgen secretion. The DHEA-S may be in the early pubertal range. It is not associated with other signs of puberty and like benign thelarche, there is no growth acceleration or significant bone age advancement. Usually, the pubic/axillary hair slowly progress without having an effect on the timing of true puberty. No treatment is needed; however, up to 15% of girls with a history of benign premature adrenarche will go on to develop polycystic ovarian syndrome.