Normal Puberty and Development
Notable puberty terms
- Gonadarche is the maturation of the gonads (testes and ovaries).
- Adrenarche is marked by increased secretion of androgens from the adrenal gland, resulting in the growth and darkening of pubic hair, axillary hair body odor, oily skin and acne.
- Thelarche is breast development and maturation.
- Pubarche is the darkening and thickening of pubic hair due to adrenarche.
- Menarche is the beginning of cyclic vaginal bleeding due to gonadarche.
Biochemical signaling of puberty
In the beginning of puberty, the zona reticularis of the adrenal glands secretes androgens (e.g. DHEA), resulting in the characteristics of adrenarche. Concurrently, the arcuate nucleus in the hypothalamus secretes GnRH in a pulsatile manner, which causes the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. LH and FSH work on various reproductive organs to induce gonadarche.
In females, LH acts on the theca cells of the ovary to convert cholesterol to androgens. A nearby granulosa cell converts those androgens to estradiol under the control of the FSH signaling. Estradiol acts on various organs to complete puberty.
In males, LH acts on the Leydig cells to convert cholesterol to testosterone. While the mechanism of puberty via the hypothalamus-pituitary-gonadal axis is well understood, less is known about the factors that control the age of pubertal onset.
Sequence of male puberty
Males tend to begin puberty between 10 and 13 years old. After adrenarche, the skin of the scrotum thins and the testes grow, testicular length is 2.5 cm or more and volume of testes is 4 ml or more which the onset of male gonadarche is. The testes enlarge from the growth and maturation of seminiferous tubules. Acne face, facialhair and slight alteration voice (hoarseness) are seen.
Next, pubarche begins in conjunction with penile enlargement. The last stage is a dramatic increase in growth velocity. Testicular enlargement that does not start before 14 years old is diagnostic of delayed puberty, and any sign of puberty before age 9 is precocious puberty.
Sequence of female puberty
Females, on the other hand, usually begin puberty earlier, between 9 and 12 years of age. Since the ovaries are located internally, female gonadarche is clinically measured by thelarche.
Enlargement of clitoris indicates the significant androgen excess. Vaginal mucosa will be deep red. Breast enlargement with increased estrogen is a reliable sign of puberty.
Thelarche is tracked and recorded using the Tanner staging system. Menarche begins about 2 to 3 years after thelarche and pubarche begin, but this time may vary. When breast development begins at age 9, menarche generally follows in 2.8 years on average.
In contrast, when breast development begins at age 12, menarche begins after 1.4 years on average. Lack of thelarche at 13 years old is diagnostic for delayed puberty, and thelarche before the age of 8 indicates precocious puberty.
Variations on normal puberty
Benign premature thelarche is isolated early breast development. If there are no other symptoms of puberty, no testing is required and the parents and patient only need reassurance and observation as treatment. Benign premature adrenarche similarly does not need testing if it is an isolated finding.
Precocious puberty is the development of secondary sexual characteristics before the age of 8 in females and 9 in males. Studies show that the age of onset of puberty in American females has become younger as compared to the same population in the 1930s, making precocious puberty a relevant topic.
Precocious puberty can create some problems like early spurt in growth but due to early maturation of bones linear growth can be ceased early so it can cause short stature.
Race may, in part, determine the onset of puberty. For example, in the US, African American girls have an earlier onset of puberty. Some experts suggest redefining precocious puberty as onset before age 6 in African American girls and 7 in all other girls.
Other factors that are correlated with the earlier onset of puberty in females are low birth weight, obesity, international adoption and absent father. While the age of onset is getting younger, the onset of menarche has not changed significantly. Precocious puberty is important to diagnose and treat because children with untreated precocious puberty tend to be much shorter in adulthood, and have a poor psychosocial wellbeing.
Etiologies of central precocious puberty
Causes of precocious puberty may be central (central nervous system) or peripheral (gonads, adrenal glands, etc.). Central precocious puberty is a GnRH-dependent process that is caused by early activation of the hypothalamic-pituitary-gonadal axis.
This results in elevated LH and FSH, as well as elevated testosterone or estradiol. The child undergoes the normal sequence of puberty as described above. These children will have normal secondary sex characteristics, advanced bone age and increased sex steroids. The following are causes for central precocious puberty:
- Benign (or familial) precocious puberty
- Tumors, such as a hamartoma, germinoma, optic or hypothalamic gliomas, astrocytoma, ependymoma
- Suprasellar cysts
- Head trauma
Etiologies of peripheral precocious puberty
In contrast, peripheral precocious puberty, a GnRH-independent condition, occurs from a surge of sex steroids without hypothalamic-pituitary-gonadal activation. GnRH, FSH and LH values tend to be suppressed or consistent with prepubertal values. Sex steroids tend to be high or consistent with pubertal concentrations. The child may not undergo the normal sequence of puberty.
The most common cause of peripheral precocious puberty is McCune-Albright syndrome, and it is more often found in females than males. This syndrome is characterized by bone malformations, café au lait spots, and ovarian hyperfunction, resulting in episodic estrogen secretion. It may also be accompanied by hyperthyroidism or acromegaly. Girls with McCune-Albright syndrome complete puberty rapidly, with menarche occurring only a few months after breast development.
Adrenal adenomas and carcinomas may also secrete androgens or estrogens, leading to precocious puberty. Any hCG-secreting tumor, such as a dysgerminoma, stimulates the secretion of LH and, subsequently, testosterone in males.
One genetic cause of precocious puberty is GnRH-independent sexual precocity. Males may have this X-linked dominant disorder that causes premature Leydig cell maturation, resulting in high levels of testosterone. Other conditions that cause peripheral preocoius puberty are ovarian cysts, congenital adrenal hyperplasia and exogenous steroid exposure.
Clinical evaluation of precocious puberty
In addition to taking a history on the symptoms, ask about the history of precocious puberty in family members, signs of a neurological condition in the patient (large head circumference, headaches, visual changes or seizures), and signs of the stages of puberty (breast development, testicular enlargement, body odor, pubic and axillary hair).
Finally, investigate if the child has had any exogenous exposure to sex steroids. A thorough physical examination should include Tanner staging, analysis of the growth chart to determine if they had a recent increase in growth velocity, a skin examination for café au lait spots, and a neurological examination.
In addition, clinicians should look for the effects of estrogens, such as breast development and menarche, and testosterone, such as deepening of the voice, enlarged testes and virilization in girls.
Laboratory studies for precocious puberty
The most important values to measure for precocious puberty are the hormones involved in puberty. Testosterone, estradiol, DHEAS and androstenedione can be measured directly.
However, GnRH, LH and FSH can be highly variable and very difficult to measure, so the gold standard for measuring gonadotropins is the GnRH stimulation test. In this test, GnRH is injected into the child and the LH and FSH levels are measured.
Before puberty, GnRH primarily stimulates FSH, but, after puberty, LH is predominately secreted in response to GnRH. After the GnRH is injected, the LH and FSH levels will determine if the hypothalamus-pituitary-gonadal axis is operating on a pre-pubertal or pubertal system.
The direct hormone measurement and the GnRH stimulation test will determine if the cause is central or peripheral. Further investigations may include hand X-ray for bone age, ultrasound to reveal a gonadal cyst or tumor, MRI if a brain tumor is suspected, serum hCG if a hamartoma is suspected, and serum 17-hydroxyprogesterone if congenital adrenal hyperplasia is suspected.
Treatment of precocious puberty
Treatment depends on the cause of the precocious puberty. All malignancies should be treated with the appropriate surgical, chemo- and radiotherapy. Central, progressive precocious puberty can be treated with a continuous release of GnRH. The continuous release (instead of the physiologic pulsatile release of GnRH) will suppress LH and FSH secretion, shutting down the hypothalamic-pituitary-gonadal axis.
Continuous GnRH therapy causes modest gains in height, as compared to the predicted height, and its side effects include menopausal symptoms, increased fat mass, and decreased bone density.
Treatment for McCune-Albright syndrome may include antiandrogen agents, antiestrogen therapy, such as tamoxifen, and a progesterone implant. Ovarian cysts should be treated with a progesterone implant, which inhibits steroid genesis and causes the regression of the cyst. Familial GnRH-independent sexual precocity can be treated with antiandrogens.
Delayed puberty in males is the lack of testicular enlargement by 14 years old, and for females, it is diagnosed by a lack of breast development at 13 years old. Approximately, 2.5% of healthy children experience delayed puberty.
Constitutional delay of growth and puberty
The most common cause of delayed puberty is the constitutional delay of growth and puberty (CDGP). In CDGP, the period of decelerated growth before the pubertal growth spurt is prolonged, resulting in a significant bone age delay. Puberty will commence in these children when the bone age reaches 12 years old in boys, and 11 years old in girls.
A family history of delayed puberty is usually found in children with this diagnosis. For example, mothers of children with CDGP have an average age of menarche of 14.3, while mothers of children without CDGP reach menarche on average at 12.7 years old.
Some claim that CDGP is inherited in an autosomal dominant pattern. Even though CDGP is the most common cause, it can only be diagnosed after a thorough investigation eliminates other pathological causes.
Hypogonadotropic hypogonadism is marked by low LH and FSH, resulting in low sex steroids. Anorexia nervosa, athletic amenorrhea and systemic illness are all causes of temporary hypogonadotropic hypogonadism. Permanent hypogonadotropic hypogonadism is caused by the following conditions:
- Isolated gonadotropin deficiency
- Kallmann syndrome
- Pituitary hormone deficiency like FSH,LH.
- Chemotherapy or radiotherapy
- CNS tumors, such as pituitary adenoma, glioma, prolactinoma, craniopharyngioma, astrocytoma
- Idiopathic hypopituitarism,germ cell tumour,hypothalamichamartomas.
- Long illness like coeliac disease,hypothyroidism,severeasthma,cysytic fibrosis.
Hypergonadotropic hypogonadism is also known as a primary gonadal failure. Low levels of gonadal steroids prevent the onset of puberty. Since gonadotropins are inhibited by gonadal steroids, this leads to a high LH and FSH. The following are causes of hypergonadotropic hypogonadism:
- Turner syndrome karyotype
- Chemotherapy or radiation therapy
- Gonadal dysgenesis
- Klinefelter syndrome
- Familial gonadal failure
Clinical evaluation for delayed puberty
In addition to obtaining a detailed history about growth, ask about delayed puberty in parents and siblings, history of chronic disease, cryptorchidism, and history of malignancy treated with chemotherapy and radiotherapy. Assess nutrition status and cognitive development.
After the history, observe height percentile, weight percentile and growth velocity. If growth velocity is less than 3 cm per year, suspect an underlying endocrine that inhibits growth (e.g. hypothyroidism). Obesity in boys is associated with a delay in the onset of puberty. Encourage weight loss in these patients.
In general, the physical exam should focus on identifying signs of a chronic disease, neurological abnormalities, signs of adrenarche, and the Tanner stage. In males, the testes and penile length should be measured. A testes length greater than 2.5 and a penile length greater than 3 cm indicates the onset of puberty.
In addition, the scrotal skin should be observed for signs of darkening. In females, breast tissue should be evaluated by having the child lay in the supine position. Finally, the presence of signs of Turner syndrome – arched palate, cubitus valgus, and short fourth metacarpals – should be noted.
Laboratory studies for delayed puberty
LH and FSH levels should be taken to differentiate between hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Reduced LH in the background of delayed puberty suggests hypogonadotropic hypogonadism. Elevated LH in the background of delayed puberty suggests hypergonadotropic hypogonadism, meaning the gonads themselves are not producing sex hormones in response to LH.
FSH is not as reliable as LH in predicting the onset of puberty. Lower FSH values in the background of delayed puberty indicated hypogonadotropic hypogonadism, and elevated FSH also suggest primary gonadal failure.
Estradiol or total testosterone should also be drawn to assess gonadal function. GnRH-stimulation test may be done if the clinician is unsure if puberty has commenced. CDGP and hypogonadotropic hypogonadism has a pre-pubertal response.
IGF-1 should be drawn to assess for growth hormone deficiency, and TSH should also be ordered to check the thyroid. To rule out chronic disease, order a CBC, ESR, creatinine, electrolytes, bicarbonate, alkaline phosphatase, albumin, thyrotropin, and free T4.
An X-ray of the hand would assess bone age. One of the criterion for CDPG is a bone age delay of greater than 2 years, but this is not specific to CDPG. Delayed bone age is also seen in children with gonadal failure, hypogonadotropic hypogonadism and children with chronic illness.
If a tumor is suspected, prolactin and hCG levels may aid in diagnosis. The child should only have an MRI if there is a strong suspicion for a lesion. An MRI should be deferred until age 15 if possible. If a genetic cause is suspected, conduct genetic testing. A celiac screen may be conducted at the clinician’s discretion.
Treatment of delayed puberty
As CDGP is a normal variant of puberty, children can be treated with observation and reassurance. Parents and children should be consoled on realistic expectations of adult height. Children with CDGP are at risk for low bone density, and should be given calcium supplementation.
Upon request, males may be treated with testosterone for 4 to 8 months to accelerate the onset of puberty via bone maturation. Aromatase inhibitors may increase adult height in addition to initiating puberty.
Females may be treated with estrogen, although no clear benefit to this therapy has been proven. Females should also undergo a workup for primary amenorrhea before a diagnosis of CDGP is made.
Children with transient hypogonadotropic hypogonadism may achieve fertility after the underlying cause is addressed. However, those with permeant hypogonadism will never achieve spontaneous fertility; life-long sex steroid hormone replacement is the only known treatment to achieve puberty and maintenance of secondary sex characteristics. Children with hypergonadotropic hypogonadism are also unlikely to become fertile spontaneously.
Girls with Turner syndrome benefit from growth hormone supplementation to promote normal adult height. Cyclic estrogen/progesterone is used for secondary sex characteristics. These children may achieve pregnancy with in vitro fertilization with donated ovum.
The correct answers can be found below the references.
1. How do you diagnose a child who you suspect has CDGP?
- Hand X-ray
- No clinical testing is needed if there is a strong family history
- CDGP is a diagnosis of exclusion
- LH and FSH levels, as well as a GnRH suppression test
2. Which of the following is a cause of peripheral precocious puberty?
- McCune-Albright syndrome
3. What is the treatment for central, progressive precocious puberty?
- Estrogen or testosterone, depending on the sex
- GnRH agonists
- Antiandrogen or antiestrogen, depending on the sex
- Weight loss