Approach to delayed puberty: Clinical sciences

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Introduction0:00–0:48

Puberty refers to the transition phase between childhood and adulthood, during which an individual develops secondary sexual characteristics and becomes capable of reproduction.
In biological females, delayed puberty refers to the absence of breast development by age 13; while in biological males, it refers to the absence of testicular enlargement by age 14.
The most common type of delayed puberty is the constitutional delay of growth and puberty, which is a normal developmental variant.
However, delayed puberty can also be secondary to underlying causes, such as hypothyroidism, hyperprolactinemia, and hypo- or hypergonadotropic hypogonadism.

Focused H&P0:48–2:15

Now, if your patient is presenting with chief concerns suggesting delayed puberty, first, perform a focused history and physical examination, including Tanner staging, and measure weight and height.
Here’s a high-yield fact! Puberty begins with activation of the hypothalamic-pituitary-gonadal or HPG axis, which is when the hypothalamus releases gonadotropin-releasing hormone or GnRH that stimulates the anterior pituitary gland to secrete gonadotropin hormones called luteinizing hormone, or LH for short, and follicle-stimulating hormone, or FSH for short.
These hormones then travel through the bloodstream to the gonads, where they stimulate the production of sex hormones like estradiol and testosterone!
This process of gonadal activation, growth and maturation is also known as gonadarche. On the other hand, adrenarche is associated with adrenal gland maturation and increased adrenal hormone production, leading to the development of signs like axillary and pubic hair!
In other words, adrenarche is independent of the HPG axis, so to determine the true onset of puberty, you should always look for signs of gonadarche, not adrenarche.Alright, let’s look at some findings in delayed puberty.

Delayed puberty2:15–3:20

In biological females, the history will reveal the absence of breast development by age 13; while in biological males, it will reveal no testicular enlargement by age 14.
Additionally, the physical exam could reveal delayed linear growth, as well as the presence of axillary and pubic hair. Next, take a look at Tanner staging, also known as the sexual maturity rating, which classifies secondary sex changes that individuals go through in puberty!
In delayed puberty, your patient will present with stage 1 of breast or testicular development. This means that biologically female individuals will have flat breasts with only nipples raised, while biologically male individuals will have small testes, usually 3 milliliters in volume or less.
With these findings, you can diagnose delayed puberty, so your next step is to assess your patient’s linear growth velocity!
Let’s start with reduced linear growth velocity, which can be associated with several different conditions, including hypothyroidism, hyperprolactinemia, and growth hormone deficiency!

Linear growth velocity reduced3:20–3:52

Now, to determine the exact cause, you have to order additional labs, including TSH, free T4, and prolactin, as well as insulin-like growth factor 1 or IGF-1 for short.If the lab results reveal abnormal TSH, low free T4, and normal prolactin and IGF-1 levels, you can diagnose hypothyroidism as a cause of delayed puberty!

Hypothyroidism3:52–4:15

In this case, severe primary hypothyroidism or Hashimoto thyroiditis is the most likely cause of delayed puberty.However, if labs reveal normal TSH and free T4 levels, in combination with elevated prolactin and normal IGF-1 levels, you can diagnose hyperprolactinemia.

Hyperprolactinemia4:15–4:50

Keep in mind that, in order to affect pubertal development, prolactin must be significantly elevated. So, in this case, the most likely cause is a prolactin-secreting tumor, such as a pituitary adenoma, but certain medications like antipsychotics and antidepressants can also cause hyperprolactinemia.Next, if labs show normal TSH, free T4, and prolactin levels, but low IGF-1 levels, you can diagnose growth hormone deficiency as a cause of delayed puberty!

Growth hormone deficiency4:50–5:04

Finally, if lab findings are normal, you should consider hypogonadism as a cause of delayed puberty. Now, let’s go back and take a look at individuals presenting with unaffected growth velocity.

Consider hypogonadism5:04–5:11

Linear growth velocity not reduced5:11–5:44

In this case, again, consider hypogonadism as a cause of delayed puberty. Be sure to assess the function of the HPG axis by ordering additional labs, including LH, FSH, as well as estradiol in biological females, and testosterone in biological males.
Finally, order an X-ray of the patient’s left hand to assess their bone age.Prepubertal, or in other words, low levels of LH and FSH suggest that the pituitary gland is not producing enough hormones or that it’s not getting stimulated by the hypothalamus.

Hypogonadotropic hypogonadism5:44–6:22

As a result, there's no stimulation of gonads to produce sex hormones, so estradiol and testosterone levels will also be low.
With these lab results, you can diagnose hypogonadotropic hypogonadism, so your next step is to assess the underlying cause.First, let’s discuss functional hypogonadotropic hypogonadism.

Functional hypogonadotropic hypogonadism6:22–8:00

In this case, your patient may report significant emotional stress, disordered eating, or participation in a high-performance physical activity.
Alternatively, they might have a pre-existing chronic condition, such as diabetes or cystic fibrosis, or an underlying condition associated with malabsorption, such as celiac disease or inflammatory bowel disease.
You can consider these conditions as stressors that can affect the activation of the HPG axis and subsequently delay puberty.
Additionally, the physical examination might demonstrate an underweight patient with a body mass index below 20; while the left-hand X-ray could reveal delayed bone age.
With these findings, you can diagnose functional hypogonadotropic hypogonadism, which usually resolves with the treatment of the underlying cause.Now, here’s a high-yield fact!
Puberty that begins at a normal age but subsequently halts or regresses is also considered delayed puberty and requires evaluation.
One example is the female athlete triad, which is a type of functional hypogonadotropic hypogonadism. You should suspect this diagnosis if your patient is a biological female who participates in intense exercise and develops disordered eating, which results in amenorrhea and decreased bone density.

Kallmann syndrome8:00–9:29

Next up is Kallmann syndrome. These patients will report a decreased or absent sense of smell, and some may have a midline defect, such as a cleft lip or palate.
Physical examination often reveals other sensory deficits, such as hearing loss or color blindness. Some patients could also present with bimanual synkinesia, also known as mirror movement, where voluntary movement of one hand results in involuntary movement of the other hand.
Additionally, the left-hand X-ray might reveal delayed bone age. With these findings, consider congenital hypogonadotropic hypogonadism, and order genetic testing as well as a scratch-and-sniff smell test.
If the genetic testing reveals an ANOS1 or KAL1 gene mutation, and the smell test is positive for hyposmia or anosmia, you can diagnose Kallmann syndrome.Here’s a high-yield fact!
There are also other forms of congenital GnRH deficiency in which patients have an intact sense of smell! In rare cases, congenital hypogonadotropic hypogonadism can be a manifestation of global hypopituitarism, or it may be associated with another condition such as CHARGE or Noonan syndrome.

CNS tumor9:29–10:38

Next up are CNS causes of hypogonadotropic hypogonadism. These patients often describe frequent headaches and, in some cases, visual disturbances.
Meanwhile, the physical exam may reveal decreased visual acuity or visual field loss; while the left-hand X-ray might reveal delayed bone age.
In this case, consider acquired hypogonadotropic hypogonadism, and order an MRI of the brain and pituitary gland.Imaging could reveal an intracranial, parasellar mass; or the compression of the pituitary gland or hypothalamus, confirming the diagnosis of a CNS tumor.
The most likely tumor is a craniopharyngioma, but other possible tumors include germinomas, gliomas, or pituitary adenomas.
Rarely, acquired hypogonadotropic hypogonadism can be caused by head trauma, as well as an infiltrating or inflammatory disease of the pituitary gland.Finally, let’s take a look at constitutional delay of growth and puberty, which is the most common cause of delayed puberty!

Constitutional delay10:38–11:30

In this case, your patient will likely report a family history of delayed onset of puberty and delayed onset of adrenarche with no evidence of chronic conditions, malnutrition, or stress.
Additionally, the left-hand X-ray will reveal delayed bone age. With these findings, you can diagnose the constitutional delay of growth and puberty!
Here’s another clinical pearl! Most children with constitutional delay eventually activate the HPG axis, so their hormone levels over time reach normal, pubertal levels.
As a result, these individuals achieve their expected adult height without any medical intervention. Alright, let’s go back and take a look at hormone levels one more time!

Hypergonadotropic hypogonadism11:30–12:12

Elevated LH and FSH levels mean that the pituitary gland is firing on all cylinders, but gonads are not responding, which eventually results in prepubertal or low estradiol and testosterone levels.
Additionally, the left-hand X-ray could show delayed bone age. With these findings, you can diagnose hypergonadotropic hypogonadism, which is also known as primary hypogonadism.
Your next step is to determine the underlying cause! First, let’s discuss inherited causes, which include Turner and Klinefelter syndrome.

Inherited causes12:12–13:38

If your patient is biologically female, they might have a history of congenital heart disease. On the flip side, if your patient is biologically male, they might have a learning disability, language, and processing defects, as well as a history of attention deficit hyperactivity disorder or even depression.
Next, the physical exam of biological females might demonstrate short stature and possibly, a low hairline or a webbed neck.
On the other hand, the physical exam of biological males typically reveals tall stature, gynecomastia, and micropenis. At this point, you should consider inherited causes of hypergonadotropic hypogonadism, so your next step is to order a karyotype.
If the karyotype is 45, X; or 45X/46XX, diagnose Turner syndrome. However, if the karyotype is 47, XXY, the diagnosis is Klinefelter syndrome.
While Turner syndrome classically presents with absent signs of gonadarche, Klinefelter syndrome typically presents with normal onset of puberty, followed by delayed or incomplete pubertal progression.Finally, let's discuss the acquired causes of hypergonadotropic hypogonadism.

Acquired hypergonadotropic hypogonadism13:38–14:18

In this case, the diagnosis is based on the patient’s history, which may reveal previous testicular trauma, perinatal injury of the testes, or surgical manipulation of the gonads.
Additionally, your patient might have been exposed to chemotherapy or radiation therapy; or they might have a previously diagnosed autoimmune disorder, such as type I diabetes, Hashimoto thyroiditis, or Addison disease.
These findings are highly suggestive of acquired hypergonadotropic hypogonadism.Alright, as a quick recap… In biological females, delayed puberty refers to the absence of breast development by age 13, while in biological males, it refers to the absence of testicular enlargement by age 14.

Review14:18–14:54

The most common type of delayed puberty is the constitutional delay of growth and puberty, which is a normal developmental variant.
However, delayed puberty can also be secondary to underlying causes, such as hypothyroidism, hyperprolactinemia, and growth hormone deficiency as well