Approach to delayed puberty: Clinical sciences

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.

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. 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! 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! 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. 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! 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. 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. 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. 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.