Arrested Development: Exploring Delayed Puberty’s Causes

Delayed puberty is not the mystery it once was. However, determining its causes can often present clinicians with a difficult puzzle to piece together.

Although delayed puberty is a common pediatric endocrine condition, determining its etiology can present a hefty clinical challenge. Defined as gonadarche in boys or thelarche in girls occurring later than 95% of the rest of the population (ages 14 and 13, respectively), overall delayed puberty affects about 3% of the population, but the precise incidence of this complex problem is unknown.

Boys are more often referred for clinical evaluation than girls, but some studies demonstrate that the condition affects both sexes about equally. Slowed growth commonly accompanies delayed puberty, as growth hormone (GH) secretion is linked to stage of puberty rather than calendar age.

“Before you can treat it, you have to defi ne it,” says Alan D. Rogol, MD, PhD, professor emeritus at the University of Virginia School of Medicine, in Charlottesville. “Ninety-fi ve percent of adolescents with delayed puberty have a variant of normal [physiologic]. Only 5% are pathologic.” Although boys account for most overall referrals for delayed puberty, girls account for more cases of pathologic delayed puberty. Regardless of specifi c etiology, most delayed puberty stems from a delay in activation of the hypothalamicpituitary-gonadal axis and, compared to peers, a relative gonadotropin-releasing hormone (GnRH) defi ciency, which makes thorough evaluation that might reveal underlying illnesses or a familial predisposition even more critical. Th is overlap in clinical fi ndings and lab evaluation can pose quite a conundrum. Although some clinical features and hormonal evaluations are more typical for each condition, they are not limited to one or the other. Clinicians must tease out the underlying mechanisms to differentiate among types.

Defining It

Constitutional delay of growth and puberty (CDGP), which is by far the most common cause, represents a diagnosis of exclusion and is, by defi nition, transient. Th e three other main causes accounting for delayed puberty can be subdivided into primary and secondary hypogonadism, which distinction may be made by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Primary hypogonadism, also called hypergonadotropic hypogonadism, is characterized by high LH and FSH concentrations, usually as a result of gonadal disease, whereas secondary hypogonadism is characterized by low or normal serum LH and FSH concentrations, often as a result of a hypothalamic dysfunction. Secondary hypogonadism, hypogonadotropic hypogonadism (HH), can be permanent — the result of an impaired hypothalamic-pituitary axis — or transient, functional hypogonadotropic hypogonadism (FHH) — in which dysfunction is the result of another underlying (often systemic) disorder. To date, a defi nitive test does not exist to distinguish CDGP from other causes of delayed puberty. Th erefore, a complete history and physical can off er important clues about the cause and should be undertaken fi rst, before any diagnostic testing or imaging. Additionally, delayed puberty might point to a range of latent problems, from hypothyroidism to psychosocial deprivation.

CDGP has a strong genetic component, which is no surprise given that so much (as much as 50%–80%) of the variation in the timing of puberty relates to genetic factors, and more than half of CDGP cases reveal a family history of socalled “late bloomers.” Th e key driver in CDGP is inadequate sex hormone secretion, which is caused by diminished production of hypothalamic GnRH, in turn causing delayed LH and FSH secretion, compared to peers. Importantly, these adolescents also have slowed but not stalled growth and skeletal maturation, as the growth pattern assessment will demonstrate. Th e detailed history should also include diet, exercise, prior illness, prior radiation therapy, and medication usage. Restricted or inadequate nutrition can delay puberty onset. Th is is an issue of energy balance; therefore, both intake and output should be considered.

Tanner staging is a key component of the physical exam. Micropenis or gynecomastia in males likely indicates permanent hypogonadism. A history of anosmia or hyposmia points to Kallmann syndrome, which is the result of a rare genetic mutation and can affect boys and girls. Resulting from a chromosomal abnormality, Klinefelter syndrome (47,XXY) patients often start pubertal maturation but then do not progress due to testicular failure. Other clinical signs include those of other manifestations of permanent hypogonadism in addition to behavioral and cognitive abnormalities. Adolescent girls with Turner syndrome (45,X) likewise present with behavioral and cognitive problems as well as underdeveloped, nonworking ovaries.

Functional hypogonadism can result from chronic, systemic conditions, such as cystic fibrosis and inflammatory bowel syndrome, poor nutrition (energy balance), and various endocrinopathies, such as hypothyroidism and hyperprolactinemia, all of which result in symptoms in either the patient or the patient’s parents that can sometimes be elicited during history-taking.

What the history and examination reveal guides next steps algorithmically. First tests should include biochemical studies and bone imaging. For example, an elevated FSH level suggests hypergonatropic hypogonadism, which prompts karyotyping. Low/normal LH and FSH suggest multiple differential diagnoses and may prompt genetic testing or additional testing for underlying chronic conditions. “We must be aware of clinical parameters ( found in the patient’s and his or her family’s history and physical) that may signal the underlying condition,” says Luiz Claudio G. Castro, of the Universidade de Brasília Medical School, in Brasilia, Brazil. “Sometimes we also use hormonal stimulation tests and brain images as tools to support the diagnosis or the presumptive diagnosis. Other times we may even start hormonal replacement for a short period, the patient develops puberty, then it’s withdrawn and we evaluate if the patient is able to keep puberty development spontaneously or not.”

Variations on Normal

“Adolescents with secondary hypogonadism are often variations on normal,” says Rogol. “The pathways for spermatogenesis and ovulation are asleep and just need to be given that awakening signal.” Furthermore, because much of the overall incidence of delayed puberty is transient, the decision to treat should be weighed very carefully. With CDGP, expectant management and reassurance may be all that is needed, with the decision to start sex steroid administration belonging to the patient, according to Mark Palmert, MD, PhD, associate professor, Department of Pediatrics at the Hospital for Sick Children, in Toronto, Canada. Psychosocially, the delayed puberty adolescent may be experiencing significant distress when comparing him or herself to peers and want to start sex steroid supplementation.

If the evaluation has uncovered any latent condition, therapy begins with targeting it, resolution of which can sometimes itself prompt sexual maturation, which identifies the delayed puberty as being due to FHH. “In any state of poor health, HH may occur and will reverse if the disease or condition is successfully treated and good health is restored,” says Bradley D. Anawalt, MD, of the University of Washington, in Seattle.

However, as mentioned, teasing out other causes to determine a treatment basis is complicated by their shared relative GnRH deficiency component. In general, clinicians have two options in the latter case, either expectant management or prescribing sex steroid hormone therapy. For many patients, reassurance that they will catch up to their peers is sufficient.

Although many with CDGP undergo spontaneous progression through puberty, treatment with testosterone for boys and estrogen for girls can have benefits besides hastening the process. Improvements in bone mass and muscle composition are seen, accelerating growth, and psychosocial anxiety may be significantly ameliorated. Moreover, short-term administration of sex steroids has not demonstrated significant adverse effects. Unless the patient has delayed puberty along with true GH deficiency (e.g., as might be seen with combined pituitary hormone deficiency), says Palmert, combined treatment of sex steroids and GH is not usually warranted, even with short stature/slowed growth. “In patients with delayed puberty, administration of exogenous sex steroids not only leads to development of secondary sexual characteristics but usually also leads to acceleration in linear growth. Treatment with GH does not appear to result in substantial gains in height compared to the administration of sex steroids alone, and its use is quite expensive,” says Palmert. With permanent hypogonadism, sex steroid hormone therapy is initiated to induce secondary sex characteristics.

The Big Picture

The take-away for clinicians here is that distinguishing among causes of delayed puberty, although ultimately important, is neither easy nor necessarily critical at the initiation of therapy. “The real conundrum is how to discriminate permanent congenital hypogonadotropic hypogonadism (CHH) from CDGP,” says Anawalt. “A family history of delayed puberty, delay in bone age, and stature below expected based on parental height are clues that the patient has the more common diagnosis, CDGP. Small testes and penis, bilateral cryptorchidism, and decreased sense of smell suggest CHH. Many times the only reliable way to discriminate between CDGP and permanent CHH is the passage of time. If there is no sign of puberty by 18, then permanent CHH is the diagnosis.”

Castro agrees: “One important aspect is that there is not a rigid protocol with well-established test responses for diagnosing HH or CDGP, because patients are different, and even the ones with similar clinical features and biochemical findings at one moment may have different maturation and outcomes throughout time. Although HH is an organic disease in which sex hormone replacement is the standard therapy, CDGP is expected to be a normal variant of growth and pubertal maturation. There is no specific single test that can clearly make this differentiation, but we have to analyze clinical, hormonal, and imaging data in a dynamic way throughout the patient’s follow-up. It’s like building a puzzle, looking, at the same time, at each and every obtained piece and the way they fit with each other. The ‘big picture’ is our main tool used to discriminate between HH and CDGP.”

— Horvath is a freelance writer based in Baltimore, Md.
She wrote about thyroid storm in the August issue.

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