Clinical challenge: When is delayed puberty is more than a “late bloomer”?

Abstract

Delayed puberty is a common reason for adolescents seeking consultation; most have constitutional delay of puberty (CDP) and will initiate puberty spontaneously although later than their peers. However, some individuals will not initiate or progress through puberty (i.e., congenital hypogonadotropic hypogonadism [CHH]). Differentiating CDP from CHH is diagnostically challenging. This article provides a high-level overview of this clinical challenge, underscores the importance of clinical ‘red flags’ facilitating diagnosis, and highlights a holistic, comprehensive approach to care.

Introduction

Puberty is perhaps the most striking period of human development. Puberty results from the activation of the hypothalamic-pituitary-gonadal (HPG) axis and culminates in full reproductive capacity. Wide ranging changes of puberty include development of secondary sex characteristics, accelerated linear growth, changes in body composition, as well as increased strength and bone mass. Testicular enlargement (testicular volume of 4 mL) is the initial sign of male pubertal onset while breast budding (Tanner II breast development) notes onset in females. Typically, girls begin puberty earlier than boys and a range of factors influence pubertal timing including heredity/genetics, nutrition, general physical health, and environmental cues (i.e., endocrine disrupting chemicals).

Delayed puberty is statistically defined (i.e., >2 standard deviations from the mean). As such, 2-3% of adolescents will have delayed puberty and it is more common in males compared to females (Raivio & Miettinen, 2019). In males, delayed puberty is defined as lack of testicular development (testicular volume <4mL) at age 14 years. In females delayed puberty is defined as either lack of breast development (Tanner I) at age 13 years or absent menses at age 16 years. Most adolescents and young adults (AYAs) with delayed pubertal onset will spontaneously initiate and complete puberty without intervention – albeit later than their peers. However, some individuals with delayed puberty will never initiate or complete puberty on their own (i.e., congenital hypogonadotropic hypogonadism, CHH). Pubertal timing is largely accounted for by genetics and a detailed family history often uncovers other cases of delayed puberty in the family. Genome wide association studies have identified hundreds of common variants contributing to later pubertal initiation (Raivio & Miettinen, 2019). While CDP is relatively common, CHH is rare - occurring in 1 in 10,000-48,000 (Young et al., 2019). More than 60 genes have been identified to underlie CHH yet identified genes account for roughly half of cases. Importantly, the genetic architecture of CDP and CHH differ (Young et al., 2019), so genetic testing is not effective in differentiating transient delayed puberty (CDP) from abiding hypogonadism (CHH). Importantly, disrupted puberty can have significant impact on both physical and psychosocial well-being (Dwyer et al., 2019).

Approach to differentiating delayed puberty and abiding hypogonadism

Both CDP and CHH are diagnoses of exclusion meaning that potential causes of pubertal delay must be ruled out. Functional causes include chronic conditions (e.g., thyroid disease, malabsorption syndromes), disordered eating (e.g., anorexia nervosa, bulimia), and energy deficits (e.g., competitive distance running, gymnastics, etc.,). Clinicians should calculate mid-parental target height (mean of the parental heights, +6.5 cm [males] or −6.5 cm [females]) and record the AYA’s current height on the growth chart to visualize trends in growth relative to predicted mid-parental height. Markedly delayed growth (<3 cm/year) and low BMI may point to a functional etiology. Delayed puberty may also result from iatrogenic causes such as past treatment exposures (e.g., chemotherapy/radiation therapy) and medications (e.g., glucocorticoids). Thus, taking a comprehensive past medical and family history is an essential first step in evaluating AYAs presenting with pubertal delay (Figure 1).

Figure 1. Simplified schematic depicting approach to delayed puberty.

(A) Detailed history and physical exam is an important first step that can elicit evidence of functional and iatrogenic causes. Particular attention should be given to ‘red flags’ of CHH. (B) Elevated serum gonadotropins point to aneuploidies (i.e., Klinefelter syndrome, Turner Syndrome). (C) Presence of ‘red flags’ can direct further evaluation for permanent hypogonadism like CHH. LH: luteinizing hormone, FSH: follicle stimulating hormone, CDP: constitutional delay of puberty: CHH: congenital hypogonadotropic hypogonadism (Adapted from Young et al., 2019)

Biochemically, childhood is a hypogonadal state as the HPG axis is not yet activated. Accordingly, AYAs presenting with delayed puberty will likely have very low sex steroid levels (i.e., testosterone in males, estradiol in females). However, measuring serum gonadotropin levels (i.e., luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) can provide important clues for ruling out primary gonadal failure. An abnormal number of sex chromosomes, termed aneuploidy, underlie Klinefelter (47, XXY) and Turner (45, X) syndromes that cause primary gonadal failure (i.e., hypogonadism in the setting of elevated LH/FSH) which may manifest as lack of spontaneous pubertal development. If serum gonadotropins are elevated, karyotyping or microarray testing are indicated. If serum LH/FSH levels are prepubertal, particular attention should be paid to so-called ‘red flags’ that can help identify permanent forms of hypogonadism (i.e., CHH).

Differentiating delayed puberty from permanent hypogonadism

Taking a detailed history and performing a full physical examination is critically important because currently, there is no ‘gold standard’ test that effectively differentiates CDP from CHH (Young et al., 2019). Hormone measurements (i.e., LH, FSH, sex steroids, inhibin B) are ineffective given the similar hormonal profiles between CDP and CHH. Dynamic stimulation tests including gonadotropin-releasing hormone (GnRH) stimulation and FSH-stimulated inhibin B have been proposed - yet lack sufficient specificity to accurately discriminate the conditions. Recent research identifies kisspeptin stimulation as a promising test for differentiating CDP and CHH (Chan et al., 2020). Kisspeptin is a neuropeptide “upstream” of the hypothalamus that triggers release of GnRH from hypothalamic neurons activating the HPG axis. Accordingly, kisspeptin is a plausible probe for testing the integrity of the HPG axis - yet further work is needed to prove the effectiveness of kisspeptin stimulation as a diagnostic test.

‘Red flags’ suggesting permanent hypogonadism

Several findings on history and physical exam can suggest permanent hypogonadism (i.e., CHH) thereby facilitating timely diagnosis. Unfortunately, many individuals with CHH are thought to be “late bloomers” (i.e., CDP) and the standard “watchful waiting” approach is not effective. Unlike CDP, individuals with CHH will not have pubertal progression. The resulting delayed diagnosis is often traumatic for individuals with significant psychosocial consequences including stigmatization and bullying (Dwyer et al., 2019). Thus, careful attention to red flags can shorten the “diagnostic odyssey” for AYAs with CHH and support timely initiation of sex steroid treatment to mitigate psychosocial morbidity.

Notably, sensory deficits are key “red flags”. Lack of sense of smell (anosmia/hyposmia) is evident in half of all CHH cases (Young et al., 2019). When anosmia occurs with CHH it is termed Kallmann syndrome. Accordingly, AYAs presented with delayed puberty should be queried about their ability to smell (i.e., flowers, coffee, etc.). Similarly, hearing loss can be associated with CHH so eliciting any hearing deficits is indicated. Particular attention should be paid to genitalia at birth. The HPG axis is active during the first six months of neonatal life (termed minipuberty) and disrupted minipuberty in CHH can manifest as maldescended testes (cryptorchidism) as well as micropenis (Raivo & Maittinen, 2022). Any history suggestive of disrupted minipuberty should steer the diagnostic workup away from CDP and towards elucidating underlying causes of permanent hypogonadism. Any syndromic presentation including midline defects (i.e., cleft lip/palate) or skeletal/dental anomalies (fused digits, missing teeth) should raise suspicion and merit further investigation. On physical examination, a rapid evaluation for mirror movements (i.e., involuntary movement of the contralateral fingers/toes) can identify synkinesia – an associated sign in some cases of CHH. When “red flags” are identified in an AYA presenting with delayed puberty, referral for endocrine consultation is warranted for definitive diagnosis and sex steroid treatment to induce secondary sexual characteristics.

Holistic approach to congenital hypogonadotropic hypogonadism

Recent publications provide comprehensive overviews of the diagnostic evaluation (Young et al., 2019) and treatment of CHH (Federici et al., 2022). From a nursing perspective, several key considerations merit noting. First, receiving a diagnosis of CHH can be challenging for an AYA. While CHH is not life threatening, it is a life altering condition, and it is important for nurses to create a psychologically safe space for AYA’s to discuss their psychosocial and psychosexual concerns. Patients should be asked about their priorities for care and engaged in shared decision-making around their treatment modality. Typically, AYAs are focused on appearing more like their peers. Anticipatory guidance is critical for setting appropriate expectations for treatment. Sex steroid therapy is a process requiring slow, incremental dose increases to ensure individuals reach their high potential. Patients should be informed that while development of secondary sexual characteristics will be accelerated (compared to normal puberty) developing secondary sexual characteristics will take time. Second, CHH is a treatable form of infertility and about 75% of individuals will be able to develop fertility potential with appropriate hormonal therapy (Young et al., 2019).

A comprehensive holistic approach to care includes attention to disease management such as titrating sex steroid dose, normalizing hormone levels, measuring growth, assessing bone density (i.e., baseline dual X-ray absorptiometry), and monitoring metabolic health. Health promotion (i.e., health diet, exercise, weight management) are important points that should be discussed regularly. Therapeutic education should include emphasis on adherence to treatment (discussed at every visit), self-management skills (i.e., teaching aseptic self-injection technique when applicable), and coaching for behavior changes (i.e., healthy lifestyle). Additionally, establishing a therapeutic, trusting relationship is critical for supporting effective coping and creating a safe environment for AYAs to discuss concerns around intimate relationships, sexual function, and fertility issues. The psychosocial aspects of care are particularly salient as AYAs with CHH may struggle with psychosexual problems, body image concerns, and feelings of isolation and shame (Dwyer et al., 2019). Last, as many individuals with CHH are diagnosed in pediatric care, nurses can play a critical role in supporting a purposeful, planned, and timely transition from pediatric to adult oriented care to avoid gaps in care and treatment (Dwyer et al., 2019).

Conclusions

Delayed puberty is a common reason for AYAs to present for consultation. In most cases, delayed pubertal onset represents and extreme variant of puberty and most individuals will spontaneously initiate and complete puberty without intervention. A careful history and physical examination is a crucial component of evaluating delayed puberty. Identifying ‘red flags’ can help steer evaluation towards identifying permanent forms of hypogonadism (i.e., CHH). Attention to ‘red flags’ is key for accelerating diagnosis, shortening the “diagnostic odyssey”, and treatment initiation. Timely diagnosis and treatment both improve physical health and supports psychological wellbeing. Nurses can play a key role in providing comprehensive, holistic care for CHH that can enhance psychosocial outcomes.