Puberty Evaluation: When Less Is More

Educational Objectives

The goal of this program is to improve puberty evaluation. After hearing and assimilating this program, the clinician will be better able to:

1. Review the normal sequence of pubertal events.
2. Treat central precocious puberty.
3. Optimize management of delayed puberty in adolescents.

Summary

Puberty: the normal pubertal trajectory is shifting over time; in girls, puberty begins with breast bud appearance, pubic hair, growth spurt, body hair, breast maturity, menarche, and adult height; in boys, growth of the testes is the first sign of puberty, followed by pubic hair appearance, growth of the penis, axillary hair, growth spurt, deepening of the voice, and adult height; adrenarche occurs first in 15% of young people, leading to concerns about body odor and acne; timing — girls experience breast development between 8 and 9 yr of age, followed by menarche at an average 12.4 yr of age; testicular enlargement occurs usually between 11 and 12 yr of age; puberty takes about 3 to 5 yr until final adult height is achieved

Trend: 50% to 75% of variation in pubertal onset is genetically determined; according to data from 1975 to 2015, the age of Tanner stage 2 is decreasing, which is challenging because the landmarks for normalcy have not shifted; understand the effect of sex, age, and race; reset timing when precocity or delay occurs; consider an individualized approach toward the patient

Early Puberty

Central precocious puberty (CPP): caused by early activation of the hypothalamic-pituitary-gonadal axis (idiopathic in nature in most girls); central nervous system (CNS) lesions are rare (should be ruled out); genetic mutations and other factors, eg, family history and obesity, can affect puberty; epidemiology — occurs in 1 in 5000 to 10,000 boys and 1 in 1000 to 5000 girls; the discrepancy between the sexes is likely because of pathophysiology

Differential diagnosis: discuss the diagnosis process, reasons for concern, and potential treatments; start the conversation early as it could be idiopathic or a normal variant; rule out CNS disorders, exogenous hormone exposure, gonadal causes, and adrenal causes; the majority of the evaluations have normal variants aligning with the genetic potential of the family; other causes include McCune-Albright syndrome, hyperthyroidism, and other sexual development disorders; be open and transparent about the causes to rule out while normalizing things with an individualized approach; discuss the impact of larger body size on puberty in primary care; bone age assessment is a cost-effective way to understand continuous and high-level exposure to androgen, which can lead to advancement; if there is no exposure, it is more likely to be a normal variant or appropriate for the family's genetic tempo; follow up with laboratory testing; ensure that pediatric-sensitive assays are used to accurately measure variations in luteinizing hormone, follicle-stimulating hormone, and sex steroids

Peripheral precocious puberty: discuss peripheral precocious puberty with patients and families based on their symptomatology; rule out CNS causes; peripheral precocious puberty has no treatment; evaluate for underlying causes (generally rare) like tumor processes or undiagnosed conditions, eg, congenital adrenal hyperplasia; differentiation is helpful for families to understand and have appropriate expectations, as the workup and evaluation can be anxiety-inducing

Diagnosis: an evaluation for early puberty should involve a thorough medical history, including a multiple-generation family history, detailed growth history, complete family history, physical examination, and bone age assessment; biochemical testing is done only if bone age is advanced in CPP; stimulation testing can be considered if findings are unclear; magnetic resonance imaging is used rarely (eg, a boy has a higher likelihood of a CNS lesion); the appropriate workup should be done stepwise to avoid overmedicalizing normal variants and address underlying pathophysiology

Treatment processes: leuprolide (eg, Camcevi, Eligard, Lupron) can be used in girls with CPP (<9 yr of age); consider the family's preferences in a shared medical decision-making model; more patients are declining blockade lately (mentioning genetic history); implantation and other 6-mo preparations are other options that made the process easier; patients usually are treated until 11 yr of age, then the blockade is removed to allow normal progression

Delayed Puberty

Introduction: criteria include absence of breast development by 12 or 13 yr of age in girls and absence of testicular enlargement by 13 or 14 yr of age in boys; extreme variations in timing are observed by race and ethnicity; prevalence is ≈5%; constitutional delay of puberty, which goes with growth and puberty, is most common in boys than girls (with different prevalences); functional hypogonadotropic hypogonadism occurs in ≈20% of people; primary hypogonadism occurs in ≈13%; other causes account for ≈13%, and 3% with unidentified etiology

Constitutional delay of growth and puberty (CDGP): most common cause of delayed puberty and short stature; educate families that if growth velocity is delayed in early elementary years, it may lead to a delay in the pubertal process as well; this is a transient defect in production of gonadotropin-releasing hormone (GnRH; not permanent); individual genetic variation and inheritance patterns (primarily autosomal dominant) can be seen

Kallman syndrome: has a prevalence of 1 in 10,000 in men and 1 in 50,000 in women; anosmia is most common in a young person with delayed puberty; color blindness and mirror movements can also be observed over time; acquired defects — nutrition and intracranial processes; childhood cancer can affect pubertal progression significantly; primary gonadal defects are rare but important, often causing anxiety and concern among parents; oncologists should educate patients about posttreatment complications (sometimes it can be missed during the immediate acute treatment period)

Other syndromes: Turner syndrome — a complete or partial absence of the second chromosome; leads to ovarian insufficiency; the prevalence rate is increasing; important to identify and treat these young individuals as it can sometimes be blurred by the presence of other chronic diseases, eg, obesity; Klinefelter syndrome — an uncommon but important factor to consider

Diagnostic approach: a patient-focused approach; shared medical decision-making with conversations about puberty, pubertal tempo, and genetic variation can help; bone age assessment can help; patient examination includes assessment for Tanner stage and dysmorphic features; the biochemical workup is more extended in delayed puberty; consider karyotype; the stepwise approach is more patient-focused and cost-effective and avoids unnecessary medical workups when the condition is likely to be a normal variant

Treatment of CDGP: no consensus statement; understanding the needs of patients and parents can help determine the treatment; if short stature, impaired self-esteem, anxiety, depression, or social isolation are present, treat the patient in concordance with the patient’s and parents’ preference; the goal is to inhibit the effect of delayed puberty on spinal growth; ensure to promote bone mineral density; often a combination of growth hormone and testosterone (T) is given, which can affect trunk development and lead to disproportionate adult stature; psychosocial sequelae (both positive and negative) can occur; approach — watchful waiting approach is recommended; T is the primary treatment; monthly intramuscular (IM) injections and transdermal patches are available; weekly subcutaneous T injections that can be administered at home are now available; aromatase inhibitors with T can be used to promote puberty (do not advance the bone age too fast, which can impact adult height); growth hormone may also be added to these treatments to ensure they align with the patient's and parents' goals

Considerations: The standard treatment is T IM injections initiated at 50 mg every 3 to 4 wk, typically done in a subspecialty clinic or primary care office; patch and gel forms are also available; subcutaneous T can result in consistent T concentration; easier to match the dose to the stage of puberty; the Turner syndrome guidelines are commonly used for inducing puberty in young girls because of extensive studies; slow and steady treatment methods that mimic the normal pubertal tempo should be considered; the estradiol patch (eg, Climara, Lyllana, Vivelle) is the easiest option, applied twice weekly and can be titrated every 6 mo; once menarche is achieved, switch to a combined oral option

Fertility: often depends on the underlying origin and the ability to correct and treat it; hypogonadotropic hypogonadism requires the addition of cyclical gonadotropin or pump-driven GnRH therapy at the time of desired conception; in almost all cases of hypergonadotropic hypogonadism, fertility cannot be achieved; counseling should be thoughtful and based on current knowledge (much information is not clear)

Readings

Khan L. Puberty: Onset and progression. Pediatric Annals. 2019;48(4):pe141–e145. doi: 10.3928/19382359-20190322-01; Belmont AP, Rosano J, Criscione J, et al. When leuprolide acetate is essential to care: A review of the literature and framework for assessing drug allergy. J Allergy Clin Immunol Glob. 2024;3(2):100210. Published 2024 Jan 19. doi:10.1016/j.jacig.2024.100210; Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. New England Journal of Medicine. 2007;357(9):p863–873. doi: 10.1056/NEJMoa066494; Soliman AT, Sanctis VD. An approach to constitutional delay of growth and puberty. Indian Journal of Endocrinology and Metabolism. 2012;16(5):p698–705. doi: 10.4103/2230-8210.100650; Wei C, Crowne EC. Recent advances in the understanding and management of delayed puberty. Archives of Disease in Childhood. 2016; Zhu J, Liu E, Feld A, et al. Approaches to identify factors associated with pubertal timing in self-limited delayed puberty. Hormone Research in Paediatrics. 2023;96(3):p267–277. doi: 10.1159/000526590.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Vidmar is a member of the advisory boards for Rhythm Pharmaceuticals and Soleno Pharmaceuticals. Members of the planning committee reported nothing relevant to disclose. Dr. Vidmar’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Vidmar was recorded at the 45th Annual Las Vegas Seminars: Pediatric Update, held December 13-15, 2024, in Las Vegas, NV, and presented by the American Academy of Pediatrics, California Chapter 4. For information on upcoming CME activities from this presenter, please visit aap.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

FP731202

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.