Puberty Evaluation in Pediatric Patients

Educational Objectives

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

1. Explain the Pediatric Endocrine Society race-based criteria for defining precocious puberty.
2. List the features of Klinefelter syndrome.
3. Optimize use of testosterone in constitutional delay of growth and puberty.

Summary

Sequence of pubertal events: for girls, the typical sequence includes breast buds, pubic hair, growth spurts, body hair, breast maturity, and menarche; for boys, testes growth followed by pubic hair, penis growth, axillary hair, and growth spurt; adrenarche occurs independently in ≈10% of children, which highlights its importance in precocious puberty workups

Timing of puberty: data from 2019 show that the average onset of puberty for girls started 6 mo to 1.5 yr earlier, with the timing of thelarche decreasing from 1975 to 2015, which is important in assessing puberty because it relies on the normal timing of puberty; in 1999, the Pediatric Endocrine Society recommended race-based criteria for defining precocious puberty, which state that breast development should be considered precocious in Black girls <6 yr of age and White girls <7 yr of age; data set (Biro et al [2013]) reveals that non-Hispanic White participants had a mean age of 9.6 yr at Tanner stage 2 development, with the mean age shifting backward

Central precocious puberty (CPP): involves the early activation of the hypothalamic-pituitary-gonadal axis; 80% to 90% of cases in girls are idiopathic; central nervous system lesions are rare and are often caused by genetic mutations (most of which remain unidentified)

Constitutional delayed puberty (CDP): refers to the absence of breast development in girls by the age of 12 to 13 and the absence of testicular enlargement in boys by the age of 13 to 14, with variations based on race and ethnicity; this condition affects ≈5% of healthy young people; CDP affects 63% of boys and 33% of girls, with 20% experiencing functional hypogonadotropic hypogonadism (HH), 13% experiencing primary hypogonadism, 13% having other causes, and 3% having undefined causes

Constitutional delay of growth and puberty (CDGP): the most common cause of delayed puberty; transient genetic variation in gonadotropin hormone-releasing hormone (GnRH) production and individual genetic variation; there is also a family pattern of inheritance, with an autosomal dominant pattern that occurs in multiple generations; the patient’s history is important in congenital defects, eg, isolated GnRH deficiency, isolated gonadotropin deficiency, X-linked congenital adrenal hypoplasia, Kallmann syndrome (usually in boys) may cause it; over the past 5 yr, delayed puberty consults have increased, highlighting the social impact of early puberty

Kallmann syndrome: is characterized by several features including anosmia or hyposmia, HH, mirror movements, and color blindness; it is an X-linked disorder, usually caused by mutations in the ANOS-1 or KAL-1 gene, with a prevalence of 1 in 10,000 in men and 1 in 50,000 in women; radiologic findings typically show hypoplasia of the olfactory bulbs and tracts; patients may also present with gonadotropic deficiency and hypopituitarism; Kallmann syndrome can coexist with other conditions such as pituitary transcription gene mutations, optic nerve hypoplasia, hypothalamic pituitary stalk transection, holoprosencephaly syndrome, and midline cleft defects

Impact of obesity: genetic components, such as Prader-Willi syndrome, leptin-receptor deficiency, and prohormone convertase gene mutation should be considered; obesity is a major contributing factor to the alteration of pubertal timing; adipose tissue, which contains estrogen, affects pubertal onset; in girls, extra adipose tissue can contribute to precocious puberty; in boys, increasing estrogen in those who are overweight can lead to precocious puberty, while severe obesity may delay puberty

Acquired defects: can lead to delayed puberty, which include undernutrition, isolated deficiency of GnRH or gonadotropin, and suprasellar tumors; these children are typically treated in subspecialty care, with a focus on addressing the primary defect; it is crucial to understand the primary oncologic process in order to effectively manage delayed puberty; other factors such as accidental or surgical trauma, infectious conditions like meningoencephalitis and hydrocephalus, as well as untreated endocrinopathy, can also impact the timing of puberty; delayed puberty has a comprehensive differential diagnosis

Gonadal defects: congenital causes include syndromes associated with genital ambiguity, genetic syndromes, and mutations of the luteinizing hormone and follicle-stimulating hormone receptor (rare); acquired causes include chemotherapy and radiation; it is important to help families understand how these factors can affect puberty over time

Turner syndrome: associated with complete or partial absence of the second chromosome and ovarian insufficiency; patients present with HH caused by gonadal dysgenesis; require puberty induction and maintenance; despite the classic phenotype, more mosaics with Turner syndrome are being identified at various time points

Klinefelter syndrome: characterized by the most common karyotype of 46 XXY; some features of this condition include average to tall stature, gynecomastia, learning disability, small and firm testes, and hyalinization of the Sertoli cells leading to infertility; it is important to note that there may be mosaic findings with slight differences in presentation; learning disabilities are significant but can sometimes be mild

Diagnostic approach: includes a thorough medical history, detailed growth history, family history, physical examination, and bone age assessment; determine if puberty development is absent or stalled; check if the patient has any nutritional habits, medical illnesses, congenital abnormalities, neurologic symptoms, or family history; check the sense of smell; examine the body for dysmorphic features and establish Tanner staging; bone age is an economic and easy diagnostic tool that can help rule out late bloomers and determine the necessary laboratory evaluations; the speaker emphasizes the importance of thoughtful referral pathways and a clear stepwise approach

Treatment of CDGP: children with CDGP will eventually go through puberty normally; they will have enough sex steroids to support their metabolic, bone, and cerebral health; psychological factors also play a role in their overall development, and wellness, which may lead to concerns; at 13 yr of age, if there is significant short stature, impaired self-esteem, anxiety, depression, and social isolation, treatment with testosterone is considered with shared medical decision-making involving the patient and their parents, which is more for the child's support and general wellness, rather than for medical indication; reasons for testosterone — the inhibitory effect of delayed puberty on spinal growth, which affects peak bone mineral density; consequences — risk for short trunk and disproportionate adult stature, as bone age advances slightly more rapidly than without treatment; a slight increased risk for osteopenia in late adulthood, as well as psychosocial and educational sequelae

Options: “watchful waiting” for the treatment of children with psychosocial distress; having more tools can help evaluate testosterone therapy options; combining aromatase inhibitors with testosterone can be more effective and have a shorter treatment course; growth hormone can be considered; low-dose intramuscular testosterone, starting at 50 mg every 3 to 4 wk, with an annual incremental increase of 50 mg; patches and gels are available, but they can be challenging because patches can fall off and cause itchiness, while gels can affect other individuals with whom the patient comes into physical contact; subcutaneous testosterone preparations are available, making it easier to match the dose to the stage of puberty and titrate

Induction of puberty in girls: the gold standard guideline for inducing puberty in young girls is the use of testosterone, which aims to mimic the natural pubertal trajectory through administration of estrogen and progesterone; it works well through Tanner stage 2 to menarche; estrogen patches (eg, Elestrin, Depo-Estradiol, Vivelle-Dot) are easy to use and changed twice a week, and then progestin is introduced

Fertility: HH requires cyclical gonadotropin or pump-driven GnRH therapy at the time of desired contraception; fertility cannot be achieved in most cases of HH; pediatric endocrinologists focus on achieving normal puberty and refer patients to fertility experts to assess their fertility potential over time

Readings

Bearelly P, Oates R. Recent advances in managing and understanding Klinefelter syndrome. F1000Res. 2019;8:F1000 Faculty Rev-112. doi: 10.12688/f1000research.16747.1; Biro FM, Greenspan LC, Galvez MP, et al. Onset of breast development in a longitudinal cohort. Pediatrics. 2013;132(6):1019–1027. doi: 10.1542/peds.2012-3773; Gaudino R, Filippo GD, Bozzola E, et al. Current clinical management of constitutional delay of growth and puberty. Ital J Pediatr. 2022;48(1):45. doi: 10.1186/s13052-022-01242-5; Khan L. Puberty: Onset and progression. Pediatr Ann. 2019;48(4):e141-e145. doi: 10.3928/19382359-20190322-01; Kaplowitz PB, Oberfield SE. Reexamination of the age limit for defining when puberty is precocious in girls in the United States: Implications for evaluation and treatment. Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society. Pediatrics. 1999;104(4 Pt 1):936-941. doi: 10.1542/peds.104.4.936; Klein KO, Rosenfield RL, Santen RJ, et al. Estrogen replacement in Turner syndrome: Literature review and practical considerations. J Clin Endocrinol Metab. 2018;103(5):1790-1803. doi: 10.1210/jc.2017-02183; Raivio T, Falardeau J, Dwyer A, et al. Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med. 2007;357(9):863-873. doi: 10.1056/NEJMoa06649; Swee DS, Quinton R, Maggi R. Recent advances in understanding and managing Kallmann syndrome. Fac Rev. 2021;10:37. doi: 10.12703/r/10-37; Wood CL, Lane LC, Cheetham T. Puberty: Normal physiology (brief overview). Best Pract Res Clin Endocrinol Metab. 2019;33(3):101265. doi: 10.1016/j.beem.2019.03.001.

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 consultant for Rhythm 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 Pediatric Potpourri: State of the Art 2024, held February 24 to March 1, 2024, on Maui, HI, and presented by the Children’s Hospital Los Angeles Medical Group. For information on upcoming programs from this presenter, please visit https:// www.chla.org/chla-medical-group/cme-conferences. 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 0.75 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 0.75 CE contact hours.

Lecture ID:

PD702901

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.