Advances in Pediatric Endocrinology

Puberty represents a phase of extraordinary development in a young girl’s life. It encompasses a complex set of interactions involving genetics, prenatal history, and environmental factors that can affect the age at onset of puberty and progression. Disorders of puberty can significantly impact a child’s physical and emotional well-being. In the March 2022 issue of Seminars in Reproductive Medicine, Sharon E. Oberfield, MD, Chief of Pediatric Endocrinology, Diabetes, and Metabolism, and Aviva B. Sopher, MD, MS, a pediatric endocrinologist, NewYork-Presbyterian Morgan Stanley Children’s Hospital, in collaboration with Dr. Selma Witchel of the University of Pittsburgh Medical Center, provide a comprehensive review of abnormalities in pubertal development in females and potential treatments to consider.

Dr. Sharon Oberfield

Dr. Aviva Sopher

From gonadarche to adrenarche to menarche, any changes in the levels or timing of hormone production can result in disorders of varying severity during these pubertal milestones. For example, certain genes, chronic diseases, eating disorders, body weight, and excessive exercise can alter the timing of pubertal onset. The Breast Cancer and Environment Research Program found that the age of menarche, breast development, and puberty could also vary from one to two years among different ethnic groups.

Dr. Oberfield and Dr. Sopher stress that patients with symptoms of concern related to the onset and progression of puberty should undergo an evaluation by an endocrinologist who can determine the cause and plan an appropriate course of treatment. In females, disorders of puberty are classified as either precocious – puberty prior to 8 years old, or delayed – lack of breast development by 13 years old or menarche by 16 years old.

“Earlier puberty may be associated with increased risk for breast and endometrial cancer due to longer estrogen exposure and delayed puberty is associated with increased risk for osteopenia and osteoporosis.” To help prevent the long-term health effects associated with both early and delayed puberty, the authors recommend ongoing monitoring of children diagnosed with precocious or delayed puberty.

Precocious Puberty

Patients with precocious puberty or central precocious puberty typically present as appearing older than their age due to early activation of the gonadotropin-releasing hormone (GnRH) pulse generator within the hypothalamus. That age and appearance discrepancy can negatively impact mental health; girls with central precocious puberty have been found to be at an increased risk for sexual abuse and early pregnancy.

Causes of central precocious puberty include genetic mutations and central nervous system lesions – hypothalamic hamartomas and neurofibromatosis I – but 90 percent of cases are idiopathic in females. The gold standard of treatment of progressive central precocious puberty includes GnRH agonists, such as leuprolide, given every 28 days or every three or six months; triptorelin given every six months; or surgically implanted histrelin. These GnRH agonists can reduce luteinizing hormone levels and the concentration of sex steroids. Generally, pubertal progression is halted within three months of beginning treatment.

GnRH-independent precocious puberty, or peripheral precocious puberty, indicates the onset of puberty without the activation of the GnRH pulse generator. Causes include gene mutations – GNAS1, CYP21A2, HSD3B2, CYP11B1 – that result in excessive gonadal or adrenal steroid secretion/exposure, or exposure to exogenous sex steroids. This typically results in incomplete pubertal development.

While symptoms can help to diagnose the specific pubertal disorder, a thorough assessment of the patient’s family history is important in identifying genetic causes. Additionally, a GnRH stimulation test or an adrenocorticotropic hormone (ACTH) stimulation test can evaluate hormonal imbalances. Imaging tests, such as X-ray, MRI, CT, or pelvic ultrasounds, are used to identify skeletal maturation, central nervous system lesions, or abnormal growths.

Delayed Puberty

Delayed puberty affects some 2 percent of girls and may be categorized as constitutional, hypogonadotropic, or hypergonadotropic. Children with constitutional delay in growth and puberty present with shorter stature due to delayed skeletal maturation. Without a specific diagnostic test available, constitutional delay is a diagnosis of exclusion.

Congenital hypogonadotropic hypogonadism is caused by decreased GnRH production due to irregular development of the hypothalamus. Patients can have varying presentations depending on the severity of GnRH deficiency, which can be caused by mutations of genes involved in GnRH neuron function or central nervous system tumors.

In hypergonadotropic hypogonadism, which includes gonadal dysgenesis, puberty is typically delayed or absent often as a result of a chromosomal abnormality as seen in Turner’s syndrome and Sywer’s syndrome. Hypergonadotropic hypogonadism also can arise from disruption of the hypothalamus-pituitary-gonadal (HPG) axis due to treatment for childhood cancers with chemotherapy or radiation therapy, which can damage DNA and impact fertility.

When assessing delayed puberty, patients with a short stature or virilization should undergo karyotyping and monitoring of hormone concentrations. Imaging tests are helpful in identifying delays in skeletal development and a brain MRI can identify potential hypothalamus or pituitary abnormalities. Treatment options include estrogen replacement therapy (ERT).

According to Dr. Oberfield and Dr. Sopher, treatment is not always indicated and watchful waiting may be the best course in many cases. ERT is indicated in patients who may experience psychosocial issues related to their delayed puberty. Bone health should also be assessed, and occasionally, brief courses of low-dose ERT may be warranted. “The goal of estrogen replacement therapy is to mimic normal estradiol secretion to induce development of secondary sexual characteristics, to promote linear growth acceleration, and to maintain bone health,” note the authors. “ERT is generally initiated around the age of 12 so that girls with hypogonadism will experience menarche at the same time as their peers.”

The pediatric endocrinologists at NewYork-Presbyterian Morgan Stanley Children’s Hospital note that precocious and delayed puberty are wide-ranging classifications that describe deviations from normally timed puberty and are associated with a range of medical and psychosocial issues. They recommend that patients presenting with pubertal differences undergo a comprehensive assessment to determine the underlying etiology and to develop an effective treatment plan.