Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium

Abstract

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

“…The gold standard to establish a biochemical diagnosis is an assessment of gonadotropins, predominantly LH, after administration with exogenous GnRH or GnRH agonists (24). However, basal LH levels are also being utilized in some settings, as improved laboratory methods for LH assays have become available (24,26). In contrast to serum estradiol levels in girls, which are typically not helpful, in boys, serum testosterone levels are an excellent marker of precocious puberty, although do not differentiate between central or peripheral etiologies (24).…”

“…Commonly used imaging studies include bone age X-rays, which typically demonstrate a skeletal age that is advanced by 2 years or more from chronologic age (24). Pelvic ultrasonography can indicate uterine exposure to estradiol and help identify an etiology of peripheral precocious puberty, but it is not a part of the diagnostic criteria for precocious puberty (24,26). Brain MRI is an important part of the diagnostic evaluation in order to exclude a hypothalamic hamartoma or other organic abnormalities, especially before the CPP is classified as 'idiopathic' (24,26).…”

Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty

“…The histrelin implant is inserted every year and may be effective for up to 2 years ( 10 , 11 ). Insertion and removal of implants may require anesthesia (often local, sometimes general) ( 2 , 10 ), and they may be left in situ for longer than intended if the patient is lost to follow-up ( 11 , 12 ). Commonly reported local adverse events (bruising, pain, injection reactions, and sterile abscesses) are likely associated with methods of administration and the excipients necessary to prolong release of active drug and clinical effect ( 13-17 ).…”

“…When first used as therapy, GnRHas were administered by daily subcutaneous injection ( 18 ). An international consortium of pediatric endocrinology society representatives recently identified a preference for long-acting subcutaneous injections over the intramuscular route as an example of an improvement in clinical care, by lowering injection site trauma ( 2 ).…”

Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog

“…Long-acting GnRHas are the treatment of choice for CPP, and outcomes after treatment of idiopathic CPP have been described in several studies [3,10,30]. In contrast, long-term follow-up of patients with CPP due to loss-of-function mutations of MKRN3 after GnRHa withdrawal has not been reported so far [6,31,32].…”