On the 20th anniversary of the U.S. Food and Drug Administration’s approval of growth hormone (GH) treatment for idiopathic short stature (ISS), Adda Grimberg, MD, and Colin P. Hawkes, MD, PhD, both of the Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, published a mini-review in The Journal of Clinical Endocrinology & Metabolism, covering the expansion of GH treatment, how GH works, the non-GH–deficient uses of GH as a height-promoting agent, biological constraints to GH action, and future directions.
Grimberg and Hawkes start with a quote that pediatric endocrinologists will probably hear more and more of: “We want to look into growth hormone treatment for [my son]. I know some people do it just because.”
The authors point out that this complaint highlights the perceptions that GH treatment is effective at enhancing height and offering inherent advantages, without regard to an underlying diagnosis or the mechanisms of GH action, and with minimal to negligible safety concerns. “It epitomizes the evolution of GH treatment as expansive biotechnology, spreading from treatment of an authentic disease (GH deficiency [GHD]) to treatment of conditions that blur the boundary between disease and variation,” Grimberg and Hawkes write.
The authors write that four main factors have contributed to the expansion of GH treatment: reliance on provocative GH testing to distinguish patients with GHD from those with adequate GH production, leading to a greater tendency toward falsely diagnosing children with GHD; heightism, the prejudice that taller stature is beneficial in achieving social success; financial and professional incentives to expand GH use; and positive reinforcement to parents and clinicians from the early growth acceleration experienced by most children treated with GH. “In sum, national commercial insurance claims data showed an almost tripling of the annual prevalence of youth treated with GH in the United States from 2001 to 2016,” the authors write.
And as the availability of GH has increased, so has its use in children with non-GH deficient short stature, including children with Turner syndrome and Noonan syndrome, as well as children who are small for gestational age, and children with ISS. For example, in children with ISS, Grimberg and Hawkes write: “Systematic reviews demonstrated a mean increase in adult height of 0.65 SD (4.2 cm females, 4.6 cm males) with GH treatment. However, these are all mean results, with a wide variation in responses at the individual level. This includes some children who did not increase their adult heights, reflecting the vastly heterogeneous nature of the ISS categorization. Magnitude of bone age delay at start of treatment was associated with ‘response’ to GH treatment on multiple regression analysis, suggesting that perceived GH response may be realization of delayed bone age-associated growth potential.”
Grimberg and Hawkes write that because of the biological constraints on GH action — negative feedback loops, growth plate senescence, other local growth plate factors, and systemic and cellular factors regulating GH production/secretion and action — the fact that GH treatment is less effective for non-GHD disorders, including ISS, shouldn’t be surprising.
For instance, according to the authors, negative feedback loops tightly regulate both GH production/secretion and GH signaling to attenuate or terminate GH activity. The authors write that an intracellular negative feedback loop terminates signaling by the GH receptor, a member of the class I cytokine receptor superfamily that signals primarily through the JAK/STAT pathway; GH induces expression of various suppressors of cytokine signaling (SOCS)/cytokine-inducible SH2 (CIS)-containing protein family proteins, which in turn inhibit STAT signaling.
“Thus, rather than exogenous GH treatment simply adding to endogenous GH in non-GHD conditions, it may lead to loss of at least some endogenous GH activity via the negative feedback loops before a net gain in GH activity is achieved,” Grimberg and Hawkes write. “This is supported by a pharmacokinetic study in healthy men of recombinant 20-kDa human GH that found marked suppression of endogenous 22-kDa human GH secretion in a time-dependent manner.”
In their conclusion, the authors again point to the fact that it seems like more and more parents are bringing their children to pediatric endocrinologists seeking GH treatment to achieve a predetermined height of their choosing. And while GH replacement has done wonders for patients with GHD, GH therapy for non-GHD disorders has resulted in responses ranging from comparable to those in patients with GHD to partial or short-term responses to negligible or no response at all. “[Twenty] years’ clinical experience following approval of the ISS indication and our increasing understanding of growth and GH biology have shown us that no, [achieving a predetermined height of choice via GH treatment] is not always possible and yes, the underlying diagnosis does matter,” Grimberg and Hawkes write.
Loading ...