GH/GnRHa Increases Adult Height in Very Short Children: Study

Marlene Busko

April 22, 2019

Combined growth hormone (GH) and gonadotrophin-releasing hormone analog (GnRHa) therapy increased adult height in a cohort of "challenging-to-treat" children and teens with idiopathic short stature (ISS), new data suggest.

Previously, researchers have hypothesized that adding GnRHa therapy to GH therapy would prolong puberty and lengthen the pubertal growth spurt, which would increase the odds of attaining normal adult height. However, results in small studies have been mixed.

Now this larger, retrospective, single-center observational study in 192 children demonstrated that combined GH/GnRHa therapy was effective in improving adult height outcomes in children with ISS who had early normal puberty onset or were starting GH treatment in mid-puberty.

Moreover, "the addition of GnRHa to GH therapy in these challenging groups enabled not only an attainment of an adult height within the normal population range and comparable to that of the ISS patients treated with GH alone, but also an adult height exceeding their genetic height range," lead author Liora Lazar, MD, Schneider Children's Medical Center of Israel, Petah Tikva told Medscape Medical News in an email.

The beneficial effect was also more pronounced in children who were prepubertal at initiation of GH therapy and in girls, researchers report in an article published online March 26 in the Journal of Clinical Endocrinology & Metabolism

The study reflects real-world clinical practice, the authors note, and it "makes two substantial contributions towards meeting the challenge of management of ISS children with relatively early puberty and adolescents in mid-puberty at initiation of GH treatment."

It demonstrated the benefit of combined GH and GnRHa therapy in this patient population, and it showed the positive impact of GH therapy on adult height even when started at puberty.

"However," the authors caution, "to fully assess whether GnRHa, by extending the pubertal growth period, can increase adult height outcome in all GH-treated ISS children, additional prospective, randomized controlled trials are needed."

Extending Puberty to Promote Height in ISS

Short stature — defined as an adult height that is more than two standard deviations below the mean for age and gender, which corresponds to the shortest 2.3% of individuals — is "one of the most frequent reasons for referral to pediatric endocrinologists," Lazar said.

And ISS is short stature without a deficit of GH.

"In the United States the regulatory authorities approved GH treatment for children shorter than –2.25 SDS [standard deviation score, for height] for the indication of ISS, and a predicted adult height below 160 cm for males and 150 cm for females," she noted, adding that "short stature in children of short parents is considered familial (genetic) short stature."

Pediatric Endocrine Society guidelines advise that "for children who meet FDA criteria, we suggest a shared decision-making approach to pursuing GH treatment for a child with ISS...on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits...The addition of GnRHa in GH-treated short children is taken in accordance with the clinical judgment of the treating endocrinologist."

To investigate optimal therapy in prepubertal and pubertal patients with ISS, the researchers identified 110 boys and 82 girls with ISS born between 1985 and 2000 who attained adult height by 2018 and had received treatment at their institution.

At the start of GH therapy, 66% of the children (74 boys and 52 girls) were prepubertal. None of the children had a GH deficiency.

GH was given as a daily subcutaneous injection of recombinant human GH (Genotropin, Pfizer; Norditropin, Novo Nordisk; Biotropin, Pharmacia).

Based on the clinical judgment of the treating endocrinologist, some patients also received pubertal suppression with a depot preparation of the GnRH analog D-Trp6-LHRH (Decapeptyl, Ferring).  

Of the participants, 70% were treated with GH alone: 71% of these patients were prepubertal (62 boys, 33 girls) and 29% were pubertal (28 boys, 11 girls).

The other 30% of patients were treated with combined GH/GnRHa: 53% were prepubertal (12 boys, 19 girls) and 47% were pubertal (8 boys, 19 girls).

In the prepubertal group, GnRHa was given to children with relatively early pubertal onset (boys age 9.5 to 11 years; girls age 8.5 to 10 years) and fast transition (< 1 year) from Tanner stage 2 to 3. 

In the pubertal group, GnRHa was given to adolescents who were already in mid-puberty (Tanner stage 3-4) at referral.

The mean duration of GnRHa treatment was similar in boys and girls (2 years vs 1.8 years, respectively).

In the prepubertal group, the duration of puberty was significantly longer, and the total pubertal growth was significantly greater in boys and girls treated with combined GH/GnRHa than those treated with GH alone (P < 0.001, for both parameters in both sexes).

Similarly, in the pubertal group, the duration of puberty was significantly longer, and the total pubertal growth was significantly greater in boys and girls treated with combined GH/GnRHa than those treated with GH alone (boys: P = .004 and P = .003, respectively; girls: P = .008 and P = .046, respectively).

Most of the study participants, whether treated with GH or GH/GnRHa, reached an adult height within their mid-parental height range.

"In-line with previous studies," the researchers report, "combined GH/GnRHa therapy for 1.5 to 3 years increased the total pubertal height gain of our ISS patients by slowing their bone maturation rate while maintaining an appropriate growth velocity."

"The positive effect of the combination therapy in both ISS patients with relatively early puberty who had been treated with GH since childhood and in those presenting with advanced puberty who were naive to GH treatment justifies the addition of GnRHa to pubertal ISS patients with poor height prognosis, and the initiation of GH therapy in adolescents presenting in the endocrine clinic in mid-puberty because of ISS," they state.

The study did not receive any funding. Lazar has reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

J Clin Endocrinol Metab. Published online March 26, 2019. Abstract

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