Histrelin implant can safely curb precocious puberty

By Larry Hand

NEW YORK (Reuters Health) - A long-term histrelin implant effectively and safely suppresses gonadotropin in children with central precocious puberty (CPP), according to new research.

"Hormonal and physical evaluations confirmed that ongoing pubertal development was halted during treatment, while statural growth continued and significant improvement was made in the PAH (predicted adult height) and bone age/chronological age ratio," Dr. Lawrence A. Silverman, of Goryeb Children's Hospital - Atlantic Health System, Morristown, New Jersey, and colleagues reported online March 24 in the Journal of Clinical Enocrinology & Metabolism.

Within six months of stopping the therapy, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increased to pubertal levels and allowed the hypothalamic-pituitary-gonadal (HPG) axis to recover, they wrote.

The data are from an extension of a phase 3 open-label trial involving girls ages 2 to 8 and boys 2 to 9 with evidence of CPP who had not received gonadotropin-releasing hormone analog (GnRHa) therapy, plus girls ages 2 to 10 and boys 2 to 11 who had received standard GnRHa therapy for at least six months.

Subcutaneous implants were placed in the medial aspect of the upper arm; each implant delivered an average of 65 micrograms/day of histrelin for 12 months. Patients were followed for up to six years.

Of 36 children enrolled in the initial trial, 31 started in the extension study, and 22 (71%) received at least three implants. Nine did not complete a third year because of age inappropriateness, progression into puberty, or parental decision. Only one of three boys in the study received more than two implants.

After their final implant was removed, nine patients continued for up to a year in an optional post-treatment follow-up period.

Within one month of starting treatment, LH levels fell below a predetermined peak pubertal response of 4 mIU/mL, "indicative of HPG axis suppression," the researchers wrote.

LH remained consistently suppressed during the evaluation period, and no patient had an on-therapy stimulated LH level exceeding 2.3 mIU/mL.

The researchers observed statistically significant peak LH levels at one month, 48 months, and 60 months (p<0.05), and by six months after removal of the implant, LH concentrations increased to pubertal levels.

They also observed significant reductions in mean peak FSH throughout the study (p<0.05), and FSH concentrations increased to pubertal levels six months after implant removal.

Mean estradiol concentrations remained consistently below a predetermined threshold of 73.43 pmol/L throughout the study regardless of whether the children had received previous GnRHa therapy. Girls who had received previous treatment showed little evidence of further maturation.

"Overall, physical evidence of continued pubertal development while patients were undergoing therapy was minimal," the researchers wrote.

The most frequent treatment-related adverse events were implant-site reactions, including bruising (18), incisional pain (18), and discomfort (11). One patient had a benign pituitary tumor (deemed possibly study-related) and one patient experienced amblyopia (deemed unlikely to be study-related). One child died from acute bronchopneumonia and Dravet syndrome, but the death was not considered study related.

Implant breakage occurred in 25 of 113 explants. The possible breaking of the device is one potential disadvantage of using extended-duration GnRHa therapy, along with the need for repeated implantation and the difficulty of explantation.

However, advantages include continuous suppression of the HPG axis and flexibility of scheduling the annual implant appointments, the researchers wrote.

"The histrelin implant for CPP has been established in pediatric endocrinology practice for many years," coauthor Dr. E. Kirk Neely, professor of pediatric endocrinology and diabetes at Stanford School of Medicine, Palo Alto, California, told Reuters Health by email.

"Superb treatment efficacy in suppressing both gonadotropins and sex steroids is beyond question," he continued. "One question that will need to be answered by individual pediatric endocrinology practitioners is whether to follow (Food and Drug Administration)-approved annual reimplantation" or to rely on one group's independent report (http://bit.ly/1FidLAW) that the implant lasts for up to two years.

He added, "The remaining research issues are the major ones for all GnRHa use in CPP: Is final height augmented by therapy, particularly in children with borderline age at initiation, and are there any long-term problems?"

Endo Pharmaceuticals funded the research and employs two of the coauthors; four coauthors reported receiving research support or fees from pharmaceutical companies, including Endo.

SOURCE: http://bit.ly/1c7WBtp

J Clin Endocrinol Metab 2015.

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