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Novel treatments seem promising for central precocious puberty

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Novel treatments seem promising for central precocious puberty

While GnRHa analogs remain standard treatment, hydrogel implants are currently being studied.

by Paul Saenger, MD, MACE


Central precocious puberty is the premature activation of the hypothalamic-pituitary?gonadal axis that causes the development of secondary sex characteristics, accelerated growth and accelerated bone maturation, which may compromise adult stature.


Psychosocial problems also abound in CPP. It occurs much more commonly in girls. The U.S. incidence figures are approximately 1 in 5,000 to 1 in 10,000 children. There are approximately 200 new cases annually in the United States alone. The female to male ratio is as high as 10-to-1.


Paul Saenger


In girls, 70% to 90% of cases do not show an identifiable lesion; in boys, 50% of cases are caused by an identifiable lesion, such as hypothalamic hamartomas, optic gliomas, intracranial tumors such as neurofibromatosis and, rarely, pituitary tumors. Any form of insult to the brain such as structural defects, trauma, meningitis and cerebral palsy increase the risk for CPP. A lesion of the central nervous system is much more common in patients under age 4.


The biochemical signs are increased basal or stimulated LH secretion and elevated sex steroid levels. The clinical signs are premature activation of the HPG axis in girls younger than 8 years and boys younger than 9 years. In girls we see breast development and increased uterine volume; in boys, increased testicular volume (.4 mL). Bone is usually advanced, and BMI is often increased. Precocious puberty must not be confused with premature adrenarche or premature thelarche, variants of normal puberty.


GnRH analogs are the standard


To date, CPP has been treated with long-acting GnRH analogs, which have been the standard worldwide since their development in the 1980s. Although several drugs and routes of administration are available, the most commonly prescribed GnRHa in this country is depot leuprolide, which is typically given via intramuscular injections at intervals of one month.


Assuming good compliance, which is often difficult to achieve, GnRHa therapy results in prompt and reliable suppression of puberty and favorable long-term outcomes in adult height, reproductive function, bone mineral density and body composition.


Although a three?monthly intramuscular administration of depot leuprolide has been used, a direct comparison of the different dosing regimens has indicated potential problems with insufficient suppression using this dosage schedule.


Furthermore all GnRHa formulations cause an initial, albeit transient, agonist reaction ? a flare-up of signs and symptoms. It stands to reason, therefore, that monthly injections of GnRHa could cause a monthly transient flare-up.


Hydrogel implant for children


To this end, a longer acting compound was actively sought. Positive experience with a hydrogel implant containing the potent GnRHa histrelin in men with prostate cancer led to the intriguing concept that this novel device might also be applicable to the treatment of CPP in children.


U.S. investigators recently published a one-year multicenter trial investigating safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment na?ve as well as previously treated patients. This was a phase-3, open label, prospective study with an optional one-year extension, which is now underway. The two-year data will be presented at the spring meetings.


The study was performed at nine U.S. medical centers. Girls aged 2 to 8 years (na?ve) or 2 to 10 years (previously treated), and boys aged 2 to 9 years (naive) or 2 to 11 years (previously treated) with robust clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible.


At baseline a 50-mg histrelin subdermal implant was inserted into the inner aspect of the upper arm. The implant was 3.5 cm in length and 3 mm in diameter and has a wall thickness of 0.5 mm (latex free).


Implant procedure


Histrelin diffuses from the implant at an average rate of 65 mcg/day. One size implants fits all. The implant procedure is done by a pediatric surgeon using conscious sedation or local aneasthesia on an out-patient basis.


Thirty-six children (33 girls) were enrolled; of these, 20 were treatment naive. Average height Z score was 1.5?1.4 at baseline, BMI Z ?score was 1.5 ?0.8. The majority of the girls were at Tanner III breast development at study entry.


By one month, already peak LH fell from 28.2?19.97 (na?ve) to 0.8?0.39 mIU/mL (P<.001) and from 2.1?2.15 (previously treated) to 0.5?0.32 mIU/mL (P<.0056). Estradiol was suppressed from 24.5? (na?ve) to 5.9?2.37 pg/mL(P=.0016) and remained suppressed in previously treated participants, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred.


The comparatively greater potency of histrelin as compared to other GnRHa drugs such as leuprolide is readily apparent from the statistically significant further decrease in peak LH concentration from baseline to one month that was observed in the previously treated group, who were already clinically but not completely biochemically suppressed at study entry. Mean histrelin concentration was highest at month one and decreased through month 12, remaining above the limit of detection at most time points, documenting continuous release of histrelin.


Reimplantation chosen by most


Most study participants opted for reimplantation at the end of year one, and they are now in the second year of treatment. Although formal assessments were not performed, continuation rates and unsolicited feedback from participants indicated nearly uniform enthusiasm about this form of treatment, compared with traditional monthly injections. Larger scale prospective studies are needed to confirm these promising results.


The advent of an ultra-long-acting GnRHa implant is another entry designed to aid patients and physicians in the increasing challenge of improving compliance with chronic medications. In this ongoing quest to improve compliance we saw first the long-acting insulins, then long-acting somatostatins, then long-acting GHRHa, and now an ultra-long-acting GnRHa has arrived.


Several large pharmaceutical companies are rushing to develop long-acting growth hormone formulations to get away from tedious daily injections of growth hormone. To increase not only convenience but also compliance, long-acting formulations of drugs will be a cornerstone of new drug development in the years to come.


This is in line with the recent efforts of the WHO, which published an evidence-based guide for clinicians to improve strategies of medication adherence. To quote the former U.S. Surgeon General C. Everett Koop: ?Drugs don?t work in people who don?t take them.?


Paul Saenger, MD, MACE, is a Professor of Pediatrics at the Albert Einstein College of Medicine, Bronx, NY, and is a member of Endocrine Today?s Editorial Board.


For more information:


Badaru A, Wilson DM, Bachrach LK, et al. Sequential comparisons of one-month and three- month depot-leuprolide regimens in central precocious puberty. J Clin Endocrinol Metab. 2006;91:1862-1887.

Carel C, Blumberg J, Seymour C, et al. Three-month sustained release triptorelin (11.25 mg) in the treatment of central precocious puberty. Eur J Endocrinol. 2006;154:119-124.

Eugster EA, Clarke W, Kletter GB, et al. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. J Clin Endocrinol Metab. 2007;92:1697-1704.

Osterberg L, Blaschke T. Adherence to medication. N Eng J Med. 2005;353:487-497.

Spitz IM, Chertin B, Lindenberg T, Farkas M. A long-acting gonadotropin releasing hormone to maintain medical castration for two years in men with prostate cancer. N Eng J Med. 1999;340:1439-1444.



Link to article: http://www.endocrinetoday.com/view.aspx?rid=26832

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