Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2007-2090
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 7 2751-2754
Copyright © 2008 by The Endocrine Society
The Aromatase Inhibitor Anastrozole Is Ineffective in the Treatment of Precocious Puberty in Girls with McCune-Albright Syndrome
Jakub Mieszczak,
Elizabeth S. Lowe,
Paul Plourde and
Erica A. Eugster
Department of Pediatrics (J.M., E.A.E.), Section of Pediatric Endocrinology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46202; AstraZeneca (E.S.L.), Wilmington, Delaware 19850; and EUSA Pharma (P.P.), Doylestown, Pennsylvania 18901
Address all correspondence and requests for reprints to: Jakub Mieszczak M.D., James Whitcomb Riley Hospital for Children, 702 Barnhill Drive, Room 5960, Indianapolis, Indiana 46202. E-mail: jmieszcz{at}iupui.edu.
 |
Abstract
|
|---|
Context: Precocious puberty (PP) in girls with McCune-Albright syndrome (MAS) is characterized by episodic development of large unilateral ovarian cysts followed by sudden onset of vaginal bleeding. Some patients experience frequent bleeding as well as accelerated linear growth and advanced skeletal maturation. The use of anastrozole for the treatment of PP in this condition has not been well studied.
Objective: The objective of the study was to determine the safety and efficacy of the aromatase inhibitor anastrozole for the treatment of PP in girls with MAS.
Design and Settings: This was a prospective international multicenter study in which subjects received anastrozole 1 mg daily for 1 yr.
Patients: Twenty-eight girls 10 years of age or younger with MAS and progressive PP were enrolled.
Main Outcome Measures: Vaginal bleeding, rate of skeletal maturation (change in bone age over change in chronological age), growth velocity, and uterine/ovarian volumes were measured. These indices were compared with a 6-month pretreatment interval.
Results: No difference in vaginal bleeding (mean number of days per year) was noted. Mean change in 
BA/CA, which was 1.25 ± 0.77 at baseline, was –0.25 ± 1.02 at study end (P = 0.22). Average growth velocity z score was 1.40 ± 3.15 at study entry and 0.26 ± 2.71 at 12 months (P = 0.10). Mean ovarian/uterine volumes were unaffected by anastrozole, and no significant adverse events occurred.
Conclusions: Although it appears safe, anastrozole for 1 yr was ineffective in halting vaginal bleeding, attenuating rates of skeletal maturation, and linear growth in girls with MAS. Pharmacological strategies other than anastrozole should be pursued for the treatment of PP in this population.
|
Introduction
|
|---|
McCune-Albright syndrome (MAS) is a rare disease classically defined as the clinical triad of precocious puberty (PP), fibrous dysplasia of bone, and café au lait spots (1). An activating mutation in exon 8 of the gene encoding Gs
(GNAS), at the codon for Arg201 results in constitutive, ligand-free activation of affected cells (2). PP is the most common endocrinologic manifestation of MAS (3) and is diagnosed much more frequently in girls than boys.
Girls with MAS usually present with sudden onset of painless vaginal bleeding from resolution of large estrogen-producing ovarian cysts (4). Additional features include mild but acute breast development along with elevated estradiol and suppressed serum gonadotropins (5). Although long periods of quiescence may occur, a subset of girls develop progressive PP marked by frequent vaginal bleeding, increased growth velocity, and rapid bone age advancement with the potential for significant compromise in adult stature. It is in these patients that pharmacological intervention is typically pursued.
The treatment of PP in girls with MAS has included medications aimed at reducing the level of serum estrogen or minimizing its effect on target tissues. The ultimate aim of therapy is to attenuate vaginal bleeding, pubertal development, rates of skeletal maturation, and growth velocity. There has been significant interest in the therapeutic potential of third-generation nonsteroidal aromatase inhibitors such as anastrozole, which should theoretically decrease serum estradiol concentrations, in girls with PP and MAS. To date, only anecdotal and conflicting reports of its efficacy have been available (6, 7). Therefore, the purpose of this study was to prospectively investigate the safety and efficacy of anastrozole for 1 yr in a cohort of girls with MAS and PP.
|
Subjects and Methods
|
|---|
This open-label study was conducted in 13 medical centers located in six countries. Institutional review board or independent ethics committee approval was obtained at each center before patient enrollment. Written informed consent was obtained for each subject. Inclusion criteria included girls between 2 and 10 yr of age with a diagnosis of MAS and progressive PP. Exclusion criteria included prior treatment with a third-generation aromatase inhibitor (AI), any concomitant treatment of precocious puberty associated with MAS, hypersensitivity to any component of study medication, or liver function tests 3 times or greater the upper limit of reference range for age.
After subjects were enrolled, a 6-month retrospective period before the start of anastrozole therapy was used for collection of pretreatment data from chart review and parent recall (vaginal bleeding). Variables analyzed included the number of vaginal bleeding days, rate of skeletal maturation (change in bone age over change in chronological age), growth velocity, and clinical evidence of pubertal progression. All patients were assessed for hyperthyroidism with thyroid function tests and central precocious puberty with a GnRH stimulation test at baseline. The subjects received anastrozole 1 mg daily for 1 yr in tablet form. Clinic visits occurred at baseline and 3, 6, and 12 months. A physical examination including Tanner staging and determination of growth velocity was performed at all clinic visits. Serum levels of estradiol, testosterone, dehydroepiandrosterone sulfate (DHEA-S), LH, and FSH were measured at every visit. All blood samples were analyzed by Quintiles Laboratories (Research Triangle Park, NC). The LH, FSH, and testosterone levels were checked using a chemoluminescence assay (Bayer, Elkhart, IN), whereas the DHEA-S and estradiol levels were evaluated using a RIA. Pretreatment bone age radiographs as well as ones obtained at baseline and 6 and 12 months were centrally read at the Lifespan Health Research Center (Kettering, OH). Pelvic ultrasounds for measurement of uterine and ovarian volumes were performed at each site at baseline and 6 and 12 months. Diary cards were used to record the number of vaginal bleeding days during the study period, and pill counts were used to assess compliance. A two-sided paired t test was used to calculate a 5% level of significance and the corresponding 95% confidence interval. Data are expressed as means ± SD, and the statistical analyses were performed using SAS software (version 8.2 or higher; SAS Institute, Cary, NC).
|
Results
|
|---|
Twenty-eight girls (26 Caucasian) with a mean age of 5.9 ± 2.03 (median of 5.6 and range 3.2–11.0) years were enrolled. One patient had her 11th birthday between her screening and enrollment visits. All had been diagnosed with PP before age 8 yr, with 25 (89%) having been diagnosed at age 4 yr or younger. Of these, 27 completed the 1 yr of study. One patient withdrew because of progression of PP. Compared with the pretreatment interval, no difference in vaginal bleeding (mean number of days per year) was noted, and only three subjects had complete cessation of bleeding throughout the trial. Mean change in bone age over change in chronological age was 1.25 ± 0.77 at baseline and 1.04 ± 0.66 during treatment, resulting in a change of –0.25 ±1.02 (P = 0.22). Individual results for vaginal bleeding and rates of skeletal maturation are shown in Fig. 1
. Average growth velocity z score was 1.40 ± 3.15 at study entry and 0.26 ± 2.71 during treatment, a change of –1.22 ± 3.62 (P = 0.10). No difference in pre- and posttreatment Tanner staging was noted. As expected, the mean ovarian and uterine volumes of study patients appeared to be greater than the age-appropriate normal values (8) but were unaffected by anastrozole (Fig. 2). No significant changes in serum estrogen, testosterone, or gonadotropin levels were observed. A slight increase in average DHEA-S, consistent with progression of adrenarche, was seen at 12 months, compared with baseline (Table 1). None of the subjects were diagnosed with central precocious puberty either at baseline or during the course of the study. One subject had a diagnosis of hyperthyroidism, which was controlled with propylthiouracil at study entry and throughout the study. Three other patients had subclinical abnormalities in thyroid function that did not require treatment, one of whom also had GH excess well controlled with octreotide. Data analysis without these four subjects did not change the results. The treatment was well tolerated and no significant adverse events occurred.
View larger version (20K):
[in this window]
[in a new window]
|
FIG. 1. Individual number of days of vaginal bleeding (upper panel) and rates of skeletal maturation (lower panel) at baseline and 12 months.
|
|
|
Discussion
|
|---|
Even though advancements have been made, the treatment of PP in girls with MAS remains challenging. Initial enthusiasm regarding use of the first generation and least potent AI testolactone was subsequently tempered by reported problems with efficacy and compliance (9). The second-generation agent fadrozole was also found to have insufficient potency along with a propensity for adrenal suppression (10). A recent report of letrozole, the most potent (11) third-generation AI, had mixed results. In this study, letrozole treatment for 24–36 months in nine girls was associated with significant declines in vaginal bleeding, rates of skeletal maturation, and linear growth velocity (12). However, mean ovarian volumes tended to increase over time, and one subject experienced ovarian torsion after development of a large ovarian cyst. Thus, further study is needed before letrozole can be recommended in the clinical setting. Until now, information about the therapeutic utility of anastrozole in MAS has been inconclusive because only a handful of isolated and contradictory case reports have been available (5). This study represents the first systematic prospective trial of anastrozole for the treatment of PP in girls with MAS. Given the uniformly negative results, we believe that it definitively establishes the lack of efficacy of anastrozole in this disease. Taken on balance, experience with currently available AIs in MAS has been disappointing.
An alternative approach to PP in MAS is with the selective estrogen receptor modulator tamoxifen. A multicenter study of 25 girls treated for 1 yr indicated promising efficacy in terms of vaginal bleeding and other indices of PP (13). However, the same trial reported progressive increases in uterine volumes throughout the 12 months of the study, the significance of which is unclear. Thus, no therapy studied to date has proved uniformly effective and unequivocally safe.
The reason that anastrozole failed to decrease serum estradiol concentrations and improve indices of PP in our patients is unclear. One possibility is that the potency of the drug or the dose administered was insufficient, although it is equal to that used in other pediatric indications involving children who are considerably larger and heavier than the girls in our study (14). Alternatively, there may have been insufficient tissue and intracellular concentrations achieved to allow clinically significant inhibition of aromatization in the setting of the strikingly high estradiol levels typical of MAS. Flaws of our study include that it was uncontrolled and that the pretreatment data were collected retrospectively. The highly symptomatic and heterogeneous nature of the condition as well as the extreme rarity of affected patients represent significant obstacles to the implementation of rigorous controlled trials. As in similar studies in MAS, the girls in this trial served as their own controls. An additional potential confounding factor could have been the presence of undiagnosed GH excess because this was not systematically evaluated. Whereas this could potentially have affected skeletal maturation, it would not have impacted vaginal bleeding episodes, which clearly did not improve on anastrozole therapy.
In summary, anastrozole for 1 yr was ineffective in treating PP in girls with MAS. Although less important than the other parameters studied, the lack of adverse effects on uterine and ovarian volumes and favorable safety profile observed in the study lends support to continued investigation of other third-generation AIs in this disorder. Other novel strategies such as use of a pure estrogen receptor antagonist should also be pursued (15). Continued collaborative investigation and long-term follow-up will hopefully one day establish the gold standard for the treatment of PP in girls with MAS.
|
Acknowledgments
|
|---|
The following investigators participated in this study: Professor Norbert Albers (Kinderhospital, Osnabrueck, Germany); Philippe F. Backeljauw, M.D. (Cincinnati Children’s Hospital Medical Center, Cincinnati, OH); Caroline Brain, M.D. (Great Ormond Street Hospital for Children, London, UK); Professor Jean-Claude Carel (Groupe Hospitalier Cochin-St. Vincent de Paul, Paris, France); Professor Helmuth-Guenther Doerr (Klinik mit Poliklinik fur Kinder und Jugendliche der Universitat Erlangen-Nurnberg, Erlangen, Germany); Emily Germain-Lee, M.D. (Johns Hopkins Hospital, Baltimore, MD); Professor Annette Grueters-Kieslich (Kinderklinik der Charite, Berlin, Germany); Roberto Lala, M.D. (Ospedale Infantile Regina Margherita, Torino, Italy); Daniel Marks, M.D. (Oregon Health and Science University, Portland, OR); Professor Valentina Peterkova (Centre of Endocrinology, Moscow, Russia); Professor Michel Polak (Hopital Necker-Enfants Malades, Paris, France); Dennis Styne, M.D. (University of California, Davis, Medical Center, Sacramento, CA); Professor Charles Sultan (Hopital Arnaud de Villeneuve, Montpellier, France).
|
Footnotes
|
|---|
This work was supported by AstraZeneca and involves off-label use of anastrozole for the treatment of precocious puberty in girls with McCune-Albright syndrome.
Disclosure summary: J.M. has nothing to disclose. E.S.L. is employed by AstraZeneca. P.P. was formerly employed by AstraZeneca, owns AstraZeneca stock, and is currently employed by EUSA Pharma. E.A.E. serves as a consultant for AstraZeneca, Indevus Pharmaceuticals, and Genentech and has received lecture fees from Indevus Pharmaceuticals, Eli Lilly, and Genentech.
First Published Online April 8, 2008
Abbreviations: AI, Aromatase inhibitor; DHEA-S, dehydroepiandrosterone sulfate; MAS, McCune-Albright syndrome; PP, precocious puberty.
Received September 18, 2007.
Accepted April 2, 2008.
|
References
|
|---|
- Albright F, Butler A, Hampton A, Smith P 1937 Syndrome characterized by osteitis fibrosa disseminate, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. N Engl J Med 216:722–746
- Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM 1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695[Abstract]
- Foster CM 1993 Endocrine manifestations of McCune-Albright syndrome. Endocrinologist 3:359–364
- Foster CM, Feuillan P, Padmanabhan V, Pescovitz OH, Beitins IZ, Comite F, Shawker TH, Loriaux DL, Cutler Jr GB 1986 Ovarian function in girls with McCune-Albright syndrome. Pediatr Res 20:859–863[Medline]
- Eugster EA 2004 Aromatase inhibitors in precocious puberty: rationale and experience to date. Treat Endocrinol 3:141–151[CrossRef][Medline]
- Roth C, Freiberg C, Zappel H, Albers N 2002 Effective aromatase inhibition by anastrozole in a patient with gonadotropin-independent precocious puberty in McCune-Albright syndrome. J Pediatr Endocrinol Metab 15(Suppl 3):945–948
- Kunz GJ, Mao CS, Gottschalk ME Anastrozole use during precocious puberty in McCune-Albright syndrome. Program of the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, June 19–20, 2003, p 293 (Abstract P1-673)
- Buzi F, Pilotta A, Dordoni D, Lombardi A, Zaglio S, Adlard P 1998 Pelvic ultrasonography in normal girls and in girls with pubertal precocity. Acta Paediatr 87:1138–1145[CrossRef][Medline]
- Feuillan PP, Jones J, Cutler Jr GB 1993 Long-term testolactone therapy for precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 77:647–651[Abstract]
- Nunez SB, Calis K, Cutler Jr GB, Jones J, Feuillan PP 2003 Lack of efficacy of fadrozole in treating precocious puberty in girls with the McCune-Albright syndrome. J Clin Endocrinol Metab 88:5730–5733[Abstract/Free Full Text]
- Azim AA, Costantini-Ferrando M, Lostritto K, Oktay K 2007 Relative potencies of anastrozole and letrozole to suppress estradiol in breast cancer patients undergoing ovarian stimulation before in vitro fertilization. J Clin Endocrinol Metab 92:2197–2200[Abstract/Free Full Text]
- Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT 2007 Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: a pilot study. J Clin Endocrinol Metab 92:2100–2106[Abstract/Free Full Text]
- Eugster EA, Rubin SD, Reiter EO, Plourde P, Jou HC, Pescovitz OH 2003 Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. J Pediatr 143:60–66[CrossRef][Medline]
- Mauras N, Welch S, Rini A, Klein KO 2004 An open label 12-month pilot trial on the effects of the aromatase inhibitor anastrozole in growth hormone (GH)-treated GH deficient adolescent boys. J Pediatr Endocrinol Metab 17:1597–1606[Medline]
- Ariazi EA, Lewis-Wambi JS, Gill SD, Pyle JR, Ariazi JL, Kim HR, Sharma CG, Cordera F, Shupp HA, Li T, Jordan VC 2006 Emerging principles for the development of resistance to antihormonal therapy: implications for the clinical utility of fulvestrant. J Steroid Biochem Mol Biol 102:128–138[CrossRef][Medline]
Top
Abstract
Introduction
