This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nunez, S. B. Articles by Feuillan, P. P. Search for Related Content PubMed PubMed Citation Articles by Nunez, S. B. Articles by Feuillan, P. P.

Lack of Efficacy of Fadrozole in Treating Precocious Puberty in Girls with the McCune-Albright Syndrome

Developmental Endocrinology Branch (P.P.F.), National Institutes of Child Health and Human Development, and Warren G. Maguson Clinical Center (K.C., J.J.), National Institutes of Health, Bethesda, Maryland 20892; Children’s National Medical Center (S.B.N.), Washington, D.C. 20010; and Lilly Research Laboratories (G.B.C.), Eli Lilly and Company, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Penelope P. Feuillan, M.D., Developmental Endocrinology Branch, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, 9000 Rockville Pike, Bethesda, Maryland 20892. E-mail: pfeuill{at}helix.nih.gov.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We administered the aromatase inhibitor fadrozole to 16 girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome. The girls’ ages ranged from 3.2–9.7 yr, and their bone ages ranged from 5.75–14.25 yr. After baseline evaluations, fadrozole was started at a dose of 240 µg/kg·d (equivalent to the dose recommended for therapy of estrogen-dependent breast cancer) for 12–21 months and increased to 480 µg/kg·d for an additional 12 months in 10 girls. During treatment, seven girls had evidence of central precocious puberty; hence, the GnRH agonist deslorelin (4 µg/kg·d sc) was added to their regimen. One girl was on a long-acting GnRH agonist from the start of treatment. Patients were evaluated at 2–6-month intervals throughout treatment. After the first 6–12 months of treatment, fadrozole showed some benefits in 10 girls, including decrease in frequency of menses and/or rates of linear growth and bone maturation; however, fadrozole had no significant benefit in the group as a whole. The seven girls with evidence of central precocious puberty had no slowing in the progression of their puberty during the combined fadrozole and GnRH analog treatment. Adverse effects of fadrozole included inhibition of cortisol and aldosterone biosynthesis at the dose of 480 µg/kg·d, without clinical evidence of adrenal insufficiency. In addition, three patients complained of nonspecific abdominal pain during fadrozole treatment. In one patient, this resolved with a reduction in dose from 480 to 240 µg/kg·d; in two patients, it resolved spontaneously. One girl had muscle weakness and constipation on the 480 µg/kg·d. This resolved after discontinuation of the drug. We conclude that fadrozole is not sufficiently potent to block estrogen synthesis in most girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome and may impair the adrenocortical stress response.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THE MCCUNE-ALBRIGHT syndrome (MAS; polyostotic fibrous dysplasia, café-au-lait pigment, precocious puberty, and other forms of endocrine hyperfunction) (1) is a sporadic disorder caused by an activating missense mutation (Cys or HisArg²⁰¹) in the gene for the -subunit of the stimulatory G protein (2). In MAS girls, precocious puberty is due to autonomous synthesis of estrogens, is independent of gonadotropins, and fails to respond to GnRH analog treatment (3, 4).

The development of nonsteroidal aromatase inhibitors has been a significant advance in the therapy of estrogen-dependent neoplasms. One such compound, fadrozole hydrochloride (CGS 16949A, CIBA-GEIGY, Basel, Switzerland) (5), is effective in women with breast cancer (6, 7, 8) and is in clinical use outside the United States. Although fadrozole is not specific to aromatase (studies have shown a blunting of ACTH-stimulated cortisol and aldosterone levels in adult subjects) (9), no signs of adrenal insufficiency were seen.

To test the hypothesis that a potent aromatase inhibitor might improve the treatment of gonadotropin-independent precocious puberty, we administered fadrozole to 16 girls with MAS.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects (Table 1)

The subjects were 16 girls with MAS or a variant thereof. Gonadotropin-independent precocious puberty was confirmed in all girls by documenting suppressed or prepubertal LH and FSH after 100 µg gonadorelin. Technetium bone scan revealed fibrous dysplasia in 11 girls, and five girls had no evidence of bone disease. Twelve girls had café-au-lait pigmentation. Four girls also had thyroid abnormalities such as suppressed TSH and multinodular goiter. Patient no. 7 had presented at age 3 months with cushingoid appearance and a pelvic mass and underwent left ovariectomy. Precocious puberty occurred at age 10 months. Five girls had been previously treated with testolactone. One girl was on a long-acting GnRH agonist before treatment was initiated, and one girl had been treated with Depo-Provera (Pfizer Inc., New York, NY). All girls had discontinued these treatments for at least 6 months before starting fadrozole.

Methods

Patients were admitted to the Clinical Center at the National Institutes of Health and were evaluated at 2–6-month intervals before and during fadrozole treatment. Height was determined at 0800 h as the average of 10 measurements on a stadiometer. Growth velocity was determined as SD units vs. CA. The frequency of menses was determined from a parental diary. Ovarian volumes were calculated using pelvic ultrasonography according to the following formula: volume = length x width x thickness x 0.52 (10). The mean ovarian volume (MOV) is the mean of the volume of the right and left ovary. When one ovary was absent, the MOV is the volume of the remaining ovary. BA was determined according to the method of Greulich and Pyle (11). Plasma levels of estradiol (E2), estrone (E1) (12), testosterone (T) (13), and androstenedione (A) (14) were measured at 1000, 1400, 2200, and 0200 h and are presented as the mean of the four levels. Peak LH (15) and FSH (16) levels were measured after the administration of 100 µg gonadorelin iv at 0800 h. Cortisol levels were measured at 0800 h, and 0, 30, and 60 min after 0.25 µg ACTH iv. Supine and upright plasma renin activity levels were measured (17) at 0800 h.

The protocol was approved by an institutional review board, and informed consent was obtained from a parent.

Protocol

After baseline evaluations at -3 and 0 months, fadrozole was administered for an initial 6-month trial period to assess its safety and effectiveness. After 3 months off treatment, fadrozole was restarted and continued for 12–21 months. Patients no. 1–10 started fadrozole at a dose of 60 µg/kg·d, and the dose increased after 3 wk to 240 µg/kg·d, divided two times a day. All other patients started fadrozole at the full dose of 240 µg/kg/d. Due to inadequate response in 10 patients (no. 1–4, 6–10, and 12), the dose was increased to 480 µg/kg·d, divided three times a day, for an additional 6–18 months.

Statistical analysis

The results are presented as the mean ± SD of the -3 and 0 time points before treatment compared with the mean of the +4- and +6-month time points after initiation of treatment at 240 µg/kg·d and with the +12-month time points at 240 (15 patients) and at 480 µg/kg·/d (nine patients). The student’s paired t test was used to compare pretreatment hormonal parameters to the hormonal parameters during treatment. Menstrual frequency was assessed using the Wilcoxon rank sign test. The rates of growth and BA advance ( BA/ CA) are presented as annualized rates. The frequency of menses is presented as the number of episodes of bleeding during each 6-month interval.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Hormonal parameters and MOV (Table 2): Menses

After the initial 6-month pilot trial and even after long-term therapy at 240 and 480 µg/kg·d, there were no significant decreases in the mean levels of E2, E1, or MOV compared with before treatment. However, we observed significant, although modest, elevations in the levels of T (the biochemical precursor of E2) and A (the precursor of E1). These levels did not exceed those expected in normal early puberty, and no girl became virilized.

Growth rate and BA/ CA

During the 12 months of uninterrupted treatment, the growth rate SD decreased in 10 girls (no. 1, 3, 4, 5, 6, 11, 12, 13, 15, and 16); however, it increased in four girls, thus, the mean growth rate SD for the group as a whole was not significantly less than before therapy (1.97 ± 0.53 vs. 1.53 ± 3.49). Similarly, the rate of BA advance ( BA/ CA) decreased in nine girls (no. 1, 3, 4, 5, 6, 7, 12, 13, and 15) but increased in seven, so the mean ± SD BA/ CA for the group as a whole was not improved compared with before treatment (1.7 ± 0.5 vs. 1.6 ± 1.5). There was no significant improvement in mean predicted adult height over the 12–15 months of uninterrupted therapy; six girls had a decrease in their predicted height. Thus, although response to treatment was variable and not significant for the group as a whole, some girls appeared to benefit temporarily with respect to growth, bone maturation, and/or menstrual frequency.

Adverse effects of fadrozole (Fig. 1)

As demonstrated by others, fadrozole caused a dose-dependent inhibition of adrenal steroid biosynthesis. Whereas the mean ± SD serum cortisol and upright plasma renin activity were normal at the start of therapy, during treatment, cortisol decreased and plasma renin activity increased significantly to levels indicative of partial adrenal insufficiency (peak cortisol < 8 µg/dl after ACTH). Three girls (no. 1, 7, and 12), who were found to have biochemical evidence of adrenal insufficiency, had replacement doses (12 mg/m²·d) of hydrocortisone added to their regimen. Three girls (no. 9, 11, and 12) complained of intermittent abdominal pain while on the 480 µg/kg·d dose; in two girls, the pain resolved spontaneously without treatment or a change in dose, and in one girl, it resolved after decreasing the dose to 240 µg/kg·d. No girl had weight loss, fatigability, salt craving, orthostatic hypotension, or electrolyte abnormalities.

View larger version (20K): [in this window] [in a new window]   FIG. 1. Mean ± SD peak cortisol (upper panel) and upright plasma renin activity (lower panel) in girls with MAS before therapy and during treatment with 240 and 480 µg/kg·d fadrozole (to convert cortisol to nmol/liter, multiply by 27.59). *, P > 0.05 compared to before treatment.

Ineffectiveness of GnRH agonist

After 3–26 months of fadrozole treatment, seven girls (no. 1, 2, 6, 7, 9, 10, and 15; CA, 5.8–8.9 yr; BA, 11.0–12.0 yr) had evidence of central activation of the pituitary-gonadal axis (LH > 15 mIU/ml; LH/FSH > 0.66 after 100 µg GnRH iv). At this point, the GnRH agonist deslorelin (4 µg/kg, sc, every day) was added to their treatment regimen, and GnRH testing (measurement of LH after FSH after 100 µg GnRH) was repeated on subsequent visits to confirm suppression of the axis. Despite confirmed suppression of LH and FSH, we did not observe a decrease in mean estrogen levels, MOV, or growth rates over the period of combined deslorelin and fadrozole therapy. Five girls (no. 1, 2, 6, 7, and 10) who were having irregular menses (two to six episodes per 12 months) before deslorelin had increased frequency of menses (four to nine episodes per 12 months) after deslorelin was started.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The treatment of girls with gonadotropin-independent precocious puberty remains a challenge. Although this study was limited by small sample size and the patients’ variable responses to treatment, it was disappointing to observe no consistent decreases in mean levels of E1 and E2, MOV, or frequency of menses, and no significant slowing of mean rates of BA advance in this group of MAS girls, even at doses of 480 µg/kg·d. There are several possible explanations the ineffectiveness of treatment. In the earlier studies in postmenopausal women, estrogens did not decrease to undetectable levels, even in subjects in whom E1 and E2 were relatively low (15–25 pg/ml) before treatment. MAS patients may develop markedly elevated estrogen levels (>200 pg/ml) and large ovarian cysts, indicating an abundance of intraovarian aromatase that could exceed the quantity of available inhibitor. Other factors include the possibility that serum levels were too low to block estrogen biosynthesis. We were not able to measure levels of fadrozole, and were thus not able to confirm adequate absorption. It is unlikely, however, that serum levels were inadequate because we observed increases in T and A, the precursors of E2 and E1, suggesting inhibition of aromatase, as well as significant inhibition of adrenal steroid biosynthesis.

It was also disappointing that a GnRH agonist failed to control the puberty in girls who had evidence of central puberty. Boys with familial male precocious puberty can be well controlled when GnRH agonists are added to a regimen of androgen- and estrogen-blocking agents (18). In contrast, in our MAS patients treated with fadrozole and deslorelin, the levels of estrogens and the MOV remained elevated, one girl who had never menstruated began her menses after deslorelin was added, and frequency of menses increased in three other girls. Although the mechanism is not clear, it indicates that the formation and release of ovarian estrogens in MAS remain independent of pituitary gonadotropin stimulation even after the patient’s age is in the pubertal range and when her gonadotropin responses to GnRH indicate central puberty.

A further limitation of fadrozole was the evidence for inhibition of adrenal steroid biosynthesis. Although no patient had clinical signs or symptoms of adrenal crisis, the possibility that subjects, such as our patient no. 7, may be uniquely at risk for adrenal insufficiency cautions us to be vigilant in monitoring the actions of these new therapies. Newer drugs such as letrozole (Femara, Novartis, East Hanover, NJ) and anastrozole (Arimidex, Astra-Zeneca, Wilmington, DE), which are selective, potent, and reportedly do not inhibit glucocorticoid and mineralocorticoid biosynthesis (19), may prove to be better and safer treatment options.

	Footnotes

 
Abbreviations: A, Androstenedione; BA, bone age; CA, chronological age; E1, estrone; E2, estradiol; MAS, McCune-Albright syndrome; MOV, mean ovarian volume; T, testosterone.

Received May 19, 2003.

Accepted August 24, 2003.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Albright F, Butler AM, Hampton AO, Smith P 1937 Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction with precocious puberty in females: report of five cases. N Engl J Med 216:727–746
2. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Speigel AM 1991 Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 325:1688–1695[Abstract]
3. Foster CM, RossJL, Pescovitz OH, Loriaux DL, Cutler Jr G, Comite F 1984 Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome. J Clin Endocrinol Metab 58:1161–1165[Abstract]
4. Comite F, Shawker TH, Pescovitz OH, Loriaux DL, Cutler Jr G 1984 Cyclic ovarian function resistant to treatment with luteinizing hormone releasing hormone in girls with McCune-Albright syndrome. J Clin Endocrinol Metab 59:801–805[Abstract]
5. Steele VE, Mellor LB, Sawyer WK, Wasvary JM, Brown LJ 1987 In vitro and in vivo studies demonstrating potent and selective estrogen inhibition with the nonsteroidal aromatase inhibitor CGS 16949A. Steroids 50:147–161[CrossRef][Medline]
6. Santen RJ, Demers LM, Adlercreutz H, Harvey H, Santner S, Sanders S, Lipton A 1989 Inhibition of aromatase with CGS 16949A in postmenopausal women. J Clin Endocrinol Metab 68:99–104[Abstract]
7. Falkson G, Raats JI, Falkson HC 1992 Fadrozole hydrochloride, a new nontoxic aromatase inhibitor for the treatment of patients with metastatic breast cancer. J Steroid Biochem Mol Biol 43:161–165[CrossRef][Medline]
8. Demers LM, Lipton A, Harvey HA, Hanagan J, Mulagha MT, Santen RJ 1993 The effects of long-term fadrozole hydrochloride treatment in patients with advanced stage breast cancer. J Steroid Biochem Mol Biol 44:683–685[CrossRef][Medline]
9. Trunet PF, Mueller PH, Girard F 1992 The effects of fadrozole hydrochloride on aldosterone secretion in healthy male subjects. J Clin Endocrinol Metab 74:571–576[Abstract]
10. Sample WF, Lippe BM, Gypes MT 1977 Grey scale ultrasonography of the normal female pelvis. Radiology 125:477–483[Abstract]
11. Greulich WW, Pyle SI 1950 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press
12. Loriaux DL, Ruder HJ, Lipsett MB 1972 Measurement of estrone sulfate in plasma. Steroids 18:463–472
13. Nieschlag E, Loriaux DL 1972 Radioimmunoassay for plasma testosterone. Z Klin Chem Klin Biochem 10:164–168[Medline]
14. Cutler Jr G, Glenn M, Bush M, Hodgen GB, Graham CE, Loriaux DL 1978 Adrenarche: a survey of rodents, domestic animals and primates. Endocrinology 103:2112–2118[Abstract]
15. Odell WD, Ross GT, Rayford PL 1967 Radioimmunoassay for luteinizing hormone in human plasma or serum: physiological studies. J Clin Invest 46:248–255
16. Cargille CM, Rayford PL 1970 Characterization of antisera for human follicle-stimulating hormone radioimmunoassay. J Lab Clin Med 175:1030–1040
17. Menan J, Catt KJ 1972 Measurement of renin activity concentration and substrate in rat plasma by radioimmunoassay of angiotensin I. Endocrinology 98:422–430
18. Leschek EW, Jones J, Barnes KM, Hill SC, Cutler Jr GB 1999 Six-year results of spironolactone and testolactone treatment of familial male-limited precocious puberty with addition of deslorelin after central puberty. J Clin Endcrinol Metab 84:175–178[Abstract/Free Full Text]
19. Bhatagnar AS, Hausler A, Schieweck K, Lang M, Bowman R 1990 Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new, nonsteroidal aromatase inhibitor. J Steroid Biochem Mol Biol 37:1021–1027[CrossRef][Medline]

This article has been cited by other articles:

				J. Mieszczak, E. S. Lowe, P. Plourde, and E. A. Eugster The Aromatase Inhibitor Anastrozole Is Ineffective in the Treatment of Precocious Puberty in Girls with McCune-Albright Syndrome J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2751 - 2754. [Abstract] [Full Text] [PDF]

				D. I. Shulman, G. L. Francis, M. R. Palmert, E. A. Eugster, and for the Lawson Wilkins Pediatric Endocrine Society Use of Aromatase Inhibitors in Children and Adolescents With Disorders of Growth and Adolescent Development Pediatrics, April 1, 2008; 121(4): e975 - e983. [Abstract] [Full Text] [PDF]

				P. Feuillan, K. Calis, S. Hill, T. Shawker, P. G. Robey, and M. T. Collins Letrozole Treatment of Precocious Puberty in Girls with the McCune-Albright Syndrome: A Pilot Study J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2100 - 2106. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nunez, S. B. Articles by Feuillan, P. P. Search for Related Content PubMed PubMed Citation Articles by Nunez, S. B. Articles by Feuillan, P. P.