Treatment of Precocious Puberty in McCune-Albright Syndrome

Abstract

McCune-Albright syndrome (MAS) is typically defined as a triad of precocious puberty (PP), café au lait spots and fibrous dysplasia of bone. PP is the most common endocrinological manifestation of this rare disease and is much more common in girls than in boys. The treatment options for PP associated with MAS have evolved over the last twenty plus years. Therapy in girls typically includes the use of an anti-estrogen, while treatment options in boys include an antiandrogen in combination with an aromatase inhibitor (Al). This article will briefly review the older therapies and explain why they have largely been supplanted by newer approaches. We will discuss current pharmacotherapy options for the treatment of PP in MAS and finally describe potential novel therapies that will hopefully enable optimal care for affected patients.

Introduction

MAS is traditionally defined as a clinical triad of PP, café au lait spots and fibrous dysplasia of bone (1). An activating mutation in exon 8 of the gene encoding G_Sα (GNAS), at the codon for Arg²⁰¹ results in constitutive, ligand free activation of affected cells (2). PP is the most common endocrinologic manifestation of this rare disease that is diagnosed much more frequently in girls than in boys (3). Since it is not mediated by the hypothalamic-pituitary-gonadal axis, it is a form of peripheral, rather than central PP (CPP). Girls present with painless vaginal bleeding of varying duration and frequency that is usually concurrent with acute breast development. Historically, treatment of PP in girls with MAS has included medications such as medroxyprogesterone and ketoconazole. While ketoconazole has anecdotally been reported to be effective (4), concern about safety problems such as hepatotoxicity (5) have limited its use. Medroxyprogesterone may stop vaginal bleeding, but there is no evidence that it alleviates accelerated skeletal maturation. Therefore, these medications have been replaced by more modern pharmacologic approaches consisting primarily of Als and a selective estrogen receptor modulator. The primary goals of treatment are the cessation of vaginal bleeding and delaying the rate of bone age advancement in hope of preventing premature epiphyseal fusion and compromised adult height (6). Due to the low incidence of MAS, the largest and most informative studies have come from prospective multicenter clinical trials in which patients act as their own controls.

Clinical Characteristics of PP in Girls with MAS

Although it may present during infancy (7), PP in girls with MAS usually becomes manifest during early childhood. Sudden onset of vaginal bleeding is commonly the initial sign of the disorder. Due to the extremely heterogeneous nature of MAS, making the diagnosis may be relatively straightforward or quite challenging. Although most patients present with the classic triad, some children have an atypical or forme fruste variant of the disease in which only a single clinical feature may be present (8).

The PP of MAS in girls is brought about by intermittent autonomous activation of ovarian tissue that results in formation of large ovarian cysts and extreme elevations in serum estradiol (9). Because the cysts are almost always unilateral, pelvic ultrasonography at the time of an active episode will reveal significant asymmetry in ovarian volumes between the two sides, which is not the case in girls with CPP (10). An enlarged uterus with an endometrial stripe and no evidence of ovarian cyst may also be noted. Biochemical evaluation typically reveals strikingly high estradiol concentrations which are often increased 2–3 fold over what is typically achieved during a normal menstrual cycle. Random and stimulated gonadotropin levels are usually suppressed (11). Resolution of the cyst is followed by estrogen withdrawal which precipitates shedding of the endometrium and subsequent vaginal bleeding followed by regression of uterine size.

The precise trigger that is responsible for the periodic autonomous ovarian hyperfunction in girls with MAS is unknown and the frequency at which these episodes occur is quite variable. Many children experience prolonged intervals of quiescence lasting several years. However, a subset of girls appear to have a more virulent form of the PP resulting in frequent unregulated vaginal bleeding, linear growth acceleration and advancement in skeletal maturation with the potential for significant compromise in ultimate adult height.

At the time of initial diagnosis, there is no reliable indicator of which girls with MAS will go on to have a progressive form of PP. Therefore, a period of watchful waiting is nearly always indicated. The decision to start therapy represents an area of clinical judgment and involves consideration of multiple factors such as frequency of vaginal bleeding and the rate of skeletal maturation. Although no single therapy has proved to be perfect, several pharmacologic approaches are available and the development and investigation of newer therapies continues.

Treatment in Girls

Anti-Estrogens

Als are compounds that bind reversibly to the cytochrome p450 portion of the aromatase enzyme and prevent the conversion of androgens to estrogens and therefore reduce the serum levels of estrogens. The first generation Al, testolactone, showed promising results in a preliminary trial in a small number of girls with MAS (12). A subsequent long term study involving testolactone in 12 girls with PP and MAS showed very mixed results with regards to cessation of vaginal bleeding, with no change in predicted adult height or rate of skeleton maturation (13). Fadrozole, a second generation Al, did not fare better in a study of girls with PP due to MAS (14). The study included 16 subjects and concluded that fadrozole is not potent enough to block estrogen synthesis in girls with PP due to MAS and may suppress the adrenocortical stress response. Third generation Als, such as anastrozole and letrozole, are currently being investigated in hope that their higher potency will be beneficial in the treatment of PP in these children. Results from a pilot study of 9 girls treated for 12–36 months with letrozole, which appears to be the most potent 3^rd generation Al currently available, were variable (15). While a significant decrease in growth velocity and rate of skeletal maturation was observed, mean ovarian volumes tended to increase over time and one subject developed ovarian torsion. A recently concluded prospective study of anastrozole for the treatment of PP in 27 girls with MAS found that it was ineffective in halting vaginal bleeding and attenuating rates of skeletal maturation and linear growth (16). However, the same study did establish anastrozole as being safe and opened the door for future third generation Als to be studied in hopes of greater efficacy in treating the PP in these patients.

Estrogen Receptor Blockers

Tamoxifen is a selective estrogen receptor modulator that has both agonistic and antagonistic effects that are tissue specific. Initial reports of tamoxifen use in the treatment of PP in patients with MAS showed good response in arresting pubertal progression (17). A one year multicenter clinical trial of 25 girls with MAS and PP established tamoxifen as a viable treatment with excellent results in improving vaginal bleeding and other clinical indicators of pubertal progression (18). However, the same trial also reported increased uterine volumes and therefore raised the question of the long term safety of tamoxifen in terms of uterine proliferation. The Table summarizes studies published to date on the use of anti-estrogens for treatment of PP in girls with MAS.

Table.

Studies published to date on the use of anti-estrogens for treatment of PP in girls with MAS

Author (Ref #)	Year of Pub.	Drug	Action	N	Study Design	Duration of Treatment	Efficacy	Safety Concerns
Feuillan et al. (13)	1993	Testolactone	1st Generation Al	12	Prospective, Uncontrolled	6 Mos-5 Years	Partially Effective Initially with Later Escape from Efficacy * Significant Decrease in Rate of BA Advancement but No Change in PAH	Mild Gl upset, Headache Elevated Liver Enzymes Compliance Problems
Nunez et al. (14)	2003	Fadrozole	2nd Generation Al	16	Prospective, Uncontrolled	12–33 mos	No Change in Growth Rates, BA Advancement or Menses	Inhibition of Glucocorticoid and Mineralocorticoid Biosynthesis, Abdominal Pain Muscle Weakness
Eugster et al. (18)	2003	Tamoxifen	Estrogen Receptor Modulator	25	Prospective Multicenter, Uncontrolled	12 mos	* Significant Decrease in Growth Rate and Rates of BA Advancement Decrease in Menses	Increased Uterine and Ovarian Volumes
Mieszczak et al. (Abstract) (16)	2007	Anastrozole	3rd Generation Al	27	Prospective Multicenter, Unconrtolled	12 mos	No Change in Menses, Growth Rates or BA Advancement	None Known
Feuillan et al. (15)	2007	Letrozole	3rd Generation Al	9	Prospective, Unconrtolled	12–36 months	* Significant Decrease in Growth Rate and BA Advancement	Increased Ovarian Volumes and Recurrent CYST Formation, Transient Hand and Foot Discomfort

^*p<.05

BA: Bone Age

Al: Aromatase Inhibitor

GnRH Analog Therapy

Progression to CPP may occur secondary to activation of the hypothalamic-pituitary-gonadal (HPG) axis, particularly when significant bone age advancement has occurred. Synthetic long acting gonadotrophin releasing hormone (GnRH) analogs down regulate the HPG axis and have well-established efficacy and safety for the treatment of CPP (19). GnRH analogs such as leuprolide have been reported to be beneficial as adjunctive therapy in MAS patients once the HPG axis has been activated (20).

Surgery

Normal reproductive function in women treated for PP in MAS is ultimately possible in most cases (21). Therefore, surgical excision of the ovary as primary treatment in MAS is always contraindicated and may be followed shortly by involvement of the contralateral ovary. While laparoscopic cystectomy has been reported to be effective (22), we believe it should be reserved for extreme cases in which significant abdominal pain or impending ovarian torsion is present. Misdiagnosed MAS patients sometimes undergo oopherectomy in order to remove what are thought to be ovarian tumors (23). A pediatric endocrinology consult should always be obtained to rule out MAS in girls presenting with sudden onset vaginal bleeding.

Future Directions

Fulvestrant, a pure estrogen receptor antagonist which binds to the estrogen receptor with affinity similar to estradiol, is currently in use in breast cancer patients (24). It has a novel mechanism of action involving inhibition of all estrogen receptor dependent pathways. As it displays no agonistic activity, it is hypothesized that it may have greater therapeutic benefit than other anti-estrogens in the treatment of PP in MAS. A prospective trial investigating fulvestrant for the treatment of PP in girls with MAS is currently underway. A downside of fulvestrant in pediatric patients is that it is administered via intramuscular injections. New third generation Als should also be investigated in hopes that they maybe be more efficacious than but as safe as anastrozole. Collaboration between centers is critical in order to recruit necessary patient numbers so that future studies are meaningful in terms of enhancing our knowledge and understanding of the best possible treatment of PP in MAS.

MAS in Boys

Although the true incidence may not be different, MAS is diagnosed much less often in boys than in girls. The presentation of PP also differs in that males present at a later age and usually with testicular enlargement, sexual precocity and pubertal serum testosterone levels (25). Macroorchidism without sexual precocity and a prepubertal testosterone level was reported in a patient concluded to have hyperfunction of Sertoli cells as opposed to the more typical Leydig cell hyperfunction in boys with MAS (26). An Italian study has also reported a higher than expected incidence of testicular microlithiasis in boys and men with MAS (27). While the clinical implications of this discovery are unknown in children, this finding in adults represents a higher risk for the development of testicular malignancy.

Treatment of Boys

The limited availability of patients has resulted in a paucity of published data on treatment of PP in boys with MAS. Treatment goals include slowing of virilization and prevention of epiphyseal closure in order to ultimately improve adult height. Treatment options for boys with PP because of MAS are the same as those available for boys with familial male-limited precocious puberty (FMPP), which is also a form of peripheral PP (28). One successful strategy in this condition has employed the combination of testolactone and an antiandrogen, spironolactone or flutamide (29). As is the case in other forms of peripheral PP, progression to CPP is sometimes observed in these patients. The addition of a GnRH analog such as deslorelin or leuprolide to the testolactone and spironolactone regimen significantly diminishes rates of skeletal advancement and growth (30). A recent report on the use of a nonsteroidal antiandrogen, bicalutamide, along with the third generation Al anastrozole in two FMPP patients reported marked decreases in growth velocity and skeletal advancement (31). The same article reported no side effects, but long term follow up is needed to fully assess the safety of this new combination therapy. The bicalutamide and anastrozole combination has the potential to be effective and safe in treatment of PP in boys with MAS.

Conclusion

In summary, significant advancements have been made in the treatment of PP in children with MAS. As no single approach has been uniformly successful in all patients, the quest for superior therapies continues. The rarity of the disease and the anecdotal nature of many published reports present ongoing challenges. Careful collaborative investigation and long term follow-up will hopefully one day establish the “gold standard” for the treatment of PP in girls and boys with MAS.