|
|
High Growth Rate of Girls with Precocious Puberty Exposed to Estrogenic Mycotoxins« Back to Volume 24, Issue 2, November 2008 - Table of Contents Zeranol (α-ZAL; α-zearalanol) is an anabolic estrogen that has been used for increasing muscle mass in cattle and poultry. It is produced by Fusarium, and is thus a mycotoxin. Earlier studies have shown estrogenic mycotoxins in 5 of 36 girls with early thelarche in southeastern Hungary and a high incidence of central precocious puberty (CPP) in a northwest region of Tuscany (22 to 29 times higher than that in neighboring areas), suggesting an environmental estrogen exposure as causative. Zearalenone (ZEA) and its metabolites (ie, α-ZAL, β-zearalanol [β-ZAL], α-zearalenol [α-ZOL], and β-zearalenol [β-ZOL]) are apparently able to adopt a chemical configuration that resembles 17β-estradiol (E2) and binds to estrogen receptors in target cells thus exerting estrogenic (agonist) action. The aim of this study by Massart and colleagues was to test the hypothesis that environmental estrogenic exposure through mycotoxins could be associated with CPP in girls from the Viareggio countryside of northwest Tuscany, Italy. Thirty-two girls with CPP—defined as history of increased growth velocity, Tanner 2 breast development, and bone age advanced more than one year, LH and FSH responses to gonadotropin releasing hormone (GnRH) stimulation in the pubertal range, E2 levels >25 pg/mL, and chronologic age ≤ 8 years—were studied. Group A comprised 17 girls came from the Viareggio countryside and group B were 15 girls from Pisa. In addition 31 age- and sex-matched control subjects from Viareggio (n=15, group C) and Pisa (n=16, group D) were studied as controls. Following diagnosis, all 32 girls with CPP were treated with triptorelin (TR) depot IM every 28 days for more than 12 months. Auxologic data and pubertal development were recorded initially and at 3- and 6-month intervals and bone age was done yearly and read by Greulich and Pyle method. Italian standards were used to determine height SDS, weight SDS, and height velocity SDS. Mycotoxin (ZEA, α-ZOL, β-ZOL, α-ZAL, and β-ZAL) levels were determined using high performance liquid chromatography from sera during the GnRH stimulation test at diagnosis and at 12 months of treatment. All 63 girls were born at term and appropriate for gestational age. At the start of the study there were no significant differences between the CPP groups and the control groups. The only mycotoxins detected were ZEA and α-ZOL. At diagnosis 6 of the 17 girls (35%) at Viareggio had higher serum ZEA and α-ZOL levels than the other 3 groups; ZEA and its metabolites were not detected in the 15 CPP girls from Pisa or in the control subjects. All 32 girls with CPP (groups A and B) had undetectable mycotoxin levels after 12 months of GnRH agonist treatment. In order to study the differences between the girls who were mycotoxin positive versus those in whom mycotoxins were undetectable, 2 additional groups were formed. The 6 girls who were mycotoxin positive (group E) were compared with the 26 girls who were mycotoxin negative (group F). At diagnosis there were no differences in chronologic age, target SDS in all 3 groups, and bone age and bone age/chronologic age ratio were not different in the CPP groups before and 12 months after treatment. However, group E and group F had different growth trends during treatment. Group E height SDS for chronologic age significantly increased from baseline during treatment while height SDS for chronologic age declined slightly in group F. Similarly, weight SDS for chronological age increased from baseline in group E, but not in group F. The BMI did not differ in groups with CPP at diagnosis or after 12 months of therapy. In addition, after 12 months of therapy, height SDS for bone age was higher in Group E than in Group F even though no difference was detected at the time of diagnosis. Height velocity SDS for chronologic age was also higher in group E than in group F and the control subjects, while height velocity SDS for chronologic age in group F was constant during treatment. At diagnosis serum ZEA levels correlated with height, SDS for chronologic age, weight SDS for chronologic age, and height SDS for bone age. There was no correlation detected for a-ZOL; at 12 months no correlations were detected. No differences were found in the groups with CPP at diagnosis and during treatment for LH, FSH, or for E2. The authors reviewed information known about ZEA as a non-steroidal mycotoxin produced by Fusarium species on several grains. Of note, beside the estrogenic activity, ZEA also has anabolic properties and ZEA food contamination could be either direct or indirect by carryover of mycotoxin in animal tissues such as milk and eggs after intake of contaminated feeds. In the US α-ZAL has been used widely as a growth promoter to fatten cattle. This application was banned in the EU in 1985. The ZEA metabolites mimic estrogens and act as estrogen receptor agonists; they have limited or no binding to carrier proteins. Thus they have easier access to estrogen target tissues and a potency that may be as much as 50 times greater than their actual concentrations suggest. The finding that the girls who were mycotoxin positive had a higher growth rate during TR treatment than those who were mycotoxin negative may be related to the anabolic effect of accumulated ZEA that persists despite effective GnRH agonist treatment. The authors referenced a publication that showed a prepubertal dose of estrogen replacement during TR treatment in girls with CPP is effective for at least 2 years in maintaining a height velocity of about +1 SDS without accelerating bone maturation.1 Finally, the authors noted that although ZEA is stored in adipose depots, a single dose has a half-life of only about 22 hours in human blood. Thus incidental exposure may be time limited, but could induce a central maturation of the hypothalamic pituitary gonadal axis. Editor’s CommentThere is a growing body of evidence concerning endocrine disruptors. Much of the information has been gathered from animal studies but there have been a few human studies that demonstrate a clear-cut association between such environmental agents and early puberty in children. Massart et al, in this carefully controlled study, demonstrated a significant association between an “endocrine disruptor” and CPP. The disruptor, ZEA and its metabolites, is a naturally occurring mycotoxin. Thus, the relationship between at least one estrogen disruptor and the occurrence of CPP in pediatric patients cannot be dismissed. This study should give encouragement to those who are attempting to identify other potential environmental contaminants that may be associated with endocrine disruption in the pediatric population and also should underscore the importance of taking a careful dietary and exposure history from each of our patients who present with similar clinical findings. It is disturbing that a derivative of this mycotoxin has been widely used as a growth promoter to fatten cattle in the US. Only with careful, well-documented information can these important associations be identified and exposures be limited or reduced. William L. Clarke, MD Reference - (linked to
|
Volume 26 Number 1
September 2010
www.GGHjournal.com
ISSN 1932-9032
)