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      Anastrozole plus leuprorelin in early maturing girls with compromised growth: the “GAIL” study

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          Abstract

          Purpose

          Aromatase inhibitors have been used to increase predicted adult height (PAH) in boys but in girls only in McCune-Albright syndrome. We investigated whether anastrozole combined with leuprorelin for up to 2 years is safe and effective in improving PAH in girls with early puberty and compromised growth, compared to leuprorelin alone.

          Methods

          The “GAIL” study: girls treated with an aromatase inhibitor and an LHRH analogue, ISRCTN11469487, was a 7-year prospective phase IIa study with parallel design, performed at Athens Medical Center (C-A), and Attikon University Hospital, Athens, Greece (C-B). Forty girls, consecutively referred for early puberty (onset 7.5–9 years) with a PAH <−2 or >1.5 SD lower than their target height (TH), were included. Twenty started on leuprorelin sc/im 0.3 mg/kg/month plus anastrozole 1 mg/d p.o. (group-A, C-A) and 20 on leuprorelin (group-B, C-B) for 2 years or until the age of 10 years. Groups did not differ in age, height, BMI, bone age advancement (BAA), and distance of PAH from TH. Follow-up was at 6, 12, 18, and 24 m.

          Results

          Reduction in BAA was significantly higher in group-A compared to group-B already by 6 m. Despite the transiently significant decrease in height velocity in group-A, gain in PAH SD was almost double by 12 and 18 m vs group-B and reached the maximum of +1.21 ± 0.45 (7.51 cm) vs +0.31 ± 0.37 (1.92 cm, p = 0.001) in group-B at 24 m. Group-A had no clinical or biochemical hyperandrogenism, unchanged normal bone density, and lumbar spine X-rays.

          Conclusion

          The co-administration of anastrozole with leuprorelin safely improves PAH in girls with compromised growth.

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          Most cited references 37

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          Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.

          Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
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            Precocious puberty and statural growth.

            Precocious puberty results mostly from the precocious activation of the gonadotropic axis. Although the age limits have recently been discussed, most physicians consider that onset of pubertal development before the age of 8 years in a girl or 9 years in a boy warrants at least a clinical and bone age evaluation by a paediatric endocrinologist. The major concern in precocious puberty is the underlying condition, and central nervous system or gonadal neoplasm have to be formally excluded as a first step in the diagnosis. A secondary concern is height, since precocious puberty leads to accelerated growth, accelerated bone maturation and ultimately reduced stature. Precocious puberty is heterogeneous and strict criteria should be used to define it, both in terms of age and in terms of potential for progression. Depot forms of GnRH agonists are now the standard treatment for progressive central precocious puberty and aim at alleviating the clinical symptoms of early pubertal development, their psychological consequences and the effects on growth. Here, we review the consequences of both central and gonadotropin-independent precocious puberty on adult stature and the information available on outcomes using the therapeutic regimens currently available. In girls with progressive precocious puberty, all published evidence indicates a gain of adult height over height predicted before treatment or over untreated historical controls. However, the apparent height gain (derived from the comparison of predicted and actual heights) is very variable, in large part due to the inaccuracy of height prediction methods. In girls with onset of puberty at the lower half of the normal age (8-10 years) distribution, trials using GnRH agonists have given negative results (no benefit of treatment). In boys, precocious puberty is rare and fewer results are available but point in the same direction. The most appropriate time for interrupting the treatment is still controversial. In conclusion, GnRH agonists restore adult height in children when it is compromised by precocious puberty.
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              Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial.

              In males as well as in females, estrogen is an essential regulator of bone maturation, growth plate fusion, and cessation of longitudinal growth. Therefore, an increase in predicted adult height (PAH) may be achieved in short boys by blocking estrogen biosynthesis. We tested the hypothesis that a decrease in the rate of bone maturation and an increase in PAH can be achieved in boys with idiopathic short stature (ISS) by the method of blocking estrogen biosynthesis with an aromatase inhibitor. Secondarily, we investigated the effects of aromatase inhibition on bone mineralization. This was a prospective, double-blind, randomized, placebo (Pl)-controlled clinical study. The study was performed at a university hospital out-patient clinic. Thirty-one boys, aged 9.0-14.5 yr, with ISS were studied. The boys were treated with the aromatase inhibitor letrozole (Lz; 2.5 mg/d) or Pl for 2 yr. The main outcome measure was the change in PAH after 24 months of treatment. PAH increased by 5.9 cm (P < 0.0001), and height SD score for bone age increased by 0.7 SD score (P < 0.0001) in the Lz-treated boys, whereas no changes occurred in the respective measures in Pl-treated boys. Areal bone mineral density of the lumbar spine and femoral neck, assessed by dual-energy x-ray absorptiometry, increased in a similar fashion in both groups during the treatment, whereas bone mineral apparent density increased only in those taking Lz (median increase, 4.3%; P = 0.009). Treatment with the aromatase inhibitor Lz delays bone maturation and improves PAH in boys with ISS. No adverse effects on bone mineralization were evident after 2 yr of treatment.
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                Author and article information

                Contributors
                +302103638536 , info@pedoendo.gr
                Journal
                J Endocrinol Invest
                J. Endocrinol. Invest
                Journal of Endocrinological Investigation
                Springer International Publishing (Cham )
                0391-4097
                1720-8386
                27 October 2015
                27 October 2015
                2016
                : 39
                : 439-446
                Affiliations
                [ ]Department of Pediatric-Endocrinology and Diabetes, Athens Medical Center, 58, av. Kifissias, Maroussi, 15125 Athens, Greece
                [ ]Third Department of Pediatrics, “Attikon” University Hospital, Haidari, 12462 Athens, Greece
                [ ]Third Department of Pediatrics, Hippokrateion General Hospital of Thessaloniki, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
                [ ]Department of Radiology, Mitera Maternity and Children’s Hospital, Maroussi, 15123 Athens, Greece
                Article
                399
                10.1007/s40618-015-0399-z
                4799269
                26507391
                © The Author(s) 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Italian Society of Endocrinology (SIE) 2016

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