medwireNews: A systematic review and meta-analysis suggests that girls with idiopathic central precious puberty (CPP) who are treated with gonadotropin-releasing hormone analogue (GnRHa) therapy may expect to have a higher final adult height and lower BMI than if they do not receive the treatment.

However, the authors found that evidence for other safety outcomes from GnRHa, such as the risk of infertility, was “very weak” and there was only “limited evidence available on its effects in boys.”

Xiaoping Luo and co-workers, from the Tongji Hospital of Tongji Medical College, the Huazhong University of Science and Technology in Wuhan, China, identified 98 studies of GnRHa therapy, the majority (83%) of which were single-arm studies. The 18 randomised comparative trials compared GnRHa therapy with either no treatment (n=13) or GnRHa plus growth hormone.

Of the 5475 patients included, 98.5% were female; the average age of CPP onset ranged from 4.5 to 8.0 years and GnRHa treatment was initiated at an average of 5.0–9.3 years. Formulations included leuprorelin, triptorelin, buserelin, goserelin, deslorelin and histrelin.

Writing in Clinical Endocrinology, the researchers say that the overall quality of evidence for each outcome assessed ranged from “very low to moderate” and the overall risk of bias was “critical to moderate”.

The high level of statistical heterogeneity found when data from the single-arm studies were pooled meant that “it was not possible to infer and draw meaningful conclusions from these meta-analyses”, the team reports.

There were five single-arm studies including boys with CPP; Luo and co-authors add that “the results were similar to those of girls, although the sample size of each study was very small”, at just eight to 13 patients.

Analysis of four comparative studies of final adult height including 242 patients suggested a mean increase of 4.83 cm with use of GnRHa therapy versus no therapy, while three studies of 334 patients suggested a decrease in BMI of 1.01 kg/m2 with versus without GnRHa treatment.

Meta-analysis of three comparative studies of 179 patients also indicated the incidence of polycystic ovary syndrome did not significantly differ with use of GnRHa versus no treatment, although Luo et al note that individual studies suggested that GnRHa therapy was associated with oligomenorrhoea and elevated adrenal androgen, as well as reduced ovarian volume, the ratio of luteinising hormone to follicle-stimulating hormone, and Ferriman-Gallwey scores.

There was also conflicting evidence on whether GnRHa therapy was associated with earlier or later menarche or had no impact, the researchers say.

One comparative study suggested a lower rate of pregnancy among triptorelin users than controls, a second study of pregnant women suggested that GnRHa users were less likely to require ovulation induction or in vitro fertilisation than nonusers. There was no clear difference in the rate of early miscarriage or preeclampsia between the groups.

One study reported a case of acute lymphoblastic leukaemia in a GnRHa user but follow-up to around age 30 years did not indicate an increased incidence of malignancy among patients given GnRHa.

The team urges caution in interpreting the meta-analysis findings, noting the “substantial level of statistical heterogeneity” for the endpoints of final adult height and menarche, perhaps related in part to the short treatment durations of 2–5 years reported and the inadequate description of treatment regimens given.

“Further research, particularly large-scale [randomised controlled trials] (multicenter) or high-quality comparative studies with an adequate sample size, follow-up rate, and duration, including both girls and boys, are required before firm conclusions can be drawn”, Luo et al conclude.

“In addition, it will be important to explore the main influencing factors on the long-term effects of GnRHa treatment”, they conclude.

By Lynda Williams

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Clin Endocrinol 2021; doi:10.1111/cen.14410