A new meta-analysis finds that treatment with growth hormone in IVF is associated with improved reproductive outcomes largely mediated by an effect on endometrial function, especially in poor responders.
Growth hormone has long been a ‘maybe’ intervention in ART. Maybe yes, maybe no . . . but a definite maybe. Now, a new substantial meta-analysis from Chinese specialists suggests that growth hormone, by improving endometrial function, ‘might be another vital mechanism’ by which it improves the outcomes of ART.(1)
A multitude of studies have already examined the role of GH in its effect on oocyte quality, and thereby success rates, but without clear conclusions. A Cochrane review from 2021 described the result of adjuvant GH in normal IVF responders as ‘very uncertain’, both in terms of LBR and gonadotrophin dose.(2) The effect on LBR was similarly uncertain in poor responders, although the Cochrane reviewers did report a slight increase in the number of oocytes retrieved and in pregnancy rate. The improvement in oocyte yield seen in some of these studies has been one reason for proposing a beneficial effect of GH in IVF.
The more upbeat note in this latest meta-analysis depends less on the effect of GH on oocyte quality (and yield) and more on implantation failure, two-thirds of which, the authors estimate, may be attributed to ‘inadequate uterine function’. Indeed, they add, ‘abnormal endometrial function is major challenge to fertility worldwide’, with therapies which address endometrial function urgently needed. Thus, many of the trials investigating the effect of GH on IVF outcome have tended to concentrate on poor responder patients and oocyte quality and number, ‘while the effects on the endometrium and in other [patient] populations are largely overlooked’. Clinics are thus left in a cloud of uncertainty over GH dose and timing in IVF protocols – or even an appropriate patient population who might benefit.
One recent trial in implantation failure patients treated with donor eggs found that those in the GH arm had significantly greater endometrial thickness (and LBR) than those not receiving GH – prompting the authors to explain the improvement via ‘beneficial actions on endometrial receptivity’.(3) It was studies like this which were the basis of this latest Update analysis, which included a total of 25 trials, the majority in poor responders but all investigating the effect of GH on IVF outcome. The majority of these studies (n = 17) showed that GH administration significantly increased endometrial thickness (mean difference 0.38 mm), which ‘contributed to an improved LBR’ (OR 1.67). It was further reported from the nine trials examining the effect of GH on endometrial thickness that GH given daily (<5 IU per day) in the follicular phase of the previous cycle or during GnRH agonist long protocols had a greater effect than did the other administration times or ovarian stimulation protocols.
The authors stress – as do so many meta-analyses – the heterogeneity and moderate quality of their source studies, but seem confident to state that, in poor responders at least, adjuvant GH not only increased the LBR and implantation rate, but also improved endometrial thickness, with the latter, rather than oocyte or embryo quality, explaining the overall benefit. Thus, a patient population of poor responders or with a thin endometrium ‘might benefit from GH administration’. ‘However,’ they add, ‘there was insufficient evidence to draw a conclusion for GH administration in normal responders.’
In attempting to explain the biology of their findings, they reaffirm the positive association between endometrial thickness and IVF outcome: ‘the thicker the endometrium on the day of trigger, the higher the pregnancy rate is.’(4) And add that GH has been shown to modulate endometrial growth factors leading to modified cell proliferation and tissue vascularisation – and thereby to improved endometrial receptivity.
However, while the conclusions of this review seem focused on the endometrial effects of GH, the authors acknowledge that LBR is the ‘ultimate indicator of efficacy’, and many questions remain unanswered – not least about GH dose, timing and protocols, though suggesting that ‘cotreatment with the GnRH agonist long protocol might provide even more benefits’. However, while concluding that women with a thin endometrium might benefit from GH, they propose that GH treatment should be offered ‘according to personal needs and patient conditions’. The optimal GH protocols remain open to further study.
1. Shang Y, Wu M, He R, et al. Administration of growth hormone improves endometrial function in women undergoing in vitro fertilization: a systematic review and meta-analysis. Hum Reprod Update 2022; doi.org/10.1093/humupd/dmac028
2. Sood A, Mohiyiddeen G, Ahmad G, et al. Growth hormone for in vitro fertilisation (IVF). Cochrane Database Syst Rev 2021; 11(11): CD000099.
3. Altmae S, Mendoza-Tesarik R, Mendoza C. Effect of growth hormone on uterine receptivity in women with repeated implantation failure in an oocyte donation
program: a randomized controlled trial. J Endocr Soc 2018; 2: 96–105.
4. Craciunas L, Gallos I, Chu J, et al. Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update 2019; 25: 202–223.