The use of GH as an adjunct to IVF has been studied extensively with conflicting results. As the number of patients seeking out ART that are older or fall into the category of poor responder patients increase, the need to optimize protocols and understand the importance of adjunctive treatment is critical. Our study findings revealed that co-treatment with GH in women with a history of poor ovarian response in prior cycle could improve the endometrial thickness, increase the number of oocytes retrieved, increase the number of mature oocytes, increase the number of blastocysts, increase the number of usable blastocysts and also increase the percentage of euploid blastocysts. This finding supports the metanalysis published by Li, et al in 2017 [2]. It also corroborates the more recent findings by Li and Gong in their randomized controlled trials to look at GH use in the setting of history of poor embryo development and poor responder patients respectively. Both studies supported the use of GH in IVF cycles [15,17]. This is contrast to the findings by Zhu, et al who found that live birth rate was not improved with the use of GH as adjuvant treatment. They did however, find an increase in Day 3 embryo quality [19].
One strength of the study is in the design. Utilizing patients as their own control in evaluating how the addition of GH changed cycle parameters eliminates some confounding factors present in previously published studies [11,12]. However, because of the nature of the study design pregnancy outcomes could not be evaluated. A poor outcome in the non-GH group was the incentive to proceed with a subsequent IVF cycle in which GH was utilized as an adjunct. We can assume, however, that an increased number of high-quality blasts, particularly euploid blasts, may translate to an increase in live birth rate per transfer [22]. This is an area of future study.
Many studies that have previously evaluated GH in controlled ovarian stimulation included patients that meet the Bologna criteria for poor ovarian response. As outlined in the introduction, the Bologna criteria helps define poor responder patients [3]. Interestingly, our average study patient was age 36 years with an AMH of 2.3 ng/ml which does not satisfy the traditional criteria of poor responder patients as defined by these criteria. This suggests that GH may benefit a larger range of patients and should be considered in anyone with history of poor embryo development. A recent study by Li et al, does suggest that GH supplementation improves oocyte competence in women with a history of poor embryonic development [15].
Another interesting finding is the total dose of gonadotropins used in the cycles. We know from previous studies that GH supplementation induces FSH receptor expression and should, in theory, sensitize the patient to exogenous gonadotropins [24]. This has been shown to be true in several other studies in which adding growth hormone to the protocol resulted in a lower required dose of gonadotropins [2]. Conversely, in our study, a higher dose of gonadotropins was used in the cycles with the addition of GH. This was due to provider preference. Despite this confounder, the results suggest there may be a role for growth hormone in the ovarian stimulation protocol in women who have had poor outcomes in previous cycles.
To complicate matters, there is no accepted dose or timing of administration therefore a great deal of heterogeneity exists between studies in regard to these two parameters. In the present study, we administered 3mg (9IU) per day of stimulation. The dosing is consistent with Li et al. though they did not start until the day of downregulation in antagonist cycles [14]. Bassiouny and Bayoumi used a slightly lower dose of 2.5mg/day, though they did not start until day 6 of stimulation [24,25]. Safderin had an arm receive 2.5mg/day as well though this did not start until day 8 and another arm that received 0.1mg/day from cycle day 3 of the previous cycle [18]. Gong et al, administered 4IU/day (1.3mg) starting from Day 4 of the previous cycle [17]. In the LIGHT study, 12 IU/day (4mg) from day of stimulation [14]. The variability in dosing regimens across studies makes it difficult to interpret results.