Role of growth hormone in ART cycles in poor responders: A literature review

INTRODUCTION

Infertility affects around 8% to 10% of couples worldwide, out of the 60 to 80 million couple affected, nearly 15% to 20% are from India.^[1] There is a trend to delay marriage and childbearing and many women across the world are opting for assisted reproductive techniques (ART). This poses a challenge to the ART experts due to diminished ovarian reserve with advancing age in women.^[2,3,4,5,6] Several studies have reported that ovarian reserve diminishes earlier in Indian women.^[7,8] While, various adjuvants and therapies have been described in literature and used by experts for poor responders. However, most are without any proven benefits.^[2,3,5,6,9]

Growth hormone (GH) has been used extensively in ART procedures, both in normal and poor responders. However, its use has been off label except in rare condition of GH deficiency. As shown in animal models, GH induces the production of Insulin like growth factor-1 (IGF-I), which helps in ovarian estrogen production and follicular development. It also stimulates granulosa cells and increases gonadotropin secretions.^{[2,3,5,6,9,10]} Its role in POR is based on increased number of granulosa follicle stimulating hormone (FSH) and Leutinizing hormone (LH) receptors and enhanced mitochondrial activity.

While, there has been a considerable interest in the role of GH in poor responders, the literature is diverse, in terms of criteria used for poor responders, regimes of GH administration, and it is effect on the results of the ART cycle.

The definition of poor responder has also evolved and after the Bologna criteria in 2011 and Poseidon classification, most of the recent studies have used a uniform criteria to define poor responders.

MATERIALS AND METHODS

An online search was conducted on articles related to use of growth hormone (GH) in poor responders on PubMed, Google, Google scholar, Medline, Embase, Global health, Cochrane library. Search words “growth hormone,” “poor responders,” “poor,” “ovarian reserve,” “inadequate,” and “suboptimal” were used. The studies which met the following criteria were recruited for analysis:

Outcome measures and definitions

The studies were evaluated for no. of oocytes (MII) retrieved, no. of embryos available for transfer, clinical pregnancy, live birth (if data available), miscarriage rates (Figure 1).

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Figure 1

Selection of studies.

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Clinical pregnancy: Presence of cardiac activity on ultrasound.

Live birth: Pregnancy delivered live beyond 24 weeks of gestation.

Miscarriage: Fetal loss before 20 weeks of gestation.

RESULTS

The literature search revealed 766 articles after the search words, which were narrowed down to 22 articles. Based on the selection criteria, only 12 studies were selected for review. A total of 1722 women were included in the intervention group while 3097 women were included in the control group. The main characteristics of the studies are given in Table 1 and the results in Table 2.

Table 1 Characteristics of the studies

Table 2 Results of the studies

Most of the studies referred to Bologna criterion^[3,4,5,9,11] for defining poor responders. Bologna criteria define poor responders with any two of the following:

1. Age >40 years or any other factor for poor ovarian reserve.

2. Previous poor ovarian response (≤3 oocytes on ART cycles).

3. Poor ovarian reserve test (antral follicle count <5–7, anti-Mullerain hormone <0.5–1.1 ng/ml).

Zhu et al.^[3] and Cai et al.,^[5] further classified them into Poseidon group 3 and 4. Several studies have used the European Institute of Embryology & Infertility 2011 criterion^[2,6,10,11] for defining poor responders.

The European Institute for Embryology and Infertility in 2011 gave the following definition of POR as follows (having at least two of the three following criteria):

1. Age over 40 years,

2. The evidences of POR as having a maximum of three oocyte following induction protocol), and

3. Low ovarian reserve score (AFC less than 5–7, AMH less than 0.5–1.1 ng/ml).

While most of the studies were randomized clinical trials,^{[2,3,4,6,9,10,12,13]} while one of it was a retrospective study.^[5] Many studies had a small sample size.^{[2,4,6,9,10,11,12,13]}

DISCUSSION

Poor responders remain one of the most challenging situations, now, with women delaying marriage and childbearing, it is becoming increasingly more prevalent in ART cycles. The current review intends to explore the role of GH in ART cycle.

The current data provides evidence, that supplementation of GH, might improve oocyte retrieved, number of embryos obtained for embryo transfer, clinical pregnancy, however, there was no increase in the live birth rate.

The studies are heterogenous in terms of protocol, dose, and type of GH used. Choe et al.^[12] have used sustained release GH, Noeman et al.^[13] have used recombinant GH. Irrespective of the dose/protocol used, most of the studies have demonstrated that use of GH decreases the dose/duration of gonadotropins.^[2,3,6,9,10] The number of oocytes retrieved and embryos formed in GH treated cycle are significantly more.^[2,6,9,10] GH improves oocyte quality by upregulating GH receptors on the oocytes and enhancement of its mitochondrial activity. This scientific evidence may support of the use of GH adjuvant therapy in poor responders.

Most of the studies failed to show any improvement in the clinical pregnancy rate with GH adjuvant therapy.^{[2,3,5,6,9,10,12]} Li et al.^[4] demonstrated a clinically significant increase in clinical pregnancy rate in women treated with GH. This could be explained by a smaller sample size in the study, and hence, it needs to be validated on a larger number of participants.

While some studies showed a higher endometrial thickness in women treated with GH,^[4,9] it did not translate to higher clinical pregnancies.^{[2,3,5,6,9,10,12,13]}

Zhu et al.^[3] did a subgroup analysis and the results revealed that GH treatment significantly increased the number of day 3 embryos obtained in the subgroup of young PORs along with the long down-regulation protocol (63.11% vs. 49.35%; P = 0.004). GH treatment also reduced the risk of miscarriage in young PORs when used along with GnRH antagonist protocol (0.00% vs. 12%; P = 0.023).

The mechanism by which adjunct GH treatment improves IVF outcomes:

1. It helps gonadotropin in follicle recruitment and development.

2. It enhances oocyte maturation. It upregulates IGF-1 synthesis. Serum IGF-1 and IGFBP-3 increase following exogenous GH administration and lead to improved ovarian follicular maturation and steroidogenesis.^{[2,3,5,6,9,10]}

No difference was observed in the miscarriage rate in both the treated and control group.^{[2,3,4,5,6,9,10,11,12,13]}

Choe et al.,^[12] used sustained release GH (20 mg three times: mid-luteal, late-luteal, menstrual cycle day 2) instead of recombinant GH to reduce the number of injections for patient convenience. However, the study failed to demonstrate any effect on number of MII oocytes retrieved, embryos available for transfer, Clinical Pregnancy Rate (CPR), or live births. Maybe, more experience is needed with the dosing and timing of sustained release preparation.

Norman et al.^[13] conducted a multicentered double-blind, placebo controlled, randomized clinical trial comparing human GH to placebo with maximum stimulation in ART cycle. They recruited 62 for GH and 51 in control group. The study failed to demonstrate any effect of GH adjuvant therapy on CPR, live birth rates (LBR). This study was however, criticized because of the small sample size, failure to achieve randomization due to patient preference, frozen embryos were not utilized, and definition of poor responders was not as per the standard definitions.

A previous meta-analysis by Yu et al.^[16] concluded that GH supplementation for IVF/ICSI in POR increases the number of MII oocyte, 2PN, and obtained embryos. However, it did not increase implantation rate and clinical pregnancy rates. The studies selected were much older (1995, 2006–2013) and hence, were more heterogenous as well as had differences in methodology. The current review has included more recent studies, with a more uniform definition of POR.

CONCLUSIONS AND RECOMMENDATIONS

GH adjuvant therapy in poor responders reduced the dose/duration of gonadotropin used, increased endometrial thickness, improved the number of M II oocytes retrieved, embryos formed, clinical pregnancy rate, however, it has not shown to improve live birth rates in ART cycles.

Large clinical trials need to be performed for further subgroup analysis, as there is some evidence that GH adjuvant therapy may benefit young POR.