Improving IVF outcomes with r-LH supplementation in poor responders

r-LH supplementation for specific poor responders
r-LH supplementation in IVF may benefit women with poor ovarian response (POR). In a systematic review and meta-analysis of 40 randomized controlled trials (RCTs), the subgroup of poor responders treated with r-FSH plus r-LH had greater numbers of oocytes retrieved and higher clinical pregnancy rates vs those treated with r-FSH alone. [Reprod Biol Endocrinol 2014;12:17]

However, the phase III ESPART trial (n=939) demonstrated no significant differences in the number of oocytes retrieved and live birth rate (LBR) between poor responders treated with r-FSH/r-LH and those treated with r-FSH alone. When categorizing these patients into mild, moderate, and severe POR groups based on the PROsPeR score comprising maternal age (≥40 years) and ovarian reserve (<2 oocytes in a previous cycle) or baseline serum antimüllerian hormone (AMH) level (≤0.5 ng/mL), post hoc analysis revealed higher LBRs with r-FSH/r-LH vs r-FSH alone in the moderate and severe POR groups. [Hum Reprod 2017;32:544-555] Similar results were shown in a real-world study evaluating 9,787 COS cycles in 6,370 poor responders classified by the PROsPeR score. (Table) [Reprod Biomed Online 2021;42:546-554]

“We need better classification of poor responders [to maximize benefits of r-LH supplementation in IVF],” Lantsberg pointed out.

POSEIDON classification
In the POSEIDON system, poor responders can be categorized by ovarian sensitivity to exogenous gonadotropin, maternal age, the number of oocytes retrieved in prior cycles, and ovarian reserve markers (eg, AMH). [Front Endocrinol (Lausanne) 2019:10:814]

Unexpected POR
Despite normal ovarian reserve markers (eg, AMH ≥1.2 ng/mL), some women may have unexpected POR and a poor or suboptimal number of oocytes. [Front Endocrinol (Lausanne) 2019:10:814]

r-LH supplementation can benefit women with unexpected POR. (Table) A systematic review and meta-analysis of five RCTs showed that in women with unexpected POR, r-FSH/r-LH was associated with higher number of oocytes retrieved (weight mean difference [WMD], 1.98; p=0.03), higher implantation rates (odds ratio [OR], 2.62; p=0.004) and higher clinical pregnancy rates (OR, 2.03; p=0.003) vs r-FSH alone. No significant between-group differences were observed in rates of mature oocytes and miscarriage. [Reprod Biol Endocrinol 2019;17:18]

Advanced maternal age
Poor responders aged ≥35 years are at high risk of embryo aneuploidy. [Front Endocrinol (Lausanne) 2019:10:814]

r-LH supplementation may improve ART outcomes in patients aged 35–40 years. (Table) A systematic review and meta-analysis of 12 RCTs demonstrated that in this age group, the use of r-FSH/r-LH was associated with higher clinical pregnancy rate (OR, 1.45; 95 percent confidence interval [CI]; 1.05–2.00; I², 0 percent; p=0.03) and higher implantation rate (OR, 1.49; 95 percent CI, 1.10–2.01; I², 13 percent; p=0.01) vs r-FSH alone. Although fewer oocytes were retrieved with r-FSH/r-LH vs r-FSH alone (WMD, -1.03; 95 percent CI, -1.89 to -0.17; I², 0 percent; p=0.02), the number of metaphase II oocytes remained comparable between the groups. [Reprod Biol Endocrinol 2021;19:91]

“These results suggest that r-LH supplementation [in women aged 35–40 years] may enhance [oocyte] quality over quantity,” Lantsberg said.

Other cohorts with suboptimal ART outcomes
Hypogonadotropic hypogonadism
Hypogonadotropic hypogonadism (HH) is characterized by low FSH and LH levels due to impaired neuroendocrine function, resulting in insufficient sex steroids production. For women with HH, r-LH supplementation can promote follicle growth and oestradiol production, supporting endometrial proliferation. (Table) [Front Endocrinol (Lausanne) 2022:13:907249; Fertil Steril 2002;77:1170-1177]

Iatrogenic LH deficiency in COS
Gonadotropin-releasing hormone (GnRH) analogues can suppress LH levels during COS, while FSH:LH ratio may predict clinical outcomes of IVF. [Front Endocrinol (Lausanne) 2022:13:907249; Fertil Steril 2008;90:1297-1300; Reprod Biomed Online 2009;18:205-208] “Due to limited scale of these studies, larger trials are necessary for validation,” commented Lantsberg. (Table)

Repeated implantation failure
Repeated implantation failure (RIF) occurs when good-quality embryos repeatedly fail to implant after IVF. In a pilot study in 66 patients with RIF in ≥2 IVF cycles, r-FSH/r-LH improved IVF outcomes, including positive pregnancy tests, number of gestational sacs, implantation rate and abortion rate, vs r-FSH alone. “These findings highlight potential benefits [of r-LH supplementation] for RIF, although further research is needed,” Lantsberg commented. (Table) [Eur Rev Med Pharmacol Sci 2017;21:5485-5490]

Summary
In ART, r-LH supplementation may benefit poor responders, particularly those with unexpected POR, advanced maternal age and HH. Additional research on r-LH supplementation for iatrogenic LH deficiency and RIF is warranted.