Improving fertility outcomes with rLH supplementation in selected patients
Luteinizing hormone (LH) supplementation may be appropriate for select women undergoing assisted reproductive technology (ART) treatment. At a recent webinar, Dr Anupriya Agarwal of the National University Health System in Singapore discussed the role of supplementation with a recombinant human LH (rLH), lutropin alfa, and rLH plus a recombinant human follicle-stimulating hormone (rFSH), follitropin alfa, in improving fertility outcomes such as ongoing pregnancy/live birth rates, and provided advice on identifying specific women with severe LH and FSH deficiency who may benefit from these strategies.
LH supplementation in ART
“LH is essential for follicular development, particularly in follicle steroidogenesis and oocyte maturation, making exogenous LH an important tool in ovulation induction,” said Agarwal. [Reprod Biomed Online 2006;12:406-415]
“There is robust evidence showing how low serum LH levels on the day of ovulation negatively affect fertility outcomes, leading to reduced implantation rate, increased early pregnancy loss and reduced live birth rates,” she continued. [Reprod Biomed Online 2006;12:599-607; Hum Reprod 2001;16:1636-1643; Reprod Biomed Online 2016;33:449-457; Reprod Biomed Online 2007;15:280-287; Fertil Steril 2011;96:600-604; Hum Reprod 2005;20:359-367; Hum Reprod 2002;17:2016-2021; Hum Reprod 2006;21:2645-2649; Hum Reprod 2000;15:1003-1008]
While ovarian stimulation can be efficiently achieved in many patients via exogenous FSH supplementation alone, rLH may benefit specific subgroups of women who may require supplementation of LH activity during ovarian stimulation. [Reprod Biomed Online 2006;12:599-607]
Selecting appropriate patients for LH supplementation
Not all patients will benefit from LH supplementation for follicular growth stimulation. In a systematic review, a pooled analysis of four studies demonstrated no difference in live birth rates between supplementation with rLH plus rFSH vs rFSH alone (odds ratio [OR], 1.32; 95 percent confidence interval [CI], 0.85 to 2.06; n=499; I2=63 percent, very low-quality evidence). [Cochrane Database Syst Rev 2017;5:CD005070]
Meanwhile, a pooled analysis of nine studies in the same review showed improved ongoing pregnancy rates associated with rLH plus rFSH vs rFSH alone (OR, 1.20; 95 percent CI, 1.01 to 1.42; n=3129; I2=2 percent, moderate-quality evidence). This benefit was noted among women with poor response in terms of follicle growth in previous in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, and those on gonadotropin‐releasing hormone (GnRH) agonist protocols. [Cochrane Database Syst Rev 2017;5:CD005070]
“Other possible groups of patients who may benefit from LH supplementation include women with LH and FSH deficiency,” said Agarwal.
“Gonadotropin deficiency may be congenital or acquired,” she explained. “Congenital gonadotropin deficiency is seen in patients with hypogonadotropic hypogonadism [HH] and those with LH/FSH and LH receptor/FSH receptor polymorphisms.” [Hum Reprod Update 2018;24:599-614; Endotext. South Dartmouth (MA): MDText.com, Inc.; November 25, 2013]
“Acquired LH deficiency may result from GnRH analogues and other medications used during IVF cycles,” she said. “It can also be seen in those with eating disorders, hypothyroidism or functional hypothalamic amenorrhea [HA], as well as in women of advanced reproductive age.” [Endotext. South Dartmouth (MA): MDText.com, Inc.; November 25, 2013; Hum Reprod 2006;21:2645-2649; Hum Reprod 2005;20:359-367; Clin Med Insights Reprod Health 2014;8:59-64]
WHO Group 1 anovulation patients
According to the British Fertility Society, most women with WHO Group 1 anovulation will need LH supplementation for adequate folliculogenesis. [Hum Fertil (Camb) 2013;16:228-234]
“Patients in WHO Group 1 are characterized as having a hypogonadotropic hypo-oestrogenic state,” noted Agarwal. “These include women with HA [with low to normal FSH levels and low LH and oestrogen levels], HH [with low FSH, LH and oestrogen levels] or hypopituitarism [with low FSH, LH and oestrogen levels]. They may benefit from rLH/rFSH supplementation.” [Hum Fertil (Camb) 2013;16:228-234]
Women ≥35 years of age
“Advancing reproductive age is associated with fewer functional LH receptors, less potent and biologically active endogenous LH, and impaired ovarian paracrine activity,” said Agarwal. [Maturitas 1996;23(suppl):s19-s22; Maturitas 1984;5:223-231; Semin Reprod Med 2004;22:209-217]
Serum androgen levels, which are crucial in folliculogenesis, also markedly decrease as women age. This decline is steeper during the earlier reproductive years vs the later decades of life. [J Clin Endocrinol Metab 2005;90:3847-3853]
“As such, successful fertility interventions become more challenging in women of advanced reproductive age,” Agarwal noted.
“Every oocyte matters, especially in older women, because oocyte quality also tends to decline with age,” she stressed. “This further highlights the importance of optimal ovarian stimulation strategies in older women.” [Swiss Med Wkly 2015;145:w14087; Aging Cell 2015;14:887-895; Reproduction 2015;149:147-154]
A systematic review assessed the role of rLH supplementation in ovarian stimulation for ART in specific patients. Based on four pooled studies in women aged 35–39 years, rLH supplementation resulted in increased clinical pregnancy rates (total odds ratio [OR], 1.63; 95 percent confidence interval [CI], 1.15 to 2.31; p=0.007). (Table) [Fertil Steril 2018;109:644-664, September 2020]
Low prognosis patients: POSEIDON group 4
Based on the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) criteria, women who belong to POSEIDON Group 4 (≥35 years of age) are considered to have the worst prognosis with ART due to poor ovarian reserve (ie, expected low ovarian biomarkers and low oocyte number). [Front Endocrinol (Lausanne) 2018;9:461; Front Endocrinol (Lausanne) 2019;10:814]
In a real-world retrospective clinical study, a nonsignificant trend towards higher delivery rates was noted among low-prognosis women (ie, 1–3 oocytes retrieved) who received rLH plus rFSH (9.6 percent) vs those who received rFSH alone (6.4 percent) or human menopausal gonadotropin (hMG) (6.7 percent) (p=0.948). [Front Endocrinol (Lausanne) 2019;10:282]
“This suggests that adding LH to FSH during ovarian stimulation may improve the quality of oocytes retrieved in women with poor prognosis,” said Agarwal.
Supplementation with rLH + rFSH vs FrSH alone in GnRH agonist protocols
Recombinant gonadotropins provide several possible combinations for different ovulation induction strategies.
A meta-analysis investigated the role of rLH supplementation in women treated with rFSH alone or combined with other gonadotropins. Results showed that in GnRH agonist protocols, women who received rLH plus rFSH achieved higher pregnancy rates vs those who received rFSH alone (OR, 1.27; 95 percent CI, 1.09 to 1.48; p=0.002; I2=9 percent). Similar results were noted for those who received hMG vs rFSH alone (OR, 1.17; 95 percent CI, 1.10 to 1.36; p=0.030; I2=0 percent). Higher pregnancy rates were not observed in patients who received rFSH plus human chorionic gonadotropin (hCG) vs rFSH alone, or in GnRH antagonist protocols. [Front Endocrinol (Lausanne) 2017;8:114]
Supplementation with rLH may improve fertility outcomes in women with LH deficiency who are in a hypogonadotropic hypo-oestrogenic state (ie, WHO Group 1), in those of advanced reproductive age (ie, >35 years), and those with poor ovarian reserve (POSEIDON group 4). In GnRH agonist protocols, rLH plus rFSH supplementation may also result in higher pregnancy rates vs rFSH alone.