**5. Human chorionic gonadotropin:**

hCG and LH have a significant degree of structural homology and both act on the LH receptor. hCG has a 6-8 fold affinity for the LH receptor as compared to LH only. Glycosylation additions to hCG also give it a longer half-life than LH. This has resulted in trials investigating the ability of hCG to replace LH for ovarian stimulation.

Two studies have reported the use of hCG in the early follicular phase of ovarian stimulation (100, 101). These trials and two case reports have used various dosing strategies to deliver the hCG, including 200 IU per day for four or seven days, 50 IU per day for 14 days, and 1,250 IU in a single dose on cycle day two (100-103).

In one trial, the addition of hCG resulted in significantly greater highly quality embryos (85% versus 47%) and pregnancy rates (46% versus 31%) (100). Overall, there is a lack of randomized controlled data evaluating the use of hCG from the early follicular phase, but what data is available is promising.

hCG has been evaluated as a mid-to-late cycle supplement to rFSH stimulation cycles in six trials. The dose of hCG utilized was 200IU per day in five trials and 250IU in another (104- 109). All trials were initiated with rFSH only for stimulation with hCG added when the follicles were between 12-14mm in size. Five of the trials reported a significantly higher estradiol level on the day of hCG in patients randomized to receive hCG stimulation, with increases in estradiol ranging from 700-1500 pg/ml (104-107, 109). A study by Filicori *et al.* further demonstrated a significantly higher fertilization rate in patients receiving hCG versus rFSH only (74% versus 48%) (104). The remainder of the trials did not show any differences in outcomes with hCG with regards to fertilization, implantation, or pregnancy (105-107, 109). These RCT total 614 patients and demonstrate that the addition of hCG results in higher estradiol levels and at least comparable ART outcomes to rFSH stimulation only.

In a retrospective analysis, Van Horne *et al.* demonstrated that the addition of daily hCG (50-100 IU per day) to a rFSH only stimulation protocol resulted in a decrease in average FSH administration by 1000IU per patient and resulted in a cost savings of \$600 in a military healthcare facility (110). In a subsequent publication, this same group demonstrated that low dose hCG was effective at significantly improving implantation rates (54% vs. 19%) and live-birth rates (64% vs. 25%) in patients who had endogenous LH levels ≤ 0.5 IU/L, while it had no benefit in patients with LH levels >0.5 IU/L (58). A metaanalysis of over 1,000 patients has demonstrated that the addition of hCG to ovarian stimulation results in a decreased requirement for rFSH, leading to a cost savings with comparable outcomes (108).

The Use of rLH, HMG and hCG in Controlled Ovarian Stimulation for Assisted Reproductive Technologies 65

pregnancy, both the largest trial and the meta-analysis suggest a clinical benefit to including

It has also been suggested that poor responders will benefit from the addition of LH. A common approach to increase LH in poor responders involves the use of the microdose flare protocol. This protocol avoids the profound suppression of endogenous LH and FSH in the early follicular phase normally achieved with long luteal downregulation protocols. Scott and Novat's initial investigation of the microdose flare found it to have higher peak estradiol, more mature follicles and more mature oocytes than a traditional agonist protocol (112). While this protocol represents a well-established approach to increasing endogenous LH and FSH, randomized controlled trials have been small and inconclusive on whether this protocol increases live birth rates (113-116). One RCT did not show any benefit to adding either rLH or low-dose rHCG to a microdose flare protocol for poor responders (117). A Cochrane review has suggested that poor responders may benefit from the addition of rLH (98). In this meta-analysis there was a marked increase in live birth with the use of

1. rLH increases implantation and clinical pregnancy in patients 35 years and older

The action of LH is vital to both natural and assisted human reproduction. Normogonadotropic patients often have adequate endogenous LH levels, even after GnRH analogue pituitary downregulation, to have successful assisted reproduction with FSH stimulation alone. However, the addition of LH activity to ovarian stimulation has been demonstrated to improve the odds of achieving a live birth. We find the 3-4% improvement in live birth with the use of LH activity to be clinically relevant. The inclusion of LH in the stimulation of poor responders and women thirty-five and older has been shown to improve ART outcomes. Since there are currently no proven methods to determine which patients will benefit most from the addition of LH, we recommend clinicians consider some form of

*Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA* 

*Uniformed Services University of the Health Sciences, Department of Obstetrics and Gynecology,* 

rLH in the ovarian stimulation of patients with advanced reproductive age.

rLH (OR 1.85, 95%CI 1.10-3.11) (98).

2. rLH increases live birth in poor responders

LH activity in the ovarian stimulation of all patients.

**6.1. Summary points** 

**7. Conclusion** 

**Author details** 

Anthony M. Propst

*Bethesda, MD, USA* 

Micah J. Hill

A recent meta-analysis summarized the evidence on the use of hCG in ovarian stimulation (111). The analysis included 11 RCT and 1,068 ART cycles. While the conclusions were limited due to heterogeneity with the source studies, significant conclusions were reached. It was demonstrated that the total dose of FSH was decreased by over 800 IU in patients who were supplemented with hCG. The use of hCG resulted in a small decrease in the number of MII oocytes retrieved (WMD -0.30, 95%CI -0.44 to -.66) (111). This data is consistent with the effect of LH on follicular growth discussed earlier in the chapter and a reduction of 0.3 oocytes per patient may be of small clinical impact. In analysis of 3 of trials reporting on early follicular phase hCG administration, there was no demonstrable benefit in clinical pregnancy. However, analysis of five of the trials reporting on late follicular phase hCG demonstrated a significant benefit in clinical pregnancy (RR 1.32, 95%CI 1.06- 1.64).
