The findings of our study suggest that the level of LHHCG can affect the IVF/ICSI outcome in the follicular-phase long protocol in a young population.
The ‘‘two cell–two gonadotropin’’ model has been the key to our understanding of folliculogenesis (4). According to this model, LH stimulates theca cells, thereby advancing androgen production, and FSH governs the proliferation of granulosa cells (GCs) and promotes E2 synthesis. Both FSH and LH play an important role in folliculogenesis. The details of the specific role of LH in folliculogenesis have not been fully studied.
The follicular-phase long protocol uses a single dose of 3.75 mg GnRH-a in the early follicular phase for pituitary downregulation. Two weeks after a single injection of 3.75 mg GnRH-a, endogenous sex hormones are almost completely inhibited. The FSH levels gradually recover after 3–4 weeks, and the E2 levels begin to rise after 7–8 weeks, whereas the inhibitory effect on LH lasts up to 8 weeks after administration (13). After 30 days, as the FSH level gradually recovers, gonadotropin (Gn) is used to stimulate the development of multiple follicles in the ovary. In the follicular-phase long protocol, due to pituitary desensitization, endogenous LH levels are very low in the later stage of stimulation. In addition, approximately 50% of patients undergoing IVF/ICSI using GnRH-A are LH deficient. Therefore, adding recombinant LH (rLH) to the process of COH may be beneficial to the outcome (3). Therefore, when the serum LH concentration after pituitary downregulation is between 0.5–2.5 U/L, we can obtain a normal ovarian response (14). Too high or too low is not ideal.
LH, which is well known for its importance in the late follicular phase, supports theca cells in the ovary to provide androgens and hormonal precursors for estradiol production. LH not only promotes the growth of larger follicles but also increases FSH activity in granulosa cells by increasing androgen synthesis (15). During the development of a dominant follicle, its dependence on FSH gradually declines, whereas its dependence on LH gradually increases. FSH’s partial role is replaced by LH in the late follicular phase. This facilitates the selection and maintenance of the dominant follicle.
Physiological levels of LH are clearly important for follicle development. If the LH level is abnormal, it will lead to abnormal follicular development. Therefore, it was speculated that there should be an LH threshold window. The Asia-Pacific consensus on the application of LH in assisted reproductive treatment published in 2011 concluded that the reasonable threshold window for LH ranges from 1.2–5 IU/L (16). However, some studies found that in the process of COH, when the LH level was lower than 1.2 IU/L on the HCG day, it did not affect the clinical outcome (17), whereas for the follicular-phase long protocol, LH was very rarely elevated due to suppression. In this study, the LH concentration was greater than 10 IU/L in only 10 cases, and there was only 1 case with LH > 20 IU/L, and the P concentrations on the HCG day were all normal.
Our study found that in the follicular-phase long protocol, with an LH ≤ 0.5 IU/L on the hCG day, patients had a higher number of oocytes retrieved, a better embryo rate, and more embryos, but there was no significant difference in the live birth rate compared with the other groups. So we speculate that when the LH ≤ 0.5 IU/L, although there may be pituitary hypersuppression leading to inadequate LH secretion in the late follicular phase, it does not affect the outcome. This is similar to the study of Brjercke et al. (18), that is, a lower LH can satisfy the development of follicles. As long as less than 1% of LH receptors are occupied, they can play a normal physiological role (18). However, when there are older women, a low response, a slow response, etc. in the COH cycle, adding LH may be beneficial. With a normal ovarian response, a low LH concentration does not affect the fertilization outcome (19).
However, as LH increases, the numbers of oocytes retrieved, embryos, and high-quality embryos and the number of 2PN decreased gradually, which may be because excessive LH levels may cause the ovaries to secrete more androgens, resulting in follicular atresia and then fewer oocytes retrieved. However, the pregnancy rate did not decrease, which may be because the increase in LH level only affected the number of oocytes retrieved but did not affect the quality of the oocytes, the embryo development potential or endometrial receptivity. For PGT patients, it may be more suitable to control the LH at a lower level on the HCG day to retrieve more oocytes.
The main limitations of this article are as follows: 1. The current measurement of LH levels may not accurately reflect the true level of internal LH; 2. Our study mainly enrolled young people, which is a specific group. This may have a certain influence on the outcome; 3. According to follicular development in the later stage, HMG or rLH may be added, which may cause the conclusion to be inaccurate. The cumulative pregnancy rate and cumulative live birth rate were not calculated. The data sample is still not large enough, and additional prospective large-sample studies are needed to confirm this idea.
In conclusion, in the follicular-phase long protocol, the LH level is maintained at a low level throughout COH. From the data of our study, we should pay more attention to LHHCG. Elevated LH levels on the hCG day may lead to a reduction in oocyte retrieval. However, even when LH ≥ 5 IU/L, approximately 10 oocytes are retrieved, which, for clinical purposes, is sufficient. However, those who undergo PGT may benefit more when the LH level is controlled within a certain range. Therefore, in the follicular-phase long protocol among young women, monitoring of LHHCG has clinical applications.