The primary objective of the present research was to discuss the relationship between pregnancy outcomes and total dose of HMG in couples undergoing HMG-stimulated IUI cycles with 75 IU as the initial dose. Analysis of 1,230 HMG-stimulated IUI cycles indicated that higher PR and LBR were associated with increasing HMG dose, and higher PR was also linked to enhancing HMG day after adjusting for potential confounders. These results suggest that increasing HMG dose appropriately would optimize PR and LBR of patients in HMG-stimulated IUI cycles, and longer days of stimulation cycle should not be abolished.
Using gonadotropin stimulated in IUI cycles has been widespread . PR and LBR of each gonadotropin cycle, higher than oral ovulation drugs, were reported as 6.9–16.9% and 9.1–20.5%, respectively, consistent with our study . Daily injection of appropriate doses of gonadotropins, an efficient and convenient treatment to mimic pulsatile gonadotropin-releasing hormone stimulation and normal ovarian function, could induce physiologic follicle development, normal estrogen level, appropriate EMT, and natural luteal function . Both follicle-stimulating hormone (FSH) and LH are primary hormones for follicle development and maturation, fertilization ability of oocyte, and endometrium implantation capacity. According to a two-cell two-gonadotropin theory model, LH provides the major drive to thecal androgen synthesis, which is the substrate for FSH-induced estrogen synthesis in granulosa cells . FSH leads to follicle growth, estrogen concentration, and endometrial proliferation. LH actives embryogenesis, meiotic division, and follicular wall proteolysis, which releases the oocyte . LH was also believed to furnish appropriately estrogenic environment for normal follicular ontogeny, decrease development of small follicles, and optimize dominant follicle selection, alleviating risks of OHSS and multiple pregnancies . Urine human menopausal gonadotropin (HMG), the combination of FSH and LH, is a low-cost and efficient ovulation medicine used in IUI cycles . Earlier initial days and longer usage days of HMG were connected with a higher HMG dose in this study, which was meaningless after adjustment, indicating that HMG dose might be the essential factor in HMG-stimulated IUI cycles.
One of the considered mechanisms leading to high PR and LBR is the augment of E2. Our study manifested a positive relationship between postovulatory E2 level and HMG dose, consistent with the two-cell two-gonadotropin theory that both FSH and LH regulate estrogen production. Increased circulating high E2 released by follicles stimulates GnRH receptor expression in the pituitary gland, which then stimulates LH and follicle release . Previous literature showed that infertility females with higher E2 levels during the whole cycle were tended to have better chances of being pregnant . The embryos with a higher E2 level would obtain a better quality and development dynamics during in vitro fertilization . Exogenous hormone experiment also showed that a gradual and constant augmentation, instead of a rapid increase, in the thickness of the endometrium stimulated by circulating estrogen was more likely to induce vasodilation and endometrial blood flow and increase the endometrial size during periovulatory periods, explaining why longer days of HMG were related to a better pregnancy outcome . However, supraphysiologic estradiol levels are deemed to adversely affect endometrial receptivity and thereby implantation, resulting in an increased perinatal risk . Consequently, physiologic estradiol level is required in IUI cycles. In the 75 IU HMG-stimulated cycle, no OHSS case was reported because follicles number was controlled, and the estradiol level remained at an adaptive level which might be explained by the low initial dose of HMG.
The improvement of endometrial proliferation and receptivity, one of the most essential processes in successful mammalian implantation, may be another reason for the association between higher dose, longer days of HMG, and superior outcomes . Many studies have explored the relationship between EMT and pregnancy outcomes in IUI and IVF treatments, but the consensus in the existing studies is inconsistent at best [20, 23]. Overall, most literature has shown that better pregnancy outcomes are observed with increasing EMT, which is in line with our results. For example, a study showed that within gonadotropin treatment IUI cycles, the mean EMT in women achieving the outcome of live birth was greater than those who failed, and 12.2% of live births were observed in cycles with an EMT of more than 13 mm . Quaas et al. stated a positive association between peak EMT and PR in the setting of gonadotropin cycles with a peak EMT as between 10.5 and 13.9 mm . Another report concerned about 1005 IUI cycles showed an increasing thickness of endometrium and PR in letrozole plus HMG protocol compared with letrozole cycles . However, a multicenter randomized controlled trial manifested that HMG cycles led to a significantly thicker endometrium compared to clomiphene citrate in IUI for unexplained subfertility without a consistent association between EMT and ongoing PR . The contradiction above might be explained by the different scope of endometrium thickness compared in the study above, and the excessive EMT is detrimental to the mammalian implantation, which should be controlled within reasonable bounds.
The number of preovulatory follicles was also a crucial element in embryogenesis success. Our results indicated that a growing mean number of follicles was connected with increased HMG dose but limited to three. Gonadotropin cycles tend to access more follicles than oral treatment, including clomiphene citrate and letrozole [7, 25]. More follicles do have more opportunity to get fertilized, but excess follicles could not contribute to PR and LBR because synchronization among different follicles would damage the endometrial receptivity . As a result, adverse pregnancy outcomes should be avoided by limiting the number of follicles. Clinicians most widely use low staring dosages such as 37.5 to 75 IU HMG to control follicle number and lower adverse pregnancy outcomes such as hyper-stimulation syndrome and multiple pregnancies, so we selected 75 IU as the initial unified dosage [15, 28]. With a low initial dose, HMG overdose could be avoided, and optimal number of follicles could be managed. Increasing the dose and day of HMG appropriately to trigger one dominant follicle, physiological dose of estrogen, and endometrial development would improve IUI outcome to advantage.
This study's salient strengths are sample size and inclusion of 75 IU dose as initial stimulated dose the first time. To date, there have been few reports examining the effect of dose and day of HMG on pregnancy outcomes. Simultaneously, we acknowledge the retrospective nature of the present study as a limitation, but the bias of influences of other variables on pregnancy outcomes was eliminated by recruiting patients in a strict inclusion and exclusion standard. A high-quality RCT concerning more significant pregnancy outcomes in future studies is warranted.