The following is the summary of “LH increases the response to FSH in granulosa-lutein cells from sub/poor-responder patients in vitro” published in the January 2023 issue of Human reproduction by Sperduti, et al.

Is there a way to rescue the sub- or poor-response of human primary granulosa lutein cells (hGLCs) to follicle-stimulating hormone (FSH) in vitro by adding LH to the mix? Sub- or poor-responding women may benefit from a picomolar dose of LH to restore the FSH-induced cAMP and progesterone synthesis of hGLC. Clinical trials have shown that co-treatment with FSH and LH improves ovarian response in sub- and poor-responders following ovarian stimulation during Assisted Reproductive Technology(ART).  hGLC samples were collected from 286 unidentified women undergoing oocyte retrieval for ART between October 2017 and February 2021. hGLCs were isolated, cultivated, genotyped, and treated in vitro with escalating amounts of FSH (nM) ±0.5 nM LH from women receiving ovarian stimulation during ART. Progesterone and cyclic adenosine monophosphate (cAMP) levels were determined after 3 and 24 hours, respectively. The ovarian response of the donors was used to stratify the in vitro data into normo-, sub-, and poor-responder groups for statistical comparison. LH was added to FSH in all groups, and the results were compared to those of FSH alone.

In vitro studies showed that hGLCs from normo-responders were more responsive to FSH treatment than those from sub-/poor-responders. Higher cAMP (about 2.5- to 4.2-fold) and progesterone plateau (roughly 1.2- to 2.1-fold) levels were elicited by equimolar FSH doses in cells from normo-responder women than those from sub-/poor-responder women (ANOVA; P<0.05). The levels of cAMP and progesterone showed that FSH was much more effective across the board when LH was added to the cell treatment (P>0.05). These in vitro outcomes were comparable between the sub-/poor responder group treated with (FSH + LH) and the normo-responder group treated with FSH alone. No significant differences in allele frequency or FSH receptor (FSHR) gene expression were seen between groups, ruling out differences in gonadotropin and their receptor genes as a cause of the normo-, sub-, and poor-response. Overall, ovarian lutein cells respond to FSH in a phenotype-dependent manner. Furthermore, LH supplementation may bridge the gap between the cAMP and steroid production patterns of normo- and sub/poor-responders.

Clinical trials are needed to show if the endpoints studied here represent parameters of successful ART, despite the large number of experimental replicates overall for an in vitro investigation. Ovarian stimulation may alter the hGLC’s ability to replicate the granulosa cell’s response to hormones in the antral follicular stage. This in vitro assay has the potential to characterize the individual response and tailor the ART stimulation protocol to the normo-, sub-, and poor-responder status. Moreover, this in vitro study underscores the necessity to perform adequately planned, randomized clinical trials addressing the tailored use of LH in assisted reproduction. This work was financed by Merck KGaA. Both M.L. and C.C. work for either Merck KGaA or Merck Serono SpA. There are no conflicts of interest to report among the other authors.