Signal Transduction of hCG Induces Decidualization and Uterine Receptivity

All independent experimental data on epithelial and glandular cells lines of human endometrium support the evidence for a rapid production of eicosanoids from the LH/hCG receptors when exposed to the hCG hormone. Prostaglandins rapidly act on the surrounding endometrial stromal cells throughout the adenylyl cyclase enzyme leading to very large amounts of cAMP and angiogenic factors (VEGF) production. The cAMP is the most important intracellular second messenger and along with progesterone accomplishes the full process of decidualization and acquisition of receptivity after estrogenic priming of the endometrium. The status of uterine receptivity lasts few days only and timing for successful embryo-signal transduction system activation by the endometrium is probably short. In absence of in vivo embryonic signals it is impossible to predict, on individual bases, how the intensity of all the complex interlinked molecular changes of decidualization might ever be in case of exposure to native hCG. In other terms, amount of prostaglandins and cAMP produced in response to variably glycosylated hCG are all, in vivo, not measurable variables and should be viewed as a “wave” of biochemical chain reactions. Embryonic hCG is secreted in form of multiple isomers having an unpredictable variable level of glycosylation and control of this variable remains elusive. During cycles of ovarian stimulation many drugs (FSH, LH, HCG) interact with different G-protein coupled receptors (GPCRs) making it possible to alter the prostaglandins-mediated decidualization process ready to be elicited only by hCG of pregnancy. Since the molecules (cAMP and progesterone) controlling endometrial stromal cells differentiation into decidual cells are critical for successful implantation and placenta formation, the evidence of fast eicosanoids production associated with endometrial LH/hCG receptors exposure to hCG and the potential by human endometrium to produce, in response, very large amounts of cAMP has biological and clinical relevance. DOI : 10.14302/issn.2576-2818.jfb-14-553 Corresponding author: Luca Bernardini e-mail: ostgin-sarzana@libero.it Running title: GPCR-signal transduction and uterine receptivity


Introduction
The estimated natural fecundity rate of the general population is about 20% per month, and estimated rates of conceiving naturally are 45%, 65%, and 85% after 3, 6, and 12 months, respectively [1]. Optimal estimatesrepresenting the likelihood of a live birth when there are no barriers to treatment continuation -support the hypothesis that similar rates can be achieved by means of assisted reproduction technology, in the context of favorable patient characteristics such as uterine environment, embryo quality, treatment method, with cumulative live-births rates from two attempts shown to be greater than 70% [1]. This notwithstanding, there is still a 30% of couples who will never get pregnant and among those who become pregnant an unpredictable and interposed number of pregnancy losses will sooner or later occurs before a successful live birth [2].
We don't know why in humans, as compared to most other mammalians, the process of embryo implantation is so an inefficient phenomenon associating with so high degree of pre-clinical and clinical abortions. Studies outcome after IVF, based on HCG measurement in serially daily urine samples collected from 9 to 19 days after oocyte retrieval, show that implantation is totally absent in almost half of the cases (48.6%) and when implantation occurs (51%) the rates observed for preclinical pregnancy loss, biochemical pregnancy, clinical miscarriage, and ongoing pregnancy are 33.7%, 3.7%, 14.9% and 47.7%, respectively [3].
The low monthly conception rates observed in humans (20%), irrespective of the maternal age and type of conception (natural or IVF), is in most cases the natural consequence of the extremely high prevalence of gross chromosomal instability present in human embryos due to mitotic and meiotic errors [4]. Part of the losses however are subclinical, occurring early during the preimplantation period, in absence of embryonic chromosomal imbalances and regardless how good looking embryos or blastocysts may appear. These implantation failures probably deal with the uterine side of the problem.
It is not our intention here to enter into the updated information today available in the field of human embryo implantation [5,6,7,8,9,10]. Among the number of possible embryo-derived signals known to regulate the endometrial response to the pre-implanting embryo (PIF, EPF, EGF, interleukins, hCG) [11,12], we will recapitulate here some of the recent insights about hCG and signal transduction systems of uterine receptivity. A possible interfering action on this signal transduction is played by gonadotropins used for controlled ovarian hyper-stimulation (COH). This and other clinical implications will be also here addressed.
The ligand: hCG is not one but many Different

Signals at the Same Time
Human chorionic gonadotropin (hCG) is classically regarded as signal for maternal recognition of pregnancy affecting the corpus luteum to prevent luteolysis and stimulating the ovary to produce progesterone. Intact hCG is the predominant form of hCG produced by the trophoblast during pregnancy and is a hetero-dimer of hCGα and hCGβ subunits. It is often erroneously referred to as hCGβ but β subunit of hCG is other thing (freeβ) [13]. Either high or diminished concentrations of intact hCG have been associated with maternal or embryo-placenta abnormalities. Its measurements becomes a useful method to detect higher risk of miscarriage, ectopic pregnancy, predict pre-eclampsia, intrauterine fetal growth restriction, fetal hydrops or identify trisomy [14].
Recently an electrochemiluminescence (ECL) method has been able to detect intact hCG secreted by embryos in spent culture media of day 1, day 3 and day 5 [15]. The embryonic hCG secretion was found to be associated with morphological grading in blastocyst stage and embryos having strong implantation potential both on day 3 and     After that if the invading embryo doesn't start to produce, by itself, the right amount and type of hCG, we doubt that implantation might really be enhanced. 3) The suspect that during ovarian stimulation the endometrial receptivity might be reduced as compared to natural or hormone replacement cycles has been a concern since long time, subject of debate and classically attributed to the supra-physiological circulating levels of ovarian steroids [76,77,78,79,80,81,82,83]. In particular, a detrimental impact on endometrium due to increased circulating progesterone levels on the day of hCG injection and oocyte retrieval responsible for a dis-synchronic glandular-stromal maturation [84,85] and a premature appearance of endometrial pinopodes has been emphasized [86].