**2. Hypothalamic-pituitary-gonadal axis**

An integrated hypothalamic-pituitary-gonadal axis with several main actors including the gonadotropin-releasing hormone (GnRH), the gonadotropins (luteinizing hormone (LH) and follicular-stimulating hormone (FSH)), and the gonadal hormones are recognized as a key mechanism on human reproduction [6]. Hypothalamic gonadotropin-releasing hormone, as a crucial regulator of the HPG axis, with characteristic pulsatile secretion pattern, plays a dominant role in the endocrine control of reproduction and its possible effects on implantation by regulating downstream hormones which have been widely concerned so far [7]. Two GnRH molecules termed GnRH I (default as GnRH) and GnRH isoform II (GnRH II) can be found in humans, and both of them play an important role during the implantation period as shown in **Figure 1** [6, 8].

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*The Role of Neuroendocrine in Embryo Implantation DOI: http://dx.doi.org/10.5772/intechopen.87863*

**2.1 GnRH functions in implantation via the pituitary-gonadal axis**

fluctuation of the estrogen and progesterone level [6, 11].

embryo implantation.

tive" for blastocyst implantation [19, 20].

tion and pregnancy maintenance [19].

In the HPG axis, after releasing from the hypothalamus in a pulsatile manner, GnRH then binds to GnRH receptors (GnRHRs) on the pituitary gland, in response, that LH and FSH are synthesized and secreted in pulse by the pituitary to match the GnRH signal. Subsequently steroid hormones including progesterone and estrogen are released from the gonads and form a loop by exerting a positive or a negative feedback effect on GnRH releasing and gonadotropin [8]. Although it has been reported that human type II receptor for GnRH II shows specific expression of the receptor in the anterior pituitary and it also has been suggested that these receptors might act together to regulate the biosynthesis and secretion of both LH and FSH, further investigation should be completed [9, 10]. Thus here, we focus on the functions of GnRH in implantation via the pituitary-gonadal axis. Since natural GnRH has a short half-life, several GnRH synthetic analogues have been developed including agonists and antagonists, which can be used to stimulate or block, respectively, the pituitary-gonadal axis in an assisted reproductive technology (ART), particularly often applied to prevent premature LH surge [11]. In women undergoing IVF, GnRH agonist may improve the luteal phase support, used to trigger the final oocyte maturation and to improve implantation and live birth rates [12]. Although the effects of embryo implantation are still controversial, both of them are thought to tightly correspond to the pituitary-gonadal axis and eventually result in the

Estrogen and progesterone regulate uterine cell proliferation and are necessary for the changes in both the blastocyst and uterine epithelium for successful adhesion, so an imbalance between estrogen and progesterone during the luteal phase may lead to implantation defects [13]. Thus, it is quite clear that a deep understanding of the action of estrogen and progesterone on the human endometrium will allow a clear insight into the mechanism of determining endometrial receptivity in

So far, the molecular mechanism of estrogen regulation of maternal uterus in implantation remains unclear. Some studies implicated that estrogen was not essential for embryo implantation due to its receptor disappearance at the time of implantation [14, 15]. However, some studies believed that only after sufficient exposure to estrogen could progesterone exposure drive the endometrial receptivity to embryo implantation in a brief period [16, 17]. In addition, it has been proven that early growth response 1 (Egr1) as the downstream target is regulated by estrogen expression via leukemia inhibitory factor-signal transducer and activator of transcription 3 (LIF-STAT3) signaling pathway in the uterus of a mouse, and it further regulates stromal cell decidualization by regulating Wnt4 [18]. Furthermore, some studies suggested that estrogen was a trigger to close the window of implantation via insulin-like growth factor 1 pathway and made the endometrium "recep-

Progesterone production reaches its peak during the mid-luteal phase of the cycle, and this is the time when the secretory endometrium is appropriately prepared for the implantation of an embryo [8]. During the luteal phase, progesterone is produced, in turn stimulating the proliferation of the lining of the uterus to prepare for implantation by blocking the production of matrix metalloproteinase (MMP) and stimulating the production of tissue factor (TF) and plasminogen activator inhibitor 1 (PAI-1) [21, 22]. The phenomenon that a luteal phase support with progesterone can improve the implantation and pregnancy rates indicates lower progesterone and lower implantation [23, 24]. A review by Yoshinaga further confirms that progesterone is also an indispensable factor for successful implanta-

**Figure 1.** *Schematic of the HPG axis functions in implantation.*

rate after IVF-ET.

**2. Hypothalamic-pituitary-gonadal axis**

the implantation period as shown in **Figure 1** [6, 8].

fertilization and embryo transfer (IVF-ET) is always confronted with recurrent implantation failure [4], which is in the means of the situation when the transferred embryo repeatedly, failed to implant after IVF-ET [5]. A strong association between pregnancy rate following IVF-ET and recurrent implantation failure has been investigated [4], but less studies mention directly about the role of neuroendocrine in recurrent implantation failure. A thorough understanding of the processes governing human embryo implantation would be of significant benefit for the treatment of infertility. Hence, this review provides a summary of current empirical researches on the impacts of neuroendocrine aspects in implantation so that we more understand the maternal environment at the time of embryo implantation and might optimize it by altering neuroendocrine regulation to increase the success

An integrated hypothalamic-pituitary-gonadal axis with several main actors including the gonadotropin-releasing hormone (GnRH), the gonadotropins (luteinizing hormone (LH) and follicular-stimulating hormone (FSH)), and the gonadal hormones are recognized as a key mechanism on human reproduction [6]. Hypothalamic gonadotropin-releasing hormone, as a crucial regulator of the HPG axis, with characteristic pulsatile secretion pattern, plays a dominant role in the endocrine control of reproduction and its possible effects on implantation by regulating downstream hormones which have been widely concerned so far [7]. Two GnRH molecules termed GnRH I (default as GnRH) and GnRH isoform II (GnRH II) can be found in humans, and both of them play an important role during

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**Figure 1.**

*Schematic of the HPG axis functions in implantation.*
