Long pentraxin 3 and vitamin D receptor mRNA expression pattern of cumulus granulosa cells isolated from PCOS oocytes at different stages of nuclear maturation.

BACKGROUND: A fine-tuned pro-inflammatory and anti-inflammatory balance in the follicular unit is essential for cumulus expansion and successful ovulation. While the long pentraxin 3 (PTX3) gene is required for the expansion of cumulus cells (CCs), ovulation, resumption of meiosis and fertilization, the vitamin D receptor gene (VDR-X2) is required for intra-follicle redox balance. This study was planned to determine the expression pattern of VDR-X2 and PTX3 mRNA in CCs isolated from germinal vesicle (GV), metaphase I (MI), and metaphase II (MII) oocytes of PCOS patients with ovulatory dysfunction. METHODS: The relative expression of CC-PTX3 and CC-VDR-X2 mRNA were evaluated using qRT-PCR in a total of 79 CC samples collected from individual cumulus-oocyte complex of 40 infertile patients (20 PCOS and 20 non-PCOS normal responders) who underwent ovarian stimulation with the GnRH antagonist protocol. RESULTS: Relative PTX3 mRNA expressions of CCMI-control and CCMII-control showed 3- and 9-fold significant upregulation compared to CCGV-control, respectively. The relative PTX3 mRNA expression of CCMII-control increased approximately three fold compared to CCMI-control. Compared to CCGV-pcos, a 3-fold increase was noted in the relative PTX3 mRNA expression of CCMI-pcos and an approximately 4-fold increase in the PTX3 mRNA expression of CCMII-pcos. Relative PTX3 mRNA expression values of CCMII-pcos and CCMI-pcos were similar. A 6-fold upregulation of relative PTX3 mRNA and a 4-fold upregulation of VDR-X2 mRNA were detected in CCMII-control compared to CCMII-pcos. CC-VDR-X2 expression patterns of the PCOS and control groups overlapped with the CC-PTX3 pattern. Fertilization rates of the PCOS group exhibiting failed transcript expression were similar to normal responders. CONCLUSION: The fact that relative CC-PTX3 and CC-VDR mRNA expression does not increase during the transition from MI to MII stage in PCOS as in normal responders suggests that PTX3 and VDR expression may be defective in cumulus cells of PCOS patients with ovulatory dysfunction.

Endometrial Injury Upregulates Expression of Receptivity Genes in Women with Implantation Failure.

BACKGROUND: Homeobox genes A10 (HOXA10) and A11 (HOXA11), members of the abdominal B gene family, are responsible for embryonic survival and implantation. This study was planned to investigate whether endometrial injury alters the expression of both transcripts in women with implantation failure. METHODS: A total of 54 women with implantation failure were divided into two equal groups as experimental (scratching) and sham (no scratching). Participants in the scratching group were exposed to endometrial injury in the mid-luteal phase, and those in the sham group were exposed to endometrial flushing. The scratching group, but not the sham group, underwent prior endometrial sampling. A second endometrial sampling was performed on the scratching group in the mid-luteal phase of the following cycle. The mRNA and protein levels of the HOXA10 and 11 transcripts were determined in endometrial samples collected before and after injury/flushing. Participants in each group underwent IVF/ET in the cycle after the second endometrial sampling. RESULTS: Endometrial injury caused a 60.1-fold (p < 0.01) increase in HOXA10 mRNA and a 9.0-fold increase in HOXA11 mRNA (p < 0.02). Injury resulted in a significant increase in both HOXA10 (p < 0.001) and HOXA11 protein expression (p < 0.003). There was no significant change in HOXA10 and 11 mRNA expressions after flushing. Clinical pregnancy, live birth, and miscarriage rates of the both groups were similar. CONCLUSIONS: Endometrial injury increases homeobox transcript expression at both mRNA and protein levels.

Biomechanical Forces Determine Fibroid Stem Cell Transformation and the Receptivity Status of the Endometrium: A Critical Appraisal.

Myometrium cells are an important reproductive niche in which cyclic mechanical forces of a pico-newton range are produced continuously at millisecond and second intervals. Overproduction and/or underproduction of micro-forces, due to point or epigenetic mutation, aberrant methylation, and abnormal response to hypoxia, may lead to the transformation of fibroid stem cells into fibroid-initiating stem cells. Fibroids are tumors with a high modulus of stiffness disturbing the critical homeostasis of the myometrium and they may cause unfavorable and strong mechanical forces. Micro-mechanical forces and soluble-chemical signals play a critical role in transcriptional and translational processes' maintenance, by regulating communication between the cell nucleus and its organelles. Signals coming from the external environment can stimulate cells in the format of both soluble biochemical signals and mechanical ones. The shape of the cell and the plasma membrane have a significant character in sensing electro-chemical signals, through specialized receptors and generating responses, accordingly. In order for mechanical signals to be perceived by the cell, they must be converted into biological stimuli, through a process called mechanotransduction. Transmission of fibroid-derived mechanical signals to the endometrium and their effects on receptivity modulators are mediated through a pathway known as solid-state signaling. It is not sufficiently clear which type of receptors and mechanical signals impair endometrial receptivity. However, it is known that biomechanical signals reaching the endometrium affect epithelial sodium channels, lysophosphatidic acid receptors or Rho GTPases, leading to conformational changes in endometrial proteins. Translational changes in receptivity modulators may disrupt the selectivity and receptivity functions of the endometrium, resulting in failed implantation or early pregnancy loss. By hypermethylation of the receptivity genes, micro-forces can also negatively affect decidualization and implantation. The purpose of this narrative review is to summarize the state of the art of the biomechanical forces which can determine fibroid stem cell transformation and, thus, affect the receptivity status of the endometrium with regard to fertilization and pregnancy.

Genome-wide expression analysis of endometrium before and after endometrioma surgery.

OBJECTIVE: This study was planned to investigate possible alteration in the number of differentially expressed genes (DEGs) in eutopic endometrium before and after laparoscopic removal of the ovarian endometrioma. STUDY DESIGN: Six infertile women with ovarian endometrioma who underwent laparoscopic endometrioma cystectomy and six fertile control subjects who underwent tubal sterilization were included the study. Endometrial samples were collected before and 3 months after surgery throughout the mid-luteal phase. Genome-wide expression profiling was performed with Illumina Human HT-12V4 microchip, a high density silica bead-based microarray which utilizing more than 47.000 probs. Illumina microsequence system was used to assess detection of p value for each probe in every sample. Probes revealing significant assessment (p < .05) were selected for comparative analysis. RESULTS: We have detected 1478 DEGs in the comparison between endometrium of women with endometrioma and fertile controls. 118 out of 1478 genes (7.9 %) were significantly increased or decreased more than 1.5-fold in their expression. When the preoperative values of the control and patient groups are compared the number of DEGs was 243 (7.5 %). In 9 out of 243 genes, the fold change was found to be 1.5 and more (3.7 %). Comparison of the number of DEGs after endometrioma surgery and tubal ligation revealed that expression patterns of 1036 genes (33.7 %) were changed in endometrioma group. In 105 out of 1036 genes, the fold change was found to be 1.5 and above (10 %). A comparison using 2706 probes revealed changes in the expression patterns of 106 different genes (3.9 %) after endometrioma resection. In 4 out of 106 genes, the fold change was found to be 1.5 and above (3.7 %). The comparison using 6035 probes revealed changes in the expression patterns of 93 genes (1.5 %) after tubal ligation. None of the 93 genes had a fold change of 1.5 or higher. The number of DEGs in endometrioma groups after surgery was approximately 3-fold higher than control group. CONCLUSIONS: Endometrium of women with endometrioma displayed abnormal expression of genes associated with implantation, immunological, endocrine and neuracrine functions. Positive alteration of the expression pattern of DEGs and signal transduction pathways following endometrioma surgery can improve the receptive capacity and implantation rates of eutopic endometrium.

Factors preventing materno-fetal transmission of SARS-CoV-2.

Although many pregnant women have been infected by coronavirus, the presence of intrauterine vertical transmission has not been conclusively reported yet. What prevents this highly contagious virus from reaching the fetus? Is it only the presence of a strong placental barrier, or is it the natural absence of the some receptor that the viruses use for transmission? We, therefore, need to comprehensively understand the mechanism of action of the mammalian epithelial barriers located in two different organs with functional similarity. The barriers selected as potential targets by SARS-CoV-2 are the alveolo-capillary barrier (ACB), and the syncytio-capillary barrier (SCB). Caveolae are omega-shaped structures located on the cell membrane. They consist of caveolin-1 protein (Cav-1) and are involved in the internalisation of some viruses. By activating leukocytes and nuclear factor-κB, Cav-1 initiates inflammatory reactions. The presence of more than one Cav-1 binding sites on coronavirus is an important finding supporting the possible relationship between SARS-CoV-2-mediated lung injury. While the ACB cells express Cav-1 there is no caveolin expression in syncytiotrophoblasts. In this short review, we will try to explain our hypothesis that the lack of caveolin expression in the SCB is one of the most important physiological mechanisms that prevents vertical transmission of SARS-CoV-2. Since the physiological Cav-1 deficiency appears to prevent acute cell damage treatment algorithms could potentially be developed to block this pathway in the non-pregnant population affected by SARS-CoV-2.

Combating sars-cov-2 through lipoxins, proteasome, caveolin and nuclear factor-κb pathways in non-pregnant and pregnant populations.

It can be misleading to think that the new severe acute respiratory syndrome coronavirus (SARS-CoV2) which has a very strong mutation and adaptation capabilities, uses only the angiotensin-converting enzyme II (ACE2) pathway to reach target cells. Despite all the precautions taken, the pandemic attack continues and the rapid increase in the number of deaths suggest that this virus has entered the cell through different pathways and caused damage through different mechanisms. The main reason why the ACE2 pathway comes to the fore in all scientific studies is that this receptor is located at the entry point of basic mechanisms that provide alveolo-capillary homeostasis. SARS-CoV-2 has to use nuclear factor-κB (NF-kB), caveloae, clathrin, lipoxin, serine protease and proteasome pathways in addition to ACE2 to enter the target cell and initiate damage. For this reason, while new drug development studies are continuing, in order to be beneficial to patients in their acute period, it is imperative that we are able to come up with drugs that activate or inhibit these pathways and are currently in clinical use. It is also critical that we adopt these new pathways to the treatment of pregnant women affected by SARS-CoV-2, based on the scientific data we use to treat the general population.

Intra-ovarian stem cell transplantation in management of premature ovarian insufficiency: towards the induced Oogonial Stem Cell (iOSC).

The specialized resident-stem cells in gonads are tasked with restorating damaged ovarian cells following injury to maintain sequential reproductive events. When we talk about premature ovarian insufficiency (POI) we accept the existence of decreased stem cell and their regenerative abilities. The present study was to explain how restorating damaged ovarian cells following injury to maintain sequential reproductive events in evidence-based medicine indexed in PubMed and Web of Science. The exact mechanism is unclear stem cells transfer may improve compromised ovarian function and fertility outcome in women with POI. Soluble factors secreted by stem cell may rescue impaired mitochondrial function in oogonial stem cells, enhance metabolic capacity of resident stem cells, induce local neovascularization in the ovary, and activate gene shifting between transferred stem cells and germ cell precursors. This review may provide insight into how stem cells show some of their beneficial effects on compromised ovarian microenvironment and germ cell niche and paves the way for clinical trials for improving ovarian function of women with POI. We also had the opportunity to share our hypothesis about the design and development of induced oogonial stem cell (iOSC) and its use in POI.

Laparoscopic Ovarian Drilling Improves Endometrial Homeobox Gene Expression in PCOS.

The study was designed to investigate whether laparoscopic ovarian drilling (LOD) of ovaries alters the expression levels of HOXA-10 and HOXA-11 mRNA in the endometrium of infertile women with clomiphene-resistant PCOS. Expression of HOXA-10 and HOXA-11 mRNA in the endometrium obtained before and after LOD during the midsecretory phase was measured. Expression of each gene was evaluated using real-time reverse transcriptase polymerase chain reaction (RT-PCR). Expression levels of HOXA-10 and HOXA-11 mRNA were lower in endometrium of patients with PCOS before LOD compared with fertile controls. But the differences failed to show statistical significance. Compared with fertile subjects, LOD of PCOS ovaries up-regulated endometrial HOXA-10 and HOXA-11 mRNA expression. Fold changes of HOXA-10 and HOXA-11 mRNA after LOD were found to be 4.46 and 4.19, respectively. Fold change increase in HOXA-10 and HOXA-11 mRNA was found to be statistically significant (P < .01, P < .02). There is a receptivity defect in the endometrium of women with PCOS that affects fertility regardless of other causes of infertility. LOD increases endometrial HOXA-10 and HOXA-11 mRNA expressions and improves receptivity in patients with clomiphene-resistant PCOS.

Testis spectroscopy may predict sperm retrieval rate in men with non-obstructive azoospermia undergoing micro-TESE: A pilot study

Objective: To investigate whether prior testis magnetic resonance spectroscopy predicts the success or failure of micro-dissection testicular sperm extraction (micro-TESE) in patients with non-obstructive azoospermia (NOA). Material and Methods: Nine men with NOA who were scheduled for micro-TESE for the first time, 9 NOA men with a history of previous micro-TESE and 5 fertile men were enrolled. All NOA patients and fertile controls underwent testis spectroscopy. A multi-voxel spectroscopy sequence was used. Testicular signals of choline (Cho), creatine (Cr), myo-inositol (MI), lactate, and lipids were analyzed quantitatively and compared with the results of the micro-TESEs. Results: The most prominent peaks were Cho and Cr in the fertile controls and NOA subjects with positive sperm retrieval in the micro-TESE. A high Cho peak was detected in 87% of the NOA men with positive sperm retrieval. NOA men without sperm at the previous micro-TESE showed a marked decrease in Cho and Cr signals. For positive sperm retrieval in micro-TESE, the cut-off value of Cho was 1.46 ppm, the cut-off value of Cr was 1.43 ppm, and the cut-off value of MI was 0.79 ppm. Conclusion: Testis spectroscopy can be used as a non-invasive screening method to predict the success or failure of micro-TESE.

Nppc/Npr2/cGMP signaling cascade maintains oocyte developmental capacity.

The follicle must fulfill the following criteria if it is to survive the period between early embryonic life and the luteinizing hormone (LH) peak. It should (i) be surrounded by pregranulosa cells; (ii) complete the first meiotic division and become dormant; and (iii) continue metabolism during the dormant stage. Interaction between the natriuretic peptide precursor type C (Nppc) and its receptor, natriuretic peptide receptor 2 (Npr2), affects female fertility through the production of oocytes with developmental capacity and maintain oocyte meiotic arrest. While Nppc is expressed in mural cells, cumulus cells express Npr2. Nppc/Npr2 system exerts its biological function on developing follicles by increasing the production of intracellular cyclic guanosine monophosphate (cGMP). This pathway not only contributes to the development of ovary and the uterus, but aids the formation of healthy eggs in terms of their morphological and genetic aspects. A defect in this pathway leads to asmall ovarian size, string-like uterine horns, and thin endometrium and myometrium. Disorganized chromosomes, abnormal cumulus expansion and early meiotic resumption occur in animals with defective Nppc/Npr2 signaling. The types and number of oocytes also decrease when there is incompetent Nppc/Npr2 signaling. This paper extends on most recent and relevant experimental evidence regarding Nppc/Npr2/cGMP signaling with regard to its crucial role in maintaining oocyte meiotic arrest and the production of oocytes with developmental capacity. We further discuss whether the agonist or antagonist forms of the members of this exciting pathway can be usedfor triggering final oocyte maturation.

Molecular role of peptides/proteins in subfertility of polycystic ovarian syndrome.

Obesity and hyperandrogenemia are known to have adverse effects on both developing follicle and endometrium receptivity in polycystic ovarian syndrome (PCOS). Insulin resistance also contributes to this dilemma as a cause or a consequence and leads to worsening of the clinical picture. The difficulty in obtaining pregnancy despite the presence of a large number of oocyte has concentrated our attention on oocyte quality and development. However, the occurence of subfertility has also caused us to investigate the presence of different etiologic agents in non-obese PCOS women with normal androgen and insulin levels. In this context peptides have become the most accused and investigated molecules in cases of impaired fertility due to PCOS. Most of the studies investigating the relationship between PCOS and peptide did not support each other. The difficulties in measuring peptide levels as well as the individual variations in peptide synthesis and release are possible causes of this incongruity. For all these reasons, the incorporation of studies investigating the relationship between PCOS, peptide and subfertility in an article has become critical to pioneering future work. Understanding the association between peptides and subfertility will help us to understand the effects of peptides on failed fertility in PCOS. Moreover, updating our knowledge about peptides may allow us designing new drugs to to treat subfertility in PCOS. This review provides a general summary of the mechanisms of action of neuroendocrine peptides in regulating reproductive events. Since it is not usual to discuss all peptides in this context, only the effects of key central and peripheral peptides on fertility in PCOS have been extensively addressed.

Navigation problems of ICSI or naive blastocyst can be solved with artificial blastocyst.

Embryos have evolved a remarkable capacity to find implantation site. The impressive navigation ability of natural blastocysts may rely on highly sensitive signals arising from embryos and specialized signal processing strategies in the endometrium. Navigation capabilities may be compromised in ICSI embryos because of altered biochemical signaling. The design and delivery of artificial blastocyst (AB) carrying strong chemical signals may allow ICSI embryos to more easily locate to and be retained in the implantation zone. ICSI embryos will attach easily to the implantation zone after it is found by the AB. Co-transfer of the AB together with the ICSI embryo may overcome potential difficulties in implantation due to impaired embryo-maternal communication in cases with implantation failure.

Patatin-like phospholipase domain containing 3-gene (adiponutrin), preptin, kisspeptin and amylin regulates oocyte developmental capacity in PCOS.

This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome (PCOS). A total of 40 infertile volunteers undergoing IVF/ICSI were included in the study. They were divided into two groups as PCOS (n=20) and control group without PCOS (n=20). The controls were recruited from subjects with a poor ovarian response. The PCOS and control participants were matched according to their body mass index (BMI). Each group of participants underwent ovarian stimulation with GnRH antagonist protocol. Blood and FF samples of one dominant follicle were obtained from each subject during the oocyte pick-up. FF and serum levels of PNPLA3, preptin, kisspeptin and amylin were measured through ELISA. Amylin and adiponutrin median values were not different according to study groups (p>0.05). FF-preptin median values in the control group were similar to the serum preptin values of control and PCOS groups (Z=0.970, p=1.000 and Z=2.631, p=0.051, respectively). Medians of the serum preptin in control and PCOS groups were the same (Z=1.649; p=0.595). FF-preptin median values of PCOS group were significantly lower than the preptin median values of the control group. Serum preptin levels were positively correlated with HOMA-IR, but not with pregnancy rates and the number of retrieved oocytes. Serum kisspeptin levels were negatively correlated with the number of retrieved oocytes and pregnancy rates. While amylin and adiponutrin have no role in the folliculogenesis, kisspeptin and preptin work together for regulating follicle developmental capacity in PCOS.

DHEA supplementation improves endometrial HOXA-10 mRNA expression in poor responders.

OBJECTIVE: The study was planned to investigate whether DHEA supplementation had an impact on endometrial receptivity in women who were poor responders (POR). MATERIAL AND METHODS: Twenty-eight POR women who were undergoing hysteroscopy and five fertile control subjects were included. The POR women were equally subdivided into two separate groups as patients who were currently using DHEA and those who were not. Endometrial samples of the subjects were obtained during hysteroscopy at the late follicular phase. Expression levels of endometrial HOXA-10, HOXA-11, and LIF mRNA were measured with the using real-time polymerase chain reaction. Spontaneous clinical pregnancy rates were also noted. RESULTS: Compared with POR women who were not given DHEA, upregulated endometrial HOXA-10 (7.33-fold) and HOXA-11 (2.39-fold) mRNA expression were detected in POR women on DHEA. The increase in HOXA-10 mRNA was significant (p<0.03). The fold increase in HOXA-11 mRNA was found as 2.39, which indicated a positive upregulation. However, this fold increment was insignificant (p<0.45). An insignificant increase in spontaneous clinical pregnancy rates in POR women on DHEA (53.3%) was observed compared with POR women who were not given DHEA (43.8%). CONCLUSION: Oral DHEA supplementation in POR upregulates endometrial HOXA-10 mRNA expression, which is known to positively modulate endometrial receptivity.

Hypothesis: Co-transfer of genuine embryos and implantation-promoting compounds via artificial containers improve endometrium receptivity.

As with other organs endometrial functions are altered with the advancing age. Age related decrease in reproductive functions leads to decline in the number of oocytes retrieved and the synthesis of endometrial receptivity molecules. Despite the significant improvement in assisted reproductive technologies we do not have so many options to enhance endometrial receptivity. Due to lack of drugs having endometrium receptivity enhancement properties, oocyte donation seems to be the only solution for women with implantation failure. The euploid oocytes come from young and healthy donors may overcome age associated endometrial receptivity defect. Nevertheless, many reasons restrict us from using oocyte donation in women with implantation failure. We, therefore, hypothesized that by mimicking a young blastocyst's effect on endometrium, the transfer of genuine embryos and implantation-promoting compounds together might be the new treatment option for infertile women with recurrent implantation failure. Artificial beads, MI or GV oocytes, and empty zona can be used as a container for intrauterine replacement of implantation-promoting compounds.

Anti-cyclic citrullinated peptide antibodies are not frequently observed in children with type 1 diabetes mellitus: a single-center study.

Type 1 diabetes mellitus (DM) and rheumatoid arthritis (RA) have been reported to occur concurrently in some cases. This study aimed to evaluate the presence of anti-cyclic citrullinated peptide (CCP) antibodies, which have been reported to have diagnostic value for RA, in children with type 1 DM. The study included 90 children with type 1 DM (Group 1) and 76 control cases (Group 2). The rates of reported family histories of RA and rheumatoid factor positivity did not differ between groups. In group 1, one case (1.1%) was positive for anti-CCP antibodies, whereas none of the controls were positive. The anti-CCP positive patient had no relevant joint complaints. Anti-CCP antibodies were rarely found in cases of pediatric type 1 DM. Thus, relevant screening in the follow-up of pediatric patients does not appear to be rational in the absence of any signs or symptoms of arthritis. The single case exhibiting a high anti-CCP level needs to be followed up for RA, although this positive result might be nonspecific and transient.

Expression of Endometrial Receptivity Genes Increase After Myomectomy of Intramural Leiomyomas not Distorting the Endometrial Cavity.

This study was designed to investigate whether endometrial receptivity genes are altered in infertile patients with intramural leiomyomas (IM) not distorting the endometrial cavity undergoing myomectomy. We measured endometrial HOXA-10, HOXA-11, LIF, ITGB3, and ITGAV messenger RNA (mRNA) expressions levels before and after myomectomy/metroplasty during mid-luteal phase in participants with IM, submucosal leiomyomas (SM), and septate uterus and fertile participants without fibroids. Initial endometrial sampling was obtained at the time of surgery, and second sampling was obtained 3 months after myomectomy/metroplasty. Expressions of each gene were evaluated using real-time reverse transcriptase polymerase chain reaction (RT-PCR). A trend toward decreased endometrial HOXA-10, HOXA-11, and ITGAV mRNA expression was detected in both SM and IM groups before myomectomy when compared to both fertile group and septate uterus. However, the differences failed to show statistical significance. After myomectomy of IM, we have detected 12.8-fold increase in endometrial HOXA-10 mRNA expression and 9.0-fold increase in endometrial HOXA-11 mRNA expression. This increase in endometrial HOXA-10 and 11 mRNA expression was significant. Accordingly, 2 patients having intramural fibroids greater than 5 cm were able to remain pregnant after myomectomy. Conversely, submucosal myomectomy did not cause any significant effect on endometrial receptivity markers. Likewise, all markers of endometrial receptivity remained unchanged after metroplasty. Myomectomy of IM have favorable effect on endometrial HOXA-10 and 11 mRNA expression.

Great migration: epigenetic reprogramming and germ cell-oocyte metamorphosis determine individual ovarian reserve.

Emigration is defined as a synchronized movement of germ cells between the yolk sack and genital ridges. The miraculous migration of germ cells resembles the remigration of salmon traveling from one habitat to other. This migration of germ cells is indispensible for the development of new generations. It is not, however, clear why germ cells differentiate during migration but not at the place of origin. In order to escape harmful somatic signals which might disturb the proper establishment of germ cells forced germ cell migration may be necessary. Another reason may be to benefit from the opportunities of new habitats. Therefore, emigration may have powerful effects on the population dynamics of the immigrant germ cells. While some of these cells do reach their target, some others die or reach to wrong targets. Only germ cell precursors with genetically, and structurally powerful can reach their target. Likewise, epigenetic reprogramming in both migratory and post-migratory germ cells is essential for the establishment of totipotency. During this journey some germ cells may sacrifice themselves for the goodness of the others. The number and quality of germ cells reaching the genital ridge may vary depending on the problems encountered during migration. If the aim in germ cell specification is to provide an optimal ovarian reserve for the continuity of the generation, then this cascade of events cannot be only accomplished at the same level for every one but also are manifested by several outcomes. This is significant evidence supporting the possibility of unique individual ovarian reserve.

Ghrelin action on GnRH neurons and pituitary gonadotropes might be mediated by GnIH-GPR147 system.

Acylated ghrelin (AG) effect on GnRH secretion is mediated, at least in part, by GH secreta-gogue receptor (GHS-R) which is present in the GnRH neurons. As the acylation is mandatory for binding to GHS-R, unacylated isoform of ghrelin (UAG) action on gonadotropin secretion is likely to be mediated by other receptors or mediators that have not been identified yet. UAG, therefore, may act partially via a GHS-R-independent mechanism and inhibitory impact of UAG on GnRH neurons may be executed via modulation of other neuronal networks. Ghrelin and gonadotropin inhibitory hormone (GnIH), two agonistic peptides, have been known as important regulators of reproductive events. Potential impact of ghrelin on the activity of GnIH neurons is not exactly known. Both GnIH and ghrelin are potent stimulators of food intake and inhibitors of gonadotropin release. By binding G-protein coupled GnIH receptor (GnIH-R), GPR147, which is located in the human gonadotropes and GnRh neurons, GnIH exerts an inhibitory effect on both GnRH neurons and the gonadotropes. The GnIH-GPR147 system receives information regarding the status of energy reservoir of body from circulating peptides and then transfers them to the kisspeptin-GnIH-GnRH network. Due to wide distribution of this network in brain GnIH neurons may project on ghrelin neurons in the arcuate nucleus and contribute to the regulation of UAG's central effects or vice versa. Together, the unidentified ghrelin receptor in the hypothalamus and hypophysis may be GnIH-R. Therefore, it is reasonable that ghrelin may act on both hypothalamus and hypophysis via GnIH-GPR147 system to block gonadotropin synthesis and secretion.