Human Chorionic Gonadotropin and Early Embryogenesis: Review

Human chorionic gonadotropin (hCG) has four major isoforms: classical hCG, hyperglyco- sylated hCG, free β subunit, and sulphated hCG. Classical hCG is the first molecule synthesized by the embryo. Its RNA is transcribed as early as the eight-cell stage and the blastocyst produces the protein before its implantation. This review synthetizes everything currently known on this multi- effect hormone: hCG levels, angiogenetic activity, immunological actions, and effects on miscarriages and thyroid function

What's new at the maternal-foetal interface: role of the hCG/LH-hCG receptor couple during embryo implantation

peer reviewedImplantation of the embryo into the maternal endometrium represents a unique biological process, combining an immunological (tolerance of an allograft) and biological (adhesion of two epitheliums) paradox. The success of implantation depends on a receptive endometrium, a functionally normal blastocyst and a synchronized cross-talk between embryonic and maternal tissues. Though sexual steroids control the process, a cascade of growth factors or cytokines are the prime paracrine mediators of the dialogue at the maternal-embryonic interface. HCG is one of the molecules most precociously produced by the embryo and is the most specific marker of its presence. HCG is a luteotropic factor which relays the inadequate support provided by the reduced rates of LH, but also influences the pregnancy on a paracrine mode by a local action on implantation process, probably by interacting with its receptor, the LH/hCG-R that we have evidenced on endometrial epithelium. We demonstrate that embryo actively participate into its implantation, tolerance and placentation

Restoration of Fertility in Patients with Spontaneous Premature Ovarian Insufficiency: New Techniques under the Microscope.

Premature ovarian insufficiency (POI), a condition affecting up to 1% of women by the age of 40 years, is characterized by an extremely low chance of spontaneous pregnancy. Currently, fertility restoration options are virtually nonexistent for this population. To become pregnant, the only solution is egg donation. Interestingly, animal studies have provided encouraging results in terms of fertility restoration, and consequently, research has begun into the most promising approaches for women suffering from POI. The PubMed database was searched for studies in which techniques aiming at restoring fertility in women with spontaneous POI were tested. Although robust studies are lacking, the literature suggests a positive effect of certain techniques on fertility restoration in women with POI. The most promising approaches seem to be intraovarian injection of autologous platelet-rich plasma or of mesenchymal stem cells. In addition to these, in vitro and mechanical activation of dormant follicles and etiology-driven therapies have also been studied with mixed results. No safety concerns were raised in these studies. The absence of robust studies does not allow us to draw meaningful conclusions on the efficacy or superiority of any single technique at this stage, and so research in this area should continue using robust study designs, i.e., multicenter randomized controlled trials including sufficient subjects to achieve statistical power

Human endometrial epithelial cells modulate the activation of gelatinase a by stromal cells.

peer reviewedMetalloproteinases (MMPs) are central effectors in endometrial physiology. Their production is tightly regulated by ovarian steroids and cytokines. Using zymography, we investigated MMP-2 production by human endometrial cells treated with estradiol-17beta + progesterone (E(2)+P) and by various key cytokines in endometrial physiology (IL-1beta, LIF, TGF-beta, and TNF-alpha). No gelatinase activity was detected in the culture media of epithelial cells. In basal conditions, stromal cells produced the pro form of MMP-2. MMP-2 production/activation was not directly affected by cytokine treatment. Interestingly, activated MMP-2 was only detected after treatment of stromal cells with culture medium from epithelial cells. Cytokine treatment of epithelial cells increased the capacity of conditioned medium to stimulate stromal cells to activate MMP-2. As the tissue inhibitor of MMP-2 (TIMP-2) is a regulator of gelatinase A activity, its concentration was measured by ELISA. TIMP-2 production by stromal cells was not affected by cytokines or by epithelial cell-conditioned medium. These results strongly suggest that regulation of stromal MMP-2 activation involves soluble factor(s) derived from the epithelial compartment

Impact of laser-assisted hatching on pregnancy rate in fresh and frozen-thawed cycles

peer reviewe

Human endometrial leukemia inhibitory factor and interleukin-6: control of secretion by transforming growth factor-beta-related members.

peer reviewed[en] OBJECTIVE(S): The implantation process is closely linked to the fundamental question of the tolerance of the maternal immune system. The main objective of this study was to investigate whether different members of the transforming growth factor-beta (TGF-beta) superfamily could intervene in the first steps of embryo implantation by modulating the secretion of proimplantatory leukemia inhibitory factor (LIF) and in the tolerance of the fetal graft by regulating proinflammatory interleukin (IL)-6 secretion by human endometrial epithelium (EEC) in vitro. METHODS: EEC were isolated from biopsies collected from 16 informed and consenting fertile women and were cultured for 72 h. Cytokine measurements (LIF and IL-6) were realized by ELISA. RESULTS: TGF-beta(1) (from 10(-12) to 10(-8)M), -beta(2), -beta(3) and activin A (10(-10) and 10(-8)M) increased LIF secretion by EEC cultures. Inhibin B (10(-10) and 10(-8)M) did not stimulate LIF production by human EEC. Contrastingly, TGF-beta(1) (from 10(-12) to 10(-8)M), -beta(2), -beta(3) and activin A (10(-10) and 10(-8)M) reduced IL-6 release by the same cells. Activin A at 10(-8) M also significantly reduced the stimulating effect of IL-1beta (10(-9)M) which is known to stimulate LIF production by EEC. Only the highest concentration of inhibin B (10(-8)M) reduced IL-6 secretion by EEC, but did not modulate IL-1beta-induced stimulation of IL-6 secretion. CONCLUSION(S): Besides their role in the control of the process of implantation and in the induction of embryonic mesoderm, different members of the TGF-beta superfamily may also contribute in the reproductive process by enhancing endometrial proimplantatory LIF secretion and reducing proinflammatory IL-6 release by EEC

Azoospermie non obstructive : auto-immunité, génétique, histologie testiculaire et résultats d’une prise en charge endocrinienne dans une série prospective de 29 patients

peer reviewedIntroduction : L’azoospermie non obstructive (NOA) est l’absence de spermatozoïdes dans l’éjaculat, secondaire à une anomalie de la spermatogenèse. L’étiologie de cette atteinte est souvent méconnue. Patients et Méthodes : Depuis 2020, nous suivons une série de 29 hommes( (32 ans) avec NOA, consultant pour une infertilité primaire. Ils ont bénéficié d’un bilan endocrinien et urologique, incluant une échographie testiculaire, un spermogramme, une bactériologie et une sérologie virales. Une première étude du caryotype, CFTR et micro délétions AZF(29 patients) a été suivie d’un panel de 130 gènes d’hypogonadisme (10 patients). Résultats : Une auto-immunité thyroïdienne a été retrouvée chez 14/29. Des anomalies génétiques sont présentes chez 11/29 cas incluant : XXY (1cas), délétion AZF (2cas), CFTR (2 cas), une mutation hétérozygote connexine 30-26, associant une surdité congénitale (1 cas), 2 mutations non décrites du récepteur aux androgènes, une mutation SRD5A2, maladie de Wilson (1cas), CYP21A2 (1cas). L’histologie testiculaire retrouve un arrêt de la spermatogenèse chez 11/14 cas et un Sertoli only syndrome chez 3/14 cas, avec une orchite localisée (auto-immune ?) chez 2 cas. Après stimulation de 3 à 6 mois par clomifène 50 mg/j (26 cas), létrozol 2.5mg/j (5 cas), et supplémentation par hydrocortisone (1 cas) ou lévothyroxine (13 cas), on observe à ce jour une faible production de spermatozoïdes chez 6/29 patients. Conclusions : L’auto-immunité et les causes génétiques incluant la voie des androgènes sont des mécanismes sous-estimés chez les patients avec NOA. Une prise en charge endocrinienne est susceptible d’améliorer la fertilité chez des patients soigneusement étudiés.Introduction: Non-obstructive azoospermia (NOA) is the absence of spermatozoa in the ejaculate, secondary to an abnormality of spermatogenesis. The etiology of this disease is often unknown. Patients and Methods: Since 2020, we followed a series of 29 men (with NOA, consultant for primary infertility). They underwent an endocrine and urological assessment, including testicular ultrasound, spermogram, bacteriology and viral serology. A first study of karyotype, CFTR and AZF microdeletions (29 patients) was followed by a panel of 130 hypogonadism genes (10 patients). Results: Thyroid autoimmunity was found in 14/29 patients. Genetic abnormalities were present in 11/29 cases including: XXY (1 case), AZF deletion (2 cases), CFTR (2 cases), a heterozygous connectin 30-26 mutation, associating congenital deafness (1 case), 2 undescribed androgen receptor mutations, an SRD5A2 mutation, Wilson's disease (1 case), CYP21A2 (1 case). Testicular histology showed arrest of spermatogenesis in 11/14 cases and Sertoli only syndrome in 3/14 cases, with localized orchitis (autoimmune?) in 2 cases. After stimulation of 3 to 6 months with clomiphene 50 mg/day (26 cases), letrozol 2.5 mg/day (5 cases), and supplementation with hydrocortisone (1 case) or levothyroxine (13 cases), low sperm production has been observed to date in 6/29 patients. Conclusions: Autoimmunity and genetic causes including the androgen pathway are underestimated mechanisms in patients with NOA. Endocrine management has the potential to improve fertility in patients who have been carefully studied

Human chorionic gonadotropin and growth factors at the embryonic-endometrial interface control leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) secretion by human endometrial epithelium

peer reviewedBACKGROUND: The elucidation of the molecular mechanisms by which the embryo contributes to its implantation is an area of extensive research. The main objective of this study was to investigate the pattern of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) secretion by human endometrial epithelium, and their regulation by human chorionic gonadotropin (hCG) and other growth factors present at the embryonic-endometrial interface. METHODS: Endometrial epithelial cells (EEC) were isolated from biopsies collected at both proliferative and secretory phases of fertile women. RESULTS: HCG (1-50 IU/ml) increased LIF secretion by EEC cultures derived from follicular phase (up to 285+/-75%) or from secretory phase (up to 212+/-16%). In contrast, hCG reduced IL-6 secretion by EEC in both phases. The hCG/LH receptor gene was transcribed by EEC as evidenced by RT-PCR. Insulin-like growth factors 1 and 2 increased LIF secretion by EEC. Transforming growth factor beta1 stimulated LIF and reduced IL-6 secretion. CONCLUSIONS: Through hCG, the blastocyst may be involved in the control of its implantation (via an increase of proimplantatory LIF) and tolerance (via an inhibition of proinflammatory IL-6). Other growth factors present at the embryonic-endometrial interface are also involved in the control of LIF and IL-6 endometrial secretion

Implantation: the first maternal-embryo crosstalk

peer reviewedImplantation : the first maternal-embryo crosstalk. Despite progress in assisted reproduction technologies, the lack of control of implantation remains a major obstacle to obtain successful pregnancies. It is of prime importance to determine the characteristic features of a receptive endometrium. Embryo implantation is a complex event involving apposition followed by the adhesion of the blastocyst to the maternal endometrium, and finally the invasion of this endometrium. Though implantation could occur in any human tissue, the endometrium is the only tissue where embryo implantation cannot occur except during a restricted period called the “implantation window”. During this window, the endometrium is highly receptive to the embryo. Maternal-embryo crosstalk is favored by the implantation window. The molecular basis of the implantation window remains to be defined In the present study, we investigated the role of hCG, TGFß1, IGF1 and IGF2 in the secretion of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) by human epithelial endometrial cells in culture. Epithelial endometrial cells were obtained from endometrial biopsy in 28 fertile women. HCG and TGFß1 added to primary cultures of human epithelial endometrial cells showed a stimulatory effect on LIF secretion and a reducing effect on IL-6 secretion. All these findings suggest a role for hCG and TGFß1 in human embryo implantation