An appropriate functioning of the H2S releasing machinery is essential to the maturation of both male and female gametes and to embryo development.
Gametogenesis in women
Estrogens are a strong inducer of a main H2S generating enzyme, CSE. This has been proposed as a reason for the relative resistance of fertile women to cardiovascular damages, however the main function of this regulation is related to female gametogenesis.In vitro maturation experiments with porcine oocytes showed that a fall of H2S characterize the onset of oocyte ageing and that the application of H2S donors prevents this ageing. Further experiments demonstrated that the antiageing effect is mediated by the ability of H2S to modulate KATP and Ca channels. In other experiments it was shown that the application of H2S donors triggered and improved porcine oocyte maturation in vitro. More recently, it was shown that the H2S generating system plays an important role in the propagation of the pre-ovulatory cascade and rupture of the follicle at ovulation, i.e. it is essential for final follicle and oocyte maturation.
Krejcova et al. Hydrogen Sulfide Donor Protects Porcine Oocytes against Aging and Improves the Developmental Potential of Aged Porcine Oocytes. PLoS One 2015; 10(1): e0116964. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116964
Nevoral J et al. Involvement of K+ATP and Ca2+ channels in hydrogen sulfide-suppressed ageing of porcine oocytes. Biol Res 2018; 51: 38. https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0716-97602018000100401
Nevoral J et al. Dual Effects of Hydrogen Sulfide Donor on Meiosis and Cumulus Expansion of Porcine Cumulus-Oocyte Complexes. PLoS One 2014; 9(7): e99613. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099613
Nevoral j et al. Endogenously produced hydrogen sulfide is involved in porcine oocyte maturation in vitro. Nitric Oxide Volume 51, 1 December 2015, Pages 24-35. https://www.sciencedirect.com/science/article/abs/pii/S1089860315300215
Estienne a et al. The endogenous hydrogen sulfide generating system regulates ovulation. Free Radic Biol Med 2019 Jul;138:43-52. https://pubmed.ncbi.nlm.nih.gov/30930295/
Gametogenesis in men
In the testes, the H2S producing CSE is localized in Sertoli cells and immature germ cells whereas CBS is expressed in Leydig cells, Sertoli cells and germ cells. It is pretty clear that H2S, in co-ordination with NO and CO, is a main regulator of testicular and spermatic function, although the specific mechanisms remain elusive. It was found that both subfertile and infertile patients, especially asthenospermic patients, exhibited decreased concentration of H2S in their seminal plasma and diminished expression of H2S-generating enzymes. The administration of H2S donors to oligoasthenospermic men resulted in a significant improvement of sperm number and motility.
H2S is also involved in the resistance of testes to the heat shock, which is involved into the damages from varicocele. Testicular heat exposure in mice caused a fall of the endogenous production of H2S. Moreover, the application of a H2S donor to testicular germ cell exposed to heat stress abrogated the apoptotic response and improved the mitochondrial bioenergetics. This was further confirmed by a varicocele rat model where the administration of a H2S donor prevented the testicular damages to a large extent.
The human seminal plasma is known to carry lymphocytes, including Treg type. These Tregs, possibly sperm antigen specific, pass to the women at time of coitus and are supposed to contribute to the generation of immune tolerance to the fetus in the women, thus contributing to implantation, and thereafter to expand during pregnancy to sustain over time such immune tolerance. H2S is a strong inducer of Treg differentiation and its function in the testes likely involves this immunotolerant imprint. Accordingly, a defective H2S activity may be involved in cases of couple infertility due to implantation failure or early miscarriage.
Morales Martinez Aet al. A randomized clinical study assessing the effects of the antioxidants, resveratrol or SG1002, a hydrogen sulfide prodrug, on idiopathic oligoasthenozoospermia. As Pac J Reprod 2015; 4(2): 106-111. https://www.sciencedirect.com/science/article/pii/S2305050015300051
Kadlec M et al. The Roles of NO and H2S in Sperm Biology: Recent Advances and New Perspectives. Int. J. Mol. Sci. 2020; 21: 2174. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139502/
Wang J et al. Hydrogen Sulfide As a Potential Target in Preventing Spermatogenic Failure and Testicular Dysfunction. Antiox & Redox Sign 2018;28(16): 1447–1462. https://www.liebertpub.com/doi/full/10.1089/ars.2016.6968
Li G et al. Hydrogen sulfide protects testicular germ cells against heat induced injury. Nitric Oxide 2015; 46: 165-171. https://www.liebertpub.com/doi/full/10.1089/ars.2016.6968
Ning J-Z et al. The protective effects of GYY4137 on ipsilateral testicular injury in experimentally varicocele‑induced rats. Exp Theraup Med 2018; 15: 433-439. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768093/
Tsuda S et al. New Paradigm in the Role of Regulatory T Cells During Pregnancy Front Immunol 2019; 10: Article 573. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443934/
Yang R et a. Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. Immunity 2015 Aug 18;43(2):251-63. https://pubmed.ncbi.nlm.nih.gov/26275994/02944017306041
The release of H2S is of paramount importance in the establishment of a pregnancy. Indeed the embryo exposes paternal antigens and may be recognised and attacked by the immune system. To avoid this and to allow embryo implantation, the uterus becomes immuno-tolerant by colonization from specialized white blood cells called regulatory T-lymphocytes (Treg). The critical differentiation of lymphocytes to the Treg type is indeed induced by the release of H2S. Therefore, it was postulated that failure of the H2S system in fertile women may be responsible for repeated implantation failure.
Besides immuno-tolerating the embryo/fetus, the placenta has the task to feed the embryo, which requires amounts of blood to flow through the placenta. This is possible by a massive and fast proliferation of blood vessels and any deficit in blood supply is known to result in pregnancy loss, which may happen at any stage of pregnancy. In natural human pregnancy the rise in uterine artery blood flow appears consequent to the VEGF-stimulated release of H2S by increased CBS expression in the endothelium. In the uterine artery, both CBS expression and H2S release have been demonstrated to be increased in the proliferative phase of non-pregnant women and in pregnant women as compared to the secretory phase of non-pregnant women, which strongly confirms a role in the uterine hemodynamics. Inasmuch, adequate H2S release is necessary for both the immunotolerance at time of implantation and for the proper development of uterine and placental vascularization allowing the maintenance of the pregnancy and the development of the fetus.
H2S keeps its pregnancy maintenance function up to the very end and at time of labor the fall of H2S exerts a permissive role. Accordingly, an inappropriate early fall of H2S may contribute to a pre-term labor and a supportive treatment may prevent it.
Yang R et a. Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. Immunity 2015 Aug 18;43(2):251-63. https://pubmed.ncbi.nlm.nih.gov/26275994/
Zhang H-H et al. Pregnancy Augments VEGF-Stimulated In Vitro Angiogenesis and Vasodilator (NO and H S) Production in Human Uterine Artery Endothelial Cells J Clin Endocrinol Metab. 2017; 102(7): 2382–2393. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505189/
Sheibani L et al. Augmented H2S production via cystathionine-beta-synthase upregulation
plays a role in pregnancy-associated uterine vasodilation Biol Reprod 2017; 96(3): 664–672. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505189/
Sun Q et al. Reduced Expression of Hydrogen Sulfidee Generating Enzymes Down-Regulates
15-Hydroxyprostaglandin Dehydrogenase in Chorion during Term and Preterm Labor. Am J Pathol 2018; 188(1): 63-71. https://www.sciencedirect.com/science/article/pii/S0002944017306041