Serotonin (5-HT) is one of the neurotransmitters involved in mood regulation and has been implicated in the development of mood and anxiety disorders.  Serotonin transporters (SERT) facilitate the transfer of serotonin into neurons; serotonin reuptake inhibitor (SSRI) antidepressants bind to these transporters and appear to exert their effect on mood by inhibiting the reuptake of serotonin and thus increasing the levels of this neurotransmitter at the synapse.

Serotonin is also present in the female reproductive organs of various species, including humans (Amenta et al, 1992, Il’kova et al, 2004, Amireault et al, 2005a, Sosa et al, 1988, Bodis et al, 1992a).  Different serotonin receptor subtypes exist in human oocytes (Nelson et al, 2000) and granulosa cells (Graveleau et al, 2000), the cells surrounding the growing oocyte.  Serotonin transporters have also been detected in mouse oocytes and early embryos (Amireault et al, 2005a).

In serotonin receptor knockout mice, genetically engineered so that the gene encoding for the serotonin receptor has been inactivated or “knocked out”, fertility and early embryonic development appear to be unaffected.  However, in knockout mice lacking tryptophan hydroxylase or TPH, an enzyme essential for the synthesis of serotonin, there was a reduction in the size of the embryos, suggesting that serotonin may play an important role in early embryonic development (Cote et al, 2007).

In other studies, the addition of serotonin to human granulosa cells leads to the production of progesterone and estrogen (Bodis et al, 1992b, Graveleau et al, 2000, Koppan et al, 2004). In a mouse model, depleting serotonin prior to gestation (day 0 to day 5) results in the inability to reproduce (Acharya et al, 1989).  On the other hand, the addition of serotonin during the pre-implantation stage leads to a reduction in the number of cells in the developing embryo (Ilkova et al, 2004, Vesela et al, 2003).

Taken together, these studies confirm that serotonin plays an important role in oocyte maturation and the early stages of embryonic development. Hence, one could hypothesize that the appropriate regulation of maternal serotonin levels is crucial to ensure fertility and normal embryonic development.  These studies may also lend support to the finding that mothers with depression, who presumably have some degree of serotonergic  dysregulation, are more likely to have low birth weight infants.

Thus far, no studies have explored how SSRIs may influence oocyte maturation, fertilization, implantation, or early embryonic development.   Future studies are clearly needed to clarify the roles of serotonin and the potential effects of SSRIs on early embryonic development.

Snezana Milanovic, M.D., M.Sc

 

References:

Acharya, S.B., Goswami, N.G., Debnath, P.K., 1989. Uterine and placental 5-HT profile in different gestational period of albino rats. Indian Journal of Experimental Biology 27 (6), 505–509.

Amenta, F., Vega, J.A., Ricci, A., Collier, W.L., 1992. Localization of 5- hydroxytryptamine-like immunoreactive cells and nerve fibers in the rat female reproductive system. Anatomical Record 233 (3), 478–484.

Amireault, P., Dubé, F., 2005a. Serotonin and its antidepressant-sensitive transport in mouse cumulus–oocyte complexes and early embryos. Biology of Reproduction 73 (2), 358–365.

Amireault, P., Dubé, F., 2005b. Intracellular cAMP and calcium signaling by serotonin in mouse cumulus–oocyte complexes. Molecular Pharmacology 68 (6), 1678–1687.

Bodis, J., Bognar, Z., Hartmann, G., Torok, A., Csaba, I.F., 1992a. Measurement of noradrenaline, dopamine and serotonin contents in follicular fluid of human graafian follicles after superovulation treatment. Gynecologic and Obstetric Investigation 33 (3), 165–167.

Bodis, J., Torok, A., Tinneberg, H.R., Hanf, V., Hamori, M., Cledon, P., 1992b. Influence of serotonin on progesterone and estradiol secretion of cultured human granulosa cells. Fertility and Sterility 57 (5), 1008–1011.

Côté, F., Fligny, C., Bayard, E., Launay, J.M., Gershon, M.D., Mallet, J., Vodjdani, G., 2007. Maternal serotonin is crucial for murine embryonic development. Proceedings of the National Academy of Sciences (USA) 104 (1), 329–334.

Il’kova, G., Rehak, P., Vesela, J., Cikos, S., Fabian, D., Czikkova, S., Koppel, J., 2004. Serotonin localization and its functional significance during mouse preimplantation embryo development. Zygote 12 (3), 205–213.

Graveleau, C., Paust, H.J., Schmidt-Grimminger, D., Mukhopadhyay, A.K., 2000. Presence of a 5-HT7 receptor positively coupled to adenylate cyclase activation in human granulosa-lutein cells. Journal of Clinical Endocrinology and Metabolism 85 (3), 1277–1286.

Koppan, M., Bodis, J., Verzar, Z., Tinneberg, H.R., Torok, A., 2004. Serotonin may alter the pattern of gonadotropin-induced progesterone release of human granulosa cells in superfusion system. Endocrine 24 (2), 155–159.

Neilson, L., Andalibi, A., Kang, D., Coutifaris, C., Strauss 3rd, J.F., Stanton, J.A., Green, D.P., 2000. Molecular phenotype of the human oocyte by PCR-SAGE. Genomics 63 (1), 13–24.

Sosa, A., Ortega-Corona, B.G., Chargoy, J., Vargas, J., Hernandez, O., Rosado, A., 1988. Presence of biogenic amines in human follicular fluid and seminal plasma. Acta Cientifica Venezolana 39 (3), 245–248.

Vesela, J., Rehak, P., Mihalik, J., Czikkova, S., Pokorny, J., Koppel, J., 2003. Expression of serotonin receptors in mouse oocytes and preimplantation embryos. Physiological Research 52 (2), 223–228.