Fluoxetine Disrupts Ovarian Serotonin Signaling and Oocyte Competence in Mice
Nina M Alyoshina1, Maria V Beketova1, Maria D Tkachenko1
1Koltzov Institute of Developmental Biology, 26 Vavilov Street, Moscow 119334, Russia.
Abstract:
Background: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, yet their direct impact on ovarian function remains poorly understood. While serotonin signaling is known to occur within the ovarian follicle, the specific molecular consequences of its disruption by SSRIs are unclear. This study aimed to elucidate the direct, intra-ovarian mechanisms by which fluoxetine, a common SSRI, affects follicular development and oocyte competence. Methods: We administered fluoxetine (20 mg/kg) or vehicle daily for seven days to both prepubertal and adult female mice to model short-term therapeutic exposure. Results: Fluoxetine treatment successfully blocked peripheral serotonin uptake, reducing serum levels by over 90%. Crucially, this occurred without altering circulating levels of estradiol, FSH, or LH and without disrupting the estrous cycle, indicating a mechanism independent of the central hypothalamic-pituitary-gonadal axis. Instead, we pinpoint a direct ovarian effect: fluoxetine inhibited serotonin transport activity in oocytes and significantly downregulated the expression of the pivotal oocyte-derived growth factor Gdf9. This was accompanied by reduced expression of genes crucial for granulosa cell function (Lhr, Fshr) and steroidogenesis (Cyp19a1). Functionally, these molecular changes manifested as a decline in oocyte quality and a significant reduction in ovulation rates in adult mice. Notably, these detrimental effects were more pronounced in prepubertal mice, indicating a heightened vulnerability during early follicular development. Conclusions: Our findings reveal a direct, intra-ovarian mechanism of fluoxetine-induced disruption. By inhibiting oocyte serotonin transport and downregulating GDF9, fluoxetine impairs critical oocyte-granulosa cell communication, thereby compromising oocyte competence and reducing fertility outcomes. This work identifies follicular development as a critical window of susceptibility to SSRI exposure, holding significant clinical implications for reproductive-aged and adolescent populations.
Insights
Selective serotonin reuptake inhibitors (SSRIs) directly impact ovarian function by disrupting serotonin transport in oocytes. This impairs follicular development and reduces fertility, particularly in younger populations.
Area of Science:
- Reproductive Biology
- Endocrinology
- Pharmacology
Background:
- Selective serotonin reuptuptake inhibitors (SSRIs) are widely used, but their direct effects on ovarian function are not well understood.
- Serotonin signaling occurs in ovarian follicles, but the molecular impact of SSRI disruption is unclear.
Purpose of the Study:
- To investigate the direct intra-ovarian mechanisms by which fluoxetine affects follicular development and oocyte competence.
- To determine if fluoxetine's effects are mediated through the central hypothalamic-pituitary-gonadal axis or directly within the ovary.
Main Methods:
- Administered fluoxetine (20 mg/kg) or vehicle daily for seven days to prepubertal and adult female mice.
- Measured serum hormone levels (estradiol, FSH, LH), estrous cycle, oocyte serotonin transport, gene expression (Gdf9, Lhr, Fshr, Cyp19a1), and ovulation rates.
Main Results:
- Fluoxetine significantly reduced peripheral serotonin uptake (>90%) without altering systemic reproductive hormones or the estrous cycle.
- Fluoxetine inhibited oocyte serotonin transport and downregulated Gdf9 expression, impacting granulosa cell function and steroidogenesis.
- Oocyte quality declined, and ovulation rates were reduced, with more pronounced effects in prepubertal mice.
Conclusions:
- Fluoxetine exerts direct intra-ovarian effects by inhibiting oocyte serotonin transport and downregulating GDF9, disrupting oocyte-granulosa cell communication.
- This disruption compromises oocyte competence and fertility outcomes.
- Follicular development represents a critical window of susceptibility to SSRI exposure, with implications for reproductive-aged and adolescent populations.
