Along with luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH), human chorionic gonadotrophin (hCG) is a member of the family of glycoprotein hormones. These are all composed of the common α-subunit and a hormone-specific β-subunit. hCG is produced by trophoblast cells of the blastocyst, and later on, during pregnancy it is secreted in large amounts by differentiated syncytiotrophoblasts of the human placenta (Fishel et al., 1984; Fournier 2020). The human pituitary gland has also been demonstrated to produce trace levels of hCG (Hoermann et al., 1990). Additionally, advanced phases of neoplastic conditions such as colon, lung, bladder, pancreas, prostate, breast, and gonadal malignancies are linked to ectopic expression of hCGβ/hCG (Iles et al., 2010; Cole and Butler 2012; Fournier 2020; Jankowska and Szczerba, 2020).

At the initial phase of human gestation, hCG induces the corpus luteum of the ovary to produce progesterone, which is essential for the maintenance of pregnancy. Due to its similar action, but longer half-life, hCG is widely used as a highly active analogue of LH to induce ovulation in assisted reproduction and to stimulate gonadal steroidogenesis in hypogonadotropic men and women. It is now widely recognized that hCG has pleiotropic functional roles, not limited to modulating steroidogenesis, including local immune tolerance, angiogenesis, endometrial receptivity, and placental and fetal growth and differentiation (Zygmunt et al., 2002; Cole and Butler, 2012; Choi and Smitz, 2014; Theofanakis et al., 2017; Fournier 2020; Gridelet et al., 2020). Even though LH and hCG bind to the same G protein-coupled receptor (LHCGR), there are differences in the signalling pathways (Choi and Smitz, 2014; Casarini et al., 2018). Additionally, LHCGRs have been suggested to be localized to numerous fetal and adult extragonadal organs and in various tumours (Iles et al., 2010; Casarini et al., 2018). The physiological relevance of the extra-gonadal LHCGR expression remains unclear, while clinical and epidemiological studies have demonstrated a link between dysregulation of gonadotrophin secretion and action, and reproductive pathologies in both sexes (Pakarainen et al., 2007; Mandai et al., 2007; Choi et al., 2007; Casarini et al., 2018; Young et al., 2019).

Transgenic (TG) mouse models have provided further insights into the physiological role of gonadotrophins and their potential pathological effects in the hypothalamic-pituitary-gonadal axis, for example in the form of inducing gonadal granulosa cell tumours and luteomas (Risma et al., 1995; Rulli et al., 2002; Matzuk et al., 2003; Rulli and Huhtaniemi, 2005; Jonas et al., 2014). Teratomas belong to the most common types of ovarian tumours in humans, representing around 20% of tumours (Ulbright 2005), and are composed of differentiated ectodermal, mesodermal and endodermal tissues in a disorganized pattern. Even though the majority of teratomas are benign, their malignant transformation occurs at an incidence of approximately 1–2%, resulting most frequently in squamous cell carcinomas (Ulbright 2005). The pathogenesis of teratomas has usually been linked to aberrations of meiotic division, and also to defective folliculogenesis in a permissive genetic background (Colledge et al., 1994; Hashimoto et al., 1994; Eppig et al., 1996; Hsu et al., 1996; Thurisch et al., 2009; Youngson et al., 2011; Northrup et al., 2012; Yang et al., 2015; Naser et al., 2021). Even though epidemiological studies have revealed no causative factors, and genetic connections to the condition are weak, several reports have described the development of ovarian lesions and fast-growing cystic teratomas during pregnancy (Patacchiola et al., 2005; Donnadieu et al., 2006; Kumar et al., 2006). However, the association between endocrine disturbances and their aetiology in humans remains unknown.

To investigate the effect of chronically enhanced hCG action on ovarian physiopathology, we developed a TG mouse model overexpressing both the common alpha (hCGα) and hCGβ subunits under the ubiquitin C promoter, resulting in ubiquitous expression of the hormone.