Oogenesis is a complex process that is regulated by multiple factors both inside and outside of the ovary. The synthesis and accumulation of RNA and protein play a crucial to the growth, maturation, fertilization, and subsequent embryonic development of oocytes. Initially, primary oocytes are derived from oogonium through rapid mitosis. Subsequently, communication between oocytes and their surrounding granulosa cells (GCs) become important for the development of both the oocyte and the granulosa cells [1]. The interaction between oocytes and somatic cells controls the changes in the microenvironment within the follicle, which is essential for folliculogenesis and oocyte development. In the early stages of follicular development, cells are closely arranged, and direct contact between cells is the primary mode of interaction [2]. However, as the follicle develops, the presence of structures such as the follicular cavity makes it challenging to maintain direct contact communication between oocytes and somatic cells. Consequently, other cellular communication pathways, such as receptor-ligand interaction, receptor tyrosine kinase, intercellular contact via transzonal projections, and autocrine/paracrine factors, come into play to ensure effective communication between the cells [3]. These cellular communication models enable oocytes to influence the follicular microenvironment, thereby determining their own fate and providing the necessary conditions for subsequent oocyte development. Throughout follicle development, proteins derived from transforming growth factor-β (TGFβ) interact with the surrounding somatic cells, coordinating oocyte growth in a bidirectional manner. This bidirectional oocyte-somatic signaling undergoes changes over time, allowing follicle development to synchronize with oocyte maturation [4].

With more than 20 members, bone morphogenetic proteins (BMPs) form the largest subfamily of the TGFβ superfamily [5]. Among the family members of oocyte-derived BMPs, GDF9 and BMP15 are closely related in terms of expression patterns and function in the ovaries, and they interact with each other. Extensive research has been conducted on their biological and physiological activities, and their essential roles in female fertility have been identified in several mammalian species [[6], [7], [8], [9]]. In most species, the mRNA and proteins of GDF9 and BMP15 are founded only in oocytes, indicating that oocytes are the primary source of these factors [10,11]. As major secretory factors of oocytes, GDF9 and BMP15 bind to their respective receptors in the GCs, regulating downstream signaling cascade transduction [12]. In addition to significantly improving oocyte development, they can promote granulosa cell proliferation, inhibit granulosa cell apoptosis, support granulosa cell differentiation into cumulus cells, accelerate the expression of genes related to cumulus cell expansion, and regulate oocyte ovulation [[13], [14], [15], [16], [17]]. Moreover, GDF9 and BMP15 can form a stable heterodimer complex (named cumulin). Cumulin exhibits high biological activity on GCs, activates Smad2/3 and Smad1/5/8 signaling pathways, and promotes the expression of genes related to GCs differentiation. Compared to the homodimer, cumulin is more effective [11,18].

Estrogen, a crucial reproductive hormone in female mammals, plays a vital role in regulating various reproductive processes. It is a cholesterol derivative and a steroid female sex hormone that is synthesized in the ovaries, placenta, testes, and adrenal cortex. Estrogen is responsible for inducing and developing secondary sex characteristics [19]. The cellular receptors of estrogen are the key mediators of estrogen function, including the nuclear receptor family (estrogen receptors alpha, Esr1/ERα and estrogen receptors beta, Esr2/ERβ) and membrane receptor G-protein-coupled estrogen receptor (GPER) [20]. The physiology of estrogen and its receptors is particularly complex. The combination of estrogen and receptors can regulate the expression of target genes through classical genomic pathways as transcription factors. Additionally, they can also regulate various biological processes through non-classical pathways, which mediate the rapid conduction of intracellular signal cascades [[21], [22], [23], [24], [25], [26], [27], [28]]. Studies have demonstrated that both OSFs and estrogen are vital for the development and function of mammalian ovarian follicles, working together to regulate follicle development [29,30]. In the presence of oocytes, estrogen enhanced the biological effects of follicle-stimulating hormone (FSH)-induction in granulosa cells [30]. OSFs significantly influence estrogen-regulated biological processes in cumulus cells [29]. However, it remains unexplored whether paracrine oocyte factors regulate the effect of estrogen in cumulus cells by altering in the expression of estrogen receptors in cumulus cells. Therefore, the present study aims to investigate the specific mechanism through with paracrine factors influence the biological effects of estrogen in cumulus cells, utilizing the goat cumulus oocyte complexs (COCs) and oocytectomized complexes (OOXs) as experimental models.