The ovary, the organ housing female gametes, consists of ovarian follicles that serve as functional structures. Each follicle contains an oocyte surrounded by a stratified epithelium called the granulosa layer. Outside this layer lies a connective tissue layer, called the theca layer, enveloping the follicle. Both granulosa and theca cells provide nutrients and trophic support to the oocyte and produce steroid and peptide hormones that regulate various bodily functions. The process by which a follicle grows and matures is termed folliculogenesis or follicular development.

The follicle begins as an oocyte surrounded by a single layer of pregranulosa cells, forming what is known as the primordial follicle. The number of primordial follicles represents a female’s ‘follicular reserve,’ which reflects her potential reproductive capacity. In women, follicle formation occurs during gestation, while in rodents, during early postnatal life (until PND4) (1). These follicles are recruited for growth throughout life until depleted (2). The sequential transition of primordial follicles into primary, secondary, and tertiary (antral) follicles, with some selected to ovulate, is the process that determines reproductive capacity. After ovulation, the selected follicles transform into corpora lutea through the luteinization of granulosa and theca cells. All non-selected follicles are discarded via atresia, a controlled mechanism of cell death (2).

In the ovary, follicles and corpora lutea are embedded in a connective tissue rich in extracellular matrix, known as the stroma. The stroma is currently an active object of study for its diverse properties beyond just supporting the follicles. Blood vessels and nerves enter the ovary through the hilum and interweave within the stroma surrounding the follicles (3). Ovarian function, including follicle development and cyclic hormone production, relies on several internal feedback mechanisms (4), and environmental cues. In this sense, the sympathetic nervous system is a key player since it responds to various stimuli such as stress by cold exposure (5) or even the metabolic status of the body (6). In the following section, we will describe the sympathetic innervation of the ovary and provide an overview of the physiological action of this extrinsic ovarian innervation.

It is well established that the ovary is innervated by autonomic nerves. The parasympathetic nerves from the Vagus nerve innervate the blood vessels. However, there is also compelling evidence of a complete and functional intracrine cholinergic system within the organ (7). In rats, sympathetic nerves reach the ovary primarily through the superior ovarian nerve (SON) and the ovarian plexus (OP) (8). The SON emerges from the suprarenal ganglion, but the SON also communicates with the ovaries through the celiac ganglion (CG), superior mesenteric ganglion (SMG), and stellate ganglion (SG), suggesting that both autonomic and sensory information from the ovaries is processed in these three ganglia (8).

Adrenergic receptors are present in the ovarian blood vessels and the follicular structures. While α-1 adrenergic receptor predominates in blood vessels, β-2 adrenergic receptors are mainly found in granulosa or luteinized cells (9). Sympathetic nerves and adrenergic receptors in the rat ovary are present from neonatal age; however, the entire functional development of these nerves occurs near puberty (10). In this sense, before puberty, sympathetic nerve release is basal and calcium-independent, while after puberty, the norepinephrine release is mostly vesicular and calcium-dependent.

Several in vitro, ex vivo and in vivo studies have demonstrated that adrenergic receptor pharmacological activation or blockade can modify sex hormone secretion in the ovary. For example, incubation of ovaries with the selective β-2 adrenergic agonist terbutaline increases cAMP production and induces progesterone secretion. This effect is inhibited by propranolol, a non-selective β-adrenergic antagonist, and butoxamine, a selective β-2 adrenergic antagonist, but not by practolol, a selective β-1 adrenergic antagonist (11). Additionally, isoproterenol, a non-selective β-adrenergic agonist, amplifies the response of theca-interstitial cells to hCG, thereby increasing the release of androstenedione (12).

The sympathetic nervous system (SNS) profoundly influences the regulation of follicular development. Initially, follicle development is independent of gonadotropins. Instead, neurotransmitters such as norepinephrine and vasoactive intestinal peptide (VIP) stimulate the expression of follicle-stimulating hormone receptors (FSHR) in small follicles, priming them for subsequent recruitment by FSH (13). The guanethidine-mediated sympathetic denervation alters follicle dynamics by retarding the progression of follicles, leading to abnormal estrous cycles (14). Also, the surgical denervation of the SON leads to abnormal follicle development and impaired steroid production (15). This underscores the critical role of the sympathetic nervous system in these crucial aspects of ovarian function.

In an early study conducted by Gerendai et al., using retrograde viral tracers, the authors mapped a complex neural pathway that originates in the hypothalamus, descends through the brainstem and spinal cord, and ultimately innervates the ovarian tissue via postganglionic sympathetic nerves. The study involved the injection of the pseudorabies virus into the ovary, followed by an examination of the spinal cord and brain for infected neurons. Virus-labeled nerve cells were identified using immunocytochemical techniques, revealing a polysynaptic neural route that connects the ovary to the central nervous system (CNS) and providing insights into the CNS cell groups responsible for regulating the activity of ovarian innervation (16). Interestingly, the hypothalamus, specifically the paraventricular nucleus (PVN), is one of the regions of the brain that were extensively immunolabelled, showing that PVN neurons regulate the sympathetic innervation to the ovary. The PVN is a highly integrative nucleus weighing the magnitude of different external stimuli to integrate a physiological response through the sympathetic nervous system.

The PVN is a crucial region that regulates SNS activity. Often referred to as the “autonomic master controller” (17), the PVN contains two central neuronal regions: magnocellular and parvocellular. Magnocellular neurons project the posterior pituitary gland and secrete hormones such as oxytocin and vasopressin directly into the bloodstream. In contrast, parvocellular neurons can be divided into two distinct populations. One group consists of neurosecretory cells that project to the median eminence, where they release neuropeptides like corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) into the hypothalamic-pituitary portal system. The other is the parvocellular population, which includes pre-autonomic cells that project to the medulla and spinal cord, allowing them to regulate autonomic nervous system functions (18). Some parvocellular neurons in the PVN also synthesize and release oxytocin and vasopressin (19, 20).

The PVN parvocellular neurons project to several pre-autonomic relay stations, such as the motor pressor nucleus of the rostral ventrolateral medulla (RVLM) and the Nucleus of the solitary tract (NTS). These second-order neurons in the RVLM connect with sympathetic preganglionic neurons (SPNs) in the thoracic and lumbar intermediolateral nucleus (IML) and from there to the SNS nerves in the kidneys and cardiovascular system (21, 22). Although most of the pre-autonomic neurons in the paraventricular nucleus (PVN) project to the RVLM and then to the IML (22) some of them connect directly the NTS. Mutual connections exist between the PVN and the NTS, which can control RVLM activity (23). The NTS is also involved in parasympathetic control, and evidence supports the role of PVN in controlling the RVLM by inhibiting parasympathetic effects, resulting in increased sympathetic output (24). Some spinally projecting pre-autonomic neurons (SPANs), project directly to the intermediolateral spinal columns in the IML, a central integration center and origin of motor sympathetic preganglionic neurons (SPNs) that descend ipsilaterally through the brainstem and spinal cord (21, 22, 25). The last group of pre-autonomic parvocellular neurons from the PVN innervates SPNs in the IML and sends collaterals to the RVLM, potentially having a dual role in controlling SNS output (22).

The PVN plays a role in the polysynaptic pathway that controls ovarian sympathetic innervation, which is of particular significance. This function emphasizes the broad influence of PVN on physiological processes. Specifically, thyrotropin-releasing hormone (TRH)-expressing neurons within the PVN are essential for mediating the activation of sympathetic nerves innervating the ovary (26–29). Hypothalamic manipulation of ceramides during early life in the PVN influences ovarian function without affecting GnRH control but instead influences changes in the maturation of the sympathetic nervous system in the ovary (30). This role of the PVN in controlling ovarian sympathetic innervation is a key area of research in the field of neuroendocrinology, and its implications are far-reaching.

The hypothalamic PVN receives diverse inputs from various brain regions, including the prefrontal cortex, amygdala, locus coeruleus, and hippocampus, as well as other hypothalamic nuclei such as the arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and lateral hypothalamic area (LHA) (17, 20). These inputs relay information about the bodily physiological state to the PVN. The ARC plays a central role in sensing and integrating metabolic signals related to the body’s energy status and nutrient availability (31). Two key neuron populations within the ARC detect and relay this information. POMC/CART neurons, which express pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, are activated by signals of energy sufficiency, such as elevated levels of nutrients and hormones like leptin and insulin. Activation of POMC/CART leads to the release of the neurohormone alpha-Melanocyte-stimulating hormone (α-MSH) in the PVN, promoting satiety, suppressing appetite, and increasing the activity of sympathetic nerves (32, 33). In contrast, NPY/AgRP neurons, which express neuropeptide Y and agouti-related peptide, are activated by signals of energy deficiency, such as low levels of nutrients and hormones. Activation of NPY/AgRP neurons stimulates appetite, promotes food-seeking behaviors, and decreases cardiovascular sympathetic activity and thermogenesis (34, 35). Taking together, through activating POMC/CART neurons or inhibiting NPY/AgRP neurons, leptin, insulin or other signals could activate TRH-ergic and other neurons in the PVN, which may impact the sympathetic regulation of the ovary.

It is well known that polycystic ovary syndrome (PCOS) in humans is associated with increased sympathetic nervous system activity and a heightened cardiovascular risk. In animal models of PCOS, which can be induced by early administration of androgens or estrogens, an increase in the activity of ovarian sympathetic nerves has been observed (75, 76). Notably, denervation of the sympathetic nerves to the ovaries can partially restore ovulation, improve estrous cyclicity, and enhance follicle development (77). Additionally, insulin resistance and leptin resistance, along with hyperleptinemia and hyperinsulinemia, are also present in animal models of PCOS (74, 78, 79). Consequently, elevated levels of leptin and compensatory hyperinsulinemia may lead to increased activity in the sympathetic nerves that innervate the ovaries. Moreover, interventions such as weight loss, regular physical exercise, metformin, and GLP-1 agonists have demonstrated favorable outcomes in enhancing follicle development, promoting ovulation, and alleviating the symptoms associated with PCOS (80–84). All of these treatments improve insulin sensitivity, leading to decreased insulin and leptin levels due to a reduction in body fat. However, it remains uncertain whether these improvements also reduce sympathetic activity in the ovaries or other organs. In summary, these insights emphasize the need for further research to determine whether the modulation of sympathetic nerve activity through lowered leptin or insulin levels plays a central role in the effects of these treatments.

In the complex relationship between metabolism and reproduction, leptin plays a crucial role in regulating how metabolism affects reproduction by controlling the endocrine HPG axis. Our proposal suggests that leptin also influences the sympathetic innervation of the ovary, leading to increased neural activity. This implies that in cases of obesity, leptin’s altered control of the SNS could significantly impact ovarian function and contribute to conditions like PCOS. Additionally, early exposure to obesity or overfeeding may raise leptin levels during early development, potentially changing the relationship between the hypothalamus and SNS. This could result in an increased susceptibility to chronic diseases in offspring due to overactivation of the SNS.