Abstract
The process of reproduction necessitates a highly coordinated interaction between peripheral organs and the nervous system to create conditions conducive for the successful continuation of the species. Central to this coordination is the hypothalamic-pituitary-gonadal (HPG) axis, which integrates reproductive actions with the timing of ovulation. The primary neuroendocrine driver, gonadotropin-releasing hormone (GnRH), regulates anterior pituitary cells that secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). As ovarian follicles mature, they secrete estradiol, which acts to inhibit further GnRH and FSH secretion. When estradiol levels reach their peak, they trigger a positive feedback mechanism that induces a surge in GnRH release, stimulating an LH surge that causes ovulation. Moreover, GnRH release within the brain modulates reproductive behaviors, serving as a crucial regulatory node for reproduction. This review addresses key questions: how the HPG axis functions across species with differing reproductive strategies; the internal and external factors that influence GnRH synthesis and release; the ways GnRH affects reproductive behavior in the hypothalamus; and how pathological conditions alter HPG axis activity.
Keywords
HPG axis; GnRH; estradiol; LH surge
Introduction
The regulation of the hypothalamo-pituitary-gonadal (HPG) axis involves multiple layers of control, including peripheral hormone feedback and a sophisticated network of neurons and glial cells. Despite the fact that the ultimate neuroendocrine signal, gonadotropin releasing hormone (GnRH), is singular, its secretion is finely tuned by an interplay of diverse internal and external cues. Different species exhibit varying sensitivities to environmental factors; some primarily respond to photoperiod changes, while others are more affected by temperature shifts, olfactory signals, nutritional status, or auditory inputs. Additionally, internal modulators such as steroid hormone feedback and protein hormones contribute to this regulation. Overall, the integration of external environmental signals with internal hormonal cues converges on the GnRH system, which serves as the final common pathway converting these influences into reproductive function. This complex physiological control ensures that GnRH induces ovulation while simultaneously coordinating reproductive behaviors essential for successful procreation.
Female mammals experience a dynamic hormonal environment that fluctuates daily and can be disrupted by external factors. Although reproductive control mechanisms may vary in their reliance on external or internal inputs across species, estradiol synthesized by ovarian follicles remains a pivotal hormone. The production of estradiol in the ovaries is meticulously regulated through feedback loops involving the hypothalamus, anterior pituitary, and ovaries. This hormone modulates neural circuits by either suppressing or enhancing GnRH release, which in turn stimulates the pituitary to produce FSH or LH, promoting ovulation and associated reproductive behaviors.
In rodents, female sexual behavior is regulated by a neural circuit that integrates olfactory, hormonal, and environmental signals and is precisely synchronized with ovulation. The initial activation involves estradiol acting on the arcuate nucleus of the hypothalamus (ARH), which projects to the medial preoptic nucleus (MPN), a region that integrates olfactory and limbic inputs. This leads to activation of the ventromedial nucleus of the hypothalamus (VMH), which sends descending projections to the periaqueductal gray, vestibular complex, and ultimately motor neurons that govern reproductive behaviors. Various reproductive strategies have evolved based on environmental stimuli, yet all animals are exposed to stressors and diseases. This review explores how the LH surge that induces ovulation is regulated and dysregulated, the hypothalamic control of reproductive behavior, and how photoperiod and pathological states influence these neuroendocrine circuits.
Control of the LH Surge
The LH surge is initiated by a positive feedback mechanism triggered by a rapid elevation in plasma estradiol levels. In both rats and humans, the surge in LH release is influenced by the combined effects of estradiol and progesterone. During the early estrous cycle, low estradiol levels suppress the secretion of GnRH. However, as estradiol sharply increases during proestrus, this inhibition is lifted, causing GnRH release, which in turn induces LH secretion. The subsequent LH release stimulates ovarian production of progesterone. This release of GnRH is not a direct effect of estradiol acting on GnRH neurons; instead, it is mediated via intermediary neurons that express the neuropeptide kisspeptin. Kisspeptin has been identified as essential for stimulating GnRH secretion, with its receptor, GPR54, located on GnRH cells (reviewed in [1]). Micevych et al. (reviewed in [2]) describe two principal effects of estradiol on the female GnRH neural-glial network. Rising estradiol during diestrus induces progesterone receptor (PR) expression on kisspeptin neurons, which robustly activate GnRH neurons. At the peak of estradiol on proestrus, estradiol binds to membrane estrogen receptors (ERs) on astrocytes, leading to activation of metabotropic glutamate receptor 1a (mGluR1a), initiating rapid synthesis of neuroprogesterone (neuroP) ([2,3]). Locally produced neuroP stimulates kisspeptin neurons to release kisspeptin onto GnRH neurons, promoting GnRH secretion to the pituitary. Cabrera and colleagues propose an alternative mechanism where GnRH release is modulated by the neurosteroid allopregnanolone, synthesized from progesterone. Allopregnanolone enhances glutamate release, activating NMDA receptors on GnRH neurons, thereby strongly promoting GnRH secretion [4]. Neurosteroids may exert their effects both through classical receptors and by modulating ionic channels, such as GABA_A [5] and glutamate receptors [6], which rapidly alter neuronal excitability. Additional data show that GABAergic neurons may facilitate LH release [7] through modulation of catecholaminergic pathways controlling GnRH secretion. Cabrera et al.’s work further supports the physiological relevance of allopregnanolone via its action on NMDA receptors [4], demonstrating that its stimulatory effect on GnRH is blocked by the NMDA antagonist AP-7. The reduction in allopregnanolone’s effect on glutamate release also implies presynaptic NMDA receptor involvement at glutamatergic terminals. These proposed mechanisms—estradiol positive feedback through neuroP and allopregnanolone—are not mutually exclusive, as neuroP can be converted to allopregnanolone by enzymes present in astrocytes, such as 5-alpha reductase and 3-alpha hydroxysteroid oxidoreductase [5]. It is likely that both pathways contribute. Wu and colleagues highlight the complexity of GnRH regulation, focusing on GnRH-(1–5), a biologically active pentapeptide metabolite of GnRH consisting of its first five amino acids [8–12]. Previous experiments demonstrated that GnRH-(1–5) enhances GnRH mRNA expression in GT1-7 neuronal cells [12] and increases GnRH pulse amplitude in hypothalamic explants [13]. In contrast, intact GnRH exerts a negative autoregulatory effect on its own gene expression and peptide release, suggesting that these pentapeptide effects occur independently of the GnRH receptor (GnRH-R). Furthermore, GnRH-(1–5) can regulate reproductive behaviors [11]. This peptide is generated by the endopeptidase EP24.15 (thimet oligopeptidase), first identified in rat brain soluble fractions [14] and widely expressed across tissues [15–19]. EP24.15 activity is modulated by protein kinase A [19] and requires zinc as a cofactor due to its thermolysin-like metalloendopeptidase nature [20]. Its substrate specificity favors peptides under 17 amino acids without strict sequence preference, though hydrophobic residues in key positions increase affinity [21,22]. These findings confirm GnRH-(1–5)’s biological activity and underscore EP24.15’s role in extracellular peptide processing, adding a further regulatory layer to this complex neuroendocrine system.
In species with seasonal breeding patterns, non-reproductive hormones influence LH secretion. In avian species, it is proposed that changes in day length upregulate type 2 iodothyronine deiodinase (Dio2), which locally activates thyroid hormone in the mediobasal hypothalamus (MBH). Recent studies report that long photoperiods induce Dio2 expression, enhancing conversion of thyroxine (T4) into its more active form triiodothyronine (T3), resulting in a tenfold increase in hypothalamic T3 compared to short-day conditions [23]. Intracerebroventricular administration of T3 can trigger testicular growth in quail kept under short-day conditions. Additionally, the enzyme Dio3 (type 3 deiodinase), which inactivates thyroid hormones by converting T4 and T3 to inactive metabolites, shows high expression during short days and low expression during long days, while Dio2 exhibits the opposite pattern [24,25]. This reciprocal regulation amplifies thyroid hormone action and initiates neuroendocrine changes that precede GnRH release, though direct measurement of GnRH synthesis or secretion in this context is lacking. The mechanism linking local thyroid hormone regulation to GnRH activation remains unclear but may involve glial mechanical actions in the median eminence [26]. Further, a wave of gene expression including elevated thyrotropin (TSH) beta-subunit expression in the pars tuberalis has been identified 14 hours into a long day [27]. Central TSH administration to short-day quail stimulates gonadal growth and Dio2 expression, suggesting TSH’s involvement in photoperiodic regulation. However, some evidence indicates Dio2 may not be essential for photoperiodic responses, as thyroidectomized birds still show gonadal growth without circulating T4 for conversion to T3 [28]. Moreover, in certain wild songbird populations, LH secretion increases without Dio2 induction, suggesting population-specific variation in Dio2/Dio3 regulation [29]. Both northern and southern populations ultimately increase FSH mRNA and LH secretion despite differing Dio expression. These findings imply that Dio2/Dio3 regulation is not strictly necessary for GnRH or gonadotropin stimulation, highlighting ecological and evolutionary influences on reproductive timing.
Ovulation and Disease
Dysfunctional ovulation can arise in pathological states such as cystic ovarian disease (COD) in cattle, where elevated LH secretion is frequently observed. This condition reflects disturbances in the hypothalamic-pituitary-gonadal axis attempting to maintain hormonal balance. COD is marked by disrupted folliculogenesis and cyst formation within the ovaries, which correlate with altered expression patterns of estrogen receptors ERα and ERβ, androgen receptor (AR), and progesterone receptor (PR). Increased ERα expression occurs in granulosa and theca cells of cystic follicles, accompanied by decreased ERβ expression in cattle [30,31], rats [32], and humans [33]. Gonadotropins and estrogens downregulate granulosa ERβ isoforms [34,35], while both ER subtypes tend to be co-upregulated as follicular fluid estrogen rises, alongside increases in LH and FSH receptors [36]. ERα overexpression in mice causes downregulation of ERβ and leads to subfertility [37], suggesting the ERβ decrease in cystic follicles may be secondary to ERα upregulation. ERα knockout mice show anovulation but normal follicular recruitment and early differentiation, indicating ERα’s importance in later follicular growth stages, critical in COD pathology [38]. Progesterone receptors are predominantly expressed in bovine granulosa cells [39,40], but cystic follicles demonstrate higher PR expression in theca cells compared to healthy follicles [31]. Multiple PR isoforms, notably the 116 kDa PRb and 94 kDa PRa, possess distinct, cell- and promoter-specific transcriptional roles despite similar ligand and DNA binding affinities [41]. PRb is markedly increased in granulosa cells of cystic follicles [31]. Although selective ablation of PRb alone does not impair ovarian function, simultaneous knockout of PRa and PRb prevents ovulation [42]. Cattle with COD generally exhibit elevated circulating estrogen and LH levels [43], which may alter PR expression. A shift in PR isoform ratios could modulate progesterone activity, leading to functional hormone withdrawal without changes in circulating progesterone or total receptor-binding activity [44–47]. Ovaries from COD-affected animals display altered steroid receptor profiles compared to controls, and extensive evidence supports the presence of disrupted steroid signaling in cystic follicles. Therefore, changes in ovarian steroid receptor expression likely play a pivotal role in the pathogenesis of COD.
Reproductive Behavior
In female mammals, reproductive behavior is precisely timed to align with ovulation. Because reproduction often involves risks to the animal’s well-being, these risks become justifiable only during ovulation, when pregnancy is possible. The hormone estradiol, produced by developing ovarian follicles, initiates the activation of neural circuits responsible for receptive behavior. Within the arcuate nucleus of the hypothalamus (ARH), estradiol rapidly stimulates membrane estrogen receptor alpha (mERα) and subsequently transactivates metabotropic glutamate receptor 1 (mGluR1) [48]. Estradiol also increases dendritic spine density in both the ventromedial hypothalamus (VMH) and the ARH [49, 50]. This rise in spine density is crucial for modulating female sexual behavior [50]. The formation of estradiol-induced spines is believed to influence the timing of sexual responsiveness. When an ovariectomized rat receives a bolus of estradiol, it initially forms immature filopodial spines, which lack sufficient maturity for effective synaptic transmission. However, as time progresses and the female reaches sexual receptivity, these spines mature into fully functional, mushroom-shaped spines.
This synaptic remodeling underpins essential modifications in neuronal connectivity within the circuit regulating lordosis behavior. Experimental inhibition of spinogenesis in the ARH prevents females from expressing complete sexual receptivity. The interaction between ERα and mGluR1, known to be vital for reproductive behaviors [48], is also critical for estradiol-driven spinogenesis [50]. The actin depolymerizing factor cofilin undergoes rapid phosphorylation and inactivation during spinogenesis. Estradiol facilitates the phosphorylation of cofilin; however, when mGluR1 is blocked, estradiol fails to promote cofilin phosphorylation, leading to a reduction in new spine formation.
Conclusion
The control of reproduction is complex and involves multiple regulatory layers. It begins with the ovarian regulation, where the amount of estradiol secreted determines the system’s readiness to progress through fertility stages. The release of luteinizing hormone (LH) is controlled through several mechanisms. A critical threshold of estradiol must be surpassed, alongside the synthesis of progesterone and allopregnanolone by astrocytes in the mediobasal hypothalamus (MBH). These neurosteroids exert various effects but ultimately facilitate the release of gonadotropin-releasing hormone (GnRH) and, consequently, LH. Additionally, GnRH levels are fine-tuned by an enzyme that cleaves the hormone, thereby increasing its local concentration and release.
Ovarian diseases that disrupt sex steroid secretion cause disturbances throughout the hypothalamic-pituitary-gonadal (HPG) axis. Alterations in estradiol secretion interfere with the animal’s ability to generate the LH surge necessary for proper axis regulation. Indeed, any dysregulation along this axis results in impaired reproductive behaviors. Since ovulation is tightly linked to reproductive conduct, the estradiol responsible for stimulating LH release also modulates synaptic connections within the hypothalamus, enhancing the female’s sexual receptivity. Sexual behavior manifests only when the entire reproductive system is functional and primed for reproduction.
Seasonally breeding animals must recognize the correct period for reproduction, relying on internal changes triggered by shifts in day length. One possible mechanism involves the upregulation of the thyroid hormone-activating enzyme Dio2, which may prepare these animals for mating seasons. The regulation of reproduction involves an intricate network of central and peripheral systems integrating both internal signals and external environmental cues. Much has been uncovered about neurosteroids and enzymes that centrally govern GnRH release and the peripheral roles of steroids and their receptors. However, many questions remain open, such as the coordination of neuroprogesterone (neuroP) and allopregnanolone systems in GnRH regulation, whether steroid receptor loss in conditions like polycystic ovary disease (PCOD) is causal or consequential, and if similar receptor changes occur in other diseases or during reproductive aging. Furthermore, the timing of these changes remains unclear.
While neuroendocrinology has elucidated many physiological processes requiring brain-body coordination to adapt to the environment and ensure reproductive success, numerous critical questions are still unanswered. Resolving these issues is essential to understanding how the reproductive neuroendocrine axis integrates diverse signals to regulate fertility.
Acknowledgments
The author thanks the Westbridge University Research Fund for supporting this study. Special gratitude is extended to Dr. Thomas Bell for his insightful discussions and critical review of the manuscript.
Conflict of Interest
The author declares no conflicts of interest related to this research.
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