Reproductive issues in dairy cattle directly impact production efficiency and farm profitability [1]. Conditions such as anestrus, repeat breeding, and delayed conception are especially prevalent during early lactation, when physiological and metabolic demands are highest [2]. Globally, ovarian hypofunction (OH) affects approximately 10%–30% of postpartum dairy cows, with higher prevalence in intensive production systems and during early lactation. Regional studies in developing dairy sectors report rates exceeding 35% under suboptimal nutritional and management conditions [3]. These disorders prolong the calving interval, reduce conception rates, and increase the costs of insemination and reproductive care, ultimately lowering the economic efficiency of dairy production systems [4].

OH is a major contributor to reproductive disorders in dairy cows, characterized by reduced ovarian activity that prevents dominant follicle development and normal ovulation [5]. This condition is closely associated with hormonal imbalance and metabolic disturbances during the transition period, when energy requirements rise sharply to support the onset of lactation [6]. During this phase, cows frequently experience negative energy balance (NEB), leading to excessive fat mobilization and increased circulating concentrations of non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHBA) [7, 8].

Beyond its direct effects on ovarian function, metabolic imbalance also has profound consequences for uterine health [9]. Reduced estrogen concentrations associated with OH decrease myometrial contractility and impair uterine defense mechanisms, increasing the risk of retained lochia, delayed uterine involution, and subclinical endometritis [10]. Economically, reproductive inefficiency linked to OH and uterine inflammation can result in losses ranging from tens to several hundred US dollars per affected cow per lactation, mainly due to extended days open, increased veterinary interventions, and reduced lifetime productivity [11, 12].

From a contemporary physiological perspective, immunometabolism provides a unifying framework for maintaining reproductive homeostasis by linking metabolic status with immune regulation [13]. Metabolic stress and postpartum inflammation can disrupt immune signaling in both the uterus and ovaries [14], making correction of this immune–metabolic imbalance essential for restoring reproductive function in dairy cows [15].

One non-hormonal strategy receiving increasing attention is uterine flushing therapy. This procedure involves flushing the uterine lumen with physiological or immunonutritional solutions to remove inflammatory exudates, improve endometrial perfusion, and modulate local immune responses [16]. Unlike conventional hormonal treatments that primarily induce ovulation, uterine flushing targets the uterine environment itself, with improvement in ovarian activity considered a secondary consequence of restored uterine–ovarian communication. This approach is particularly attractive for on-farm application because of its practicality and minimal interference with systemic hormonal balance [17].

Despite extensive research on postpartum reproductive disorders in dairy cows, most studies have examined OH, uterine disease, metabolic stress, and immune responses as separate entities. Existing reviews typically focus on endocrine control of ovarian activity, clinical aspects of endometritis, or nutritional management of transition cows, but rarely integrate these components into a unified physiological framework. In particular, the mechanistic links through which metabolic stress and immune activation simultaneously influence uterine recovery and ovarian reactivation remain insufficiently synthesized. Furthermore, while uterine flushing therapy has been reported as a practical non-hormonal intervention for improving uterine health, its role is often discussed primarily from a mechanical or clinical standpoint, with limited emphasis on its potential immunometabolic effects or its indirect influence on ovarian function. The lack of an integrative perspective combining metabolic biomarkers, immune signaling pathways, uterine–ovarian crosstalk, and supportive non-hormonal interventions represents a significant knowledge gap. Addressing this gap is essential for developing physiologically oriented and sustainable reproductive management strategies that move beyond symptom-based hormonal treatments toward mechanism-driven herd-level approaches.

Therefore, this narrative review aims to provide a comprehensive synthesis of current evidence on the bidirectional interactions between ovarian function and uterine health in dairy cows within an immunometabolic framework. Specifically, the review seeks to (i) summarize the endocrine, metabolic, and inflammatory mechanisms underlying postpartum OH and uterine dysfunction; (ii) elucidate how metabolic stress and immune dysregulation mediate crosstalk between the uterus and ovaries during the transition period; (iii) evaluate the biological rationale, physiological effects, and practical applications of uterine flushing therapy as a complementary non-hormonal intervention; and (iv) highlight the role of immunometabolic biomarkers and supportive management strategies in improving reproductive efficiency. By integrating these aspects, the review intends to present a coherent conceptual model linking metabolic status, immune regulation, and reproductive performance, thereby supporting evidence-based and sustainable approaches to fertility management in modern dairy production systems.

In dairy cows, ovarian function is regulated through coordinated interactions among the hypothalamic–pituitary–ovarian (HPO) axis, metabolic signals, and the animal’s physiological status [18]. The ovaries control estrous cyclicity, ovulation, and steroid hormone production, all of which are essential for fertility [19]. This section focuses on regulatory mechanisms relevant to postpartum ovarian recovery and dysfunction rather than providing a detailed description of estrous cycle phases.

Under normal postpartum conditions, ovarian cyclicity typically resumes within 20–40 days after calving, marked by dominant follicle emergence and first ovulation. In well-managed herds, regular luteal activity and estrous cycles are generally re-established by 40–60 days postpartum [20]. Delays beyond this period represent a significant deviation from normal physiology and are strongly associated with OH, NEB, and concurrent uterine inflammation, as discussed in later immunometabolic sections [21].

Follicle-stimulating hormone (FSH) initiates follicular development by stimulating a cohort of antral follicles [22]. Selection of the dominant follicle is accompanied by increased estradiol (E2) and inhibin secretion, which suppresses further FSH release [23]. Rising estradiol concentrations trigger the preovulatory luteinizing hormone (LH) surge, leading to ovulation and corpus luteum (CL) formation [24]. The CL secretes progesterone (P4), which supports luteal function and prepares the uterus for embryo implantation [25]. Physiologically, circulating progesterone concentrations exceed approximately 1 ng/mL during the functional luteal phase, whereas estradiol peaks during follicular dominance.

Postpartum OH is characterized by deviations from this physiological pattern, including persistently low estradiol concentrations, reduced LH pulse frequency, attenuated or absent LH surges, and delayed or insufficient progesterone secretion. These changes reflect impaired follicular growth and luteal insufficiency and frequently coexist with metabolic and inflammatory disturbances typical of early lactation [26].

Metabolic status plays a pivotal role in modulating ovarian responsiveness [27]. During early lactation, dairy cows commonly experience NEB due to increased energy demands for milk production [28]. This condition is associated with reduced circulating insulin and insulin-like growth factor-1 (IGF-1), both of which are critical for granulosa cell proliferation and estradiol synthesis [29]. Altered leptin signaling during NEB further compromises hypothalamic gonadotropin release, impairing follicular maturation [30]. These metabolic signals form a key link between nutrition and reproductive endocrinology and are further elaborated in Section 4 on immunometabolic ovary–uterus interactions.

Parity and genetic background also influence postpartum ovarian recovery. Compared with primiparous cows, multiparous high-producing cows often experience deeper and more prolonged NEB, increasing susceptibility to delayed ovulation. Likewise, high-yielding breeds such as Holstein–Friesian cattle are more vulnerable to metabolic stress–induced ovarian dysfunction than dual-purpose or indigenous breeds, which typically exhibit greater metabolic resilience [31].

Disruption of metabolic–endocrine balance ultimately leads to OH, defined by reduced follicular activity or failure to ovulate [32]. Oxidative stress and low-grade systemic inflammation, common during the postpartum period, play central roles in this process [33]. Excessive reactive oxygen species (ROS) production damages granulosa cells and suppresses FSH and LH receptor expression [34]. In parallel, proinflammatory cytokines such as TNF-α and IL-6 interfere with steroidogenesis and promote follicular atresia, linking immune activation to endocrine suppression [35]. Elevated NEFA and BHBA further exacerbate ovarian dysfunction through direct cytotoxic effects on oocytes and somatic ovarian cells, reinforcing the immunometabolic mechanisms discussed in subsequent sections [36].

OH is one of the most prevalent reproductive disorders affecting dairy cows during the early postpartum period [37]. Clinically, it manifests as prolonged anestrus and ovulation failure resulting from impaired endocrine signaling, metabolic imbalance, and ovarian follicular inactivity [38]. Rather than representing an isolated ovarian disorder, OH reflects a multisystem disturbance involving neuroendocrine regulation, energy metabolism, immune activation, and oxidative stress [39].

OH is typically diagnosed in cows that fail to resume ovarian cyclicity beyond 40–60 days postpartum in the absence of overt uterine pathology [40]. Practical assessment relies on repeated transrectal ultrasonography showing the absence of a functional CL, small or static follicles (<8 mm), and persistently low circulating progesterone concentrations (<1 ng/mL) [41, 42]. These indicators help differentiate OH from other postpartum reproductive conditions and align pathophysiological mechanisms with field-level diagnostic tools.

Immunometabolism refers to the integrated regulation of metabolic processes, immune function, and endocrine signaling in maintaining physiological homeostasis, including reproductive performance [58]. In dairy cows, immunometabolic balance serves as a central coordinating mechanism linking uterine recovery with ovarian reactivation during the postpartum transition period [59].

Immunometabolic interactions can be conceptualized as a sequential yet bidirectional process in which metabolic stress initially disrupts uterine immune homeostasis, whereas unresolved uterine inflammation subsequently feeds back to impair ovarian function through systemic inflammatory and endocrine signaling [60]. This framework provides a unifying synthesis of mechanisms that have often been described separately in previous reviews. Table 1 illustrates the reciprocal relationships among metabolic, immune, and hormonal systems in dairy cows during the transition period [61–78].

Excessive mobilization of adipose tissue during NEB results in elevated circulating concentrations of NEFA and BHBA [61]. These metabolites function not only as indicators of energy deficit but also as active metabolic triggers that directly modulate immune cell activity [62]. Prolonged exposure to elevated NEFA and BHBA concentrations induces oxidative stress and activates nuclear factor kappa B (NF-κB) signaling in macrophages and endometrial epithelial cells [63]. Consequently, NF-κB activation promotes overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and IL-6 [64].

Although this inflammatory response is essential for postpartum uterine defense, sustained cytokine release exerts endocrine-disrupting effects that suppress ovarian steroidogenesis, primarily through downregulation of aromatase activity and FSH receptor expression in granulosa cells. This cause–effect cascade ultimately impairs follicular dominance, ovulation, and luteal function [65].

Uterine inflammation, manifesting as clinical or subclinical endometritis, further amplifies ovarian dysfunction through well-defined inflammatory crosstalk mechanisms [66]. Bacterial infection and retained postpartum debris promote the release of lipopolysaccharide (LPS) from Gram-negative bacteria [67]. Systemic translocation of LPS represents a critical mechanistic link, as LPS binds to Toll-like receptor 4 (TLR4) expressed on ovarian granulosa and theca cells, activating NF-κB and p38 mitogen-activated protein kinase pathways [68]. This sequence establishes a direct causal pathway in which uterine inflammation precedes and induces ovarian suppression rather than merely coexisting with it [69]. Furthermore, LPS inhibits expression of steroidogenic acute regulatory protein and cytochrome P450 aromatase (CYP19A1), reducing estradiol synthesis and preventing dominant follicle development [70].

Beyond NEFA and BHBA, additional immunometabolic mediators integrate metabolic status with uterine–ovarian signaling. Adiponectin, an adipokine whose concentration declines during NEB, enhances insulin sensitivity and supports ovarian steroidogenesis; thus, reduced adiponectin levels represent a mechanistic link between metabolic stress and increased inflammatory susceptibility [71]. Cortisol, elevated during metabolic or environmental stress, exerts dual effects by transiently suppressing uterine inflammation while chronically inhibiting gonadotropin secretion and ovarian responsiveness [72]. Acute-phase proteins such as haptoglobin and serum amyloid A serve as systemic biomarkers of immunometabolic imbalance and are consistently associated with delayed resumption of ovarian cyclicity and reduced fertility [73].

At the intracellular level, integration of metabolic and immune signals is mediated through the AMP-activated protein kinase (AMPK)– mechanistic target of rapamycin (mTOR) axis [74]. Activation of mTOR during inflammatory or nutrient-excess states promotes proinflammatory protein synthesis, whereas AMPK activation under energy-deficient conditions conserves cellular energy and restrains inflammatory signaling [75]. Disruption of the AMPK–mTOR balance in uterine and ovarian tissues compromises endometrial repair, granulosa cell survival, and ovulatory capacity, reinforcing a self-perpetuating immunometabolic loop between these organs [76].

The uterine microbiota further modulate these interactions. Under healthy conditions, commensal microbial communities support mucosal integrity and immune tolerance [77]. Postpartum dysbiosis, characterized by overgrowth of pathogenic bacteria such as Escherichia coli and Trueperella pyogenes, sustains chronic inflammation and increases systemic exposure to LPS, thereby intensifying OH through persistent immunometabolic signaling [78].

An integrative schematic summarizing the cause–effect relationships among metabolic stress, immune activation, and endocrine disruption linking uterine inflammation and OH is presented in Figure 2 to enhance conceptual clarity.

Uterine health in dairy cows is tightly regulated by ovarian endocrine activity and represents a critical determinant of subsequent ovarian recovery and fertility outcomes [79]. Deficits in estrogen and progesterone directly alter uterine immune competence, myometrial contractility, and endometrial regeneration when ovarian function is impaired, particularly in cases of OH, thereby creating an intrauterine environment that further suppresses ovarian reactivation [80, 81]. Thus, OH and uterine dysfunction should be regarded as functionally interdependent rather than isolated disorders.

In postpartum dairy cows, uterine health is routinely assessed using a combination of vaginal discharge scoring, transrectal ultrasonography, and endometrial cytology, all of which provide clinically actionable information relevant to ovarian outcomes. Clinical examination focuses on discharge characteristics, whereas ultrasonography enables evaluation of uterine involution, luminal fluid accumulation, and endometrial thickness—parameters strongly associated with delayed resumption of ovarian cyclicity [82]. Endometrial cytology obtained via cytobrush or low-volume uterine lavage allows detection of subclinical endometritis based on polymorphonuclear neutrophil (PMN) proportions, a diagnostic approach particularly relevant in cows with OH that lack overt clinical signs.

Histopathologically, the uterus of cows with OH exhibits bovine-specific postpartum alterations, including reduced endometrial epithelial thickness, glandular epithelium degeneration, and persistent leukocyte infiltration within the lamina propria [83]. Unlike cyclical endometrial remodeling in nonpregnant cows, postpartum endometrial repair is highly dependent on timely estrogen and progesterone signaling. Estrogen deficiency leads to endometrial atrophy and reduced uterine gland secretory activity, compromising the uterine milieu required for sperm transport and early embryonic survival [84]. Concurrently, insufficient progesterone impairs stromal cell proliferation and downregulates growth factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-β (TGF-β), both essential for postpartum uterine repair and subsequent luteal support [85].

Clinically, endometritis severity, classified as mild, moderate, or severe based on discharge characteristics and PMN thresholds, correlates closely with ovarian functional outcomes. Increasing uterine inflammatory severity is consistently associated with prolonged postpartum anestrus, reduced dominant follicle emergence, delayed first ovulation, and diminished luteal progesterone concentrations, indicating a direct relationship between uterine pathology and OH.

From an immunological standpoint, estrogen and progesterone play species-specific regulatory roles in the bovine uterine immune system [86]. Estrogen enhances uterine defense by stimulating antimicrobial peptides (e.g., β-defensin and lactoferrin) and promoting controlled recruitment of neutrophils and macrophages into the uterine lumen [87]. In contrast, progesterone limits excessive inflammation by suppressing proinflammatory cytokines such as IL-1β and TNF-α while promoting anti-inflammatory mediators including IL-10 [88]. In dairy cows with OH, prolonged deficiency of these hormones leads to immune dysregulation characterized by impaired phagocytic activity, reduced mucus secretion, and persistent endometrial inflammation, all of which compromise fertility under commercial production conditions [89, 90].

Delayed uterine involution is a frequent clinical finding in cows with OH during the postpartum period [91]. Under normal physiological conditions, uterine involution is largely completed within 30–45 days postpartum, and ovarian cyclicity resumes with the first ovulation typically occurring around 20–35 days postpartum [92, 93]. Deviations beyond these time frames serve as practical clinical indicators of pathological uterine dysfunction [94, 95]. Low estrogen and progesterone concentrations reduce myometrial contractility, impairing clearance of lochia and placental remnants [96], thereby increasing susceptibility to secondary bacterial infection and perpetuating ovarian suppression [97].

The relationship between uterine dysfunction and OH is reciprocal and self-reinforcing [98, 99]. Chronic uterine inflammation suppresses hypothalamic gonadotropin-releasing hormone (GnRH) secretion, reduces LH pulsatility, and inhibits follicular maturation [100]. Conversely, ovarian hormone deficiency further compromises uterine immune competence and tissue regeneration [101]. This feed-forward loop highlights the clinical importance of prioritizing uterine recovery as a prerequisite for restoring ovarian cyclicity and improving conception outcomes [102].

Figure 2 illustrates the proposed mechanistic link between uterine inflammation, hypothalamic–pituitary–ovarian axis disruption, and OH.

Uterine flushing therapy is a non-hormonal intrauterine intervention primarily aimed at improving uterine health and facilitating postpartum uterine clearance in dairy cows, particularly in cases of mild to moderate endometritis and delayed uterine involution. Evidence-based studies consistently demonstrate improvements in uterine cleanliness and inflammatory status, whereas improvements in ovarian function should be interpreted as indirect secondary outcomes mediated through restoration of uterine–ovarian communication [103].

This approach involves intrauterine administration of sterile isotonic solutions, with or without adjunctive agents, to remove inflammatory exudate, reduce microbial load, and support endometrial repair [104].

Based on the key gaps identified in earlier sections, including limited field validation of immunometabolic biomarkers, lack of standardized non-hormonal intervention protocols, and challenges in translating experimental findings into herd-level practice, future research in immunometabolic-based reproductive management can be systematically organized into short-, medium-, and long-term priorities. This structured framework aims to facilitate progressive development from mechanistic understanding to practical implementation.

This review highlights that OH in dairy cows is not an isolated ovarian disorder but a multifactorial condition arising from interconnected endocrine, metabolic, immune, and uterine processes. Evidence synthesized across physiological, clinical, and immunometabolic studies demonstrates that postpartum NEB, oxidative stress, and uterine inflammation act synergistically to disrupt hypothalamic–pituitary–ovarian signaling, impair follicular development, and delay the resumption of ovarian cyclicity. The bidirectional relationship between uterine health and ovarian function underscores the importance of considering reproductive disorders within an integrated immunometabolic framework rather than as separate pathological entities.

From a practical standpoint, this integrative perspective supports a shift toward mechanism-based reproductive management. Biomarker-guided monitoring of metabolic indicators such as NEFA, BHBA, and IGF-1 enables early identification of cows at risk, while nutritional optimization and transition period management remain foundational preventive strategies. Uterine flushing therapy emerges as a physiologically oriented, non-hormonal intervention that promotes uterine clearance, immune resolution, and endometrial repair, with indirect yet clinically meaningful benefits for ovarian recovery and fertility outcomes. When applied in combination with targeted metabolic support and reproductive monitoring, such approaches may reduce reliance on blanket hormonal treatments and improve herd-level reproductive efficiency.

A key strength of this review lies in its comprehensive integration of endocrine, metabolic, immune, and clinical evidence into a unified conceptual model linking uterine inflammation, immunometabolic imbalance, and ovarian dysfunction. However, limitations include reliance on heterogeneous experimental and field studies, variable biomarker thresholds across production systems, and limited large-scale validation of emerging non-hormonal interventions.

Future research should prioritize multicenter field trials, standardized biomarker-based protocols, and translational studies evaluating integrated management strategies under diverse dairy production conditions. Ultimately, adopting an immunometabolic-based approach that combines early risk detection, uterine health restoration, and supportive nutritional management offers a promising pathway to enhance reproductive performance, animal welfare, and sustainability in modern dairy production systems.

Overall, the evidence supports immunometabolic-based reproductive management as a realistic pathway to improve postpartum uterine recovery and accelerate ovarian reactivation while enhancing animal welfare and reducing dependence on repeated hormonal treatments. Implementing feasible on-farm screening (e.g., BHBA and NEFA), strengthening transition cow nutrition, and applying uterine-focused non-hormonal therapies in appropriately selected cows can collectively deliver more sustainable fertility outcomes in modern dairy production systems.

All the generated data are included in the manuscript. The selection of articles and supplementary text can be made available from the corresponding author upon a request.

CB, IM, and ARK: Drafted the manuscript. SM, TWS, and ES: Revised and edited the manuscript. SR, RZA, and LP: Participated in preparation and critically reviewed the manuscript. BPP, WW, and SS: Edited the references. All authors have read and approved the final version of the manuscript.