Age-related canine reproductive health: impact on fertility and disorders

Aging is a progressive and multifactorial biological process marked by a gradual decline in the structure and function of virtually all physiological systems [ 1 ]. This decline results from cumulative cellular and molecular damage over time, driven by mechanisms such as genomic instability, telomere attrition, oxidative stress, and mitochondrial dysfunction [ 2 3 ]. A persistent, low-grade inflammatory state known as “inflammaging” is one of the hallmarks of aging. This process is characterized by the chronic activation of the innate immune system in the absence of infection, often triggered by cellular debris, senescent cells, and altered metabolic signaling. Inflammaging has been implicated in the pathogenesis of various age-related diseases, including neurodegenerative, cardiovascular, and endocrine disorders, because of its capacity to disrupt tissue homeostasis and accelerate functional decline [ 4 5 ]. The reproductive system is particularly susceptible to age-related deterioration, influenced by systemic and local biological mechanisms. Aging disrupts the hypothalamic–pituitary–gonadal (HPG) axis, leading to hormonal imbalances that impair gonadal function and feedback regulation [ 6 7 ]. Concomitantly, a decline in gamete quality has been well documented in female and male mouse models [ 8 9 ]. Structural degeneration within the reproductive tissues further contributes to fertility decline [ 10 11 ]. These multifactorial alterations collectively compromise reproductive efficiency and increase the susceptibility to reproductive disorders in aged individuals. Nevertheless, most of these insights are derived from rodent and human studies. Research in companion animals remains limited, resulting in a significant knowledge gap regarding how aging affects reproductive health, particularly in dogs. Compared to other companion animals, dogs have a strong emotional connection with humans. They are often treated not merely as pets, but as integral family members, which sets them apart from most other species. As veterinary care improves and canine lifespans increase, the population of dogs continues to grow, which may contribute to an increase in survival into old age. The life stage of dogs is commonly classified into puppy, juvenile, young adult, mature adult, senior, and geriatric, based on age and physiological markers [ 12 13 ]. A senior is defined as an individual who has entered the final 25% of their estimated lifespan, depending on the breed [ 12 ]. A recent study of rational age grouping referred to geriatrics as those in advanced age with likely health and cognitive issues, while senior describes older individuals who remain relatively healthy [ 13 ]. In canine aging classifications, dogs aged 7 to 11 years are typically considered senior, while those aged 12 years and above are regarded as geriatric [ 13 14 15 ]. The breed size is also a key determinant because larger breeds tend to progress through their life stages more rapidly than smaller breeds [ 16 17 ]. In addition, dogs are increasingly recognized as relevant models in aging research because of their genetic diversity, environmental similarities to humans, and individualized veterinary care [ 18 19 ]. In both sexes, aging leads to a progressive decline in reproductive functions, but the manifestations, timing, and underlying mechanisms may differ markedly between females and males. Although female dogs remain cyclic throughout life, their reproductive efficiency decreases with age, accompanied by an increasing vulnerability to reproductive tract disorders. In male dogs, aging is associated with changes in endocrine signaling and testicular functions, leading to gradual reductions in reproductive output [ 1 20 ]. These changes affect fertility and breeding outcomes, potentially reflecting systemic aging processes [ 21 ]. Despite their clinical significance, the reproductive consequences of aging in dogs remain underexplored compared to other aspects of canine health and longevity. Previous reviews have discussed canine aging in general, including the hallmarks of aging [ 22 ], physiological processes [ 23 ], genetic pathways, and translational relevance to human aging [ 24 ]. Nevertheless, these works do not encompass the broader scope of reproductive aging. One review focused on semen quality biomarkers [ 25 ]. No reviews have integrated hormonal, histological, molecular, and clinical perspectives in both sexes, nor have they examined how these changes collectively influence the fertility outcomes. This review addresses that gap by synthesizing current knowledge on reproductive senescence in dogs, emphasizing its effect on fertility and the development of reproductive disorders in male and female aspects.

Reproductive aging in females leads to changes in endocrine regulation, affecting the HPG axis in particular [ 6 ]. Although most bitches maintain regular estrous cycles throughout their lives, advancing age is often linked to a longer interestrus interval, sometimes exceeding 10–12 months [ 26 27 ]. Older bitches also show a higher incidence of prolonged anestrus and silent estrus [ 28 ], complicating estrus detection and breeding management. These irregularities are believed to reflect reduced sensitivity to gonadotropin-releasing hormone stimulation or altered feedback mechanisms from the ovaries, but the precise molecular pathways underlying this change remain unclear. In aging bitches, the progesterone levels during the luteal phase remain elevated longer than normal. This persistent progesteronemia has been linked to excess growth hormone secretion, occasionally presenting as insulin resistance or acromegaly [ 27 ]. Despite these age-associated changes in hormonal dynamics, one study reported that the ovulation timing appears to remain relatively stable with age. An investigation of 102 beagle bitches across 390 estrous cycles found that ovulation consistently occurred around 11 days following the onset of vulval bleeding, with no significant difference between young and old age groups. Despite this, the study had data limitations regarding very old age dogs because it only included dogs up to eight years old [ 29 ]. In rodent models, dysregulation of the neuroendocrine (NE) function in the HPG axis during ovarian aging is often accompanied by persistent estrus, leading to the formation of large follicular cysts and the absence of corpora lutea [ 30 ]. A progressive spectrum of histological alterations marks reproductive aging in females. In mammals, aging ovaries also show stromal fibrosis, follicular depletion, and vascular alterations [ 31 ]. The aging ovary undergoes distinct structural changes within the stromal compartment. These cells exhibited lipofuscin accumulation [ 32 ] and multiple nuclei, indicating ovarian aging, which had been previously identified in aged murine ovaries [ 31 32 33 ]. Their emergence was negatively correlated with the follicle pool and likely reflects chronic tissue stress, concurrent with macrophage fusion events in response to unresolved cellular damage and inflammation. Although detailed histological data on canine ovaries are limited, the structure and quality of cumulus oocyte complexes (COCs) can reflect age-related changes. Older bitches yielded fewer COCs, many with nuclear fragmentation or poor chromatin structures [ 34 ]. Researchers often compensate for the lack of canine-focused studies using rodent and other mammal models for comparative insights into reproductive aging. A study of uterine alterations in mice reported that uterine fibrosis is driven more by repeated estrous cycles than age alone. This process involves transforming growth factor-β-mediated fibroblast activation and collagen accumulation. Acyclic mice showed reduced fibrosis, highlighting the role of hormonal cycling. Aging also causes epithelial flattening, microvilli loss, and vascular dysfunction, all of which impair uterine receptivity [ 10 ]. In cows, adenomyosis and fibrotic invasion into the myometrium are observed more frequently in older individuals, with immunohistochemistry indicating increased estrogen and unchanged progesterone expression, potentially favoring fibrogenesis [ 35 36 ]. These findings support the concept that fibrosis may represent an early and dominant morphological characteristic of uterine aging. Further comparative studies support the cross-species relevance of uterine aging mechanisms. In humans, uterine aging is consistently associated with epithelial thinning, stromal fibrosis, and reduced glandular activity. Meta-analyses and histological studies reported decreased stromal cell proliferation, increased epithelial senescence, and fibrotic remodeling marked by collagen I/III deposition and myofibroblast infiltration [ 37 38 39 40 ]. Aging interferes with the ability of oocytes to complete maturation. Although structural quality declines with age, functional competence is equally affected. Oocytes from older bitches exhibited chromatin abnormalities and showed signs of disrupted meiotic progression and incomplete cytoplasmic development, which are key factors in fertilization failure [ 34 ]. Interestingly, unlike most mammals that ovulate mature oocytes, dogs are unique in ovulating oocytes at a still immature stage. These oocytes require additional time within the oviduct to complete nuclear and cytoplasmic maturation post-ovulation [ 41 ]. Complementing this, reduced in vitro maturation success rates have been observed in the oocytes from older bitches, potentially due to the diminished responsiveness to gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [ 42 ]. Studies in human and murine models have shown that oocyte aging is characterized by mitochondrial dysfunction, elevated reactive oxygen species (ROS), spindle defects, DNA fragmentation, and reduced expression of meiosis-regulating genes [ 20 ]. Beyond oocyte abnormalities, the aging ovary also undergoes progressive molecular remodeling. In addition to the downregulation of gonadotropin receptors such as FSH and LH receptors, aged ovarian tissue in dogs exhibits altered microRNA (miRNA) expression patterns [ 43 ]. These include increased levels of miR-151 and miR-708 , which are associated with disrupted folliculogenesis and inflammatory signaling. Supporting these findings, previous studies reported that aging ovaries in other mammals accumulate senescent granulosa and stromal cells, along with pro-inflammatory macrophage infiltration. These aging cells express elevated p16 INK4a levels as a senescence gene marker. In addition, it also secretes senescence-associated secretory phenotype (SASP) components, which increase pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, contributing to stromal fibrosis, follicular disruption, and ovarian dysfunctions [ 44 45 46 ]. In the uterus, molecular aging is characterized by mitochondrial dysfunctions, DNA repair deficits, and persistent oxidative stress [ 47 48 ]. Although species-specific data in dogs are limited, uterine aging in mice and humans has been associated with transcriptomic reprogramming, including the downregulation of cell cycle genes and upregulation of SASP-related inflammatory mediators [ 40 49 ]. Epigenetically, the aging endometrium exhibits altered histone acetylation patterns, which impair the tissue responsiveness to steroid hormones and compromise endometrial plasticity [ 50 51 ]. In the uterus, aging bitches exhibited increased miR-29a and decreased miR-125a expression, changes that may contribute to extracellular matrix (ECM) remodeling and inflammatory signaling, but uterophathy could also influence these alterations [ 43 ]. Furthermore, age-related uterine fibrosis has been linked mechanistically to the activation of the PI3K/Akt1/mTOR signaling pathway, which regulates pro-fibrotic miRNAs such as miR-34a , further supporting the role of chronic molecular remodeling in uterine structural decline [ 38 ]. In addition to endometrial dysfunctions, age-related changes in the myometrium may further compromise reproductive success. Senescent smooth muscle cells in the aging human myometrium showed mitochondrial damage, altered calcium signaling, and reduced responsiveness to oxytocin, ultimately leading to impaired uterine contractility [ 52 ]. Although canine-specific data are lacking, a similar functional decline in uterine musculature could negatively affect parturition, uterine clearance, and fertility outcomes in older bitches. The cumulative effect of hormonal, structural, and molecular changes is a decline in fertility with age. Older bitches often experience reduced conception rates, smaller litter sizes, and higher rates of early embryonic loss [ 53 54 ]. Age-related declines in reproductive performance have been confirmed in large-scale epidemiological studies. In a study involving more than 10,000 litters from 224 breeds, the mean litter size decreased significantly with advancing maternal age, particularly in large and giant breeds aged seven years or more. The negative impact of age was more pronounced in larger breeds because of the curvilinear relationship between age and litter output [ 55 ]. A retrospective study of Drever dogs showed that bitches older than four years old at first whelping produced significantly smaller litters than younger bitches. In the same study, the litter size declined progressively with each year of age beyond five, with bitches aged six to seven years and those over seven years averaging 4.48 and 4.24 pups per litter, respectively. These findings confirm that advancing age independently contributes to declining reproductive performance, regardless of parity. Interestingly, the adverse effects of age were less evident when breeding was conducted in a private kennel under optimized management conditions. This suggests that while biological aging is inevitable, its reproductive impact can be mitigated partially through careful breeding management [ 56 ]. Ovarian cysts are considered the most frequent ovarian abnormality in dogs, and one report suggested they may account for up to 80% of all ovarian pathologies [ 57 ], particularly in older or nulliparous bitches. Although the exact prevalence is difficult to determine because of the subclinical presentation and incidental detection during ovariohysterectomy or necropsy, previous reports estimate its occurrence in approximately 22.5% of the canine population [ 58 ]. Although the life expectancy of different dog breeds varies, there is a tendency for increased prevalence of ovarian cysts in dogs over the age of six [ 59 60 ]. Dysregulation of the HPG axis is one major age-related factor that predisposes individuals to ovarian cyst formation. In aged bitches, this dysregulation can impair the LH surge or reduce ovarian responsiveness to gonadotropins, resulting in the persistence of unovulated follicles. Over time, these persistent follicles may develop into hormonally active or inactive cystic structures. In addition, cumulative hormonal fluctuations and impaired follicular atresia may contribute to chronic stimulation of the ovarian surface, leading to cyst development [ 58 ]. Clinically, ovarian cysts in dogs may present with signs such as prolonged estrus, vulvar edema, serosanguinous vaginal discharge, or infertility, and their occurrence tends to increase with advancing age [ 59 60 ]. Although the clinical course is often subacute, the endocrine and histological effects of ovarian cysts may contribute significantly to uterine pathology and infertility in aging bitches. These findings highlight the importance of considering reproductive senescence as a multifactorial process that includes ovarian and uterine degeneration [ 58 ]. Previous reports of ovarian tumors estimate an occurrence between 0.5 and 6.3% of the canine population [ 61 ]. Although ovarian tumors are relatively rare in dogs, they exhibit a clear age-related pattern, with most cases occurring in bitches older than six years. The frequency of tumors tends to increase with advancing age, peaking between 8 and 12 years, while cases in dogs under three years are virtually absent [ 62 ]. This pattern suggests a strong link between aging and tumor development. Various tumor types have been identified, with epithelial-origin neoplasms such as papillary cystadenomas and adenocarcinomas dominating reported cases [ 58 61 63 ]. Epithelial tumors often present as large, multilocular cystic masses and are observed more frequently in older dogs. Nevertheless, some tumors might be found in middle-aged dogs, such as granulosa cell tumors [ 61 62 ]. The clinical expression of ovarian tumors varies according to the type, size, and hormonal activity [ 58 ]. While some neoplasms, particularly granulosa cell tumors, may influence systemic hormone levels and disrupt estrous cyclicity, others remain silent and are discovered incidentally during surgical procedures [ 62 ]. As tumors enlarge or undergo a malignant transformation, dogs may exhibit non-specific signs such as abdominal distension, anorexia, and lethargy [ 64 ]. These subtle manifestations can complicate early diagnosis [ 58 ]. Hence, older bitches may be at risk of developing ovarian tumors even if the reproductive signs are less noticeable. Uterine pathologies, particularly cystic endometrial hyperplasia (CEH) and pyometra, show a marked increase in prevalence with advancing age in intact female dogs. The combined occurrence of CEH and pyometra has been reported to range from over 20% to more than 50% in bitches up to 10 years of age [ 61 ]. The ultrasonographic findings substantiate this trend, with the CEH prevalence rising sharply from 6.8% in two-year-old bitches to more than 60% by the age of six, especially in nulliparous and retired breeding dogs [ 65 ]. The chronic non-regenerative nature of CEH is closely linked to repeated non-pregnant estrous cycles and prolonged exposure to progesterone. Local immune tolerance further promotes degenerative and inflammatory changes, which are typical in intact aging bitches [ 66 ]. CEH is a hormonally driven endometrial pathology characterized by excessive proliferation and cystic dilation of the endometrial glands. CEH often exists as a subclinical condition that may progress to pyometra, a life-threatening uterine infection [ 67 ]. Pyometra, which typically develops during diestrus, results from the bacterial colonization of a progesterone-primed endometrium. Age is a significant risk factor. A previous study confirmed that the incidence of pyometra rises markedly in dogs older than six years, with most clinical cases reported in bitches over eight years of age, increasing their susceptibility to endometrial degeneration and immune suppression within the uterus [ 27 68 ]. At the histological level, pyometra is frequently associated with pre-existing CEH, characterized by cystically dilated glands, leukocytic infiltration, epithelial hyperplasia, and progressive stromal fibrosis. One study found that in bitches with an average age of 9.3 years, all pyometra cases exhibited severe CEH, chronic purulent endometritis, varying degrees of adenomyosis, and interstitial fibrosis. Specifically, fibrosis was present in 16.7% of pyometra cases compared to 6.7% in CEH alone [ 69 ]. At the molecular level, the aging endometrium displays altered immune and hormonal signaling. One study observed the dysregulated expression of inflammation- and immunity-related genes, such as Toll-like receptors (TLR2 and TLR4), which recognize bacterial components and trigger inflammatory cascades. This leads to increased expression of cyclooxygenase-2 (COX-2) or prostaglandin-endoperoxide synthase2 (PTGS2), prostaglandin E synthase, and prostaglandin F synthases, in the endometrium, contributing to excessive prostaglandin production and chronic uterine inflammation [ 70 71 72 ]. Mammary gland tumors (MGTs) are the most prevalent neoplasms affecting intact female dogs, particularly those over the age of seven. The influence of aging is evident in the sharp rise in incidence with advancing age [ 73 74 ]. Prolonged hormonal exposure, especially to estrogen and progesterone, plays a crucial role in promoting mammary epithelial proliferation and the potential for neoplastic transformation [ 61 75 ]. Estrogen and progesterone promote mammary epithelial proliferation and reduce apoptosis, contributing to abnormal cellular growth through long-term hormonal stimulation. Estrogen also activates oncogenic pathways via nuclear receptors, while progesterone stimulates stem cell activity and local growth factor expression [ 76 ]. From a histopathological standpoint, the mammary gland undergoes lobuloalveolar regression, increased stromal fibrosis, and immune cell infiltration. These features reduce tissue elasticity and may facilitate a dysplastic or neoplastic transformation [ 77 ]. As the disease progresses, the tumor characteristics diverge significantly between benign and malignant forms. Benign neoplasms, such as adenomas and benign mixed tumors, typically maintain a ductal and myoepithelial architecture, often showing strong expression of estrogen receptor (ER) and progesterone receptor (PR). In contrast, malignant tumors, particularly simple and complex carcinomas, frequently exhibit cellular dedifferentiation marked by poor tubular formation, increased mitotic activity, and reduced hormone receptor expression. These features are indicative of a more aggressive biological behavior and diminished hormonal responsiveness, suggesting a shift toward hormone-independent growth [ 75 78 ]. Recent transcriptomic analyses of mammary tissue have revealed dysregulation in the genes involved in cell cycle control, angiogenesis, and inflammatory signaling pathways, all of which may contribute to a pro-tumorigenic microenvironment [ 75 76 79 ]. Naturally developed MGTs in dogs exhibit substantial clinical, histopathological, and molecular similarities to human breast cancer, making them a valuable model for comparative oncology research [ 80 81 ]. These similarities encompass comparable histological subtypes and the expression of ER, PR, and human epidermal growth factor receptor. Moreover, molecular profiling has shown that some canine mammary tumors share conserved oncogenic mechanisms with human breast cancer [ 81 82 83 ], mutations of genes involved in DNA repair, cell cycle control, and apoptosis [ 84 ]. The incidence in women is highest between 70–74 years and remains elevated through 75–79 years before gradually declining in the oldest groups [ 85 ]. Age is also the most significant risk factor for breast cancer, with the incidence peaking at menopause and fewer than 10% of cases occurring before 45 years of age. A similar age-related pattern is observed in dogs, whereas less than 5%–10% of tumors are detected before three to five years of age [ 86 ]. Strengthening the translational relevance of canine mammary tumors will require coordinated cross-species research using standardized histopathological, molecular, and biomarker assessment protocols, enabling robust and clinically meaningful comparisons with human breast cancer. The HPG axis becomes progressively dysregulated with age. A decline in circulating testosterone is consistently reported in older male dogs and is linked to reduced sexual functions, testicular degeneration, and prostatic changes [ 6 ]. A previous study revealed a significant negative correlation between age and testosterone levels in a large cohort of male dogs. In addition, the free androgen index, a proxy for bioavailable testosterone, declined with age and increased body weight, which may explain the reduced libido and altered accessory gland function in older dogs [ 87 ]. Despite the continued secretion of LH and FSH, aging testicular tissues may exhibit diminished responsiveness to gonadotropins caused by reduced receptor expression or disruption of intracellular signaling [ 88 ]. These hormonal shifts are central to the broader decline in reproductive functions and are often the earliest indicators of reproductive aging. Senescence induces clear structural deterioration within the testes and associated reproductive organs. Aging testicular tissues showed a marked reduction in seminiferous epithelium height, disorganization of germ cell layers, and fibrosis of the interstitial compartment. The seminiferous epithelium-to-tubular area ratio decreases with age, reflecting a decline in spermatogenic capacity. Histologically, older dogs exhibit more severe tubular degeneration, including Sertoli cell vacuolization, germ cell degeneration, disorganization of the germinal epithelium, and thickening of the tubular basement membrane, which contribute further to reduced sperm output [ 89 90 ]. These findings are consistent with earlier reports showing that the testicular volume and tubular development peak around middle age before declining in older dogs [ 91 ]. Tubular atrophy and degenerative features such as retained spermatids and gonocytes occur more frequently in dogs older than nine years [ 90 ]. In addition, the increased Sertoli cell indexand decreased spermatic index in older dogs reflect the loss of germ cells and reduced spermatogenic efficiency. These quantitative markers confirm the progressive impairment of the seminiferous epithelium with age. Interstitial fibrosis is another hallmark of testicular aging. Collagen accumulation increases significantly in the peritubular space and interstitial tissue of dogs over nine years of age, while younger dogs maintain a relatively intact architecture [ 92 ]. The total collagen area and total tubule seminiferous area ratio are significantly higher in older dogs, indicating an expansion of fibrotic tissue and reduction of the active seminiferous compartment [ 90 ]. In addition to structural degeneration, low-grade chronic inflammation (inflammaging) has been identified as a contributor to reproductive aging. The increased interstitial leukocyte infiltration and peritubular immune cell activity disrupted immune privilege in aging testes. These inflammatory changes impair the functions of Sertoli cells and may exacerbate fibrotic remodeling. The role of inflammaging highlights that testicular aging is a degenerative process involving active immune-mediated processes that compromise reproductive functions [ 93 ]. At the molecular level, aging induces selective disruption in gene expression and regulatory signaling within the testes. A previous study reported that the expression of CYP19A1 , the gene encoding aromatase, declined significantly in older dogs. Aromatase is essential for local estrogen biosynthesis in testicular tissues, and its reduction may impair the functions of Sertoli cells and spermatogenesis. In contrast, the expression of other steroidogenic genes such as STAR , CYP11A1 , and HSD3B2 remained relatively stable with age [ 94 ]. Aging in dogs is associated with transcriptomic shifts involving oxidative stress responses, inflammation, and cell cycle regulators. In addition, global DNA methylation alterations and miRNA dysregulation were detected, suggesting that age-related fertility loss is influenced by histological degeneration and epigenetic remodeling [ 23 ]. This also includes distinct shifts in miRNA expression in the testes and epididymis. Older dogs exhibit the upregulation of miR-26a , miR-125b , miR-200c , and miR-503 , alongside the downregulation of miR-34b/c , miR-449a/b , and miR-202 , changes that are implicated in inflammatory signaling, ECM remodeling, disruption of spermatogenesis, and mitochondrial functions [ 95 ]. The molecular disruptions likely contribute to decreased germ cell survival and altered immune homeostasis within the tests. In addition to these transcriptomic and epigenetic changes, aging also promotes the activation of pro-inflammatory signaling cascades in the testes of mice and human males [ 93 96 ]. A previous study reported that the TNF-α, IL-6, and IL-1β pathways are upregulated in aged male reproductive tissues, disrupting the Sertoli cell support functions and enhancing local oxidative stress. This stress is amplified by aged testicular macrophages, which overproduce ROS and prostaglandins, accelerating tissue degeneration and suppressing testosterone synthesis [ 93 97 ]. Supporting this, recent evidence has shown that systemic aging in dogs is characterized by elevated circulating levels of IL-6, IL-8, and TNF-α, consistent with a systemic pro-inflammatory state known as inflammaging [ 98 ]. This similarity of immune-inflammatory changes across species suggests shared pathophysiological mechanisms between testicular aging and idiopathic infertility. These reports clarify the concept of reproductive aging in male dogs in terms of genetic disruptions. Furthermore, immunological activation appears to be another key regulator that destabilizes the testicular function at the molecular level. Functional deterioration of sperm is one of the most clinically relevant outcomes of male reproductive aging, leading to a decrease in sperm motility, membrane integrity, and increased rates of morphologic abnormalities [ 99 100 101 ]. One study reported that the cryotolerance of sperm diminishes with age. The post-thaw motility and viability were significantly lower in dogs aged 10–11 years, and the proportion of ejaculates unsuitable for artificial insemination (AI) rose to 34% [ 102 ]. Research into senescence-related changes in sperm viability showed that older dogs exhibit increased oxidative stress and higher levels of lipid peroxidation in their sperm [ 103 ]. Aging sperm cells often exhibit increased membrane permeability, making them more fragile and prone to damage. At the same time, there is an increase in early apoptotic activity; the sperm undergo programmed cell death even if they still appear intact. In addition, aging reduces the mitochondrial membrane potential, which is essential for energy production, resulting in weaker motility and reduced fertilization ability [ 104 ]. An earlier study showed that aging in male dogs is consistently associated with a decline in sperm motility, viability, and morphological integrity. In particular, older dogs exhibit a higher percentage of midpiece and head abnormalities, reduced progressive motility, and compromised membrane functions, making the sperm more vulnerable to damage during storage or freezing. Although the semen volume and sperm concentration may remain within the normal ranges, the functional impairments significantly reduce the fertilization potential [ 101 ]. These parameters were the most consistent predictors of the fertility outcome, reinforcing their clinical relevance in aging dogs [ 99 ]. Moreover, the breeds and body size of dogs can influence the trajectory of age-related changes. In addition, larger breeds show earlier declines in sperm motility despite generally producing larger semen volumes. A breed-specific study on Great Danes confirmed significant age-related reductions in total sperm count and progressive motility, particularly in dogs over seven years of age. In addition, dogs over nine years old exhibited sharp declines in the ejaculate volume and sperm morphology, reinforcing the need for breed-sensitive considerations in fertility assessments [ 105 ]. This is also supported by an earlier study that showed that bitches inseminated with semen from older dogs had significantly lower whelping rates than those from younger donors, regardless of the season or semen transport conditions [ 106 ]. Research studies in male dogs have confirmed that aging can potentially have adverse effects on sperm quality, which can result in poorer breeding outcomes. Reproductive aging predisposes male dogs to a variety of clinical pathologies. Benign prostatic hyperplasia (BPH) is the most common condition with an incidence of up to 80% in dogs over eight years of age, and nearly all dogs over 10 years present with histological evidence of BPH [ 107 ]. The high prevalence of BPH in aging, non-neutered males underscores that BPH frequently originates subclinically from midlife and advances silently if undetected [ 61 ]. The clinical signs include serosanguineous preputial discharge, hematuria, and tenesmus, although many cases remain subclinical [ 108 ]. BPH is marked by acinar hyperplasia, cystic dilation, and epithelial infoldings. With time, intraparenchymal cysts may form and contribute to prostate enlargement [ 108 109 ]. The condition results from an altered androgen-to-estrogen ratio, where decreased testosterone and relatively increased estrogen levels stimulate epithelial and stromal proliferation [ 110 ]. The gradual decline in androgen levels and the relative increase in estrogen concentrations in aging male dogs promote a hormonal environment that favors prostatic epithelial and stromal proliferation by sensitizing the prostatic tissue to dihydrotestosterone, a potent androgen formed via 5α-reductase activity [ 111 112 ]. In addition, prolonged exposure to hormonal stimulation contributes to chronic tissue remodeling, cellular stress, and inflammation, particularly in the form of proliferative inflammatory atrophy, which is considered preneoplastic in humans and dogs [ 113 ]. Inflammaging also contributes to the pathogenesis of BPH through the sustained activation of IL-6, COX-2/PTGS 2, and nuclear factor-κB signaling pathways [ 93 108 ]. Prostatic tumors in dogs can be benign or malignant, but most reported cases are malignant, including adenocarcinomas and transitional cell carcinomas, both of which are highly aggressive and have high metastatic potential [ 114 115 116 ]. Older age is a major risk factor because most tumors are diagnosed in dogs over eight years old [ 116 ]. The incidence of prostate cancer (PCa) is notably low; a previous study estimated its prevalence at 0.2%–0.6% within the general canine population. Nevertheless, it becomes clinically significant in geriatric patients, often presenting with urinary dysfunction, weight loss, and locomotor abnormalities due to metastasis [ 117 ]. Age-related changes in the prostate may influence the growth and differentiation of epithelial subtypes, likely through alterations in stem cell activation and varying sensitivity to shifts in the steroidal microenvironment [ 118 ]. Although traditionally regarded as androgen-independent [ 117 ], canine PCa is now recognized as more complex. Secretory acinar cells remain androgen-dependent, while ductal and stromal cells are more accurately described as androgen-sensitive, and only NE cells are truly androgen-independent. After castration, acinar cells undergo atrophy, whereas ductal and stromal elements persist and proliferate, accompanied by an increase in NE cells that release growth factors promoting tumor progression [ 61 118 119 ]. These histopathological changes suggest that canine PCa most likely originates from the ductal epithelium under the conditions of altered androgen regulation and chronic inflammation [ 120 ]. The incidence of PCa in men is one of the most common malignancies worldwide [ 119 ] and is strongly increasing in aging populations, rising steeply after the age of 50 years and a median age at diagnosis of around 66 years [ 121 ]. Histologically, PCa in men is most often an acinar adenocarcinoma, different from that in dogs [ 119 120 122 ]. In men, the disease usually begins as androgen-dependent and responds to androgen-deprivation therapy, but many cases eventually progress to castration-resistant prostate cancer (CRPC) through mechanisms such as androgen receptor (AR) loss, pathway activation, and NE differentiation. In contrast, many canine prostatic tumors already express low or absent AR expression and display an androgen-insensitive response, making them biologically comparable to CRPC cases in men [ 119 123 ]. The cellular origin and early etiopathogenesis differ, arising mainly from ductal cells in dogs and from acinar epithelial cells in men. Both species ultimately develop aggressive, androgen-insensitive tumors with overlapping molecular alterations and NE expansion [ 120 123 ]. Although dogs are typically diagnosed at advanced stages with poor prognosis, humans benefit from prostate-specific antigen-based screening programs that allow earlier detection and broader therapeutic options. Despite these differences, the biological parallels highlight the value of PCa as a spontaneous translational model for advanced human disease [ 114 120 122 ]. Age is also a significant risk factor for the development of testicular tumors, with Sertoli cell tumors and seminomas being the most frequently reported types in dogs [ 124 ]. Sertoli cell tumors are hormonally active and may secrete estrogens, causing signs of feminization such as gynecomastia, alopecia, and myelosuppression [ 125 ]. Seminomas, although often benign, can exhibit local invasiveness. The incidence of testicular tumors increases markedly in cryptorchid dogs and those over 10 years of age [ 61 124 ].

This review was based on a comprehensive search of the scientific literature related to age-associated reproductive changes in dogs. The articles were identified using online databases including PubMed, Elsevier, Scopus, and Google Scholar, with no restrictions on publication year. The search terms included combinations of keywords such as “dog,” “reproductive aging,” “fertility,” and “reproductive disorder.” The studies were selected based on their relevance to structural, hormonal, and functional alterations in the reproductive system of aging male and female dogs. Comparative studies in other mammalian species were also considered to provide relevant context to reproductive aging. The selected publications were reviewed and synthesized narratively.

This review highlights how age-related changes in canine reproduction, ranging from endocrine imbalance and histological degeneration to molecular inflammation, contribute to declining reproductive performance and an increased risk of reproductive disorders ( Fig. 1 ). Hormonal dysregulation often begins with impaired feedback from the HPG axis, leading to altered gonadotropin and steroid hormone dynamics. In females, this leads to diminished ovarian reserve and uterine receptivity, while in males, it results in a gradual decline in testicular function and sperm quality. Structurally, both sexes experience fibrosis, degeneration of supporting cells, and reduced gamete competence. At the molecular level, mitochondrial dysfunction, oxidative stress, and epigenetic remodeling disrupt tissue homeostasis, while chronic low-grade inflammation accelerates fibrotic and degenerative processes, reflecting on inflammaging as a key contributor to reproductive senescence. HPG, hypothalamic–pituitary–gonadal; FSH, follicle-stimulating hormone; LH, luteinizing hormone; COC, cumulus oocyte complex; CEH, cystic endometrial hyperplasia; BPH, benign prostatic hyperplasia; miRNA, microRNA. This pattern might also be evident in dogs, with species-specific features shaped by sex, breed, and reproductive status. In female dogs, reproductive aging is strongly influenced by endocrine alterations. Advancing age is associated with prolonged interestrus intervals, silent estrus, and persistent progesteronemia, reflecting reduced ovarian responsiveness to FSH and LH. Structurally, the ovaries show progressive follicular depletion and a reduced quality of COCs. At the molecular level, chromatin abnormalities in oocytes and shifts in ovarian miRNA expression further impair gamete competence and tissue homeostasis. These changes collectively reduce the conception rate, decrease litter size, and predispose the individual to early embryonic loss. With age, susceptibility to ovarian cysts, ovarian tumors, CEH/pyometra, and MGTs increases, particularly in intact bitches exposed to prolonged estrogen and progesterone influence. In males, endocrine decline is marked by reduced testosterone levels and libido despite sustained LH and FSH secretion, suggesting diminished testicular responsiveness. Structural remodeling includes thinning of the seminiferous epithelium, Sertoli cell vacuolization, germ cell degeneration, and interstitial fibrosis, changes that underline declining spermatogenesis and impaired testicular function. At the molecular level, reductions in CYP19A1 expression and miRNA shifts in the tests and epididymis contribute to altered steroidogenesis, ECM remodeling, and impaired sperm maturation. Functionally, these processes manifest as reduced sperm motility and viability, increased morphological defects, and diminished cryotolerance, which limits the usability of semen for breeding and AI programs. With age, the risk of reproductive disorders rises, including BPH, prostatic tumors, and testicular tumors such as seminomas and Sertoli cell tumors, particularly in older dogs. Despite the progress of aging studies, most data are derived from non-canine models. More species-specific research is needed, particularly in identifying the biomarkers for reproductive aging and understanding breed-related differences. Subclinical cases of reproductive pathologies remain underdiagnosed, highlighting the need for routine screening in older dogs. Future studies should explore anti-inflammatory and antifibrotic strategies, investigate the role of inflammaging in reproductive decline, and integrate reproductive aging into geriatric health protocols. Reproductive aging in dogs is a multifactorial process, involving endocrine, structural, and molecular disruptions that impair fertility and promote changes in pathology. Recognizing and addressing these changes will be the key to improving reproductive and overall health management in the aging canine population.