The Hypothalamic-Pituitary-Ovarian Axis, Ovarian Disorders, and Brain Aging.

Neurodegenerative diseases are disorders in which a progressive loss of neurons occurs in the central or peripheral nervous system. As neurons are terminally differentiated cells, maintenance of their health is carefully controlled by numerous mechanisms ( 54 ). Disruptions to homeostatic systems are considered hallmarks of neurodegeneration, and were described thoroughly in Wilson et al in 2023 ( 54 ). We will briefly describe hallmarks relevant to our topic, including proteostasis and energy metabolism. Intracellular neuronal health is controlled by autophagy and proteostasis networks. Without recycling of disordered proteins and damaged organelles, aggregates stress intracellular machinery and cytoskeletal transport. Cytoskeletal modulation is particularly important in neurons due to axon length, making efficient transport of nutrients between the synapse and dendrites paramount for neuronal survival and signaling. Aggregates can be deposited in the extracellular space or even passed to other neurons through prion-like spread in extracellular vesicles, causing stress to whole subregions of neurons ( 54 ). In Alzheimer disease (AD), protein aggregates of amyloid beta (Aβ) plaques and tau tangles are hallmarks of disease ( 55 ). Control of synaptic signaling is essential for functionality of neuronal networks. Energy supplied by mitochondria allows neurotransmitter release and reuptake. Mitochondrial dysfunction leads to an excess of intracellular calcium, triggering neurotransmitter release to the synaptic cleft that cannot be reabsorbed by the neuron without calcium efflux. This causes an overactivation of neurotransmitter receptors on the receiving neuron. This overactivation, especially by excitatory neurotransmitters like glutamate, can prompt excess calcium influx into neighboring healthy neurons. This phenotype is called “excitotoxicity” and results in the release of reactive oxygen species (ROS), energy depletion, and neuronal death. Proper maintenance of mitochondrial health and neurotransmitter resorption is essential to prevent this feedback ( 54 ). The brain comprises neurons, glial cells, neuronal stem cells, and blood vessels. While neurons are responsible for information processing, glia perform vital support roles to maintain the health of brain tissue. Microglia are a macrophage-lineage brain-resident immune cell, exerting housekeeping and defensive functions. Overactivation of microglia drives neuroinflammation in several neurodegenerative disorders, causing chronic neuronal stress and eventual cell death. Astrocytes accomplish numerous neuroprotective tasks, including damage responses, neurotransmitter clearance from the synaptic cleft, and maintenance of the blood-brain barrier (BBB). Astrocytes become overactivated in response to excessive stimuli, altering their ability to modulate neurotransmitter recycling and promoting excitotoxicity ( 54 ). The BBB is a vascular barrier composed of endothelial cells, tight junctions, gap junctions, pericytes, and astrocytes. Endothelial cells use specialized transporters to allow the passage of nutrients and oxygen into the brain, while preventing entry of circulating ROS, toxins, and cytokines. Smaller, highly lipophilic molecules such as estradiol can freely cross the BBB, whereas larger, hydrophilic molecules like FSH and LH may require an active transport mechanism to cross ( 56 ). Endothelial cells are the most sensitive to damage from inflammatory molecules. Chronic, low-grade inflammation worsens the integrity of endothelial tight junctions over time ( 57 ). Astrocytes project endfeet to the endothelial cells, and release numerous factors including IGF1 and apolipoprotein-E to regulate distribution of occludins, claudins, and connexins. Reactive astrocytes downregulate expression of tight junction proteins of the BBB, promoting leakage and exacerbating neuroinflammation. BBB leakage also arises from damage to endothelial cells or neuroinflammation, causing infiltration of immune cells ( 58 ) and toxins into the brain, contributing to further neuroinflammation and predisposing the brain to cognitive disorders ( 54 ). Neurodegeneration can involve disruptions in any or all of the described systems, but some brain regions, such as the limbic system, are especially susceptible to initial damages. Comprising the diencephalon and lower cortex, the limbic system is a highly interconnected region responsible for memory consolidation, emotional and social processing, motivation, and learning ( 59 ). An especially vulnerable limbic structure is the hippocampus, the primary site of adult neurogenesis in the brain. The hippocampus is responsible for learning and memory tasks, specifically memory recall. During healthy aging, the hippocampus experiences one of the steepest declines in volume compared to other brain regions, rivaled only by cerebral white matter ( 60 ). The hippocampus is also especially sensitive to hypoxia, making strokes and cardiovascular disease an especially important risk factor for dementia development ( 61 ). The hippocampus contains a subpopulation of pyramidal neurons required for learning that have especially high energy demands and an abundance of glucocorticoid receptors, making them extremely sensitive to mitochondrial dysfunction, excitotoxicity, oxygen deficiency, ROS, and toxins ( 62 ). The hypothalamus, also within the limbic system, controls bodily homeostasis through prompting hormone release, controlling sleep-wake cycles, body temperature, and satiety. It is also highly susceptible to damage, with one study finding gene expression signatures with age to be the most changed in the hypothalamus of mice ( 63 ). Another study found astrocytes in the hypothalamus were more transcriptionally altered than cortical neurons, potentially hindering their immune-modulating processes ( 64 ). In presymptomatic patients with AD, Huntington disease, and amyotrophic lateral sclerosis, hypothalamic alterations related to energy metabolism and caloric intake were altered, suggesting the hypothalamus to be especially vulnerable to early pathologies ( 65 ). The prefrontal cortex is responsible for behavioral regulation, attention, focus, and executive functions. Most publications consider at least the ventromedial frontal cortical regions to be part of the limbic system ( 66 ). This area is specifically vulnerable to mitochondrial dysfunction with age. In ovariectomized (OVX) monkeys, morphological changes to mitochondria, as well as increased ROS and oxidative stress, were present in the prefrontal cortex. This effect was rescued by estradiol treatment ( 67 ), suggesting a loss of estradiol due to HPO axis dysfunction could affect normal operations. Along with increased susceptibility to disease, the hippocampus, hypothalamus, and limbic system as a whole share high expression of gonadotropin receptors ( 68 ), aromatase, and estrogen receptors ( 69 ), hinting at possible perturbations to signaling after drastic hormonal change.

This review has described common symptoms and comorbidities of ovarian disorders, and key brain regions susceptible to disease. It is remarkable that many of these symptoms share dysregulation of limbic system structures, a stress-susceptible area heavily populated by gonadotropin receptors ( 128 , 129 ). Common factors dysregulating activity of these brain structures would heavily implicate HPO axis involvement in symptomatology across the disorders. This is summarized in Fig. 1 . Common symptoms of ovarian disorders share involvement of limbic systems. A, Brain regions involved or altered in depression ( 130 ). B, Brain regions involved or altered in mood disorders ( 131 ). C, Brain regions involved or altered during hot flashes ( 132-135 ). D, Brain regions involved in sleep and altered in insomniac patients ( 136-139 ). E, Brain regions involved or altered in conditions using the broad term “ brain fog ” to describe cognitive symptoms ( 140-143 ). Abbreviations: AC, anterior cerebellum; ACC, anterior cingulate cortex; Amyg, amygdala; CC, cingulate cortex; CN, caudate nucleus; CV, cerebellar vermis; DLPFC, dorsolateral prefrontal cortex; GP, globus pallidus; HC, hippocampus; Hypo, hypothalamus; INS, insular cortex; MCC, medial cingulate cortex; MFG, middle frontal gyrus; MPFC, medial prefrontal cortex; OFC, orbitofrontal cortex; PAG, periaqueductal gray; PCC, posterior cingulate cortex; PFC, prefrontal cortex; RC, rhinal cortex; SN, substantia nigra; Str, striatum; Thal, thalamus. Specific studies highlighting the risk factors discussed in the following sections are displayed in Table 4 . Neurological risk factors for disease development arising from ovarian conditions, with evidence from literature Abbreviations: Aβ, amyloid β; AD, Alzheimer disease; APP, amyloid precursor protein; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor; HPO, hypothalamic-pituitary-ovarian; IGF-1, insulin-like growth factor 1; IL, interleukin; LH, luteinizing hormone; NLRP1, NLR family pyrin domain containing 1; OVX, ovariectomized; PCOS, polycystic ovary syndrome; PKC, protein kinase C; POI, primary ovarian insufficiency; TNF-α, tumor necrosis factor-α. Menopause and POI, or premature menopause, are characterized by high concentrations of serum gonadotropins and low concentrations of sex steroids. Insulin resistance, loss of IGF-1, and heightened cortisol often occur during this transition as well ( 4 ). Estradiol and progesterone prevent neuroinflammation and induce neuronal survival and energy homeostasis ( 144-146 ), with their loss likely promoting pathology ( 9-11 , 76 , 78 , 81 ). However, HRT post menopause has historically yielded conflicting results in reducing AD risk, with one study concluding that the greatest benefits are yielded if treatment begins in perimenopause, and continues to age 65 years ( 12 ). This may suggest that dysregulation of other HPO axis players is also a significant contributor to disease risk. FSH and LH rise considerably during early perimenopause, and may promote protein aggregation ( 148 ) and neuroinflammation in animal models ( 68 , 95 , 96 , 98 , 99 ). Although mechanisms are still being parsed, numerous correlational and human studies and mechanistic animal studies conclude high levels of peripheral LH and FSH, like what occurs during menopause, are detrimental to the health of sensitive brain regions ( 68 , 100 , 104 , 106 , 110 , 111 , 119 ). Additionally, IGF-1 loss, insulin resistance, stroke risk, and cortisol levels all contribute to disease susceptibility. Insulin resistance prevents effective transport of glucose into cells, promoting senescence and hyperglycemia. This causes impaired neuronal glucose metabolism ( 151 ), weakened synaptic plasticity, excitotoxicity of glutaminergic neurons, and improper vasodilation of blood vessels ( 55 ). Insulin resistance is primarily driven by declines in estradiol, poor sleep and stress, although not all women experience insulin resistance post menopause. Slowing of metabolism leads to increased central adiposity and increased inflammation, contributing to BBB leakage ( 45 , 46 ). Cortisol also rises in some women during menopause, and can lead to pathological protein aggregation ( 156-158 ). IGF-1 loss with age is also attributed to estradiol loss, increasing pathologies of insulin resistance ( 55 , 152 ). POI is correlated with oxidative stress and inflammatory aging ( 159 ), especially in the case of autoimmune POI, in which the immune system attacks the ovaries. Similarly, women undergoing premature menopause had significantly higher serum cytokines than fertile women ( 160 ). This can damage the BBB and promote neuroinflammation. Besides dementia risk ( 161 ), other cognitive effects, such as depression and mood changes, are seen as early as the time of POI diagnosis. The limbic system, which controls emotional responses, is especially sensitive to neuroinflammation and damage ( 166 ). High FSH and LH can negatively affect mood ( 149 , 150 ). Limbic system stress, neuroinflammation, and estradiol loss also contribute to brain fog, insomnia, and hot flashes ( 167 ). A combination of high gonadotropins and loss of BBB integrity could potentially exacerbate neuronal symptoms. PCOS is characterized most commonly by high androgens, high LH, and high free testosterone. Sometimes patients also experience low progesterone if ovulations are infrequent, and high estrogen due to increased aromatization of androgens. It is speculated that hyperandrogenic conditions desensitize negative feedback mechanisms of sex steroids and hyperexcite GnRH neurons. AMH also activates GnRH firing, perpetuating anovulation while the oocyte population remains high ( 168 ). High circulating LH can contribute to protein aggregation and cognitive decline ( 100 , 106 , 110 , 111 ), with high estradiol potentially offering a counteracting effect ( 99 , 100 , 111 ). The effects of hyperandrogenism on cognition are complex, with studies finding both benefits and hindrances on cognition ( 92 , 162 ). One review summarizes that women with PCOS were found to perform worse on tasks of verbal fluency, verbal learning, verbal memory, visuospatial and executive functions, spatial reasoning, auditory processing, and finger dexterity than controls ( 163 ). Some of these effects could be due to hyperandrogenism; however, high LH and psychological stressors could also be contributors. It is important to note that women with PCOS are more likely to experience depression, anxiety, bipolar disorder, and obsessive-compulsive disorder ( 169 ). Physical symptoms like weight gain, chronic pain, and infertility are major contributors to these diagnoses. Intriguingly, increased levels of free testosterone correlated with higher perceived stress in healthy women, suggesting hyperandrogenism could contribute to mental illness ( 170 ). Additionally, type 2 diabetic patients were found to have increased cortisol levels compared to healthy controls, suggesting an interplay between insulin resistance and stress ( 171 ). Psychiatric disorder diagnosis is associated with an increased risk of dementia development, with disruptions of neurotransmitter networks contributing to excitotoxicity and neuroinflammation ( 42 ). Future work should parse the contribution of endocrine imbalance to psychiatric disorder development, as an alternative contributor to dementia onset. Insulin resistance is a common symptom of PCOS, affecting 65% to 95% of patients ( 165 ). Twelve weeks of androgen exposure in rats induced a state of insulin resistance, suggesting hyperandrogenism can induce this symptom ( 172 ). Insulin resistance impairs synaptic integrity, promotes stroke onset, and mitochondrial dysfunction of neurons ( 153 , 154 ). Poor sleep in women with PCOS is directly correlated to insulin resistance, contributing to symptoms of brain fog and insomnia ( 167 ). PCOS is a condition of chronic, low-grade inflammation ( 155 , 164 ). Increased adipose tissue, insulin dysfunction, and glucose intake all promote further release of cytokines from circulating immune cells ( 173 ). This inflammation can weaken the BBB and may induce neuroinflammation.

Sex steroids include estrogens, progesterone, and testosterone. Their neurobiological actions are detailed in Table 2 . We will focus specifically on the estrogen estradiol, the dominant form of estrogen during reproductive years in both sexes ( 88 , 89 ). Sex steroids in the brain either enter from circulation or are produced locally by neurons. Neuronally derived estradiol (NDE) has unique effects from circulating estradiol, responding directly to injury, promoting cell survival through brain-derived neurotrophic factor (BDNF) expression, an important neuroprotective factor, and preventing neuroinflammation ( 70 ). Aromatase expression is required for NDE production, and is most highly expressed in the limbic system, suggesting damage to the limbic system could lower NDE ( 69 ) and promote disease. Neuroprotective actions of sex steroids in literature Abbreviations: AD, Alzheimer disease; ANXA1, annexin A1; APP, amyloid precursor protein; BACE1, β-secretase; Bax, Bcl-2 associated X-protein; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CD, cluster of differentiation; CREB, cAMP response element binding protein; Ho1, heme oxygenase-1; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; NDE, neuronally derived estradiol; NFκB, nuclear factor-κB; NRF1, nuclear respiratory factor-1; Nrf2, nuclear factor erythroid 2-related factor 2; PI3K/Akt, phosphoinositide 3-kinases/protein kinase B; PP2a, protein phosphatase 2A; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1. Research on the neuroprotective effects of estradiol rarely separate effects between NDE and circulating estradiol; however, one can assume that findings from the following research can largely be attributed to the higher concentration of circulating estradiol sourced from the ovaries. Estradiol promotes BDNF signaling induction ( 10 ), acts as an antioxidant and promotes cell survival ( 9 , 11 ), protects against stroke damage ( 72 , 73 ), prevents insulin resistance ( 11 ), and prevents protein aggregation of AD hallmarks Aβ ( 71 ) and phosphorylated tau (pTau) tangles ( 69 , 74 ), effectively protecting neurons from energy loss and excitotoxicity. Intriguingly, female patients with AD have significantly lower levels of estradiol than age-matched controls ( 90 ). Progesterone is also neuroprotective, promoting cell survival through similar mechanisms to estradiol, such as promoting cell survival and reducing neuroinflammation ( 78 ). However, progesterone-estradiol combination therapy can cause both positive and negative effects on brain pathology, suggesting the molecules can act both synergistically and antagonistically. In a study testing the effect of estradiol and progesterone on mitochondrial output, estradiol and progesterone could separately rescue mitochondrial function after poisoning, but this effect was lost with coadministration ( 91 ). Progesterone can inhibit estrogen receptor expression, as well as prevent estrogen receptors from binding to chromatin to exert their effects. It is unclear in which scenarios this may or may not be occurring, or if another mechanism of action is responsible for this antagonism ( 78 ). Testosterone exhibits some neuroprotective qualities as well, preventing cell death ( 83 ), protein aggregation ( 87 ), and increasing synaptic density ( 84-86 ). However, free testosterone concentration was found to correlate with impaired cognition in women with PCOS, specifically in psychomotor speed and visuospatial learning, suggesting an essential balance of sex steroids to accomplish efficient cognitive function ( 92 ). Regulating neuroinflammation is an essential protective mechanism in the brain. Estradiol and progesterone can both reduce neuroinflammation ( 77 , 79-81 ) and strengthen junctions of the BBB ( 11 , 75 , 76 , 82 ). Excessive doses of testosterone in male rats reduced expression of claudin-5 and occludin ( 93 ); however, chronic depletion of testosterone also reduced expression of claudin-5, zona occludens-1 (ZO1), and upregulated inflammatory factors tumor necrosis factor (TNF), inducible nitric oxide synthase, and cyclooxygenase-2, suggesting a balance of testosterone concentration is required to maintain BBB integrity ( 94 ). Gonadotropins refer to FSH and LH, which are cyclically released from the pituitary. Their neurobiological actions are detailed in Table 3 . Both can become chronically high with loss of sex steroid feedback ( 15 ). Neurobiological effects of gonadotropins in literature Abbreviations: Aβ, amyloid β; AD, Alzheimer disease; APP, amyloid precursor protein; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; Cx43, connexin-43; FSH, follicle-stimulating hormone; FSHR, follicle-stimulating hormone receptor; GFAP, glial fibrillary acidic protein; GluR1, glutamate receptor 1; GnRH, gonadotropin-releasing hormone; HPO, hypothalamic-pituitary-ovarian; IBA1, ionized calcium-binding adaptor molecule 1; IL, interleukin; LH, luteinizing hormone; OVX, ovariectomized; TNF-α, tumor necrosis factor-α; VGluT1, vesicular glutamate transporter 1. LH exists in two populations—one is released from the pituitary and circulates peripherally, while the other is produced from the hypothalamus and regulates expression levels of LH receptor (LHR) in the brain ( 105 ). Peripheral LH levels correlate with AD progression, Aβ load, and cognitive decline in humans ( 106 , 107 ), but it is unclear if this effect is through a direct action of LH on neurons after crossing the BBB, an indirect action by which high peripheral concentrations of LH suppress brain synthesis of LH, or an entrance of peripheral LH to the brain only after damage to the BBB. Multiple earlier works have found LH to cross the BBB to a limited extent; it is unknown if this action would change under a disease state or state of endocrine dyscrasia ( 108 , 109 ). It is clear that high peripheral LH is associated with negative neurological outcomes. In postmenopausal women, high LH correlated with poor cognitive performance ( 110 ). Older women with AD had higher levels both of LH and FSH compared to age-matched controls ( 106 ). In animal studies, LH administration induces cognitive deficits and increases amyloid deposition ( 100 , 111 ). Intriguingly, studies directly testing the effect of LH on neuronal cells find mixed results. In neuronal culture, LH increased production of plaques via increased β-secretase (BACE1) activity, but also increased production of pregnenolone, a precursor to the neuroprotective estradiol ( 98 , 101 ). When administered directly to the mouse brain, one study found LH to impair memory function ( 112 ). A separate study found this administration to ameliorate cognitive OVX symptoms ( 113 ). Notably, the former study used a much higher dose than the latter. Considering LH can dose-dependently downregulate expression of its receptor, this suggests that benefit or harm could depend greatly on dose. It has been shown that peripheral and brain LH have inverse concentrations naturally ( 114 ). Whether or not LH crosses the BBB, high peripheral LH would therefore yield low signaling through LHR, either through suppression of brain LH or through suppression of LHR expression ( 115 ). LHR is highly expressed in many disease-sensitive brain regions, including the hippocampus, hypothalamus, cortex, pons, cerebellum, thalamus, and medulla ( 116 ), and is an important contributor to memory processes and long-term potentiation through extracellular signal-regulated kinase (ERK) and protein kinase A signaling ( 117 ). A reduction in LHR signaling due to high peripheral LH is a plausible theory behind human studies correlating high LH with neurodegenerative indicators. A third possibility is that peripheral LH weakens the BBB, allowing for its own entry to the brain. In OVX mice, FSH and LH inhibition rescued a leaky BBB, indicating one or both of these molecules could allow for its own entry to the brain ( 104 ). This would suggest that other factors like toxins or inflammatory cytokines could increase brain concentrations of gonadotropins. Future studies should explore this and other possibilities. For further reading on the subject, see the 2021 review by Mey et al ( 105 ). Many studies correlate FSH concentrations with negative consequences on the brain, but a suggested mechanism has only recently been proposed in the literature. In postmenopausal women, FSH levels correlated with vascular stiffness, increasing stroke risk ( 118 ), as well as concentrations of inflammatory cytokines ( 119 ). In premenopausal women, FSH levels correlated with depression risk, which itself is a risk factor for dementias ( 120 , 121 ). FSH receptor (FSHR) brain expression is described in multiple recent studies, with transcripts identified in the mouse cerebellum, olfactory bulb, hippocampus, cerebral cortex, medulla, midbrain and pons, forebrain, thalamus, and hypothalamus ( 68 , 122 ). Another study validated findings in the yak hypothalamus, pineal gland ( 123 ), and mouse hippocampus ( 124 ). A further study found FSHR expression in the human cortex, and the mouse cortex and hippocampus ( 122 ). Similarly to LH, it is unclear if FSH is able to cross the BBB, if it exerts actions indirectly, or if it contributes to BBB destruction to enter the brain. A recent study using an AD mouse model used a fluorescent tag to observe injected FSH crossing the BBB. The researchers then showed that deleterious effects of FSH were occurring through FSHR binding and subsequent activation of the CCATT/enhancer binding proteins beta and delta (C/EBPβ/δ)-secretase pathway, including deposition of amyloid plaques and tau tangles. They also showed increased gliosis signatures, suggesting FSH modulation of microglia ( 68 ). The physical properties of FSH suggest it would have to be actively transported across the BBB, and more research will be necessary to parse how and through what circumstances endothelial transport of FSH would occur. Several studies report FSH can induce inflammatory states in immune cells in peripheral tissues ( 125 , 126 ), suggesting damage to the BBB through inflammation could be another mode of entry. Overall, more research in the coming years will be required to highlight either a similar or disparate mechanism of FSH action on the brain compared to LH, with current but limited studies hinting at a deleterious and direct action of FSH on sensitive brain regions. For further reading on the topic, see Xue et al ( 127 ). Although neurotypical women are at higher risk of developing dementia than men, men with Down syndrome are more likely to develop the disease than women with Down syndrome. In both cases, the higher risk group experiences elevated concentrations of FSH and LH, suggesting a direct link between gonadotropin concentration and disease risk, regardless of sex ( 102 ). Gonadotropin inhibition can induce BDNF expression and rescue cognition ( 102 , 103 ). More research is required to parse potential regulation of FSH and LH on each other in the brain, with regard to modulation of receptor expression in disease-sensitive brain regions.

This review highlights the distinct roles of gonadotropins and sex steroids in the brain and reproductive organs, urging a reconsideration of the HPO axis as a network of discrete hormonal effectors with multisystemic effect. Current therapies overlook the effects of ovarian dysfunction on brain health. We suggest an integrative, temporally sensitive, and mechanistically precise approach to understanding and intervening in reproductive aging and its neurological sequelae ( Fig. 2 ). Summary of potential effects of ovarian disorders on brain pathology. A, Menopause and POI comprise inflammatory aging symptoms, with potential consequences of neuroinflammation through BBB disruption, gliosis, and loss of neuroprotection through sex steroid depletion, and pathological aggregation through high gonadotropin concentration. B, PCOS comprises metabolic dyscrasia and hyperandrogenism, with potential consequences of BBB disruption from systemic inflammation, altered cerebral energy metabolism through insulin resistance, and protein aggregation through high peripheral LH.Abbreviations: AMH, antimüllerian hormone; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; FSH, follicle-stimulating hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; POI, primary ovarian insufficiency. HRT remains a cornerstone of menopausal care, but evidence suggests neuroprotective benefits diminish after age 65 years ( 12 ), demonstrating intervention should begin concurrently with initial hormone dyscrasia, requiring more careful monitoring of endocrine effectors at the suspected time of perimenopause. Additionally, estradiol and progesterone may execute counterproductive actions in the brain when administered together ( 78 , 91 ). Progesterone administration aids in uterine cancer prevention ( 174 ); thus, it could be beneficial to administer hormones more cyclically, minimizing overlap between estrogen and progesterone concurrence. Mechanisms underlying the combined therapy on other organs must be better understood. To optimize treatment strategies across the spectrum of ovarian dysfunction, future clinical trials should consider levels both of sex steroids and gonadotropins as therapeutic targets. Rebalancing the endocrine environment may be necessary to relieve the range of symptoms experienced in ovarian disorders. For example, gonadotropins rise markedly in perimenopause, making FSH and LH valuable markers for identifying critical windows for intervention. These trials should evaluate cognitive as well as ovarian health outcomes. A critical next step in HPO axis research is clarifying the mechanistic action of gonadotropins in the aging brain, as questions of BBB access and direct modulation of neurons are inconsistent ( 113 ). Future work could prioritize questions of endothelial entry of gonadotropins, as well as the development of specific inhibitors for each gonadotropin, to clarify previous findings using leuprolide acetate to inhibit both gonadotropins simultaneously ( 102-104 ). Additionally, existing drugs approved for menopause care that inhibit GnRH pulsatility, such as fezolinetant (brand name VEOZAH, manufactured by Astellas Pharma US Inc.), could potentially be repurposed for improving dementia risk ( 175 , 176 ). Future trials are needed to assess efficacy of these compounds in improving neuronal outcomes. Concurrently, BBB disruption in ovarian dysfunction and the potential role of gonadotropins warrant closer study. While animal models of menopause have advanced our understanding of how chronic inflammation compromises BBB integrity ( 104 ), comparable models for POI and PCOS remain underdeveloped. Characterizing these models will allow better understanding for ways in which ovarian disorders can contribute to BBB disruption, as well as identifying targetable mechanisms for reinforcing BBB integrity. Therapeutic strategies that modulate local inflammation may also offer long-term benefits, such as using metformin, a diabetes drug, for improving insulin-resistance–derived inflammation in menopause and PCOS ( 177 ). Finally, lifestyle interventions remain a low-risk and potentially high-reward adjunct to pharmacologic approaches. Recent studies have found that increasing dietary intake of fruits, fiber, unsaturated fats, vegetables, and lactobacillus-based probiotics increases beneficial populations of gut microbes, lowering inflammation and improving mood ( 178-182 ). Increasing physical activity also lowers vascular markers of inflammation ( 183 ) and can improve insulin resistance ( 184 ). As part of an integrative therapeutic model, such interventions should be tested in combination with targeted therapies to optimize health-span in individuals with ovarian hormone dysregulation. In sum, advancing ovarian research requires a reconceptualization of the HPO axis as a network of individual yet interdependent effectors. A multisystem, syncretic experimental approach will be critical to move beyond symptom control and toward a future of personalized endocrine aging management.