The Effect of Mild Traumatic Brain Injury on the Hypothalamic–Pituitary–Ovarian Axis: A Narrative Review

Abstract

Mild traumatic brain injury (mTBI) is the most common type of traumatic brain injury (TBI), with 2.5 million cases reported annually in the United States. mTBI involves diverse signs, symptoms, and functional impairments that typically resolve within 1 month, but may persist. Female sex is one of the most consistent predictors associated with an increased risk of mTBI and worse outcomes, including greater symptom severity and prolonged recovery. Emerging evidence also suggests that females are at greater risk of menstrual cycle dysfunction following mTBI, which could have downstream consequences on reproductive and related women’s health outcomes. Researchers have speculated that the underlying mechanism for these detrimental effects is the injury’s impact on the hypothalamic–pituitary–ovarian (HPO) axis; however, it is necessary to further clarify the extent of these disruptions, identify consistent patterns across studies, and determine potential implications for reproductive health and hormonal regulation following mTBI. The goal of this narrative review is to understand the effects of mTBI on the HPO axis, identify gaps in the research and clinical practice, and provide recommendations to address these issues in females with mTBI. We summarize: (1) sex differences observed following mTBI, including physiological variables that contribute to these differences, particularly the menstrual and ovulatory cycles in females; (2) pituitary gland functions and hormonal regulations; (3) pituitary and hormonal dysfunction after mTBI; and (4) implications of hormone dysregulation on mTBI recovery. Our review concludes by highlighting methodological gaps, research needs, strategy recommendations, and treatment referrals for patients with HPO axis dysfunction after mTBI.

Introduction

Traumatic brain injury (TBI) affects approximately 69 million people worldwide each year, with at least 3.5 million cases reported in the United States alone^1,2 and many more that may go unreported or undiagnosed.³ The cost of care for TBI is estimated to reach up to $200 billion annually.⁴ Often referred to as a “silent epidemic,” TBI is defined as any brain injury caused by an external force that impacts the head or skull, which can affect brain function and other bodily systems. Using the Glasgow Coma Scale (GCS), mild ranges from 13 to 15 points, moderate ranges from 9 to 12 points, and severe ranges from 3 to 8 points.⁵ Mild TBI (mTBI), or concussion,⁶ although the least severe of these injuries, is the most common and represents a significant public health problem, accounting for 80–90% of all TBIs in the United States.⁷

mTBI is difficult to diagnose and manage due to the heterogeneous signs (e.g., confusion, loss of consciousness, post-traumatic amnesia), symptoms (e.g., dizziness, headaches, light and noise sensitivity), and functional impairments (e.g., behavioral, neurocognitive, vestibular), as well as a lack of evidence on standard neuroimaging, which characterizes the injury.^8,9 One of the most salient factors in the variation of mTBI outcomes is biological sex,^10–23 which refers to the set of biological traits in males and females associated with gene expression, hormone function, and chromosomes.²⁴ Prior research has consistently demonstrated that females are at greater risk of sustaining an mTBI than males.^{15,18,21,23,25,26} Females also tend to exhibit greater post-concussion symptom severity, worse clinical outcomes (e.g., neurocognitive, vestibular/ocular motor), and take longer to recover than males.^{15,16,18–21,23,27,28} Biomechanical differences, such as weaker neck strength and smaller neck size, may make females more susceptible to mTBI.^23,29 In addition, some research suggests that mitochondria may play a central role in TBI pathophysiology, with notable sex differences including variations in mitochondrial respiration, antioxidant status, and dynamics potentially contributing to outcome variability in males and females.³⁰ Evidence for these underlying mechanisms following mTBI is mixed and often does not fully account for differences in clinical outcomes and recovery time between males and females.^23,27,31

Researchers have speculated that hormonal fluctuations in females may be responsible for the reported sex differences in clinical outcomes observed after mTBI.^23,32–34 A study of 144 females identified that menstrual cycle phase and progesterone concentration at the time of mTBI were associated with neurological and quality-of-life outcomes 1 month after injury.³² Other research has demonstrated that mTBI is associated with an increased risk for abnormal menstrual cycle patterns.^33,35–37 The underlying etiology of these changes may be due in part to the effect of mTBI on the hypothalamic–pituitary–ovarian (HPO) axis, which results in dysregulation of hormones such as prolactin, thyroid, and adrenal gland hormones, and subsequently, progesterone and estradiol. However, a comprehensive review summarizing the effects of mTBI on the HPO axis and the various proposed mechanisms of dysfunction is currently lacking in the literature. Such a review will provide a better understanding of the downstream consequences of mTBI on reproductive and related women’s health outcomes, as well as the importance of early identification and management of these effects to mitigate adverse outcomes.

In 2016, the National Institutes of Health (NIH) acknowledged sex as a biological variable (SABV) and emphasized the importance of integrating SABV into research, as understanding biological variability is crucial for developing targeted clinical care for different populations.^24,38 While outcomes in mTBI have been characterized across populations, their underlying mechanisms are not well understood, and despite the robust concussion literature, females remain an understudied group.^23,27 A review of recent mTBI consensus and position statements revealed a significant underrepresentation of females in the cited literature.³⁹ The studies informing consensus clinical recommendations included 80% male participants, with 40% of studies including no female participants. Therefore, a comprehensive review exploring hormonal function and the effect of mTBI on the HPO axis is warranted. Such a review will inform clinical recommendations, address disparities in the literature, and highlight further areas of research.

The aim of this narrative review is to examine the effects of mTBI on the HPO axis, an area that remains understudied, while comparing these findings with those observed in moderate-to-severe TBI populations. We acknowledge existing gaps in research and clinical practice regarding mTBI and sex-specific differences in outcomes. This review seeks to provide recommendations to enhance clinical care for females following mTBI. To advance knowledge and inform clinical practice, we focus on the following areas: (1) pituitary gland function and hormonal regulation; (2) pituitary and hormonal dysfunction following mTBI; and (3) the implications of hormone dysregulation on mTBI recovery. The review concludes by highlighting methodological gaps and research needs and recommends strategies and treatment referrals to improve clinical care for patients with HPO axis dysfunction following mTBI.

Methodology

Study design

This was a meta-narrative review that used a systematic, comprehensive approach to explore the available evidence on the effects of mTBI on the HPO axis.

Search strategy

A comprehensive literature search was conducted using several electronic databases, including PubMed/MEDLINE and Google Scholar, employing the following search terms: mild traumatic brain injury, neuropathophysiology, epidemiology, prevalence, neuroendocrine dysfunction, hypopituitarism, and sex differences.

Study duration

The review included studies published between January 1, 2000, and August 31, 2025.

Eligibility criteria

Studies were included if they met the following criteria: systematic reviews, meta-analyses, cross-sectional, observational, or cohort studies; were published in English between 2000 and 2025 to ensure relevance; focused on populations with TBI and related neuropathophysiology; and clearly described their methodology and reported measurable outcomes. Studies were excluded if they were non-peer-reviewed (e.g., editorials or opinion pieces), did not address TBI or pituitary dysfunction prevalence, were authored by a single individual, were duplicates or redundant, published in languages other than English, published prior to 2000, or lacked sufficient methodological detail or clear outcome measures.

Pituitary Gland and Hormonal Regulation

Overview of the pituitary gland

The pituitary gland, referred to as the “master gland,” regulates hormone production throughout the body. Located within the sella turcica and connected to the hypothalamus by the infundibulum (stalk) (Fig. 1A),⁴⁰ the pituitary gland consists of two main parts: the adenohypophysis (anterior pituitary) and the neurohypophysis (posterior pituitary). The hypothalamus communicates with the adenohypophysis via hormones and the neurohypophysis via nerve impulses. Anterior pituitary—primarily the pars distalis—produces prolactin, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and growth hormone (GH) (Fig. 1B). The posterior pituitary stores and releases hypothalamic hormones, including oxytocin and vasopressin.

FIG. 1.

(A) Depicts the relationship in the brain between sella turcica, pituitary, suprasellar cistern, diaphragm sella, hypothalamus, and the infundibulum stalk. (B) Illustrates the interactions in the hypothalamic–pituitary axis. The hypothalamus releases gonadotropin-releasing hormone (GnRH), growth hormone (GH), cortisol-releasing hormone (CRH), thyroid-releasing hormone (TRH), and dopamine. (+) indicates positive stimulation and (−) demonstrates negative stimulation. The pituitary then releases follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH), respectively, to stimulate the endocrine organs. GHRH, growth hormone-releasing hormone.

Regulation of key hormones

The pituitary gland is uniquely supplied by the hypothalamo–hypophyseal portal system, enabling hypothalamic control of anterior pituitary secretion. The pituitary stalk’s vascular structures are vulnerable to mechanical injury or increased intracranial pressure, potentially causing ischemic hypopituitarism. Hormonal deficiencies typically begin with GH loss, followed by ACTH, gonadotropins (FSH and LH), and TSH. The hypothalamic–pituitary axis regulates downstream endocrine organs, including the adrenal, thyroid, and gonadal systems. The hypothalamic–pituitary–adrenal (HPA) axis controls the body’s response to stress, preserving homeostasis when intact. The HPO axis is critical for female reproductive function, with pulsatile gonadotropin-releasing hormone (GnRH) release stimulating LH and FSH secretion, ovarian estrogen and progesterone production, and normal menstrual cycle regulation.^41,42

Reproductive hormones and the menstrual cycle

The female reproductive life spans from menarche to menopause. The menstrual cycle exists through a well-coordinated series of interactions between the hypothalamus, pituitary, ovaries, and endometrium, with estrogen and progesterone acting as key modulators. The cycle includes the follicular phase, during which a dominant ovarian follicle develops, and estrogen levels rise, leading to a mid-cycle LH surge and ovulation. Following ovulation, the follicle becomes the corpus luteum, which secretes progesterone to transform the endometrium into a secretory lining.⁴² If fertilization does not occur, the corpus luteum deteriorates, progesterone levels fall, and the reduced blood flow to the spiral arterioles causes ischemia and shedding of the endometrial tissue as menstruation. Within 2 days after menstruation begins, estrogen produced by the newly growing ovarian follicle(s) stimulates the regeneration of the surface endometrial epithelium.⁴² Estrogen and progesterone provide feedback to the hypothalamus and pituitary gland, adjusting the levels of GnRH, FSH, and LH to maintain homeostasis within the HPO axis, ensuring proper regulatory function.⁴³

Pathophysiology of HPO Axis Disruption in mTBI

Neuroendocrine dysfunction

mTBI can impair the function of brain areas responsible for neuroendocrine homeostasis involved in stress response, metabolic regulation, reproductive function, tissue growth, and overall quality of life. Neuroendocrine dysfunction (NED) refers to hormonal imbalances and dysregulations, particularly involving the HPO axis. In females, disruptions in this axis from mTBI can impair the regulation and secretion of estrogen and progesterone, affecting the menstrual cycle and ovulatory function. These hormonal fluctuations are believed to impact the onset, recovery, and outcomes of mTBI.⁴⁴

Several prospective studies examining changes in menstrual cycle patterns in adolescents following mTBI revealed potential menstrual changes.³³ Specifically, compared to those with non-head orthopedic injuries, adolescent and young women who suffered a concussion experienced an increased risk of having two or more abnormal menstrual cycles within 4 months following injury (odds ratio = 5.85; 95% confidence interval [CI]: 1.61–21.22).³³ Another study demonstrated that at 3–4 months post-concussion, 1 in 10 adolescents reported changes in their menstrual cycle.⁴⁵ More specific types of NED that may result from mTBI and will be discussed further below include hypopituitarism, gonadotropin deficiencies, and hyperprolactinemia.

Hypopituitarism

It is well established that the pituitary gland, in coordination with the hypothalamus, plays a central role in regulating peripheral glands by synthesizing and secreting hormones.⁴⁶ The HPA axis orchestrates the body’s response to internal and external stressors, ensuring the maintenance of physiological homeostasis.⁴⁷ As a result, damage to the hypothalamic–pituitary system from TBI can lead to both acute and chronic consequences, disrupting the regulatory system. However, the pathophysiology of pituitary dysfunction following TBI is complex and incompletely understood. Proposed mechanisms include direct pituitary trauma, disruption of the hypothalamic–pituitary axis, ischemic injury, and neuroinflammatory responses, all of which may contribute to post-TBI hypopituitarism.

The severity and type of pituitary dysfunction can vary with factors such as the nature of the injury (focal vs. diffuse), the severity of the TBI (mild, moderate, or severe), the time since the injury, and individual patient characteristics.⁴⁷ The severity of the injury is generally parallel to the severity of the TBI and its consequences on the system. Mild injury produces only microscopic multifocal damage, and moderate and severe TBI produce more severe, widespread, and long-term consequences. One potential consequence of damage to the pituitary gland or hypothalamus after mTBI is hypopituitarism, characterized by decreased secretion of pituitary hormones. Pituitary hormones not only have important cerebral effects on brain development but also allow for normal brain function necessary for brain repair and recovery.⁴⁸

Aljboor et al.⁴⁷ performed a meta-analysis of 52 studies encompassing 7,367 participants to evaluate the prevalence of pituitary dysfunction following TBI across various post-injury time points. The pooled prevalence of dysfunction affecting at least one pituitary axis was 33% (95% CI: 28–37%), underscoring a substantial burden of pituitary impairment among individuals with TBI. Temporal analyses demonstrated that prevalence peaked within the first 3 months post-injury at 40% (95% CI: 27–53%), followed by a gradual decline to 31% (95% CI: 15–47%) at 3–6 months, 26% (95% CI: 19–33%) at 6–12 months, and 32% (95% CI: 26–38%) beyond 12 months. These findings indicate an early surge in pituitary dysfunction after TBI, with partial improvement over time, although prevalence remains elevated in the chronic phase.

When dysfunction involved multiple pituitary axes, the overall pooled prevalence was lower at 7% (95% CI: 6–9%), yet remained clinically significant. Temporal analysis revealed a relatively stable prevalence across time, ranging from 13% (95% CI: 6–20%) within the first 3 months of post-TBI to 7% (95% CI: 5–9%) beyond 12 months. Collectively, these variations in prevalence highlight the dynamic nature of pituitary dysfunction following TBI and emphasize how its presentation evolves across acute and chronic phases. These clinical variations support a tailored approach to clinical management, guided by the specific pituitary axis affected and the duration of injury.⁴⁷

Pituitary hormones not only have important cerebral effects on brain development but also allow for normal brain function necessary for brain repair and recovery. For example, it is now evident that both the GH and insulin-like growth factor (IGF-I) receptors are widely distributed in the brain. GH is directly involved in vascular reactivity, tone, and central nervous system repair following a hypoxic brain injury. IGF-I is vital in myelination, preventing demyelination and protecting oligodendrocytes from tumor necrosis factor-alpha-induced apoptosis.⁴⁰ Although the pathophysiology of TBI-induced hypopituitarism is not yet fully understood, there are indications that it may significantly impact brain recovery following a TBI.⁴⁹

Hypopituitarism is often underdiagnosed after TBI because its signs and symptoms are generally non-specific. Both acute and chronic pituitary dysfunction are common following moderate-to-severe TBI. Although pituitary failure after mTBI was previously thought to be rare, it may occur in some cases. In the cases of TBI, a meta-analysis involving 1,137 patients reported a pooled prevalence of hypopituitarism at 27.5% following a TBI. The prevalence of hypopituitarism was greater in patients with severe brain injuries when compared with those with mild or moderate TBIs. The prevalence of anterior pituitary dysfunction in various studies ranged from 15% to 68%. The duration and design of pituitary assessments varied, with follow-up periods ranging from 3 months to 7 years after the trauma.⁴⁹ The degree of hypopituitarism and its reversibility depend on the location and number of affected axes. Approximately 19.8–25.3% of TBI patients experience dysfunction of a single pituitary axis, whereas involvement of multiple axes is less common.⁴¹ The growing awareness of pituitary dysfunction following TBI may involve several factors, including direct injury to the pituitary gland or stalk, and injuries leading to ischemia and infarction, therefore impacting its delicate hormonal regulation. These factors may be attributed to venous infarction in the long hypophyseal portal veins. Other secondary insults, such as hypoxia, anemia, and reduced cerebral perfusion pressure, may also play a role.⁴⁰

Overall, deficiencies in anterior pituitary hormones are more significant than those in posterior pituitary hormones. Understanding the hierarchical nature of hormonal loss is key to understanding hypopituitarism in post-TBI patients. Studies have shown that the incidence of chronic somatotroph failure (GH deficiency) is between 15% and 18%, followed by failure of gonadotropins, which results in hypogonadism, is approximately 14%. In contrast, deficiencies in corticotrophs, thyrotrophs, and posterior pituitary hormones are much less common, with prevalence rates of 8%, 5%, and 2%, respectively.⁴⁰ These findings emphasize the resilience of the adrenal, thyroid, and posterior pituitary axes, in contrast to the vulnerability of the somatotrophs and gonadotrophs.

Gonadotropin deficiencies

Gonadotropin deficiencies following TBI often present clinically in patients with menstrual disturbances, infertility, osteoporosis, reduced muscle mass, hair loss, galactorrhea, breast atrophy, cognitive dysfunction, and fatigue. Diagnostic tests show low serum gonadal sex steroid levels and low gonadotropin levels, including low testosterone, estrogen, FSH/LH, and elevated prolactin.⁴¹ A study by Agha et al.⁵⁰ tracked 50 male and female patients at 3 time points, including the acute phase, 6 months, and 12 months following a moderate or severe TBI, finding that 80% had low serum gonadotropin levels in the acute phase after injury, with most (85%) recovering after 12 months. The authors observed a significant positive correlation between admission GCS scores and 12-month functional outcomes with low serum testosterone levels.⁵⁰

Hyperprolactinemia

Serum prolactin disturbances can vary following TBI. Prolactin secretion is primarily regulated by hypothalamic dopamine inhibition, along with various endocrine modulators. It is hypothesized that TBI-related damage to the hypothalamus and pituitary, combined with changes in dopaminergic activity and the stress response, may contribute to abnormal prolactin levels post-injury.⁵¹ However, investigating the direct impact of TBI on prolactin is challenging due to the involvement of multiple physiological mediators during the stress response. Despite this, obtaining baseline prolactin levels following injury may offer valuable insight into hypothalamic–pituitary function. In the acute phase of TBI, elevated prolactin levels tend to correlate with injury severity. Conversely, during the chronic phase, prolactin may serve as an indirect marker of pituitary dysfunction and reduced gland volume.⁵¹ Further research is needed to clarify the long-term trajectory of prolactin dysregulation after TBI.⁵¹ Notably, studies have reported hyperprolactinemia in 48% of hypogonadal patients with acutely post-TBI, 28% at 6 months, and 33% at 12 months.⁴¹

Conceptual mechanistic framework

Based on the above evidence, Figure 2 depicts three proposed mechanistic pathways by which mTBI can lead to menstrual dysfunction by disrupting the HPO axis. The first pathway is via ischemic injury, whereby transient vascular compromise of the hypothalamus, infundibulum, and/or pituitary, caused by biomechanical forces of concussion, may impair neuroendocrine signaling, even without structural abnormalities. The second pathway is via hyperprolactinemia, whereby acute increases in prolactin following pituitary dysfunction inhibit hypothalamic GnRH pulsatility, reducing secretion of LH and FSH. The third pathway is via stress-induced hypercortisolemia, whereby activation of the HPA axis elevates cortisol, which suppresses hypothalamic GnRH secretion, producing central HPO axis suppression and anovulation, similar to functional hypothalamic amenorrhea. Across all pathways, reduced GnRH pulsatility leads to decreased LH and FSH release, diminished ovarian estradiol and progesterone production, and downstream alterations in endometrial function, resulting in menstrual cycle disturbances.

FIG. 2.

Hypothesized mechanisms of menstrual cycle disruption following neurotrauma. Schematic representation of three proposed pathways by which neurotrauma may disrupt hypothalamic–pituitary–ovarian (HPO) axis function and lead to menstrual cycle changes. (1) Ischemic injury: transient vascular compromise to the hypothalamus, infundibulum, and/or pituitary caused by biomechanical forces of concussion may impair neuroendocrine signaling, even without structural abnormalities. (2) Hyperprolactinemia: acute increases in PRL following pituitary dysfunction inhibit hypothalamic GnRH pulsatility, resulting in reduced secretion of LH and FSH. (3) Stress-induced hypercortisolemia: activation of the hypothalamic–pituitary–adrenal axis leads to elevated cortisol, which suppresses hypothalamic GnRH secretion, producing central HPO axis suppression and anovulation, like functional hypothalamic amenorrhea. Across all pathways, reduced GnRH pulsatility leads to decreased LH and FSH release, diminished ovarian estradiol (E2) and progesterone (P4) production, and downstream alterations in endometrial function, resulting in menstrual cycle disturbances. “+” indicates stimulatory effects and “−” indicates inhibitory effects. E2, estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; P4, progesterone.

Implications of Hormone Dysregulation on Recovery Trajectory

Estrogen and progesterone, hormones with neuroprotective effects, may play a crucial role in determining the outcomes and neurological recovery after TBI in pre-clinical models.^52,53 Women of childbearing age, who experience cyclic fluctuations of these hormones, may report worse outcomes post-injury, likely reflecting disruption of the HPO axis and downstream hormone deficits.³² A retrospective study by Ripley et al.³⁷ found that women may experience changes in their menstrual cycles, such as missed periods or complete amenorrhea, in the post-injury phase following TBI. Several studies have reported increased irregular menstrual cycles following mTBI.^33,45,54 This suggests that fluctuations in estrogen and progesterone levels could impact both the recovery time and quality of life post-injury. Other research has shown that moderate-to-severe TBI may suppress the hypothalamic–pituitary–gonadal (HPG) axis, resulting in lower levels of hormones such as LH and FSH, leading to downstream reductions in testosterone, progesterone, and estrogen.⁵⁰ The sudden withdrawal of the neuroprotective hormones may mediate the outcomes after mTBI and significantly affect symptoms and quality of life. The “withdrawal hypothesis” suggests that outcomes after mTBI may be influenced by the menstrual cycle phase at the time of injury.³² A sudden drop in progesterone—a hormone that fluctuates throughout the cycle—can impair recovery. Figure 3 demonstrates hormonal fluctuations that occur during a normal menstrual cycle (Fig. 3A), as well as possible hormonal changes following mTBI in the luteal phase with an abrupt progesterone withdrawal (i.e., withdrawal hypothesis; Fig. 3B). Figure 3C represents a hypothesis of how reproductive hormones change in subsequent menstrual cycles following injury.

FIG. 3.

Menstrual cycle hormone dynamics following concussion. (A) Normal menstrual cycle. Schematic representation of a typical 28-day ovulatory cycle demonstrating coordinated fluctuations in serum estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone (P4). A sharp mid-cycle LH surge is followed by a robust luteal P4 peak, supporting normal luteal phase length and expected timing of menses. (B) Hypothesized mechanism for concussion occurring in the luteal phase with abrupt progesterone withdrawal. Conceptual model showing concussion during the luteal phase at a time of elevated P4, followed by an abrupt decline in P4 consistent with a “withdrawal” event. After concussion, circulating reproductive hormones (E2, LH, FSH, and P4) remain suppressed at low levels with small residual fluctuations. (C) Hypothesized mechanism for post-concussion shortened cycle phenotype. Proposed pattern of menstrual cycle disruption following concussion characterized by a blunted LH surge and an attenuated luteal P4 response, resulting in earlier progesterone decline and shortened cycle length (e.g., ~23 days), clinically manifesting as more frequent menses.

Research studies on mTBI remain limited; however, Ott et al.⁵⁵ demonstrated that concussions sustained in 38 adolescent female athletes during the luteal phase—characterized by elevated progesterone levels—were associated with greater self-reported symptom burden and poorer neurocognitive performance in adolescent females during the acute recovery period. These findings may indicate hormone dysregulation during the post-injury phase.³² For instance, if an injury occurs during the luteal phase, when progesterone levels are high, the abrupt hormonal withdrawal may worsen post-injury symptoms. A review by Carr et al.⁵⁴ of five studies of 774 females concluded that hormone fluctuations, especially withdrawal of elevated progesterone, may contribute to increased symptom burden and poorer outcomes. Additionally, the menstrual cycle phase at the time of injury may influence recovery severity. This review highlights the importance of considering menstrual cycle phases in mTBI management to improve diagnostic and recovery strategies.

Neuroimaging data provide further supporting evidence that higher progesterone levels are associated with lower perceived stress and more normative cerebral blood flow after mTBI, suggesting a neuroprotective role for progesterone and that its withdrawal may exacerbate symptoms. This further highlights the importance of understanding and managing TBI and hormonal effects, particularly in females.⁵⁶ Evidence supporting the withdrawal hypothesis remains limited, warranting further research.^57,58

The studies presented above on the HPO axis following mTBI vary in sample size, study design, and measured outcomes. To improve clarity, Table 1 summarizes the available studies evaluating HPO axis function following mTBI, including key design features, measured outcomes, and associated levels of evidence.

Table 1.

Menstrual Dysfunction and Hypothalamic–Pituitary–Ovarian Axis Changes in Women Following Mild Traumatic Brain Injury: Study Characteristics and Key Findings

Study	Design	Sample size	TBI severity	Time of assessment	Key HPO findings in women	Level of evidence
Wunderle et al. (2014)32	Nested cohort study	144 women (age 16–60)	Mild TBI	1-month post-injury	Women injured during the luteal phase had significantly worse quality-of-life and neurological outcomes compared to follicular phase or oral contraceptive users	Level 2
Snook et al. (2017)33	Prospective cohort	68 concussion, 61 controls	Mild (concussion)	120 days post-injury	23.5% experienced ≥2 abnormal menstrual patterns versus 5% controls (odds ratio = 5.85, 95% confidence interval: 1.61–21.22); increased risk of irregular cycles but no amenorrhea	Level II (prospective cohort)
Roby et al. (2023)45	Prospective cohort	512 adolescents (111 at follow-up)	Mild (concussion)	Initial visit ≤28 days; follow-up 3–4 months	4% menstrual pattern change at initial visit; 10.8% at 3–4 months; menstrual phase at injury associated with symptom endorsement	Level II (prospective cohort)
Aljboor et al. (2024)47	Meta-analysis	7,367 participants (52 studies)	Mixed	3 months to >12 months	Pituitary–gonadal axis deficiency 16% overall; prevalence varied by time post-injury; women included in mixed cohorts	Level I (meta-analysis)
Ott et al. (2024)55	Prospective matched cohort	38 female athletes (age 14–18)	Sports-related concussion (mild TBI)	1-week and 1-month post-injury	Symptom scores were higher among concussed females in the luteal phase (high progesterone) at 1-week post-injury	Level 2

HPO, hypothalamic–pituitary–ovarian; TBI, traumatic brain injury.

Methodological Gaps and Research Needs

Underrepresentation of female-specific outcomes in mTBI research

Current literature has highlighted the knowledge gaps surrounding female-specific underrepresentation in mTBI research. These differences significantly impact the epidemiology, prevention, neuroprotection, secondary injury, rehabilitation timing, therapeutics, and outcomes of mTBI. The findings in the literature have underscored that females remain underrepresented in mTBI studies and clinical trials, often excluded from pre-clinical research. This exclusion has resulted in a lack of data and an incomplete understanding of mTBI in women.⁵⁹ The data that do exist in the literature include both retrospective and prospective cohorts, but are limited by small cohort sizes and limited reproductive hormonal data. It is crucial to investigate populations in which females are at higher risk for mTBI, including athletes, military personnel, and adolescents.⁶⁰ Further research is needed to highlight the importance of early screening, such as hormone evaluations, and proper post-injury monitoring using imaging techniques to examine variations in brain anatomy and function. Additionally, regular follow-ups and evaluations are essential to ensure optimal care and to track cognitive, emotional, and physical recovery in patients with mTBI.⁵⁰

Identifying hypopituitarism

It has been known for nearly a century that TBI can lead to pituitary failure, but only in the last decade have we gained a clearer understanding of the prevalence and incidence of hypothalamic–pituitary damage following mTBI. Additionally, a more recent focus has emerged on the association between mTBI-related NED and impairments in neurobehavioral health and quality of life.⁴⁰ The development of post-traumatic hypopituitarism can vary, often presenting with non-specific symptoms, making diagnosis challenging. Delayed recognition and diagnosis can lead to higher morbidity and mortality.

A prospective longitudinal study assessed the timing for detecting hypopituitarism after TBI.⁶¹ Seventy-eight patients (52 men, 26 women) with a mean age of 36 years and TBI grades I–III were compared with 38 healthy controls (25 men, 13 women). At 3 months, 56% of patients exhibited impairments in at least one pituitary axis, with the following distribution: gonadotropic (32%), corticotropic (19%), somatotropic (9%), and thyrotropic (8%). At 12 months, the number of affected patients decreased, but some new impairments were observed, and 36% of the original impairments persisted. The axes affected at 12 months were: gonadotropic (21%), somatotropic (10%), corticotropic (9%), and thyrotropic (3%). These findings suggest that HPG axis dysfunction can persist in the post-acute phase after a TBI but may normalize over time.⁶¹ However, new symptoms and cases may develop after this phase. Pituitary function following mTBI shows considerable variability, with some trauma patients experiencing elevated cortisol, GH, prolactin, and vasopressin levels as part of the acute adaptive stress response. The optimal timing for screening after mTBI remains a topic of debate.⁶²

In a consensus statement, Ghigo et al.⁶³ recommended routine basal hormonal testing for any hospitalized patient exhibiting symptoms after TBI. They also advised that individuals with mTBI who are symptomatic or hospitalized for more than 24 h, have abnormalities on initial CT scans, or show signs of pituitary failure should undergo baseline hormonal evaluations and follow-up screenings at 3 and 12 months post-injury, with further screenings if symptoms persist or new ones develop.⁶² Given the high incidence of mTBI, the question of routine endocrinology screening remains controversial. Lorenzo et al.⁶⁴ proposed to delay pituitary function evaluation until at least 1-year post-injury—especially for hormones that do not require immediate replacement, such as those in the gonadal and GH (somatotropic) axes. This is due to the overestimation of hypopituitarism in the acute phase following a TBI.

Longitudinal research on hormonal impact after TBI

A thorough understanding of pituitary hormone function is essential for effectively screening for hormone deficiencies following TBI. Hormonal regulation is crucial for understanding how TBI impacts outcomes and recovery in females. Early identification and management of menstrual irregularities in young women are vital, as amenorrhea and oligomenorrhea can be associated with hypoestrogenism. Despite progress in understanding TBI recovery and outcomes, substantial gaps remain in knowledge regarding the epidemiology, mechanisms, and effects of persistent symptoms in this population. Moreover, existing studies are typically limited by small sample sizes and limited hormone sampling time points, restricting meaningful interpretation in the context of normal menstrual cycle fluctuations.

Despite significant progress in understanding the role of sex differences in TBI recovery and outcomes for females, a large gap remains in knowledge about the epidemiology, mechanisms, and effects of persistent symptoms in women. Although hormone replacement therapy has been proposed as an adjunct in post-TBI care, the largest randomized trials (SYNAPSE and PROTECT III) demonstrated no significant benefit of progesterone over placebo in reducing mortality or improving functional outcomes, a finding confirmed by meta-analyses despite evidence of good tolerability.^51,65,66 However, these studies were limited to moderate-to-severe TBI, and the role of hormone therapy in mTBI remains largely unexplored.

The role of HRT in post-mTBI care remains understudied, with current evidence still limited, especially regarding replacement of estrogen and progesterone. One study reported hormone replacement to be the cornerstone in the treatment of patients with post-traumatic hypopituitarism.⁵ For example, in patients with decreased ACTH/cortisol, hypocortisolism should be identified early, and appropriate hydrocortisone should be administered. These patients should also be retested to ensure proper hormone replacement to reverse symptoms and risk associated with hypocortisolism. Additionally, GH supplementation in the chronic recovery phase has shown promise in improving cognitive function, body composition, and overall quality of life. However, more longitudinal research is needed to better understand chronic outcomes in women following TBI and to clarify the role of hormone replacement therapy in long-term recovery trajectories.

Clinical Implications: A Call to Action

Pituitary dysfunction following mTBI is often underrecognized and underdiagnosed by clinicians.⁶⁷ The mechanisms, risk factors, natural progression, treatment options, and recovery timelines remain poorly understood. Neuroendocrine abnormalities may be transient but can also worsen over time, leading to significant long-term consequences.⁶¹

A comprehensive understanding of pituitary hormone function is essential for clinicians to appropriately screen for hormone deficiencies.⁶¹ However, the optimal timing for screening remains controversial. Pituitary dysfunction is often not evident during the acute phase or within the first 3 weeks following TBI and does not consistently lead to long-term hypopituitarism. Consequently, limited evidence exists to support routine early screening in all patients, as it has not been shown to improve outcomes.

Criteria for determining which patients should undergo screening also remain debated. However, a consensus statement by Ghigo et al.⁶³ recommends systematic pituitary function screening for patients with mTBI who remain symptomatic or require hospitalization for more than 24 h, as well as for all patients with moderate-to-severe TBI at 3- and 12-months post-injury due to their increased risk of hypopituitarism. Importantly, symptom severity does not necessarily correlate with injury severity. Routine basal hormonal testing is particularly indicated for hospitalized TBI patients presenting with life-threatening symptoms suggestive of adrenal insufficiency.

Symptoms such as mood disturbances, memory impairment, fatigue, weakness, impaired stress response, low libido, menstrual irregularities, and reduced quality of life may suggest dysfunction of the HPO axis in females. HPO axis dysfunction can result in decreased estrogen production, impaired development of secondary sexual characteristics, and reduced bone mass and density.⁶² Even mild brain injuries may adversely affect the HPO axis function and disrupt normal menstrual cycles. Further research is needed to clarify the long-term consequences of mTBI-related HPO axis dysfunction, particularly in adolescents and young women who may be at increased risk. These findings highlight the need for close monitoring of menstrual patterns, with abnormal cycles defined as intermenstrual intervals shorter than 21 days or longer than 35 days, or bleeding durations of less than 3 days or longer than 7 days.³³

Continued medical education is critical to improving physician awareness of TBI-related endocrine dysfunction. Educating patients and their families can promote timely symptom reporting, improved follow-up, and better clinical outcomes.⁴⁹ Consistent with recommendations from the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists, clinicians managing mTBI or concussion should routinely inquire about menstrual patterns to identify females at risk for abnormal menstruation.³³

Conclusion

There is a significant need to better understand the underlying neuropathology following mTBI, particularly due to sex differences observed after brain injuries. One widely studied hypothesis is that differences in TBI outcomes arise from the injury response and the cascade of cellular, molecular, and systemic processes that follow brain injury. These processes are influenced by reproductive hormones, including estrogen, progesterone, testosterone, LH, and FSH, which can be disrupted by HPO axis dysfunction after brain injury. Consequently, understanding hormonal regulation in mTBI pathophysiology and clinical outcomes is essential for developing targeted diagnostic and therapeutic strategies, particularly for female patients. We present a conceptual model of potential mechanistic pathways by which mTBI disrupts the HPOA axis, leading to menstrual cycle dysfunction, but further research is needed to empirically evaluate the role of HPO axis dysfunction in clinical outcomes and women’s health following mTBI. Researchers should also examine the hormonal and chromosomal factors that may drive these variations. Finally, the information in this review provides an initial call to action for clinicians to assess and implement targeted strategies to address women’s health-related outcomes following mTBI.