Kristen J. Koltun

Oral contraceptive pills (OCPs) are one of the most prescribed medications, yet we lack an understanding of whether and how OCPs affect nonreproductive tissues. Given the well-documented effects of sex hormones on skeletal muscle, including on muscle mass, regeneration, and recovery, our review was aimed at assessing the impact of OCPs on skeletal muscle physiology in female humans and animals. We performed a literature search, title through full text screening, and citation search in accordance with PROSPERO guidelines. Rigor and reproducibility were assessed using the Modified Downs and Black Checklist. Meta-analyses were performed to assess the impact of OCPs on skeletal muscle outcomes. Although our search included both clinical and preclinical studies, the 40 included studies were all clinical, with no identified preclinical studies. Studies focused on young (20–30 yr) sedentary to active females with a healthy BMI (18–27 kg/m ² ) and included primarily strength and serum-based outcomes. All studies were retrospective and level III evidence. Notably, despite this literature spanning from the 1990s to 2025, rigor was in the 69th ± 6.5 percentile, and there was no correlation with rigor and year of publication. Meta-analyses did not detect an effect of OCPs on examined outcome measures; however, heterogeneity was high, suggesting the lack of rejection of the null hypothesis may be driven by variations in studies, making it challenging to draw conclusions. Taken together, we recommend prospective preclinical and well-controlled clinical studies to examine the impact of OCPs on skeletal muscle in the setting of injury, disease, and varying demographics. Our ultimate goal is to understand sex-based differences in skeletal muscle health and empower females with reliable information to inform decisions about their health. This systematic review and meta-analysis was a step toward the goal of understanding the role of OCPs on skeletal muscle health.

Anemia is prevalent among older adults and is associated with increased fracture risk, yet its relationship with bone microarchitecture remains poorly understood. We examined associations between hemoglobin (Hgb) concentrations and compartment-specific bone density, microarchitecture, structure and strength in older men and women. Methods: This cross-sectional analysis included 126 men and 185 women aged ≥70 years. Hgb quartiles and anemia status (men: <13 g/dL; women: <12 g/dL) were measured at baseline. High-resolution peripheral quantitative computed tomography (HR-pQCT) assessed bone parameters at the tibial (T) and radial (R) metaphysis (M) and diaphysis (D). Multiple linear regression models evaluated associations between Hgb quartile and anemia with sex-standardized bone parameters. Results: In men, higher Hgb was associated with greater TD total volumetric bone mineral density (Tt.vBMD; Q4 vs. Q2: β=0.67, p=0.005), but anemia status showed no significant associations. In women, lower Hgb was linked to greater total area at the TM (Q1 vs. Q2: β=0.71, p=0.002) and RD (Q1 vs. Q2: β=0.59, p=0.018). Anemic women exhibited greater total area (β=0.80, p=0.018) and cortical perimeter (β=0.75, p=0.014) but lower Tt.vBMD (β=-0.56, p=0.022, vs. non-anemic) at the RD. Conclusions: Hgb levels and anemia status exhibited sex- and site-specific associations with cortical bone structure with more pronounced effects in women. Higher Hgb in men correlated with increased bone density, while in women, it was related to smaller bone areas and more pronounced porosity. These findings suggest cortical bone is more sensitive to Hgb variations than trabecular bone, potentially due to differences in vascularization and oxygen supply.

Despite data showing half of active-duty servicewomen use hormonal contraception, its impact on physical performance during military training remains unclear. This study examined differences in general and military-specific physical performance and bone health changes based on hormonal contraceptive use. One hundred eighty-five female Marine Officer Candidates (MOCs) were grouped by self-reported menstrual/hormonal contraceptive status. Questionnaires, countermovement jumps (CMJ), isometric mid-thigh pull, physical fitness tests (PFT), peripheral Quantitative Computed Tomography (4%, 38%, and 66% tibia length), and bone biomarkers were assessed at the start and end of the 10-week program. A combat fitness test (CFT) was completed during training. Mixed ANOVAs (group ^* time) assessed training responses. Among 104 MOCs not using hormonal contraception (Non-Users; age = 25[IQR; 22, 27], BMI = 23.98 ± 1.98) and 81 MOCs using hormonal contraception (Users; age = 24[IQR; 22,26], BMI = 23.97 ± 2.19), Users showed no change in CMJ reactive strength index, while Non-Users decreased (interaction p = 0.042; Non-Users Δ = −0.03, p < 0.001). CMJ jump height was lower in Users than Non-Users (mean difference = −0.02 m, p = 0.031). CMJ performance decreased overall (all p < 0.001); braking and propulsive metrics increased ( p ≤ 0.005). PFT total points improved (Δ = 6.05 points; p < 0.001); total volumetric bone mineral density increased (4% site, Δ = 1.37 ± 0.62 mg/cm ³ ; p = 0.029), cortical density decreased (38% site: Δ = −3.04 ± 1.45 mg/cm ³ , p = 0.038, 66% site: Δ = −2.91 ± 1.35 mg/cm ³ , p = 0.033); bone formation markers (P1NP: Δ = 9.40 ± 1.91 µg/L; OC Δ = 3.42 ± 0.74 ng/mL; both p < 0.001) increased. CFT scores were similar between groups ( p ≥ 0.304). Among Non-Users, self-reported menstrual cycle irregularity increased. Users demonstrated minor differences in neuromuscular performance/fatigue, but small in effect. Hormonal contraception use was not meaningfully associated with military outcomes.

Exercise induces acute biochemical signaling between muscle, bone, and adipose tissues that may influence whole-body metabolism and musculoskeletal adaptation. This investigation examined sex-differences in concentrations of circulating biomarkers associated with metabolic and musculoskeletal regulation before and after an acute resistance exercise test. During baseline assessments for a longitudinal exercise training study, 37 participants (22 males and 15 females) completed an acute resistance exercise test consisting of a 6 set × 10-repetition back squat at 75% of their one repetition max. Blood samples were collected before and immediately after the acute resistance exercise test to quantify biomarker concentrations. Total body DXA determined body composition. Sex-differences in absolute changes from pre- to post-exercise in biomarker concentrations were examined. After adjusting for baseline lean mass, a significant interaction was observed for irisin ( p = 0.043); concentrations increased in males (∆1.1 ± 0.3 µg/mL, p < 0.001) but not females ( p = 0.515). After adjusting for baseline bone mineral content, a significant main effect of time (∆12.7 ± 1.5 pmol/L; p < 0.001) was observed for sclerostin. After adjusting for baseline fat mass, significant interactions were observed for leptin ( p = 0.040) and high molecular weight (HMW) adiponectin ( p = 0.003). Leptin concentrations decreased in females (∆−7.9 ± 2.5 ng/mL, p = 0.004) but not males ( p = 0.689). HMW adiponectin increased in females (∆630.5 ± 194.8 ng/mL, p = 0.007) but not males ( p = 0.213). A significant interaction was observed for insulin ( p = 0.004), which increased in females (∆9.7 ± 2.1 μIU/mL, p < 0.001) but not males ( p = 0.426). A significant main effect of time was observed for glucose (∆1.8 ± 0.3 mg/dL; p < 0.001). Sex-specific changes in biomarkers associated with metabolic and musculoskeletal regulation were evident following acute resistance exercise and may explain differences in health and adaptation.

This paper is the first of two publications comprising a 2025 update to the 2014 Consensus Statement on treatment and return-to-play guidelines on the Female Athlete Triad (Triad), defined as three inter-related components including energy status, reproductive function, and bone health. The Triad is initiated by exposure to varying degrees of energy deficiency with or without disordered eating/eating disorders with primary pathological outcomes to the reproductive and skeletal systems. This first paper includes a detailed update on the scientific underpinnings of the Triad and introduces a new Triad model specific to the adolescent female athlete. Energy deficiency and “metabolic compensation” are added to the energy status continuum to describe adaptations that reflect energy conservation. Ovarian steroid hormone exposure and functional hypothalamic oligo-amenorrhea are added to the reproductive function continuum. Bone stress injury is added to the bone health continuum. Rates of change are depicted for the induction and recovery of clinical outcomes within the adult model. Evidence-based statements are presented throughout the paper and supported by a high number of level A and B grades.

This is the second of two publications comprising the 2025 update to the 2014 Consensus Statement on treatment and return to play guidelines on the Female Athlete Triad (Triad). This paper pairs with the 2025 Update to the Female Athlete Triad Coalition Consensus Statement Part 1: State of the Science and Introduction of a New Adolescent Model (Sports Medicine, 2025), to focus on evidence-based revisions for screening, diagnosis, treatment, and clearance and return to play. Revised recommendations for managing eating disorders (ED)/disordered eating (DE) and non-pharmacological and pharmacological treatment of bone loss and abnormal menstrual cycles are included, as are the most recent clearance and return to play recommendations, inclusive of adolescent athletes. Recent research supports the adoption of revised criteria for defining and treating energy deficiency, moving away from the concept of an energy-availability threshold. Energy deficiency-induced menstrual disturbances can be reversed with a moderate increase in food intake and modest weight gain, but restoration of menses alone is not associated with high rates of ovulation or increased ovarian steroid levels until multiple consecutive normal length menstrual cycles are achieved. Revised guidelines for the diagnosis and treatment of functional hypothalamic oligo/amenorrhea are included with guidance on the confounding effects of hyperandrogenemia. Gynecological age and psychological stress are factors impacting the individual susceptibility to the Triad. The bone health spectrum of the Triad now includes bone stress injuries. Routes of administration via epidermal patch versus oral for pharmacological treatment of low bone density are discussed. The diagnosis, treatment, and return to play approaches for adolescents with the Triad are unique compared with those employed for adults and require age-appropriate clinical guidelines. The strength of the evidence-based statements is graded using an accepted taxonomy in which randomized controlled trials and observational data are considered the highest level of evidence.

Background/Objectives: Osteoporosis is highly prevalent and contributes substantially to morbidity and mortality, yet long-term concerns about pharmacologic therapies leave a major treatment gap. Soy isoflavones have been investigated as safer alternatives, but results across trials are inconsistent. A key unresolved issue is the equol-producer phenotype, the gut microbial ability to convert daidzein to S-equol, the most bioactive isoflavone metabolite, which may explain much of this variability. This narrative review synthesizes mechanistic, translational, and clinical evidence to clarify the potential skeletal relevance of S-equol. Methods: Literature was identified through PubMed and Scopus searches (January 2000–October 2025) for experimental, mechanistic, and clinical studies examining S-equol, estrogen receptor β (ERβ), and bone metabolism, with emphasis on equol-producing status, bone strength and bone microarchitecture. Results: S-equol acts as a high-affinity ERβ agonist with antioxidant and anti-inflammatory properties but lacks the carcinogenic or thrombotic risks linked to ERα activation. In estrogen-deficient rodent models, S-equol improves trabecular bone volume by 10–20%, increases trabecular number, and enhances biomechanical strength. These findings align with preclinical evidence demonstrating that S-equol preserves trabecular microarchitecture, enhances bone strength, and reduces bone turnover. A limited number of human trials show reductions in bone resorption by 20% at a daily dose of 10 mg S-equol. In contrast, trials of soy isoflavones in humans have produced inconsistent findings, partly because of substantial variability in equol-producer phenotype among participants and the reliance on dual-energy X-ray absorptiometry, which cannot distinguish trabecular from cortical compartments. Advanced bone imaging and microbiome-informed approaches enable the precise evaluation of S-equol’s skeletal effects on trabecular bone and cortical bone, separately. Conclusions: S-equol represents a promising model for “precision nutrition,” where microbiome, hormonal, and host factors converge with potential to prevent age-related bone fragility. Rigorous trials that integrate microbiome phenotyping and advanced imaging are needed to validate this approach, translate mechanistic promise into clinical benefit, and better define safety.

This investigation for the first time observed an association between the traditional measurement of allostatic load, the allostatic load index, and wearable-assessed physiological responses to strenuous military training stress. We found a novel digital phenotype of allostatic load characterized by chronically elevated and variable cardiometabolic activity with blunted variation in heart rate during sleep. This phenotype may serve as an at-risk profile of high allostatic load and prompt in-training modifications to enhance posttraining readiness.

Elite female tennis players are among those at high risk for developing the Female Athlete Triad (Triad), characterized by three interrelated conditions: energy deficiency/low energy availability, menstrual dysfunction, and low bone mineral density. From 1996 to 2022, the Women’s Tennis Association (WTA) developed and implemented prevention, education, and management plans for female athletes at risk for, or exhibiting symptoms of, the Triad. This article reviews the WTA Triad protocol, developed in 2018 and utilized through 2022, in collaboration with subject matter experts in the Women’s Health and Exercise Laboratory at The Pennsylvania State University. The WTA Triad protocol (1996–2022) includes prevention and management programs implemented by a multidisciplinary Performance Health Team to include screening for “red flags” during annual physicals or upon clinical presentation of a menstrual problem, bone disorder, or nutritional concern; targeted education for players, coaches, and other support team members with handouts and lectures on nutrition and body image to prevent energy deficiency; and a multidisciplinary protocol to guide treatment and return-to-play decisions. Other sport governing bodies can adopt similar multi-layered programs and practices for their athletes, coaches, and support teams to educate, screen, manage, and help to prevent the development of the Triad.