The Effects of Preoperative Pain Education on Pain Severity in Cardiac Surgery Patients: A Pilot Randomized Control Trial.

BACKGROUND: There is minimal research on the effect of individualized preoperative education on postoperative pain and postoperative pain medication intake. AIM: The study objective was to assess the effect of individually tailored preoperative education on postoperative pain severity, number of pain breakthroughs, and use of pain medication in participants receiving the intervention compared to controls. METHODS: A pilot study with 200 participants was conducted. The experimental group received an informational booklet and discussed their ideas surrounding pain and pain medication with the researcher. Controls received no intervention. Postoperative pain severity was measured by a Numerical Rating System (NRS), which was divided into mild (NRS 1-3), moderate (NRS 4-6), and severe (NRS 7-10). RESULTS: In the participant cohort, 68.8% of participants were male, and the average age was 60.48±10.7. Average postoperative 48-hour cumulative pain scores were lower in those who received the intervention compared to controls; 50.0 (IQR 35.8-60.0) vs. 65 (IQR 51.0-73.0; p < .01) participants who received the intervention had less frequent pain breakthroughs when compared to controls (3.0 [IQR 2.0-5.0] vs. 6.0 [IQR 4.0-8.0; p < .01]). There was no significant difference in the amount of pain medication taken by either group. CONCLUSIONS: Participants who receive individualized preoperative pain education are more likely to have decreased postoperative pain.

Predictors of prolonged hospitalization in modified sternoplasty following postoperative mediastinitis.

BACKGROUND AND AIM: Deep sternal wound infection (DSWI) is a serious complication following cardiac surgery, and demands early intervention as any delay in diagnosis and management may lead to increased morbidity and mortality. DSWI is associated with increased length of hospitalization (LOH) and economic burden in this patient population. The aim of this study was to determine predictors for increased length of hospitalization in patients who underwent the Modified Sternoplasty technique for deep sternal wound infection following cardiac surgery. METHODS: A retrospective study was undertaken on data from patients who underwent the Modified Sternoplasty surgery for DSWI between September 2010 and January 2020. Patients' characteristics that were recorded included medical history, type of the original heart surgery, length of hospitalizations, and risk factors including hyperlipidemia, diabetes mellitus and hypertension, and morbidity and mortality rates following the Modified Sternoplasty. RESULTS: Sixty-eight patients underwent the Modified Sternoplasty surgery with an average length of hospitalization of 24.63 + 22.09 days. Multivariable analysis showed that only gender was considered a predictor of length of hospitalization when controlling for comorbidities, with average length of hospitalization longer for women than men (35.4 vs. 20.9, p = .04). CONCLUSION: The Modified Sternoplasty surgery is a novel surgical technique for managing DSWI complicated by sternal dehiscence with exposed heart and great vessels. Female gender was associated with increased length of hospitalization in our patient cohort, with average length of hospitalization for women almost twice that of males.

Clinical factors and pre-surgical depression scores predict pain intensity in cardiac surgery patients.

BACKGROUND: Severe pain is prevalent in cardiac surgery patients and can increase cardiac complications, morbidity and mortality. The objectives of the study were to assess perioperative pain intensity and to assess predictors of pain post-cardiac surgery, including clinical characteristics and depression. METHODS: A total of 98 cardiac surgery patients were included in the study. Pain intensity was assessed using a Numerical Rating System. Pain was measured one day pre-operatively and recorded daily from Post-operative Day 2 to Day 7. Clinical data were recorded and depression scores were assessed using the Center for Epidemiological Study of Depression (CES-D). RESULTS: Pain intensity increased significantly during hospitalization from pre-operative levels, surging at 2 days post-operatively. Predictors of high pain intensity were high pre-operative CES-D scores, female gender, cardiac function, smoking and high body mass index (BMI). Significantly higher pre-operative CES-D scores were found in patients with severe pain compared to patients with no pain to moderate pain (18.23 ± 1.80 vs 12.84 ± 1.22, p = 0.01 pre-operatively). Patients with severe pain (NRS 7-10) had significantly higher levels of white blood cells (WBC) compared to patients with no pain-moderate pain (NRS 0-6), (p = 0.01). However, CES-D scores were only weakly correlated maximum WBC levels perioperatively. CONCLUSION: Pain intensity significantly increased following surgery, and was associated with depressive symptoms, female sex, cardiac function, BMI, and smoking. These factors may serve as a basis for identification and intervention to help prevent the transition from acute pain to chronic pain.

The routine use of preoperative non-contrast chest computerized tomography and carotid arteries Doppler prior to cardiac surgery.

INTRODUCTION: There is no consensus as to which patients should undergo Non-Contrast Chest Computerized Tomography (NCCCT) and carotid arteries Doppler (CD) prior to cardiac surgery. The objective of this study was to examine whether preoperative imaging modalities provide clinical benefits and a change in surgical strategy. METHODS: We routinely performed NCCCT and CD in all non-urgent cardiac surgery patients. Major NCCCT/CD findings related to cardiovascular findings (aortic calcification/atherosclerosis, carotid artery plaque/stenosis), or other incidental findings (lung kidney, thyroid, adrenal, gastrointestinal sites etc.) were documented. The results were divided into 3 categories: (A) findings requiring both changes in surgical strategy and post-operative evaluation/treatment; (B) findings requiring changes in surgical strategy, but not requiring a specific post-operative evaluation/treatment; (C) findings not requiring changes in surgical strategy but requiring post-operative evaluation/treatment. RESULTS: In this cohort, 93 (18.6%) out of 500 patients had significant cardiac and extra-cardiac findings on NCCCT and/or CD. Among the 93 patients with significant findings, 33.33% (31 patients, 6.2% of all patients) were in group A, 7.5% (7 patients, 1.4% of all patients) were in group B, and 59.14% (55 patients, 11% of all patients) were in group C. Change in surgical strategies included, for example, switching from planned on-pump Coronary Artery Bypass Graft surgery (CABG) to off-pump CABG and performing additional procedures to the originally planned heart surgery. CONCLUSION: Routine preoperative NCCCT and CD evaluation in all non-urgent cardiac surgical patients is an effective measure for uncovering cardiac and extra-cardiac findings prior to surgery.

The Modified Sternoplasty: A Novel Surgical Technique for Treating Mediastinitis.

Deep sternal wound infection (DSWI) is one of the most complex and devastating complications post cardiac surgery. We present here the modified sternoplasty, a novel surgical technique for treating DSWI post cardiac surgery. The modified sternoplasty includes debridement and sternal refixation via bilateral longitudinal stainless-steel wires that are placed parasternally along the ribs at the midclavicular or anterior axillary line, followed by six to eight horizontal stainless-steel wires that are anchored laterally and directly into the ribs. On top of that solid structure, wound reconstruction is performed by the use of bilateral pectoralis muscle flaps followed by subcutaneous tissue and skin closure. We reported mortality rates and length of hospitalization of patients who underwent the modified sternoplasty. In total, 68 patients underwent the modified sternoplasty. Two of these critically ill patients died (2.9%). The average length of hospitalization from the diagnosis of DSWI was 24.63 ± 22.09 days. The modified sternoplasty for treating DSWI is a more complex surgery compared with other conventional sternoplasty techniques. However, this technique was demonstrated to be more effective, having a lower rate of mortality, and having a length of hospitalization lower than or comparable to other techniques previously reported in the literature.

High Mitral Annulus Calcium Score in Pre-Operative Chest Computerized Tomography and Adverse Outcomes in Mitral Valve Surgery.

BACKGROUND: Severe mitral annulus calcification (MAC) is believed to bear high operative and post-operative risk during mitral valve replacement (MVR) surgery, including longer surgery time, post-surgical valvular leaks and increased rate of embolic phenomena. We hypothesized that quantification of mitral calcium in pre-operative chest computerized tomography (CCT), performed to assess aortic root before cross-clamping may help in risk assessment of adverse intraoperative and postoperative outcomes in patients undergoing MVR. METHODS: We included patients who underwent MVR between the years 2015 and 2018 at Poriya medical center. Preoperative CCT was performed using Philips iCT 256 and Agatston mitral annulus calcium score (MACS) was retrospectively calculated using Philips Intellispace portal version 8.0. Patients were divided into MACS quintiles; 1-3 quintiles were grouped (Low MACS) and compared to the 4-5 quintiles (High MACS) group for demographic, clinical operative and post-operative parameters. RESULTS: A total of 66 patients had MVR, out of which 61% were males, with mean age of 64±9. Concomitant coronary or valvular procedures were done in 60% of patients. The median MACS was 43. High MACS (≥854) was not associated with longer bypass or cross clamp times. No differences in the MVR results were found between the groups. There were 6 post-operative embolic events; 1 mesenteric and 5 cerebral, which were not associated with MACS. CONCLUSION: MACS did not seem to be related to adverse outcomes in MVR. Due to a low event rate and probable pre-selection of patients without extreme mitral annulus calcifications our results should be confirmed in larger prospective study.

Coronary artery bypass graft surgery in patients on ticagrelor therapy is not associated with adverse perioperative outcomes.

BACKGROUND: Management of patients treated with Ticagrelor is challenging, as stopping Ticagrelor prior to coronary bypass graft surgery (CABG) may increase the risk of acute stent thrombosis. The aim of the study was to compare bleeding complications in patients treated with ticagrelor combined with acetylsalicylic acid (ASA) versus ASA alone until 1 day before surgery. METHODS: Bleeding complications, defined as the composite of red blood cell transfusion ≥1000 ml, chest drainage ≥2000 ml, and bleeding requiring surgical re-exploration, were compared in 161 patients, with 101 on preoperative acetylsalicylic acid (ASA) alone (group A) and 65 on ticagrelor + ASA (group B). RESULTS: There were no differences in bleeding complications between the two groups (26% vs. 27% in group A and B, respectively), with similar chest drainage in the first 24 h (569 ± 393 ml and 649 ± 427 ml, respectively). CONCLUSIONS: Continuing ticagrelor until coronary artery bypass surgery was not associated with increased bleeding complications, suggesting that continued management with ticagrelor until surgery may be safe.

Unusual complications following left ventricular assisted device implantation: case series.

BACKGROUND: While left ventricular assisted devices (LVAD) have revolutionized the treatment of advanced heart failure, they are associated with a wide range of complications, including bleeding and infection which are the most common complications reported in the literature. Our case series report four unusual complications not related to gastrointestinal bleeding and infections and their management. CASE PRESENTATION: A 61 year old female after LVAD implantation with late onset of severe symptomatic aortic regurgitation treated by transfemoral transcatheter valve implantation (TAVI) with good long term results. A 75 year old male patient with acute pump failure secondary to cable damage, who underwent urgent pump replacement. A 49 year old female patient with a history of myoma who developed massive uterine bleeding which was treated with emergent open hysterectomy after failed gonadotropin-releasing hormone therapy replacement. A 57 year old male patient with device display failure 1 month after LVAD implantation without the ability to monitor speed, power consumption and blood flow. CONCLUSIONS: LVAD patients can be presented with a great variety of complications. Physicians should be aware of their manifestations and the management options.

Exercise rehabilitation in cardiac resynchronization: systematic review and a meta-analysis.

The benefit of exercise training in cardiac resynchronization therapy (CRT) recipients is not well established. We conducted a systematic review and meta-analysis to determine the effect of exercise training on clinical outcomes in CRT recipients.A comprehensive search until 2019 was conducted of MEDLINE, Epub, Embase, CINAHL and Cochrane databases as well as a bibliographic hand search to identify additional studies. We included all studies that compared aerobic exercise interventions in adults treated with CRT devices with adults treated with usual CRT care. These studies evaluated patient clinical characteristics, exercise testing measures, hemodynamic measures, echocardiography parameters, biomarkers and adverse events. Independent reviewers evaluated study eligibility, abstracted data and assessed risk of bias in duplicate. We used random-effect meta-analysis methods to estimate mean differences and odds ratios. Grades of Recommendation, Assessment, Development and Evaluation system were used to quantify absolute effects and quality of evidence. I2 was used to evaluate heterogeneity.We identified seven studies, six randomized control trials and one observational study, totaling 332 CRT patients in the exercise intervention and 534 patients receiving usual care. Peak VO2 was 2.4 ml/kg/min higher in the exercise group in comparison with the control group (pooled mean difference 2.26, 95% CI 1.38-3.13, I2 = 53%, high quality). AT-VO2 improved with exercise rehabilitation, and heterogeneity was considered low (pooled mean difference 3.96, 95% CI 2.68-5.24, I2 = 0.0%, moderate quality).Peak VO2 and AT-VO2 are increased with aerobic exercise in CRT recipients, demonstrating a significant improvement in functional capacity.

Clinical and echocardiographic characteristics of patients with preserved versus mid-range ejection fraction.

A wide range of ejection fraction (EF) thresholds have been used to categorize patients with heart failure (HF) with "preserved" EF. Our goal was to characterize the clinical and echocardiographic differences among patients with cardiac structural/functional alterations and mid-range EF (mrEF) (EF 40-49%) compared to preserved EF (pEF) (EF ≥ 50%), irrespective of HF. Patients with an EF ≥ 40% and echocardiographic evidence of structural alterations (left atrial enlargement and/or left ventricular hypertrophy) and/or functional alterations (evidence of diastolic dysfunction) were retrospectively selected. Patients with acute coronary syndromes and ≥ moderate left sided valvular diseases were excluded. Patients were divided according to EF to pEF group (n = 578) and mrEF (n = 86). Patients with mrEF were twice as likely to be men, had higher prevalence of hyperlipidemia, diabetes and smoking, compared to patients with pEF. History of coronary artery disease (CAD) was more frequent among mrEF (50% vs. 28%, p < 0.0001, respectively), and highest among the subgroup of patients with HF (83% vs. 35%, p < 0.0001, respectively). Patients with mrEF had increased LV mass index (131 ± 35 vs. 120 ± 26 g/m2, p < 0.001), LV end diastolic diameter (55 ± 5 vs 51 ± 3, p < 0.0001), mitral E to e' ratio (16 ± 7 vs. 14 ± 5, p = 0.001), and left atrial systolic diameter (44 ± 5 mm vs. 42 ± 4 mm, p = 0.01. respectively). Patients with mrEF demonstrated worse structural and functional echocardiographic alterations and were more likely to be men and to have CAD compared to patients with pEF.

The Levels of Insulin-Like Growth Factor in Patients with Myofascial Pain Syndrome and in Healthy Controls.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) plays an important role in muscle maintenance and repair. The role of IGF-2 in the muscle is less clear. OBJECTIVE: To compare the levels of IGF-1 and IGF-2 in participants with acute myofascial pain syndrome (MPS) versus healthy controls and to determine whether age, gender, body mass index (BMI), region of pain, and pain intensity are associated with IGF levels. DESIGN: A case-control study design included a total of 74 participants. SETTING: Hospital emergency department. PARTICIPANTS: Participants presenting with acute MPS (n = 43) and non-MPS controls (n  =  31). MAIN OUTCOME MEASURES: Serum IGF-1 and IGF-2 (pg/mL) were measured in participants with MPS within 24 hours of symptom onset, and in non-MPS controls. Group and gender differences in serum IGF-1 and IGF-2 were assessed, with group and gender as factors, while controlling for age and BMI. RESULTS: The mean IGF-1 levels were not significantly different between MPS and controls (88 554.1, confidence interval [CI], 79 724.4-97 383.7 vs. 97 911.2, CI, 85 322.8-110 493.6). Significant differences were also not observed in IGF-1 levels between men and women with MPS nor between men and women in the control group. Mean levels of IGF-2 were significantly lower in patients with MPS than in controls (226 608.9, CI, 180 057.3-273 160.5 versus 460 343.9, CI, 387 809.4-532 878.2, P < .001). There were no significant gender differences in the levels of IGF-2 in patients with MPS. Mean IGF-2 levels (pg/mL) of men and women with MPS were lower (253 343.0, CI, 179 891.0-326 795.0, and 204 524.2, CI, 141 176.4-267 872.0, respectively) than those of healthy men and women (428 177.2, CI, 368 345.7-488 008.6, and 511 274.4, 355 178.6-687 370.1, respectively). Lower BMI and younger age were associated with higher levels of IGF-2. Pain intensity was associated with IGF-2 but not with IGF-1, whereas region of pain was not associated with either IGF-1 or IGF-2 levels. CONCLUSIONS: IGF-2 levels were lower in patients with acute MPS versus healthy controls with no gender differences, and IGF-1 levels were not different among the groups. Future studies should investigate the role of IGF-2 in muscle maintenance and repair in MPS.

Clinical, Surgical, and Sociopsychological Factors and Depression After Cardiothoracic Surgery.

BACKGROUND: Depression is highly prevalent in cardiac surgical patients and is associated with mortality. The objectives of the study were to evaluate depression scores longitudinally pre- and postoperatively and to examine the association between postoperative depression scores and clinical, surgical, and sociopsychological factors. METHODS: Depression scores were assessed using the Center for Epidemiological Study of Depression (CES-D) in 100 cardiac surgical patients who underwent cardiac surgery preoperatively, during hospitalization, and at 2 and 6 week after discharge. Clinical, surgical, and sociopsychological predictors of depression scores were recorded. RESULTS: The average depression scores significantly increased from preoperative levels (14.9 ± 1.07) to during hospitalization (21.5 ± 1.05) and decreased at both 2 weeks (15.8 ± 1.07) and 6 weeks after discharge (14.0 ± 1.06), as compared with scores during hospitalization (P < .001). The percentage of patients who scored CES-D > 16 increased significantly from preoperative (39%) to hospitalization (71%) and decreased gradually at 2 weeks (45%) and 6 weeks (37%) after discharge (P < .001). Significant predictors of high postoperative CES-D scores were female gender, ejection fraction < 50%, and high preoperative CES-D scores. CONCLUSIONS: High depression scores after cardiac surgery suggest that perioperative screening and management of depression after surgery are necessary and may improve outcomes of these patients who are at high risk for depression. Further understanding of the factors that contribute to high depression scores is required to facilitate clinical intervention.

Local prolonged release of antibiotic for prevention of sternal wound infections postcardiac surgery-A novel technology.

INTRODUCTION: Sternal wound infection (SWI) is a devastating postcardiac surgical complication. D-PLEX100 (D-PLEX) is a localized prolonged release compound applied as a prophylactic at the completion of surgery to prevent SWI. The D-PLEX technology platform is built as a matrix of alternating layers of polymers and lipids, entrapping an antibiotic (doxycycline). The objective of this study was to assess the safety profile and pharmacokinetics of D-PLEX in reducing SWI rates postcardiac surgery. METHOD: Eighty-one patients were enrolled in a prospective single-blind randomized controlled multicenter study. Sixty patients were treated with both D-PLEX and standard of care (SOC) and 21 with SOC alone. Both groups were followed 6 months for safety endpoints. SWI was assessed at 90 days. RESULTS: No SWI-related serious adverse events (SAEs) occurred in either group. The mean plasma Cmax in patients treated with D-PLEX was about 10 times lower than the value detected following the oral administration of doxycycline hyclate with an equivalent overall dose, and followed by a very low plasma concentration over the next 30 days. There were no sternal infections in the D-PLEX group (0/60) while there was one patient with a sternal infection in the control group (1/21, 4.8%). CONCLUSION: D-PLEX was found to be safe for use in cardiac surgery patients. By providing localized prophylactic prolonged release of broad-spectrum antibiotics, D-PLEX has the potential to prevent SWI postcardiac surgery and long-term postoperative hospitalization, reducing high-treatment costs, morbidity, and mortality.

Correction to: Cardiac surgery in patients with Hemophilia:is it safe?

An amendment to this paper has been published and can be accessed via the original article.

Differential microRNAs expression in calcified versus rheumatic aortic valve disease.

BACKGROUND: The aortic valve (AV) is the most commonly affected valve in valvular heart diseases (VHDs). The objective of the study is to identify microRNA (miRNA) molecules expressed in VHDs and the differential expression patterns of miRNA in AVs with either calcification or rheumatism etiologies. METHODS: Human AVs were collected during valve replacement surgery. RNA was extracted and miRNA containing libraries were prepared and sequenced using the next generation sequencing (NGS) approach. miRNAs identified as differentially expressed between the two etiologies were validated by quantitative real-time polymerase chain reaction (qPCR). The receiver operating characteristic (ROC) curve analysis was performed to examine the ability of relevant miRNA to differentiate between calcification and rheumatism etiologies. RESULTS: Rheumatic and calcified AV samples were prepared for the NGS and were successfully sequenced. The expression was validated by the qPCR approach in 46 AVs, 13 rheumatic, and 33 calcified AVs, confirming that miR-145-5p, miR-199a-5p, and miR-5701 were significantly higher in rheumatic AVs as compared with calcified AVs. ROC curve analysis revealed that miR-145-5p had a sensitivity of 76.92% and a specificity of 94.12%, area under the curve (AUC) = 0.88 (P = .0001), and miR-5701 had a sensitivity of 84.62% and a specificity of 76.47%, AUC = 0.78 (P = .0001), whereas miR-199a-5p had a sensitivity of 84.62%, and a specificity of 57.58%, AUC = 0.73 (P = .0083). CONCLUSION: We documented differential miRNA expression between AV disease etiologies. The miRNAs identified in this study advance our understanding of the mechanisms underlining AV disease.

Veno-arterial extracorporeal membrane oxygenation for electrical injury induced cardiogenic shock support: a case report.

BACKGROUND: High voltage electrical injury (HVEI) of more than 1000 V is a potentially devastating form of a multisystem injury associated with high morbidity and mortality. We present the first case of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a life saving device for treating a patient with severe cardiogenic shock after a high voltage electrical injury. CASE PRESENTATION: A 26-year-old male sustained HVEI while working with a concrete mixer pump that came in contact with a high voltage cable of 10,000 V. He was immediately disconnected from the mixer pump, underwent cardiopulmonary resuscitation and was transported to the nearest medical centre with severe cardiogenic shock with an ejection fraction (EF) of < 10%. Upon arrival, he was in critical condition, sedated and mechanically ventilated, haemodynamically unstable and supported by intravenous (IV) inotropes after a few events of ventricular fibrillation, with an electrical entry point on the left hand and an exit point located on his right leg. Blood pH was 6.8, PCO2 53 mmHg, PaO2 of 57 mmHg, lactate 8 mmol/L, and Troponin 38,000 ng/dl. The EF was 10% with global severe left ventricular dysfunction. During cardiopulmonary resuscitation (CPR), including cardiac massage and few electrical shocks, he was immediately connected to the VA-ECMO via open right femoral approach with distal arterial leg perfusion. He was treated with IV broad spectrum antibiotics, and high volume fluids to prevent rhabdomyolysis-induced acute kidney injury, total parenteral nutrition, topical silver sulfadiazine cream, and Granuflex for severe electrical burns. He was gradually weaned from inotropes over the next 3 days, during which his clinical condition and bloodwork improved tremendously. His EF gradually increased to 50% and he was weaned from the VA-ECMO, and underwent decannulation 86 h after initialization. He was discharged on day 27 without any sequelae. CONCLUSION: The VA-ECMO treatment can be a lifesaving device for treating severe cardiogenic shock caused by high voltage electrical injury, and should be considered while treating these "high-mortality risk" patients.

Cardiac surgery in patients with Hemophilia:is it safe?

BACKGROUND: The life expectancy of hemophiliacs is similar to that of the general population. As a result, the prevalence of age-related cardiovascular diseases has increased. We present our experience with hemophilia patients who underwent cardiac surgery in our Medical Center between 2004 and 2019. METHODS: All hemophilia patients who underwent cardiac surgery were identified, and their peri-operative data evaluated retrospectively. RESULTS: Ten patients were identified: six with hemophilia-A, one with hemophilia-B, and three with hemophilia-C (factor XI deficiency). Cardiac procedures included ten coronary artery bypass grafts and one aortic valve replacement. Hemophilia-A and B patients were treated with factor substitution, whereas patients with factor XI deficiency were treated with fresh frozen plasma. One patient died, and one patient suffered from non-active gastrointestinal bleeding. CONCLUSIONS: While major cardiac surgery can be performed safely on patients with hemophilia, a multidisciplinary team approach and strict postoperative monitoring are essential in order to achieve optimal results.

Can improvement in hormonal and energy balance reverse cardiovascular risk factors in athletes with amenorrhea?

Female athletes display a high prevalence of hypothalamic amenorrhea as a result of energy imbalance. In these athletes with amenorrhea, decreased luteinizing hormone/follicule-stimulating hormone secretion leads to deficiency in endogenous estrogen. The severe estrogen deficiency in these athletes may increase cardiovascular risk similar to that in postmenopausal women. This review discusses the potential cardiovascular risk factors in athletes with amenorrhea as a result of hypoestrogenism, which include endothelial dysfunction and unfavorable lipid profiles. We also consider the potential to reverse the cardiovascular risk by restoring energy or hormonal imbalance along the reproductive axis in athletes with amenorrhea.