Options for ovarian failure and the development of prognostic models for outcomes in patients with different types of chronic disorders of consciousness

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Chronic disorders of consciousness are rare clinical conditions that develop after coma and are accompanied by the restoration of wakefulness without the full restoration of consciousness 28 days or longer after brain damage. The results of a comprehensive examination of patients with different types of ovarian failure, depending on the type of chronic disorders of consciousness, have not been presented in the literature. Studying ovarian function in this population may help identify markers of consciousness recovery. Methods. The study included 30 women aged 18–44 years (mean age: 29 ± 8.2 years). Etiologies of CDC were traumatic (30%) and nontraumatic (70%), including hypoxic injury, postsurgical and postpartum embolism, and infectious causes. The duration of impairment ranged from 1 to 15 months. Most patients had a normal BMI. Neurobiological markers, including BDNF, APO-1, Fas-L, and glutamate, were measured. Results. Hormonal assessments revealed universal ovarian failure, with decreased estradiol levels. Notably, all patients exhibited signs of ovarian failure, with some showing hyperprolactinemia and subclinical hypothyroidism. Vitamin D deficiency was prevalent across the cohort. BDNF levels were within reference ranges in most patients, with no correlation with the state of consciousness. Elevated APO-1 and Fas-L levels were observed in some patients, but no significant differences were found between the groups. The glutamate levels varied, with some exceeding normal ranges, but no consistent pattern emerged. These findings suggest the limited prognostic utility of these biomarkers in predicting consciousness recovery. Conclusions. Three prognostic models for favourable outcomes have been developed on the basis of blood hormone levels (FSH, TSH, AMH, prolactin, and testosterone) and patient age. This study underscores the complexity of hormonal and neurobiological interactions in CDC and highlights the potential role of disconnection within cortical and subcortical networks in ovarian failure. Further research is necessary to elucidate these mechanisms and develop reliable prognostic models for recovery. chronic disorders of consciousness ovarian failure vitamin D BDNF APO-1 Fas-L glutamate Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction The pathogenesis of ovarian hormonal failure is rooted in the disruption of cyclic ovarian activity, which is accompanied by the impairment of ovulatory and secretory functions. To date, the most widely accepted classification of ovulatory disorders, which is based on serum gonadotropin concentrations and categorizes ovulatory disturbances according to the extent of damage to the hypothalamic‒pituitary‒ovarian axis [ 1 ], has been established by the World Health Organization. In 2022, the International Federation of Gynecology and Obstetrics (FIGO) introduced a novel classification system for ovulatory disorders. This system's primary level is founded on an anatomical framework encompassing the hypothalamus, pituitary gland, and ovaries. The secondary level stratifies each anatomical component according to the presumed etiopathogenetic mechanisms underlying ovulatory dysfunction. The tertiary level delineates specific nosological entities that serve as the direct etiological factors precipitating ovulatory failure [ 2 ]. The hypothalamic‒pituitary system comprises a complex network of structures that are integral to the regulation of homeostasis, adaptation to external environmental stimuli, and survival under stress conditions. Nonetheless, disorders affecting the hypothalamic‒pituitary axis in patients with different types of chronic disorders of consciousness impairment remain insufficiently studied. Chronic disorders of consciousness (CDCs) are conditions that develop following a coma and are characterized by the recovery of wakefulness without the complete restoration of conscious activity within typically more than 28 days after brain injury [ 3 ]. In recent years, the quality of care for patients with severe brain injuries has improved, with the emergence of novel intensive therapeutic approaches for various types of brain damage. Patients more frequently transition from coma to unconscious states, such as the vegetative state or unresponsive wakefulness syndrome (UWS). The CDC encompasses UWS, the minimally conscious state (MCS) “plus,” and the MCS “minus.” The prevalence of UWS ranges from 6.4–14 cases per 100,000 individuals in the United States [ 4 ] and from 0.2 cases per 100,000 individuals in the Netherlands to 3.4 cases per 100,000 individuals in the Austrian population in European countries [ 5 ]. In Russia, a survey was conducted in the intensive care units of 15 hospitals across different regions over three years (2009–2012), with a total of 747 patients diagnosed with UWS [ 6 ]. The proposed therapeutic and rehabilitative interventions aimed at restoring consciousness lack a sufficiently robust evidence base to recommend their routine use. Currently, studies utilizing advanced neuroimaging techniques—such as functional magnetic resonance imaging, positron emission tomography with 18-fluorodeoxyglucose, and neurophysiological methods—have provided insights into brain function in patients with CDC. Notably, investigations of hormonal regulation alterations in patients with CDC have received insufficient attention. Published data include isolated studies on menstrual cycle disturbances in women with CDC [ 7 ]. Clinically, menstrual irregularities such as oligomenorrhea or secondary amenorrhea have been observed in this patient group [ 8 ]. It is hypothesized that one of the factors contributing to ovarian failure in women with CDC is the disconnection between cortical and subcortical structures of the brain. The emergence of consciousness is associated with the re-establishment of connections between the prefrontal and parietal cortices of the cerebral hemispheres and the thalamic nuclei. Studying ovarian function in this patient population may represent a promising avenue for identifying markers of consciousness. Clinical characteristics of patients The study included 30 female patients aged 18–44 years (mean age: 29 ± 8.2 years) with CDC. The diagnosis was confirmed on the basis of repeated neurological examinations in accordance with clinical guidelines. Patients were grouped according to the etiology of their consciousness disorder: traumatic (30%, n = 9) and nontraumatic (70%, n = 21) brain injuries. The nontraumatic group comprised women following hypoxic brain injuries, including anaphylactic shock reactions to medication administration, postoperative and postpartum pulmonary embolism, amniotic fluid embolism, arrhythmias, postsurgical treatment of benign brain tumors, brain malignancies, and infectious brain lesions of unspecified etiology. The duration of consciousness impairment ranged from 1 to 15 months, with an average of 3 months. One patient experienced consciousness disturbance due to acute cerebrovascular insufficiency against the background of systemic vasculitis and disseminated intravascular coagulation (DIC) syndrome, which persisted until the time of the study. Most patients (63.3%, n = 19) had a body mass index (BMI) within the normal range. In 23.3% (n = 7) of the patients, a decrease in body weight was observed, with two patients having BMI values of 13.6 and 13.5 kg/m². One patient was diagnosed with an eating disorder (bulimia). Overweight was present in 10% (n = 3) of the patients, and obesity was diagnosed in one patient, with a BMI of 31.2 kg/m² (3.3%). All women underwent assessment of their menstrual cycle characteristics, including age at menarche, duration, regularity, intensity, and pain associated with menstruation. Prior to the onset of disorders of consciousness, 96.7% (n = 29) described their menstruation as moderate. One patient had an ovarian endometriotic cyst and ultrasound signs of adenomyosis; her menstruation was heavy and painful, and she was also diagnosed with secondary infertility. The majority of patients had a regular menstrual cycle, with an average duration of 29.8 ± 2.3 days. In 6.67% of women, menstrual cycle disturbances of the oligomenorrhea type were noted before the onset of consciousness impairment, with cycle lengths ranging from 31–60 days. Half of the patients had a history of pregnancy ending in spontaneous vaginal delivery. A total of 10% of the patients had a history of cesarean section, and three patients experienced first-trimester miscarriage. One patient was on oral combined contraceptives prior to the onset of disorders of consciousness. Two patients were diagnosed with uterine fibroids, and two others underwent salpingectomy due to ectopic pregnancy. Among the comorbidities, arterial hypertension and varicose vein disease were the most common, each occurring in 10% of the patients. Degenerative-dystrophic disease of the lumbar spine was diagnosed in two patients (6.7%), Crohn’s disease in two patients (6.7%), chronic pyelonephritis in two patients (6.7%), chronic cystitis in one patient (3.3%), chronic bronchitis in one patient (3.3%), biliary dyskinesia in one patient (3.3%), and thrombosis of the anterior tibial vein at hospitalization in one patient (3.3%). On the basis of medical history, active interviews with staff and relatives, and patient monitoring in the intensive care setting, there were no episodes of menstrual bleeding. Considering the time interval since the onset of disorders of consciousness and a history of regular menstrual cycles, oligomenorrhea was diagnosed in 53.3% (n = 12) of patients at the time of examination, whereas secondary amenorrhea was observed in 46.7% (n = 14) of patients . Among patients with MCS “plus,” oligomenorrhea was present in 33.3% (n = 4) at the time of examination, and secondary amenorrhea was present in 66.7% (n = 8) of patients . All patients with MCS “minus” exhibited oligomenorrhea (n = 6). In the UWS group, oligomenorrhea was observed in 66.7% (n = 7) of patients, whereas 33.3% (n = 5) had secondary amenorrhea at the time of examination. Hormonal assessment results Hormonal evaluation revealed anovulation in all patients with chronic disorders of consciousness. Estradiol levels were decreased in 80% of women (52.4 ± 20.9 pmol/L). Elevated total testosterone levels were detected in 3.3% of patients (2.92 ± 0.97 nmol/L), whereas decreased total testosterone levels were noted in 43.3% of the cohort (0.7 ± 0.01 nmol/L, n = 13). Prolactin concentrations were within reference ranges in 90% of patients (n = 27); hyperprolactinemia was diagnosed in 10% (n = 3) of patients, including two patients in the MCS “plus” subgroup (one in the late postpartum period with a prolactin level of 1509 mIU/L and another with an endometrioid cyst identified by ultrasound with a prolactin level of 1123 mIU/L) and one patient in the MCS “minus” subgroup in the postpartum period (prolactin level of 788.6 mIU/L). Subclinical hypothyroidism was observed in 10% of patients (TSH 4.69 ± 0.9 mIU/L; free T4 17 ± 7.8 pmol/L). Free T4 levels were elevated in 13.3% of patients (27.1 ± 2.1 pmol/L) and decreased in 6.67% (1.9 pmol/L and 9.4 pmol/L). Free T3 was elevated in one patient (6.5 pmol/L) and decreased in 16.67% of patients (1.8 ± 0.4 pmol/L). Basal ACTH levels were elevated in 21.4% of patients (26.4 ± 12.3 pmol/L), whereas basal cortisol levels were increased in 56.7% of patients (449.2 ± 221.3 nmol/L). Normogonadotropic ovarian insufficiency was diagnosed in 63.3% of patients with CDC (FSH 5.04 ± 2.02 IU/L; LH 4.6 ± 3.1 IU/L), whereas hypogonadotropic ovarian insufficiency was present in 36.7% (FSH 1.17 ± 0.43 IU/L; LH 2.1 ± 1.1 IU/L). Assessment of 25(OH)D levels in peripheral blood All patients exhibited a significant reduction in peripheral blood 25-hydroxyvitamin D [25(OH)D] levels. Specifically, 26.7% demonstrated insufficiency (23.37 ± 1.5 ng/mL), 56.7% presented deficiency (14.58 ± 2.7 ng/mL), and 16.7% presented severe deficiency (7.07 ± 0.64 ng/mL), despite standard enteral nutrition and irrespective of the duration of CDC. Evaluation of Central Nervous System Injury Markers in Serum and Cerebrospinal Fluid The level of apoptosis antigen 1 (APO-1), also known as the CD95 apoptosis receptor, was measured in the serum and cerebrospinal fluid (CSF). Serum APO-1 levels were determined in 22 patients aged 18–44 years (mean age 28.0 ± 8.2 years), including nine patients in the VS/UWS group, nine in the MCS “plus” group, and four in the MCS “minus” group. The APO-1 concentrations were below the manufacturer’s reference range (1334–2411 pg/mL) in 59.1% of the patients, ranging from 363.6 to 1230 pg/mL (mean 807.2 ± 219.7 pg/mL). In 31.8% of patients, APO-1 levels were within the reference range, with an average of 1695.7 ± 430.1 pg/mL. Two patients (9.1%) exhibited markedly elevated APO-1 levels: one patient in the VS/UWS group had 5836 pg/mL, and one patient in the MCS “plus” group had 194,755 pg/mL, approximately 80-fold above the reference range. APO-1 levels in CSF were assessed in seven patients; 85.7% (n = 6) had levels below the detectable limit, while one patient had a level of 203.6 pg/mL. Reference values for APO-1 in CSF have not been established. Assessment of brain-derived neurotrophic factor (BDNF) levels in serum and cerebrospinal fluid Serum BDNF levels were measured in 23 patients aged 18–44 years (mean age 28.3 ± 8.2 years), including nine patients in the MCS “plus” group, five in the MCS “minus” group, and nine in the VS/UWS group. BDNF concentrations ranged from 8,540 to 49,820 pg/mL, with a mean value of 20,930.3 ± 9,752.9 pg/mL. In 95.7% of patients (n = 22), BDNF levels fell within the manufacturer’s reference range (6,186–42,580 pg/mL). One patient in the MCS “minus” group presented a BDNF level of 49,820 pg/mL. BDNF levels in cerebrospinal fluid were assessed in eight patients, all of whom had values below the detectable limits. Evaluation of Fas ligand (Fas-L) levels in serum and cerebrospinal fluid Serum Fas-L levels were determined in 22 patients aged 18–44 years (mean age 28.0 ± 8.2 years), including nine patients in the MCS “plus” group, four in the MCS “minus” group, and nine in the VS/UWS group. Fas-L concentrations were within the reference range in 95.5% of patients (n = 21), with a mean level of 0.22 ± 0.12 ng/mL. One patient in the MCS “minus” group presented an elevated Fas-L level of 4.73 ng/mL. CSF Fas-L levels were measured in seven patients aged 20–41 years (mean age 28.0 ± 9.0 years), including three patients in the MCS “minus” group and four in the VS/UWS group. The Fas-L concentrations ranged from 0.03 to 0.18 ng/mL, with a mean value of 0.09 ± 0.07 ng/mL. Assessment of Glutamate Levels in Serum and Cerebrospinal Fluid Serum glutamate levels were measured in 23 women aged 18–44 years (mean age 28.0 ± 8.2 years), including nine patients in the MCS “plus” group, five in the MCS “minus” group, and nine in the VS/UWS group. The glutamate concentrations exceeded the reference range in 50% of patients, ranging from 30.2 to 44.3 µg/mL. CSF glutamate levels were determined in 11 patients aged 20–43 years (mean age 30.0 ± 8.9 years), including five patients in the VS/UWS group and six in the MCS group. The mean CSF glutamate level was 2.2 ± 0.4 µg/mL. One patient in the MCS “minus” group presented an elevated CSF glutamate level of 17.2 µg/mL. Assessment of S100 protein levels in serum and cerebrospinal fluid Serum S100 protein was measured in one patient (31 years old) in the VS/UWS group, and CSF S100 protein levels were determined in three patients (two in the VS/UWS group and one in the MCS group), aged 28, 31, and 45 years. The serum S100 protein concentration was 22.7 ng/L. The mean CSF S100 protein level was 434.3 ng/L. Reference values for S100 protein in CSF have not been established. Ultrasound examination of pelvic organs All 30 patients with CDC underwent pelvic ultrasound due to oligomenorrhea or secondary amenorrhea (26 patients were examined transvaginally, 4 were examined transabdominally). The mean endometrial thickness was 2.5 ± 1.23 mm (range 0.2–5.3 mm), with no ultrasonographic signs of endometrial pathology detected. One patient (3.33%, n = 1) was diagnosed with an endometriotic ovarian cyst and ultrasonographic signs of adenomyosis. Uterine fibroids (subserosal-intramural, FIGO classification types 5–6) were diagnosed in two patients (6.67%). No dominant follicle growth, corpus luteum formation, or secretory transformation of the endometrium was observed in the examined patients. Comparison of Patient Parameters between Groups with Different CDC Levels Patients were categorized into groups on the basis of consciousness level: VS/UWS (40%, n = 12), MCS “minus” (20%, n = 6), and MCS “plus” (40%, n = 12). The groups were comparable in terms of age and body mass index (p = 0.9) (Table 1 ) but differed significantly in the duration of CDC at the time of examination (Fig. 1 ) (p = 0.02). Analysis of the obtained results revealed no statistically significant differences in the compared parameters between the groups. Table 1. Anthropometric parameters and gynecological history of patients with different types of CDC Characteristic MCS “minus” (n=6) MCS “plus” (n=12) VS/UWS (n=12) p * Age, years 33±10 29±6,7 27±8,3 0,31 Body mass index, kg/m² 19,7 (17,4; 22,9) 21,3 (19,9; 24,3) 20,5 (18,4; 22,3) 0,57 Age at menarche, years 13,1±1,4 12,4±1,9 14,1±2,4 0,86 Menstrual cycle regularity (before disorder of consciousness) Regular (83,3%) Regular (83,3%) Regular (91,6%) – Menstrual pain (before disorder of consciousness) Painful (33,3%) painless (66,7%) Painful (8,4%) painless (91,6%) Painful (16,7%) painless (83,3%) – Menstrual flow intensity (before disorder of consciousness) Moderate (100%) Moderate (91,6%), heavy (8,4%) Moderate (100%) – Duration of menstrual bleeding, days (before disorder of consciousness) 5,5±2,1 4,7±1,3 5,3±1,5 0,45 Menstrual cycle length, days (before disorder of consciousness) 29,3±1,9 31,2±2,7 30,3±2,6 0,76 *Note: p values correspond to comparisons among the three groups (MCS “minus”, MCS “plus”, VS/UWS). Assessment of the 25(OH)D Level No significant differences were detected in peripheral blood 25(OH)D levels among patients with different forms of CDC: 16.8 ± 6 ng/mL in the VS/UWS group, 13.5 ± 6.2 ng/mL in the MCS “plus” group, and 17.7 ± 4 ng/mL in the MCS “minus” group (p = 0.25). In the VS/UWS group, 25(OH)D levels were significantly decreased: 41.7% (mean 23.4 ± 1.7 ng/mL) were insufficient, 50% (14.4 ± 3.7 ng/mL) were deficient, and 8.3% (7.4 ng/mL) were severely deficient. Among patients in the MCS “plus” group, 25(OH)D levels were also significantly decreased: 16.7% (24.5 ± 0.9 ng/mL) were insufficient, 50% (14.2 ± 1.6 ng/mL) were deficient, and 33.3% (7 ± 0.6 ng/mL) were severely deficient. In the MCS “minus” group, 25(OH)D insufficiency was observed in 33.3% (22.2 ± 0.8 ng/mL) and deficiency in 66.7% (15.4 ± 2.4 ng/mL) of the patients. Comparative Analysis of CNS Injury Markers in Patients with Different CDC Levels A comparative analysis of CNS injury markers was conducted among patients with different consciousness levels (MCS “plus”, MCS “minus”, and VS/UWS). No significant differences in serum apoptotic antigen levels were detected between the groups: the median values were 1230 (916.4; 1420) pg/mL, 1375 (908.7; 1960) pg/mL, and 800 (669.1; 1173.3) pg/mL, respectively (p = 0.19). The serum BDNF levels did not differ significantly: the medians were 2282 (12660; 24450) pg/mL, 2302 (21140; 31300) pg/mL, and 1650 (669.1; 1173.3) pg/mL (p = 0.46). The serum Fas ligand (Fas-L) levels also did not significantly differ: 0.22 (0.15; 0.23) ng/mL, 0.22 (0.14; 0.33) ng/mL, and 0.23 (0.16; 0.26) ng/mL (p = 0.96). Similarly, no significant differences in CSF Fas-L levels were detected between the groups, with medians of 0.04 (0.04; 0.17) ng/mL and 0.07 (0.03; 0.08) ng/mL (p = 0.36). The serum glutamate levels also did not differ significantly among the groups: 32.5 (20; 44) µg/mL, 30.2 (17.6; 33.9) µg/mL, and 30.8 (22.7; 42.8) µg/mL (p = 0.62). No statistically significant differences were found in CSF glutamate levels between groups: a median of 1.86 (1.75; 2.06) µg/mL in the VS/UWS group and 2.53 (2.22; 9.94) µg/mL in the MCS group (p = 0.08). However, CSF glutamate levels were higher in patients with VS/UWS than in those with MCS, as illustrated in Fig. 2 . Model 1. Prognosis of Favourable Outcomes via TSH and Prolactin Levels On the basis of the analysis and identification of prognostic markers, the TSH and prolactin levels in patients with CDC significantly influenced the recovery of consciousness (Table 2 ). Table 2 – Results of the Study on the Relationship between Disorders of Consciousness and Predictors (TSH, Prolactin) Predictors Standard Error χ 2 Wald p value Odds Ratio 95% Confidence Interval Lower Upper Prolactin 0,003 1,437 0,231 0,996 0,989 1,003 TSH 0,546 4,261 0,039 3,086 1,059 8,996 TSH and prolactin levels in patients with CDC significantly affect the likelihood of consciousness recovery. The predictive formula is as follows: В1 = 1 (1) 1 + 2,72 −(−2,949+1,127×TSH 0,004×Prolactin)) A B1 value of 0.7 or lower indicates a favourable prognosis—restoration of consciousness. The model's accuracy was 92.3%, its sensitivity was 80.0%, and its specificity was 100% (Fig. 3 ). Model 2. Prognosis of Favourable Outcomes via Prolactin, FSH, Total Testosterone, and Age Model 2 examined the influence of blood hormones, prolactin, FSH, total testosterone, and patient age, on the recovery of consciousness. Regression analysis yielded the following model. The χ² value for the predictors is 11.4 with 4 degrees of freedom, p = 0.02, indicating that at least one predictor is associated with the event. The Nagelkerke R² is 0.489 (Table 3 ). Table 3 – Relationships between Consciousness Level and Identified Predictors Variables in Equation Parameter Estimate (B) Standard Error p value Odds Ratio 95% CI (Lower – Upper) Age 0,14 0,08 0,1 1,15 1–1,3 Total Testosterone 3 1,6 0,1 19,4 0,8-453,7 Prolactin 0,005 0,003 0,1 1 1 FSH 0,45 0,3 0,1 1,6 0,9 − 2,7 The regression-derived formula for the probability of belonging to group 2 (B2) is as follows: В2 = 1 (2) 1 + 2,72 −(−6,904+0,005×Prolactin−0,449×FSH+2,965×Testosterone+0,139×Age) A B2 value of 0.7 or lower indicates a favourable prognosis—restoration of consciousness. At a classification threshold of p = 0.5, the model's accuracy is 80.0%, its sensitivity is 83.3%, and its specificity is 76.9%. ROC analysis (Fig. 4 ) revealed that the area under the curve exceeded 0.8, indicating "very good" model quality. Model 3. Prognosis of Favourable Outcomes via AMH, FSH, and Total Testosterone Levels This model is based on three parameters: FSH, AMH, and total testosterone in blood serum. The χ² value for the predictors is 10.69 with 3 degrees of freedom, p = 0.014, indicating that at least one predictor is associated with the event. The Nagelkerke R² is 0.46 (Table 4 ). Table 4 – Relationships between conditions and predictors Hormones Parameter Estimate (B) Standard Error Wald χ 2 p value Odds Ratio 95% Confidence Interval Lower Upper FSH 0,4 0,3 2,4 0,1 1,5 0,9 2,5 AMH 0,3 0,1 3,8 0,05 0,8 0,6 1 Total Testosterone 2,8 1,7 2,9 0,09 16,9 0,7 426,7 The formula for calculating the probability of condition (B3), which is based on the regression В3 = 1 (3) 1 + 2,72 −(−3,218+0,402×FSH−0,26×AMH+2,825×Testosterone) A B3 value of 0.7 or lower indicates a favourable outcome—restoration of consciousness. At a classification threshold of p = 0.5, this model demonstrated an accuracy of 76.0%, sensitivity of 76.9%, and specificity of 75.0% (Fig. 5 ). Hormone Therapy The patients were scheduled to receive cyclic hormone replacement therapy: transdermal estradiol hemihydrate (1 mg daily) combined with intravaginal micronized progesterone (200 mg) once daily from days 14 to 28 of estradiol administration. However, owing to comorbidities, including subarachnoid hemorrhage, postoperative pulmonary embolism (n = 2), superficial vein thrombophlebitis (n = 5), malignant brain tumors, intraoperative aneurysm rupture, arrhythmia, and heterozygous prothrombin gene mutation, these medications were not prescribed, as they are absolute or relative contraindications. Thromboembolism risk was assessed via the Padua scale, with 80% of patients classified as high risk. After further evaluation and clarification of indications and contraindications, legal representatives, fully informed of the risks and benefits, declined hormone therapy. Outcomes of Consciousness Disorders in patients with CDC The outcomes of patients with consciousness disorders were as follows: 36.67% (n = 11) of patients regained clear consciousness; 23.67% (n = 7) remained in the VS/UWS; 16.67% (n = 5) were in the MCS “minus”; 6.67% (n = 2) were in the MCS “plus”; and outcome data were unavailable for 16.67% (n = 5) of patients. Discussion The study included 30 women with rare neurological disorders. Patients were hospitalized at a specialized center for CDC treatment at the Department of Anesthesiology and Intensive Care of the A.L. Polenov Russian Neurosurgical Institute, branch of the V.A. Almazov Federal Medical Research Center, from various regions across Russia. The inclusion criterion was reproductive age (18–44 years). Causes of disorders of consciousness included traumatic (30%) and nontraumatic (70%) brain injuries, such as hypoxic damage from arrhythmias, postsurgical benign tumor removal, and infectious causes of unspecified etiology. Notably, some cases involved obstetric and gynecological catastrophes, such as anaphylactic shock during ectopic pregnancy surgery, pulmonary artery thromboembolism, and amniotic fluid embolism. The duration of CDC ranged from 1 to 15 months (mean 3 months). One patient’s impairment resulted from acute cerebral circulatory failure against systemic vasculitis and DIC, lasting 137 months, during which time she was monitored at home without menstruation. Initially, it was expected that all patients would exhibit significant weight deficiency due to the severity of their condition. However, most had a normal BMI; only 23.3% were underweight. Prior to consciousness impairment, patients’ menstrual function was comparable to that of healthy women, with common conditions such as uterine fibroids and endometriosis. The comorbidities were also similar to those of the general population. Few studies exist on hormonal status in CDC patients, making our hormonal findings particularly relevant. In 1989, Japanese researchers identified anterior pituitary and gonadal hormone secretion disorders in 33 patients, 52% of whom presented with severe abnormalities [ 9 ]. Abnormalities included growth hormone, LH, FSH, cortisol, TSH, and prolactin in 70%, 67%, 45%, 39%, 36%, and 15% of cases, respectively. Our data revealed ovarian insufficiency in all patients: 63.3% had normogonadotropic ovarian failure (FSH 5.04 ± 2.02 IU/L; LH 4.6 ± 3.1 IU/L), and 36.7% had hypogonadotropic ovarian failure (FSH 1.17 ± 0.43 IU/L; LH 2.1 ± 1.1 IU/L). The prolactin levels were within reference ranges in 90% of the patients, with hyperprolactinemia diagnosed in 10% of the patients, which was attributed to late postpartum status or endometriosis. A study revealed a positive correlation between the severity of brain injury and prolactin levels, suggesting that prolactin is a superior marker of brain damage severity [ 10 ]. Previous research on prolactin levels in patients with CDC involved small samples and did not stratify by sex or severity. Nonetheless, most studies reported significant prolactin elevation, possibly due to side effects of the medications used for treatment. Our data revealed that all women with CDC experienced anovulation and significantly reduced serum estradiol levels, which is consistent with the absence of menstrual activity during observation. Total testosterone was decreased in 43.3% of patients, but 80% exhibited signs of hirsutism (Ferriman-Gallwey scale score: 8.3 ± 1.7). In 2018, in Nigeria, thyroid status was assessed in 115 TBI patients (85% men, 15% women) [ 11 ]. Most patients (71.7%) arrived within 24 hours post-injury. TBI severity was mild in 53%, moderate in 16%, and severe in 31% of the patients. Elevated T3 was found in 52.2% of the patients, low in 7.8%, and normal in 40%. Elevated T4 was observed in 4.3% of the patients, low in 68.7%, and normal in 27%. TSH was high in 16.5%, low in 6.1%, and normal in 77.4% of the patients. A correlation between TBI severity and thyroid hormone levels was noted; low T4 was associated with death or a persistent vegetative state (p = 0.012). In our study, subclinical hypothyroidism was found in 10% of patients; 13.3% had elevated free T4 levels (27.1 ± 2.1 pmol/L), 6.7% had decreased T4 levels (1.9 pmol/L), and 16.7% had decreased free T3 levels (1.8 ± 0.4 pmol/L). TSH, free T4, and T3 levels did not correlate with outcomes or consciousness levels. A study on circadian cortisol rhythms in 18 patients in a vegetative state receiving total enteral nutrition showed that those who were fed continuously during the day presented a normal peak at 8 a.m., similar to healthy individuals [ 12 ]. Night-fed patients presented a peak at 4 p.m., indicating cyclic secretion. In our research, cortisol levels measured in the morning and evening showed no clear pattern; only 21.4% had elevated basal ACTH (26.4 ± 12.3 pmol/L), and 56.7% had elevated basal cortisol (449.2 ± 221.3 nmol/L). Vitamin D influences steroidogenesis of sex hormones (estradiol and progesterone) in healthy women. Receptors and metabolizing enzymes are present in reproductive tissues [ 13 ]. It is hypothesized that vitamin D acts synergistically with estradiol to produce and release lysosomes, weakening the protein shell and facilitating oocyte release, possibly aiding transport and fertilization in the fallopian tubes. Its presence in the endometrial glands and corpus luteum suggests a role in endometrial proliferation [ 14 ]. All our patients had significantly reduced serum 25(OH)D levels: 26.7% had deficiency (23.37 ± 1.5 ng/mL), 56.7% had insufficiency (14.58 ± 2.7 ng/mL), and 16.7% had severe deficiency (7.07 ± 0.64 ng/mL), regardless of the duration of TBI or nutritional support. Compared with those of the controls (30.5 ± 16.7 ng/mL, p = 0.001), vitamin D levels were lower, with no significant difference between those with normo- and hypogonadotropic ovarian failure (p = 0.87). Prolonged hospitalization and limited sunlight exposure likely contributed to this deficiency; previous studies did not assess this phenomenon in CDC patients. Neurotrophin and Biomarker Studies for the Prognosis of Consciousness Recovery We measured the serum levels of neurotrophins—BDNF, APO-1, Fas-L, and glutamate—to identify potential prognostic markers. In 23 patients aged 18–44 years (mean 28.3 ± 8.2 years), BDNF levels ranged from 8,540 to 49,820 pg/mL (mean 20,930.3 ± 9,752.9). Nineteen patients were in the MCS “plus” state, five in the MCS “minus,” and nine in the VS/UWS. In 95.7% (n = 22) of the patients, BDNF levels were within the reference range (6,186–42,580 pg/mL); one patient in the MCS “minus” state had a level of 49,820 pg/mL. BDNF in cerebrospinal fluid was measured in 8 patients, all of whom were below the detectable limit. A literature review revealed one study by E.G. Yazeyeva et al. involving 26 patients (16 men, 10 women, aged 23–41, mean 27), with 14 in the vegetative state and 12 in the minimally conscious state [ 15 ]. The controls included 21 healthy volunteers. In healthy individuals, the average serum BDNF concentration was 54 pg/mL, whereas in patients with CDC, it was significantly greater (p < 0.01), averaging 770 pg/mL (range 640–950). No significant difference was found between the vegetative and minimally conscious states, indicating that BDNF is not a reliable prognostic marker in this context. Serum levels of APO-1 were measured in 22 patients. In 59.1% of the patients, the levels were below the reference range (1334–2411 pg/mL), ranging from 363.6 to 1230 pg/mL (mean 807.2 ± 219.7). In 31.8% of the patients, the levels were within the reference range (mean 1695.7 ± 430.1%). Two patients had markedly elevated levels: 5836 pg/mL (vegetative state) and 194,755 pg/mL (80 times above the reference, in the MCS “plus” state). In 7 patients, APO-1 in cerebrospinal fluid was measured; 85.7% (n = 6) had levels below the detectable limit, and one had 203.6 pg/mL. Previous studies on APO-1 in CDC patients are limited. In preeclampsia patients, APO-1 levels were significantly lower (167.07 ± 14.61 mg/dL) than those in healthy women (244.37 ± 20.84 mg/dL, p < 0.001) and were similarly lower in patients with pulmonary thromboembolism [ 16 ]. Biomarker levels in traumatic brain injury patients In our study, we measured the serum levels of the apoptosis inducer Fas-L in 22 patients. In 95.5% of patients, Fas-L levels were within reference ranges, and one patient in an MCS “minus” state had a Fas-L level of 4.73 ng/mL. A prospective observational study in five intensive care units examined patients with severe isolated TBI. Fas-L concentrations in serum measured within the first 24 hours post-injury showed that levels above 29.2 pg/mL were associated with increased mortality (risk ratio = 6.2; 95% CI = 2.6–14.8; p < 0.001). Multivariate logistic regression revealed a significant association between serum Fas-L levels and 30-day mortality in TBI patients (p = 0.004) [ 17 ]. In our research, glutamate levels were measured in 23 women with CDC. In half of the patients, glutamate exceeded the reference values, ranging from 30.2 to 44.3 µg/mL. In the cerebrospinal fluid, glutamate was assessed in 10 patients, with a mean concentration of 2.2 ± 0.4 µg/mL. One patient in a “minus” state had elevated glutamate up to 17.2 µg/mL. The literature provides no data on glutamate levels in CDC patients. We also measured S100 protein in the serum of one patient and in the cerebrospinal fluid of three patients. Serum S100 was 22.7 ng/L; CSF S100 averaged 434.3 ng/L (reference values for CSF S100 are not established). The literature indicates that serum S100 remains within reference ranges in mild TBI but is elevated in brain contusions [ 18 ]. Elevated S100 (> 0.105 µg/L) with 100% sensitivity can serve as an additional diagnostic marker to differentiate concussion from brain contusion, with CT detecting brain damage in 72.7% and MRI in 100% of mild TBI cases when S100 is elevated. Normal S100 levels suggest the absence of brain injury. A 1998 study evaluated serum S100 and neuron-specific enolase levels to predict consciousness recovery after acute global cerebral ischemia. In 64 patients, serum and cerebrospinal fluid samples were collected 24 and 48 hours post-ischemia. Serum S100 levels above 0.7 µg/L predicted the absence of consciousness recovery, with a high positive predictive value (95%) and specificity (96%). The authors concluded that S100 could serve as a marker for consciousness recovery within 24 hours after global brain ischemia. In our study, a comparative analysis of CNS damage markers revealed no significant differences between the groups. Similarly, no significant differences were found in median neurotrophin levels between patients with hypogonadotropic and normogonadotropic ovarian failure. Further research with larger patient samples is needed; currently, these neuromarkers cannot be recommended for predicting consciousness recovery. Considering the hormonal assessment results and following clinical guidelines, the possibility of hormone replacement therapy was reviewed. Patients underwent comprehensive evaluation, including cervical screening, genetic testing, ultrasound, and general clinical assessments. For 25 patients, cervical cytology was performed, and no atypical cells were detected. Atrophic changes in the multilayered squamous epithelium were observed in only 34.6% of the patients, all of whom experienced anovulation and hypoestrogenism. Such studies in patients with CDC are not described in the literature. Conclusion Predicting consciousness recovery in patients with CDC remains a significant challenge in modern intensive care. For young patients who have experienced neurological catastrophe, rapid normalization of consciousness is critically important. HNSs are considered “cortico-cortical/thalamocortical disconnection syndromes” [Laureys et al., 2002]. The primary factor underlying ovarian insufficiency in patients with CDC is likely the disconnection of cortical and subcortical brain structures. According to the classical model of hypothalamic‒pituitary‒ovarian regulation, patients with CDC exhibit decreased gonadotropin-releasing hormone (GnRH) secretion, leading to reduced gonadotropin production, secondary amenorrhea, and the development of secondary hypothalamic ovarian failure [Aylamazyan, 2006; Potin, 2004]. Normogonadotropic ovarian failure may also represent an initial stage of other forms of ovarian failure. Hormone replacement therapy can restore ovarian function via negative feedback mechanisms, potentially synchronizing gonadotropin secretion and inducing menstrual activity. Such synchronization likely contributes to the re-establishment of neural network connectivity in the cerebral cortex. Abbreviations ACTH adrenocorticotropic hormone AMH Anti-Müllerian Hormone BDNF Brain-Derived Neurotrophic Factor BMI body mass index CDC chronic disorders of consciousness CNS central nervous system CSF cerebrospinal fluid FIGO International Federation of Gynecology and Obstetrics FSH follicle-stimulating hormone GnRH Gonadotropin-releasing hormone MCS minimally conscious state TBI traumatic brain injury TSH thyroid-stimulating hormone VS/UMS vegetative state/unresponsive wakefulness syndrome Declarations Each author is expected to have made substantial contributions to the conception, design of the work, the acquisition, analysis, interpretation of data. Each author has approved the submitted version and agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Declarations of human ethics and consent to participate were observed. All authors agree to the publication of manuscripts. The study was approved by the local Ethics Committee of the D.O. Ott Research Institute of Obstetrics, Gynecology and Radiology (Protocol No. 96 dated April 23, 2019) and the Ethics Committee of the V.A. Almazov National Medical Research Center of the Ministry of Health of the Russian Federation (Extract 03/16/2019) dated March 15, 2019. F unding This research was conducted as part of a fundamental scientific study entitled "Strategy for Maintaining the Health of Women with Gynecological and Endocrine Diseases at Different Ages: Pathogenetic Justification for Drug Rehabilitation and the Development of New Organ-Preserving Surgical Interventions" (State Registration No. 1021062812154-3-3.2.2), supported by a grant from the Russian Foundation for Basic Research under research project No. 19-29-01066. References NICE. (2017) Fertility problems: assessment and treatment. London: National Institute for Health and Care Excellence (NICE), No. 156, pp. 21–24. Munro MG, Balen AH, Cho S, et al. The FIGO ovulatory disorders classification system. Int J Gynecol Obstet. 2022;159(1):1–20. 10.1002/ijgo.14331 . Piradov MA, Suponeva NA, Voznyuk IA, et al. Chronic disorders of consciousness: terminology and diagnostic criteria. Annals Clin Experimental Neurol. 2020;14(1):5–16. 10.25692/ACEN.2020.1.1 . Jennett B. The vegetative state. J Neurol Neurosurg Psychiatry. 2002;73(4):355–7. 10.1136/jnnp.73.4.355 . Pisa FE, Biasutti E, Drigo D et al. (2014) The prevalence of vegetative and minimally conscious states: a systematic review and methodological appraisal. The Journal of Head Trauma Rehabilitation, 29(4), 23–30. 10.1097/htr.0b013e3182a4469f . PMID: 24052091. Kondratyeva EA. (2005) Vegetative state: diagnostics, intensive therapy, outcome prediction [Dissertation]. Saint Petersburg: [A.L. Polenov Russian Neurosurgical Institute]. Fins JJ. Disorders of consciousness, past, present, and future. Camb Q Healthc Ethics. 2019;28(4):603–15. 10.1017/S0963180119000719 . Ivanova AO, Kondratyeva EA, Yarmolinskaya MI, et al. Cases of chronic disorders of consciousness in obstetric and gynecological practice. J Obstet Gynecol Dis. 2020;69(6):31–42. 10.17816/JOMD69631-42 . Yoshimoto H, Uozumi T. (1989) Anterior pituitary function in the vegetative state. Neurol Med Chir (Tokyo), 29(6), 490–495. Japanese. 10.2176/nmc.29.490 Amico AP, Terlizzi A, Megna M, et al. Immune endocrinological evaluation in patients with severe vascular acquired brain injuries: therapeutical approaches. Endocr Metabolic Immune Disorders - Drug Targets. 2003;13(2):204–8. 10.2174/1871530311313020009 . Malomo TA, Rabiu TB, Udoh DO, et al. Thyroid hormone profile in a population of Nigerian patients with traumatic brain injury. Nigerian J Physiological Sci. 2018;33(2):159–64. Saito M, Nishimura K, Kato H. Modifications of circadian cortisol rhythm by cyclic and continuous total enteral nutrition. J Nutri Sci Vitaminol. 1989;35(6):639–47. 10.3177/jnsv.35.639 . Lerchbaum E, Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012;166(5):765–78. 10.1530/EJE-11-0984 . Rojansky N, Brzezinski A, Schenker JG. Seasonality in human reproduction: an update. Hum Reprod. 1992;7(6):735–45. 10.1093/oxfordjournals.humrep.a137729 . Yezova EG, Legostaeva LA, Bakulin IS, et al. Influence of neuromodulation course on neurotrophic factor profile in patients with chronic disorders of consciousness. Vestnik RGMA. 2020;5:40–7. 10.24075/vrgmu.2020д.056 . Timur H, Daglar HK, Kara O, et al. A study of serum Apo A-1 and Apo B-100 levels in women with preeclampsia. Pregnancy Hypertens. 2016;6(2):121–5. 10.1016/j.preghy.2016.04.003 . Lorente L, Martín MM, Pérez-Cejas A, et al. High serum soluble Fas ligand levels in nonsurvivor traumatic brain injury patients. Neurocrit Care. 2021;35(1):249–54. 10.1007/s12028-020-01158-0 . Martens P, Raabe A, Johnsson P. Serum S100 and neuron-specific enolase for prediction of regaining consciousness after global cerebral ischemia. Stroke. 1998;29(11):2363–6. 10.1161/01.str.29.11.2363 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 06 Oct, 2025 Editor assigned by journal 01 Oct, 2025 Submission checks completed at journal 01 Oct, 2025 First submitted to journal 22 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7687762","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521824288,"identity":"23a82c73-40d0-41f8-bbc2-2de823fc8911","order_by":0,"name":"Alina Olegovna 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1","display":"","copyAsset":false,"role":"figure","size":77619,"visible":true,"origin":"","legend":"\u003cp\u003eComparative characterization of patients by duration of disorders of consciousness\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/958ac0cb7e5e9acdd30941b3.png"},{"id":92492111,"identity":"478c7970-e438-43fe-a77d-0a8de1b703ca","added_by":"auto","created_at":"2025-09-30 09:44:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74133,"visible":true,"origin":"","legend":"\u003cp\u003eGlutamate levels in the cerebrospinal fluid of patients with different levels of consciousness\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/f64c213ea5185c580c635538.png"},{"id":92493631,"identity":"947f78b4-8b93-4c4d-a08d-7d74242f1662","added_by":"auto","created_at":"2025-09-30 10:00:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":89441,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for Model 1\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/edbe92f087923a4d8a56eaab.png"},{"id":92492116,"identity":"65915715-e6d2-4a45-8b9b-74356e0b0fde","added_by":"auto","created_at":"2025-09-30 09:44:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":61758,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for Model 2\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/4fdc008ff144757c23800925.png"},{"id":92492670,"identity":"ba269b2f-6ecd-4cc8-bced-e78ac0f8a73d","added_by":"auto","created_at":"2025-09-30 09:52:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":68096,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for Model 3\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/f38b1c251212b5d9dd4583f4.png"},{"id":92494834,"identity":"09e9674e-83f0-4e15-af4b-5596bf180429","added_by":"auto","created_at":"2025-09-30 10:16:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1455712,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7687762/v1/6ae28918-d270-4366-b844-58e6d5f84aa2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Options for ovarian failure and the development of prognostic models for outcomes in patients with different types of chronic disorders of consciousness","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe pathogenesis of ovarian hormonal failure is rooted in the disruption of cyclic ovarian activity, which is accompanied by the impairment of ovulatory and secretory functions. To date, the most widely accepted classification of ovulatory disorders, which is based on serum gonadotropin concentrations and categorizes ovulatory disturbances according to the extent of damage to the hypothalamic‒pituitary‒ovarian axis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], has been established by the World Health Organization. In 2022, the International Federation of Gynecology and Obstetrics (FIGO) introduced a novel classification system for ovulatory disorders. This system's primary level is founded on an anatomical framework encompassing the hypothalamus, pituitary gland, and ovaries. The secondary level stratifies each anatomical component according to the presumed etiopathogenetic mechanisms underlying ovulatory dysfunction. The tertiary level delineates specific nosological entities that serve as the direct etiological factors precipitating ovulatory failure [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The hypothalamic‒pituitary system comprises a complex network of structures that are integral to the regulation of homeostasis, adaptation to external environmental stimuli, and survival under stress conditions. Nonetheless, disorders affecting the hypothalamic‒pituitary axis in patients with different types of chronic disorders of consciousness impairment remain insufficiently studied.\u003c/p\u003e\u003cp\u003eChronic disorders of consciousness (CDCs) are conditions that develop following a coma and are characterized by the recovery of wakefulness without the complete restoration of conscious activity within typically more than 28 days after brain injury [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In recent years, the quality of care for patients with severe brain injuries has improved, with the emergence of novel intensive therapeutic approaches for various types of brain damage. Patients more frequently transition from coma to unconscious states, such as the vegetative state or unresponsive wakefulness syndrome (UWS). The CDC encompasses UWS, the minimally conscious state (MCS) \u0026ldquo;plus,\u0026rdquo; and the MCS \u0026ldquo;minus.\u0026rdquo; The prevalence of UWS ranges from 6.4\u0026ndash;14 cases per 100,000 individuals in the United States [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] and from 0.2 cases per 100,000 individuals in the Netherlands to 3.4 cases per 100,000 individuals in the Austrian population in European countries [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In Russia, a survey was conducted in the intensive care units of 15 hospitals across different regions over three years (2009\u0026ndash;2012), with a total of 747 patients diagnosed with UWS [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The proposed therapeutic and rehabilitative interventions aimed at restoring consciousness lack a sufficiently robust evidence base to recommend their routine use. Currently, studies utilizing advanced neuroimaging techniques\u0026mdash;such as functional magnetic resonance imaging, positron emission tomography with 18-fluorodeoxyglucose, and neurophysiological methods\u0026mdash;have provided insights into brain function in patients with CDC. Notably, investigations of hormonal regulation alterations in patients with CDC have received insufficient attention. Published data include isolated studies on menstrual cycle disturbances in women with CDC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Clinically, menstrual irregularities such as oligomenorrhea or secondary amenorrhea have been observed in this patient group [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It is hypothesized that one of the factors contributing to ovarian failure in women with CDC is the disconnection between cortical and subcortical structures of the brain. The emergence of consciousness is associated with the re-establishment of connections between the prefrontal and parietal cortices of the cerebral hemispheres and the thalamic nuclei. Studying ovarian function in this patient population may represent a promising avenue for identifying markers of consciousness.\u003c/p\u003e\n\u003ch3\u003eClinical characteristics of patients\u003c/h3\u003e\n\u003cp\u003eThe study included 30 female patients aged 18\u0026ndash;44 years (mean age: 29\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years) with CDC. The diagnosis was confirmed on the basis of repeated neurological examinations in accordance with clinical guidelines. Patients were grouped according to the etiology of their consciousness disorder: traumatic (30%, n\u0026thinsp;=\u0026thinsp;9) and nontraumatic (70%, n\u0026thinsp;=\u0026thinsp;21) brain injuries. The nontraumatic group comprised women following hypoxic brain injuries, including anaphylactic shock reactions to medication administration, postoperative and postpartum pulmonary embolism, amniotic fluid embolism, arrhythmias, postsurgical treatment of benign brain tumors, brain malignancies, and infectious brain lesions of unspecified etiology. The duration of consciousness impairment ranged from 1 to 15 months, with an average of 3 months. One patient experienced consciousness disturbance due to acute cerebrovascular insufficiency against the background of systemic vasculitis and disseminated intravascular coagulation (DIC) syndrome, which persisted until the time of the study.\u003c/p\u003e\u003cp\u003eMost patients (63.3%, n\u0026thinsp;=\u0026thinsp;19) had a body mass index (BMI) within the normal range. In 23.3% (n\u0026thinsp;=\u0026thinsp;7) of the patients, a decrease in body weight was observed, with two patients having BMI values of 13.6 and 13.5 kg/m\u0026sup2;. One patient was diagnosed with an eating disorder (bulimia). Overweight was present in 10% (n\u0026thinsp;=\u0026thinsp;3) of the patients, and obesity was diagnosed in one patient, with a BMI of 31.2 kg/m\u0026sup2; (3.3%). All women underwent assessment of their menstrual cycle characteristics, including age at menarche, duration, regularity, intensity, and pain associated with menstruation. Prior to the onset of disorders of consciousness, 96.7% (n\u0026thinsp;=\u0026thinsp;29) described their menstruation as moderate. One patient had an ovarian endometriotic cyst and ultrasound signs of adenomyosis; her menstruation was heavy and painful, and she was also diagnosed with secondary infertility. The majority of patients had a regular menstrual cycle, with an average duration of 29.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 days. In 6.67% of women, menstrual cycle disturbances of the oligomenorrhea type were noted before the onset of consciousness impairment, with cycle lengths ranging from 31\u0026ndash;60 days. Half of the patients had a history of pregnancy ending in spontaneous vaginal delivery. A total of 10% of the patients had a history of cesarean section, and three patients experienced first-trimester miscarriage. One patient was on oral combined contraceptives prior to the onset of disorders of consciousness. Two patients were diagnosed with uterine fibroids, and two others underwent salpingectomy due to ectopic pregnancy. Among the comorbidities, arterial hypertension and varicose vein disease were the most common, each occurring in 10% of the patients. Degenerative-dystrophic disease of the lumbar spine was diagnosed in two patients (6.7%), Crohn\u0026rsquo;s disease in two patients (6.7%), chronic pyelonephritis in two patients (6.7%), chronic cystitis in one patient (3.3%), chronic bronchitis in one patient (3.3%), biliary dyskinesia in one patient (3.3%), and thrombosis of the anterior tibial vein at hospitalization in one patient (3.3%). On the basis of medical history, active interviews with staff and relatives, and patient monitoring in the intensive care setting, there were no episodes of menstrual bleeding. Considering the time interval since the onset of disorders of consciousness and a history of regular menstrual cycles, oligomenorrhea was diagnosed in 53.3% (n\u0026thinsp;=\u0026thinsp;12) of patients at the time of examination, \u003cb\u003ewhereas\u003c/b\u003e secondary amenorrhea was observed in 46.7% (n\u0026thinsp;=\u0026thinsp;14) \u003cb\u003eof patients\u003c/b\u003e. Among patients with MCS \u0026ldquo;plus,\u0026rdquo; oligomenorrhea was present in 33.3% (n\u0026thinsp;=\u0026thinsp;4) at the time of examination, and secondary amenorrhea \u003cb\u003ewas present\u003c/b\u003e in 66.7% (n\u0026thinsp;=\u0026thinsp;8) \u003cb\u003eof patients\u003c/b\u003e. All patients with MCS \u0026ldquo;minus\u0026rdquo; exhibited oligomenorrhea (n\u0026thinsp;=\u0026thinsp;6). In the UWS group, oligomenorrhea was observed in 66.7% (n\u0026thinsp;=\u0026thinsp;7) of patients, whereas 33.3% (n\u0026thinsp;=\u0026thinsp;5) had secondary amenorrhea at the time of examination.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eHormonal assessment results\u003c/h2\u003e\u003cp\u003eHormonal evaluation revealed anovulation in all patients with chronic disorders of consciousness. Estradiol levels were decreased in 80% of women (52.4\u0026thinsp;\u0026plusmn;\u0026thinsp;20.9 pmol/L). Elevated total testosterone levels were detected in 3.3% of patients (2.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97 nmol/L), whereas decreased total testosterone levels were noted in 43.3% of the cohort (0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 nmol/L, n\u0026thinsp;=\u0026thinsp;13). Prolactin concentrations were within reference ranges in 90% of patients (n\u0026thinsp;=\u0026thinsp;27); hyperprolactinemia was diagnosed in 10% (n\u0026thinsp;=\u0026thinsp;3) of patients, including two patients in the MCS \u0026ldquo;plus\u0026rdquo; subgroup (one in the late postpartum period with a prolactin level of 1509 mIU/L and another with an endometrioid cyst identified by ultrasound with a prolactin level of 1123 mIU/L) and one patient in the MCS \u0026ldquo;minus\u0026rdquo; subgroup in the postpartum period (prolactin level of 788.6 mIU/L). Subclinical hypothyroidism was observed in 10% of patients (TSH 4.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 mIU/L; free T4 17\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8 pmol/L). Free T4 levels were elevated in 13.3% of patients (27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 pmol/L) and decreased in 6.67% (1.9 pmol/L and 9.4 pmol/L). Free T3 was elevated in one patient (6.5 pmol/L) and decreased in 16.67% of patients (1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 pmol/L). Basal ACTH levels were elevated in 21.4% of patients (26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3 pmol/L), whereas basal cortisol levels were increased in 56.7% of patients (449.2\u0026thinsp;\u0026plusmn;\u0026thinsp;221.3 nmol/L). Normogonadotropic ovarian insufficiency was diagnosed in 63.3% of patients with CDC (FSH 5.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02 IU/L; LH 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 IU/L), whereas hypogonadotropic ovarian insufficiency was present in 36.7% (FSH 1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43 IU/L; LH 2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 IU/L).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAssessment of 25(OH)D levels in peripheral blood\u003c/h3\u003e\n\u003cp\u003eAll patients exhibited a significant reduction in peripheral blood 25-hydroxyvitamin D [25(OH)D] levels. Specifically, 26.7% demonstrated insufficiency (23.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 ng/mL), 56.7% presented deficiency (14.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 ng/mL), and 16.7% presented severe deficiency (7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64 ng/mL), despite standard enteral nutrition and irrespective of the duration of CDC.\u003c/p\u003e\n\u003ch3\u003eEvaluation of Central Nervous System Injury Markers in Serum and Cerebrospinal Fluid\u003c/h3\u003e\n\u003cp\u003eThe level of apoptosis antigen 1 (APO-1), also known as the CD95 apoptosis receptor, was measured in the serum and cerebrospinal fluid (CSF). Serum APO-1 levels were determined in 22 patients aged 18\u0026ndash;44 years (mean age 28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years), including nine patients in the VS/UWS group, nine in the MCS \u0026ldquo;plus\u0026rdquo; group, and four in the MCS \u0026ldquo;minus\u0026rdquo; group. The APO-1 concentrations were below the manufacturer\u0026rsquo;s reference range (1334\u0026ndash;2411 pg/mL) in 59.1% of the patients, ranging from 363.6 to 1230 pg/mL (mean 807.2\u0026thinsp;\u0026plusmn;\u0026thinsp;219.7 pg/mL). In 31.8% of patients, APO-1 levels were within the reference range, with an average of 1695.7\u0026thinsp;\u0026plusmn;\u0026thinsp;430.1 pg/mL. Two patients (9.1%) exhibited markedly elevated APO-1 levels: one patient in the VS/UWS group had 5836 pg/mL, and one patient in the MCS \u0026ldquo;plus\u0026rdquo; group had 194,755 pg/mL, approximately 80-fold above the reference range. APO-1 levels in CSF were assessed in seven patients; 85.7% (n\u0026thinsp;=\u0026thinsp;6) had levels below the detectable limit, while one patient had a level of 203.6 pg/mL. Reference values for APO-1 in CSF have not been established.\u003c/p\u003e\n\u003ch3\u003eAssessment of brain-derived neurotrophic factor (BDNF) levels in serum and cerebrospinal fluid\u003c/h3\u003e\n\u003cp\u003eSerum BDNF levels were measured in 23 patients aged 18\u0026ndash;44 years (mean age 28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years), including nine patients in the MCS \u0026ldquo;plus\u0026rdquo; group, five in the MCS \u0026ldquo;minus\u0026rdquo; group, and nine in the VS/UWS group. BDNF concentrations ranged from 8,540 to 49,820 pg/mL, with a mean value of 20,930.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9,752.9 pg/mL. In 95.7% of patients (n\u0026thinsp;=\u0026thinsp;22), BDNF levels fell within the manufacturer\u0026rsquo;s reference range (6,186\u0026ndash;42,580 pg/mL). One patient in the MCS \u0026ldquo;minus\u0026rdquo; group presented a BDNF level of 49,820 pg/mL. BDNF levels in cerebrospinal fluid were assessed in eight patients, all of whom had values below the detectable limits.\u003c/p\u003e\n\u003ch3\u003eEvaluation of Fas ligand (Fas-L) levels in serum and cerebrospinal fluid\u003c/h3\u003e\n\u003cp\u003eSerum Fas-L levels were determined in 22 patients aged 18\u0026ndash;44 years (mean age 28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years), including nine patients in the MCS \u0026ldquo;plus\u0026rdquo; group, four in the MCS \u0026ldquo;minus\u0026rdquo; group, and nine in the VS/UWS group. Fas-L concentrations were within the reference range in 95.5% of patients (n\u0026thinsp;=\u0026thinsp;21), with a mean level of 0.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 ng/mL. One patient in the MCS \u0026ldquo;minus\u0026rdquo; group presented an elevated Fas-L level of 4.73 ng/mL. CSF Fas-L levels were measured in seven patients aged 20\u0026ndash;41 years (mean age 28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0 years), including three patients in the MCS \u0026ldquo;minus\u0026rdquo; group and four in the VS/UWS group. The Fas-L concentrations ranged from 0.03 to 0.18 ng/mL, with a mean value of 0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07 ng/mL.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eAssessment of Glutamate Levels in Serum and Cerebrospinal Fluid\u003c/h2\u003e\u003cp\u003eSerum glutamate levels were measured in 23 women aged 18\u0026ndash;44 years (mean age 28.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years), including nine patients in the MCS \u0026ldquo;plus\u0026rdquo; group, five in the MCS \u0026ldquo;minus\u0026rdquo; group, and nine in the VS/UWS group. The glutamate concentrations exceeded the reference range in 50% of patients, ranging from 30.2 to 44.3 \u0026micro;g/mL. CSF glutamate levels were determined in 11 patients aged 20\u0026ndash;43 years (mean age 30.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.9 years), including five patients in the VS/UWS group and six in the MCS group. The mean CSF glutamate level was 2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 \u0026micro;g/mL. One patient in the MCS \u0026ldquo;minus\u0026rdquo; group presented an elevated CSF glutamate level of 17.2 \u0026micro;g/mL.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eAssessment of S100 protein levels in serum and cerebrospinal fluid\u003c/h3\u003e\n\u003cp\u003eSerum S100 protein was measured in one patient (31 years old) in the VS/UWS group, and CSF S100 protein levels were determined in three patients (two in the VS/UWS group and one in the MCS group), aged 28, 31, and 45 years. The serum S100 protein concentration was 22.7 ng/L. The mean CSF S100 protein level was 434.3 ng/L. Reference values for S100 protein in CSF have not been established.\u003c/p\u003e\n\u003ch3\u003eUltrasound examination of pelvic organs\u003c/h3\u003e\n\u003cp\u003eAll 30 patients with CDC underwent pelvic ultrasound due to oligomenorrhea or secondary amenorrhea (26 patients were examined transvaginally, 4 were examined transabdominally). The mean endometrial thickness was 2.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.23 mm (range 0.2\u0026ndash;5.3 mm), with no ultrasonographic signs of endometrial pathology detected. One patient (3.33%, n\u0026thinsp;=\u0026thinsp;1) was diagnosed with an endometriotic ovarian cyst and ultrasonographic signs of adenomyosis. Uterine fibroids (subserosal-intramural, FIGO classification types 5\u0026ndash;6) were diagnosed in two patients (6.67%). No dominant follicle growth, corpus luteum formation, or secretory transformation of the endometrium was observed in the examined patients.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eComparison of Patient Parameters between Groups with Different CDC Levels\u003c/h2\u003e\u003cp\u003ePatients were categorized into groups on the basis of consciousness level: VS/UWS (40%, n\u0026thinsp;=\u0026thinsp;12), MCS \u0026ldquo;minus\u0026rdquo; (20%, n\u0026thinsp;=\u0026thinsp;6), and MCS \u0026ldquo;plus\u0026rdquo; (40%, n\u0026thinsp;=\u0026thinsp;12). The groups were comparable in terms of age and body mass index (p\u0026thinsp;=\u0026thinsp;0.9) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) but differed significantly in the duration of CDC at the time of examination (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (p\u0026thinsp;=\u0026thinsp;0.02). Analysis of the obtained results revealed no statistically significant differences in the compared parameters between the groups.\u003c/p\u003e\n\u003cp\u003eTable 1. Anthropometric parameters and gynecological history of patients with different types of CDC\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMCS \u0026ldquo;minus\u0026rdquo; (n=6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMCS \u0026ldquo;plus\u0026rdquo; (n=12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVS/UWS (n=12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003cstrong\u003e*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e33\u0026plusmn;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e29\u0026plusmn;6,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e27\u0026plusmn;8,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0,31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eBody mass index, kg/m\u0026sup2;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e19,7\u003cbr\u003e\u0026nbsp;(17,4; 22,9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e21,3\u003cbr\u003e\u0026nbsp;(19,9; 24,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e20,5\u003cbr\u003e\u0026nbsp;(18,4; 22,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0,57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eAge at menarche, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e13,1\u0026plusmn;1,4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e12,4\u0026plusmn;1,9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e14,1\u0026plusmn;2,4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0,86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eMenstrual cycle regularity (before disorder of consciousness)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eRegular (83,3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eRegular (83,3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eRegular (91,6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eMenstrual pain (before disorder of consciousness)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003ePainful (33,3%) painless (66,7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePainful (8,4%)\u003c/p\u003e\n \u003cp\u003epainless (91,6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003ePainful (16,7%) painless (83,3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eMenstrual flow intensity (before disorder of consciousness)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003eModerate (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eModerate (91,6%), heavy (8,4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003eModerate (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eDuration of menstrual bleeding, days (before disorder of consciousness)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e5,5\u0026plusmn;2,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e4,7\u0026plusmn;1,3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e5,3\u0026plusmn;1,5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0,45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 37px;\"\u003e\n \u003cp\u003eMenstrual cycle length, days (before disorder of consciousness)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\n \u003cp\u003e29,3\u0026plusmn;1,9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e31,2\u0026plusmn;2,7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18px;\"\u003e\n \u003cp\u003e30,3\u0026plusmn;2,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0,76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e*Note: p values correspond to comparisons among the three groups (MCS \u0026ldquo;minus\u0026rdquo;, MCS \u0026ldquo;plus\u0026rdquo;, VS/UWS).\u003c/p\u003e\n\u003cp\u003eAssessment of the \u003cb\u003e25(OH)D Level\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNo significant differences were detected in peripheral blood 25(OH)D levels among patients with different forms of CDC: 16.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6 ng/mL in the VS/UWS group, 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2 ng/mL in the MCS \u0026ldquo;plus\u0026rdquo; group, and 17.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4 ng/mL in the MCS \u0026ldquo;minus\u0026rdquo; group (p\u0026thinsp;=\u0026thinsp;0.25). In the VS/UWS group, 25(OH)D levels were significantly decreased: 41.7% (mean 23.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 ng/mL) were insufficient, 50% (14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7 ng/mL) were deficient, and 8.3% (7.4 ng/mL) were severely deficient. Among patients in the MCS \u0026ldquo;plus\u0026rdquo; group, 25(OH)D levels were also significantly decreased: 16.7% (24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9 ng/mL) were insufficient, 50% (14.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.6 ng/mL) were deficient, and 33.3% (7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6 ng/mL) were severely deficient. In the MCS \u0026ldquo;minus\u0026rdquo; group, 25(OH)D insufficiency was observed in 33.3% (22.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 ng/mL) and deficiency in 66.7% (15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4 ng/mL) of the patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eComparative Analysis of CNS Injury Markers in Patients with Different CDC Levels\u003c/h2\u003e\u003cp\u003eA comparative analysis of CNS injury markers was conducted among patients with different consciousness levels (MCS \u0026ldquo;plus\u0026rdquo;, MCS \u0026ldquo;minus\u0026rdquo;, and VS/UWS). No significant differences in serum apoptotic antigen levels were detected between the groups: the median values were 1230 (916.4; 1420) pg/mL, 1375 (908.7; 1960) pg/mL, and 800 (669.1; 1173.3) pg/mL, respectively (p\u0026thinsp;=\u0026thinsp;0.19). The serum BDNF levels did not differ significantly: the medians were 2282 (12660; 24450) pg/mL, 2302 (21140; 31300) pg/mL, and 1650 (669.1; 1173.3) pg/mL (p\u0026thinsp;=\u0026thinsp;0.46). The serum Fas ligand (Fas-L) levels also did not significantly differ: 0.22 (0.15; 0.23) ng/mL, 0.22 (0.14; 0.33) ng/mL, and 0.23 (0.16; 0.26) ng/mL (p\u0026thinsp;=\u0026thinsp;0.96). Similarly, no significant differences in CSF Fas-L levels were detected between the groups, with medians of 0.04 (0.04; 0.17) ng/mL and 0.07 (0.03; 0.08) ng/mL (p\u0026thinsp;=\u0026thinsp;0.36). The serum glutamate levels also did not differ significantly among the groups: 32.5 (20; 44) \u0026micro;g/mL, 30.2 (17.6; 33.9) \u0026micro;g/mL, and 30.8 (22.7; 42.8) \u0026micro;g/mL (p\u0026thinsp;=\u0026thinsp;0.62). No statistically significant differences were found in CSF glutamate levels between groups: a median of 1.86 (1.75; 2.06) \u0026micro;g/mL in the VS/UWS group and 2.53 (2.22; 9.94) \u0026micro;g/mL in the MCS group (p\u0026thinsp;=\u0026thinsp;0.08). However, CSF glutamate levels were higher in patients with VS/UWS than in those with MCS, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eModel 1. Prognosis of Favourable Outcomes via TSH and Prolactin Levels\u003c/h2\u003e\u003cp\u003eOn the basis of the analysis and identification of prognostic markers, the TSH and prolactin levels in patients with CDC significantly influenced the recovery of consciousness (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Results of the Study on the Relationship between Disorders of Consciousness and Predictors (TSH, Prolactin)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ePredictors\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStandard Error\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eχ\u003csup\u003e2\u003c/sup\u003e Wald\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOdds Ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003e95% Confidence Interval\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUpper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProlactin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,437\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,996\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0,989\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1,003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,546\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4,261\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3,086\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1,059\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e8,996\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTSH and prolactin levels in patients with CDC significantly affect the likelihood of consciousness recovery. The predictive formula is as follows:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eВ1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e=\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e(1)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u0026thinsp;+\u0026thinsp;2,72\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;(\u0026minus;2,949+1,127\u0026times;TSH 0,004\u0026times;Prolactin))\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA B1 value of 0.7 or lower indicates a favourable prognosis\u0026mdash;restoration of consciousness. The model's accuracy was 92.3%, its sensitivity was 80.0%, and its specificity was 100% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eModel 2. Prognosis of Favourable Outcomes via Prolactin, FSH, Total Testosterone, and Age\u003c/h2\u003e\u003cp\u003eModel 2 examined the influence of blood hormones, prolactin, FSH, total testosterone, and patient age, on the recovery of consciousness. Regression analysis yielded the following model. The χ\u0026sup2; value for the predictors is 11.4 with 4 degrees of freedom, p\u0026thinsp;=\u0026thinsp;0.02, indicating that at least one predictor is associated with the event. The Nagelkerke R\u0026sup2; is 0.489 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Relationships between Consciousness Level and Identified Predictors\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables in Equation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParameter Estimate (B)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStandard Error\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOdds Ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95% CI (Lower \u0026ndash; Upper)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1,15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1\u0026ndash;1,3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal Testosterone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e19,4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0,8-453,7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProlactin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1,6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0,9\u0026thinsp;\u0026minus;\u0026thinsp;2,7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe regression-derived formula for the probability of belonging to group 2 (B2) is as follows:\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabc\" border=\"1\"\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eВ2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e=\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e(2)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u0026thinsp;+\u0026thinsp;2,72\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;(\u0026minus;6,904+0,005\u0026times;Prolactin\u0026minus;0,449\u0026times;FSH+2,965\u0026times;Testosterone+0,139\u0026times;Age)\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA B2 value of 0.7 or lower indicates a favourable prognosis\u0026mdash;restoration of consciousness. At a classification threshold of p\u0026thinsp;=\u0026thinsp;0.5, the model's accuracy is 80.0%, its sensitivity is 83.3%, and its specificity is 76.9%. ROC analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) revealed that the area under the curve exceeded 0.8, indicating \"very good\" model quality.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eModel 3. Prognosis of Favourable Outcomes via AMH, FSH, and Total Testosterone Levels\u003c/h2\u003e\u003cp\u003eThis model is based on three parameters: FSH, AMH, and total testosterone in blood serum. The χ\u0026sup2; value for the predictors is 10.69 with 3 degrees of freedom, p\u0026thinsp;=\u0026thinsp;0.014, indicating that at least one predictor is associated with the event. The Nagelkerke R\u0026sup2; is 0.46 (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Relationships between conditions and predictors\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHormones\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eParameter Estimate (B)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eStandard Error\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWald χ\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eOdds Ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e95% Confidence Interval\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eUpper\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFSH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2,4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1,5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0,9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e2,5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAMH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0,3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3,8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0,8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0,6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal Testosterone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2,8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1,7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2,9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e16,9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0,7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e426,7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe formula for calculating the probability of condition (B3), which is based on the regression\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabd\" border=\"1\"\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eВ3\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e=\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003e(3)\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003e1\u0026thinsp;+\u0026thinsp;2,72\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;(\u0026minus;3,218+0,402\u0026times;FSH\u0026minus;0,26\u0026times;AMH+2,825\u0026times;Testosterone)\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA B3 value of 0.7 or lower indicates a favourable outcome\u0026mdash;restoration of consciousness. At a classification threshold of p\u0026thinsp;=\u0026thinsp;0.5, this model demonstrated an accuracy of 76.0%, sensitivity of 76.9%, and specificity of 75.0% (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eHormone Therapy\u003c/h2\u003e\u003cp\u003eThe patients were scheduled to receive cyclic hormone replacement therapy: transdermal estradiol hemihydrate (1 mg daily) combined with intravaginal micronized progesterone (200 mg) once daily from days 14 to 28 of estradiol administration. However, owing to comorbidities, including subarachnoid hemorrhage, postoperative pulmonary embolism (n\u0026thinsp;=\u0026thinsp;2), superficial vein thrombophlebitis (n\u0026thinsp;=\u0026thinsp;5), malignant brain tumors, intraoperative aneurysm rupture, arrhythmia, and heterozygous prothrombin gene mutation, these medications were not prescribed, as they are absolute or relative contraindications. Thromboembolism risk was assessed via the Padua scale, with 80% of patients classified as high risk. After further evaluation and clarification of indications and contraindications, legal representatives, fully informed of the risks and benefits, declined hormone therapy.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eOutcomes of Consciousness Disorders in patients with CDC\u003c/h2\u003e\u003cp\u003eThe outcomes of patients with consciousness disorders were as follows: 36.67% (n\u0026thinsp;=\u0026thinsp;11) of patients regained clear consciousness; 23.67% (n\u0026thinsp;=\u0026thinsp;7) remained in the VS/UWS; 16.67% (n\u0026thinsp;=\u0026thinsp;5) were in the MCS \u0026ldquo;minus\u0026rdquo;; 6.67% (n\u0026thinsp;=\u0026thinsp;2) were in the MCS \u0026ldquo;plus\u0026rdquo;; and outcome data were unavailable for 16.67% (n\u0026thinsp;=\u0026thinsp;5) of patients.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study included 30 women with rare neurological disorders. Patients were hospitalized at a specialized center for CDC treatment at the Department of Anesthesiology and Intensive Care of the A.L. Polenov Russian Neurosurgical Institute, branch of the V.A. Almazov Federal Medical Research Center, from various regions across Russia. The inclusion criterion was reproductive age (18\u0026ndash;44 years). Causes of disorders of consciousness included traumatic (30%) and nontraumatic (70%) brain injuries, such as hypoxic damage from arrhythmias, postsurgical benign tumor removal, and infectious causes of unspecified etiology. Notably, some cases involved obstetric and gynecological catastrophes, such as anaphylactic shock during ectopic pregnancy surgery, pulmonary artery thromboembolism, and amniotic fluid embolism. The duration of CDC ranged from 1 to 15 months (mean 3 months). One patient\u0026rsquo;s impairment resulted from acute cerebral circulatory failure against systemic vasculitis and DIC, lasting 137 months, during which time she was monitored at home without menstruation.\u003c/p\u003e\u003cp\u003eInitially, it was expected that all patients would exhibit significant weight deficiency due to the severity of their condition. However, most had a normal BMI; only 23.3% were underweight. Prior to consciousness impairment, patients\u0026rsquo; menstrual function was comparable to that of healthy women, with common conditions such as uterine fibroids and endometriosis. The comorbidities were also similar to those of the general population.\u003c/p\u003e\u003cp\u003eFew studies exist on hormonal status in CDC patients, making our hormonal findings particularly relevant. In 1989, Japanese researchers identified anterior pituitary and gonadal hormone secretion disorders in 33 patients, 52% of whom presented with severe abnormalities [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Abnormalities included growth hormone, LH, FSH, cortisol, TSH, and prolactin in 70%, 67%, 45%, 39%, 36%, and 15% of cases, respectively. Our data revealed ovarian insufficiency in all patients: 63.3% had normogonadotropic ovarian failure (FSH 5.04\u0026thinsp;\u0026plusmn;\u0026thinsp;2.02 IU/L; LH 4.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1 IU/L), and 36.7% had hypogonadotropic ovarian failure (FSH 1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43 IU/L; LH 2.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1 IU/L). The prolactin levels were within reference ranges in 90% of the patients, with hyperprolactinemia diagnosed in 10% of the patients, which was attributed to late postpartum status or endometriosis.\u003c/p\u003e\u003cp\u003eA study revealed a positive correlation between the severity of brain injury and prolactin levels, suggesting that prolactin is a superior marker of brain damage severity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Previous research on prolactin levels in patients with CDC involved small samples and did not stratify by sex or severity. Nonetheless, most studies reported significant prolactin elevation, possibly due to side effects of the medications used for treatment. Our data revealed that all women with CDC experienced anovulation and significantly reduced serum estradiol levels, which is consistent with the absence of menstrual activity during observation. Total testosterone was decreased in 43.3% of patients, but 80% exhibited signs of hirsutism (Ferriman-Gallwey scale score: 8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7).\u003c/p\u003e\u003cp\u003eIn 2018, in Nigeria, thyroid status was assessed in 115 TBI patients (85% men, 15% women) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Most patients (71.7%) arrived within 24 hours post-injury. TBI severity was mild in 53%, moderate in 16%, and severe in 31% of the patients. Elevated T3 was found in 52.2% of the patients, low in 7.8%, and normal in 40%. Elevated T4 was observed in 4.3% of the patients, low in 68.7%, and normal in 27%. TSH was high in 16.5%, low in 6.1%, and normal in 77.4% of the patients. A correlation between TBI severity and thyroid hormone levels was noted; low T4 was associated with death or a persistent vegetative state (p\u0026thinsp;=\u0026thinsp;0.012). In our study, subclinical hypothyroidism was found in 10% of patients; 13.3% had elevated free T4 levels (27.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 pmol/L), 6.7% had decreased T4 levels (1.9 pmol/L), and 16.7% had decreased free T3 levels (1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 pmol/L). TSH, free T4, and T3 levels did not correlate with outcomes or consciousness levels.\u003c/p\u003e\u003cp\u003eA study on circadian cortisol rhythms in 18 patients in a vegetative state receiving total enteral nutrition showed that those who were fed continuously during the day presented a normal peak at 8 a.m., similar to healthy individuals [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Night-fed patients presented a peak at 4 p.m., indicating cyclic secretion. In our research, cortisol levels measured in the morning and evening showed no clear pattern; only 21.4% had elevated basal ACTH (26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.3 pmol/L), and 56.7% had elevated basal cortisol (449.2\u0026thinsp;\u0026plusmn;\u0026thinsp;221.3 nmol/L).\u003c/p\u003e\u003cp\u003eVitamin D influences steroidogenesis of sex hormones (estradiol and progesterone) in healthy women. Receptors and metabolizing enzymes are present in reproductive tissues [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It is hypothesized that vitamin D acts synergistically with estradiol to produce and release lysosomes, weakening the protein shell and facilitating oocyte release, possibly aiding transport and fertilization in the fallopian tubes. Its presence in the endometrial glands and corpus luteum suggests a role in endometrial proliferation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. All our patients had significantly reduced serum 25(OH)D levels: 26.7% had deficiency (23.37\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5 ng/mL), 56.7% had insufficiency (14.58\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 ng/mL), and 16.7% had severe deficiency (7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.64 ng/mL), regardless of the duration of TBI or nutritional support. Compared with those of the controls (30.5\u0026thinsp;\u0026plusmn;\u0026thinsp;16.7 ng/mL, p\u0026thinsp;=\u0026thinsp;0.001), vitamin D levels were lower, with no significant difference between those with normo- and hypogonadotropic ovarian failure (p\u0026thinsp;=\u0026thinsp;0.87). Prolonged hospitalization and limited sunlight exposure likely contributed to this deficiency; previous studies did not assess this phenomenon in CDC patients.\u003c/p\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eNeurotrophin and Biomarker Studies for the Prognosis of Consciousness Recovery\u003c/h2\u003e\u003cp\u003eWe measured the serum levels of neurotrophins\u0026mdash;BDNF, APO-1, Fas-L, and glutamate\u0026mdash;to identify potential prognostic markers. In 23 patients aged 18\u0026ndash;44 years (mean 28.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years), BDNF levels ranged from 8,540 to 49,820 pg/mL (mean 20,930.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9,752.9). Nineteen patients were in the MCS \u0026ldquo;plus\u0026rdquo; state, five in the MCS \u0026ldquo;minus,\u0026rdquo; and nine in the VS/UWS. In 95.7% (n\u0026thinsp;=\u0026thinsp;22) of the patients, BDNF levels were within the reference range (6,186\u0026ndash;42,580 pg/mL); one patient in the MCS \u0026ldquo;minus\u0026rdquo; state had a level of 49,820 pg/mL. BDNF in cerebrospinal fluid was measured in 8 patients, all of whom were below the detectable limit. A literature review revealed one study by E.G. Yazeyeva et al. involving 26 patients (16 men, 10 women, aged 23\u0026ndash;41, mean 27), with 14 in the vegetative state and 12 in the minimally conscious state [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The controls included 21 healthy volunteers. In healthy individuals, the average serum BDNF concentration was 54 pg/mL, whereas in patients with CDC, it was significantly greater (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), averaging 770 pg/mL (range 640\u0026ndash;950). No significant difference was found between the vegetative and minimally conscious states, indicating that BDNF is not a reliable prognostic marker in this context.\u003c/p\u003e\u003cp\u003eSerum levels of APO-1 were measured in 22 patients. In 59.1% of the patients, the levels were below the reference range (1334\u0026ndash;2411 pg/mL), ranging from 363.6 to 1230 pg/mL (mean 807.2\u0026thinsp;\u0026plusmn;\u0026thinsp;219.7). In 31.8% of the patients, the levels were within the reference range (mean 1695.7\u0026thinsp;\u0026plusmn;\u0026thinsp;430.1%). Two patients had markedly elevated levels: 5836 pg/mL (vegetative state) and 194,755 pg/mL (80 times above the reference, in the MCS \u0026ldquo;plus\u0026rdquo; state). In 7 patients, APO-1 in cerebrospinal fluid was measured; 85.7% (n\u0026thinsp;=\u0026thinsp;6) had levels below the detectable limit, and one had 203.6 pg/mL. Previous studies on APO-1 in CDC patients are limited. In preeclampsia patients, APO-1 levels were significantly lower (167.07\u0026thinsp;\u0026plusmn;\u0026thinsp;14.61 mg/dL) than those in healthy women (244.37\u0026thinsp;\u0026plusmn;\u0026thinsp;20.84 mg/dL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and were similarly lower in patients with pulmonary thromboembolism [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eBiomarker levels in traumatic brain injury patients\u003c/h2\u003e\u003cp\u003eIn our study, we measured the serum levels of the apoptosis inducer Fas-L in 22 patients. In 95.5% of patients, Fas-L levels were within reference ranges, and one patient in an MCS \u0026ldquo;minus\u0026rdquo; state had a Fas-L level of 4.73 ng/mL. A prospective observational study in five intensive care units examined patients with severe isolated TBI. Fas-L concentrations in serum measured within the first 24 hours post-injury showed that levels above 29.2 pg/mL were associated with increased mortality (risk ratio\u0026thinsp;=\u0026thinsp;6.2; 95% CI\u0026thinsp;=\u0026thinsp;2.6\u0026ndash;14.8; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Multivariate logistic regression revealed a significant association between serum Fas-L levels and 30-day mortality in TBI patients (p\u0026thinsp;=\u0026thinsp;0.004) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our research, glutamate levels were measured in 23 women with CDC. In half of the patients, glutamate exceeded the reference values, ranging from 30.2 to 44.3 \u0026micro;g/mL. In the cerebrospinal fluid, glutamate was assessed in 10 patients, with a mean concentration of 2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4 \u0026micro;g/mL. One patient in a \u0026ldquo;minus\u0026rdquo; state had elevated glutamate up to 17.2 \u0026micro;g/mL. The literature provides no data on glutamate levels in CDC patients.\u003c/p\u003e\u003cp\u003eWe also measured S100 protein in the serum of one patient and in the cerebrospinal fluid of three patients. Serum S100 was 22.7 ng/L; CSF S100 averaged 434.3 ng/L (reference values for CSF S100 are not established). The literature indicates that serum S100 remains within reference ranges in mild TBI but is elevated in brain contusions [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Elevated S100 (\u0026gt;\u0026thinsp;0.105 \u0026micro;g/L) with 100% sensitivity can serve as an additional diagnostic marker to differentiate concussion from brain contusion, with CT detecting brain damage in 72.7% and MRI in 100% of mild TBI cases when S100 is elevated. Normal S100 levels suggest the absence of brain injury. A 1998 study evaluated serum S100 and neuron-specific enolase levels to predict consciousness recovery after acute global cerebral ischemia. In 64 patients, serum and cerebrospinal fluid samples were collected 24 and 48 hours post-ischemia. Serum S100 levels above 0.7 \u0026micro;g/L predicted the absence of consciousness recovery, with a high positive predictive value (95%) and specificity (96%). The authors concluded that S100 could serve as a marker for consciousness recovery within 24 hours after global brain ischemia.\u003c/p\u003e\u003cp\u003eIn our study, a comparative analysis of CNS damage markers revealed no significant differences between the groups. Similarly, no significant differences were found in median neurotrophin levels between patients with hypogonadotropic and normogonadotropic ovarian failure. Further research with larger patient samples is needed; currently, these neuromarkers cannot be recommended for predicting consciousness recovery.\u003c/p\u003e\u003cp\u003e Considering the hormonal assessment results and following clinical guidelines, the possibility of hormone replacement therapy was reviewed. Patients underwent comprehensive evaluation, including cervical screening, genetic testing, ultrasound, and general clinical assessments. For 25 patients, cervical cytology was performed, and no atypical cells were detected. Atrophic changes in the multilayered squamous epithelium were observed in only 34.6% of the patients, all of whom experienced anovulation and hypoestrogenism. Such studies in patients with CDC are not described in the literature.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePredicting consciousness recovery in patients with CDC remains a significant challenge in modern intensive care. For young patients who have experienced neurological catastrophe, rapid normalization of consciousness is critically important. HNSs are considered \u0026ldquo;cortico-cortical/thalamocortical disconnection syndromes\u0026rdquo; [Laureys et al., 2002]. The primary factor underlying ovarian insufficiency in patients with CDC is likely the disconnection of cortical and subcortical brain structures. According to the classical model of hypothalamic‒pituitary‒ovarian regulation, patients with CDC exhibit decreased gonadotropin-releasing hormone (GnRH) secretion, leading to reduced gonadotropin production, secondary amenorrhea, and the development of secondary hypothalamic ovarian failure [Aylamazyan, 2006; Potin, 2004]. Normogonadotropic ovarian failure may also represent an initial stage of other forms of ovarian failure. Hormone replacement therapy can restore ovarian function via negative feedback mechanisms, potentially synchronizing gonadotropin secretion and inducing menstrual activity. Such synchronization likely contributes to the re-establishment of neural network connectivity in the cerebral cortex.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eACTH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eadrenocorticotropic hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAMH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAnti-M\u0026uuml;llerian Hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBDNF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBrain-Derived Neurotrophic Factor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebody mass index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003echronic disorders of consciousness\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecentral nervous system\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecerebrospinal fluid\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFIGO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational Federation of Gynecology and Obstetrics\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFSH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003efollicle-stimulating hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGnRH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eGonadotropin-releasing hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMCS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eminimally conscious state\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTBI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etraumatic brain injury\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTSH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ethyroid-stimulating hormone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eVS/UMS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003evegetative state/unresponsive wakefulness syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEach author is expected to have made substantial contributions to the conception, design of the work, the acquisition, analysis, interpretation of data.\u003c/p\u003e\n\u003cp\u003eEach author has approved the submitted version and agreed both to be personally accountable for the author\u0026apos;s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.\u003c/p\u003e\n\u003cp\u003eDeclarations of human ethics and consent to participate were observed.\u003c/p\u003e\n\u003cp\u003eAll authors agree to the publication of manuscripts.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the local Ethics Committee of the D.O. Ott Research Institute of Obstetrics, Gynecology and Radiology (Protocol No. 96 dated April 23, 2019) and the Ethics Committee of the V.A. Almazov National Medical Research Center of the Ministry of Health of the Russian Federation (Extract 03/16/2019) dated March 15, 2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003cstrong\u003eunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was conducted as part of a fundamental scientific study entitled \u0026quot;Strategy for Maintaining the Health of Women with Gynecological and Endocrine Diseases at Different Ages: Pathogenetic Justification for Drug Rehabilitation and the Development of New Organ-Preserving Surgical Interventions\u0026quot; (State Registration No. 1021062812154-3-3.2.2), supported by a grant from the Russian Foundation for Basic Research under research project No. 19-29-01066.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNICE. (2017) Fertility problems: assessment and treatment. 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Stroke. 1998;29(11):2363\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.str.29.11.2363\u003c/span\u003e\u003cspan address=\"10.1161/01.str.29.11.2363\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"chronic disorders of consciousness, ovarian failure, vitamin D, BDNF, APO-1, Fas-L, glutamate","lastPublishedDoi":"10.21203/rs.3.rs-7687762/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7687762/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e\u003cp\u003eChronic disorders of consciousness are rare clinical conditions that develop after coma and are accompanied by the restoration of wakefulness without the full restoration of consciousness 28 days or longer after brain damage. The results of a comprehensive examination of patients with different types of ovarian failure, depending on the type of chronic disorders of consciousness, have not been presented in the literature. Studying ovarian function in this population may help identify markers of consciousness recovery.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e\u003cp\u003eThe study included 30 women aged 18\u0026ndash;44 years (mean age: 29\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2 years). Etiologies of CDC were traumatic (30%) and nontraumatic (70%), including hypoxic injury, postsurgical and postpartum embolism, and infectious causes. The duration of impairment ranged from 1 to 15 months. Most patients had a normal BMI. Neurobiological markers, including BDNF, APO-1, Fas-L, and glutamate, were measured.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e\u003cp\u003eHormonal assessments revealed universal ovarian failure, with decreased estradiol levels. Notably, all patients exhibited signs of ovarian failure, with some showing hyperprolactinemia and subclinical hypothyroidism. Vitamin D deficiency was prevalent across the cohort. BDNF levels were within reference ranges in most patients, with no correlation with the state of consciousness. Elevated APO-1 and Fas-L levels were observed in some patients, but no significant differences were found between the groups. The glutamate levels varied, with some exceeding normal ranges, but no consistent pattern emerged. These findings suggest the limited prognostic utility of these biomarkers in predicting consciousness recovery.\u003c/p\u003e\u003ch2\u003eConclusions.\u003c/h2\u003e\u003cp\u003eThree prognostic models for favourable outcomes have been developed on the basis of blood hormone levels (FSH, TSH, AMH, prolactin, and testosterone) and patient age. This study underscores the complexity of hormonal and neurobiological interactions in CDC and highlights the potential role of disconnection within cortical and subcortical networks in ovarian failure. Further research is necessary to elucidate these mechanisms and develop reliable prognostic models for recovery.\u003c/p\u003e","manuscriptTitle":"Options for ovarian failure and the development of prognostic models for outcomes in patients with different types of chronic disorders of consciousness","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 09:44:07","doi":"10.21203/rs.3.rs-7687762/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-06T05:38:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-02T02:48:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-02T02:47:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2025-09-22T20:05:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"31921715-d747-4de0-abe6-83532e00a771","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-01-04T01:38:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 09:44:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7687762","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7687762","identity":"rs-7687762","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}