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Introduction
Surgical menopause is defined as the cessation of menstruation following bilateral oophorectomy or iatrogenic ablation of ovarian function [1-3]. In women who undergo hysterectomy without concomitant oophorectomy, establishing the diagnosis of menopause may be challenging due to the absence of menstrual criteria. Therefore, international guidelines recommend that menopause in these patients be diagnosed primarily on the basis of vasomotor symptoms, with or without biochemical confirmation using hormonal markers such as serum follicle-stimulating hormone (FSH) levels [4, 5].
Although the incidence of hysterectomy has declined in many developed countries owing to the increasing availability of minimally invasive treatments for benign gynecological disorders, the procedure remains highly prevalent worldwide. Reported prevalence rates reach approximately 38% in Sweden, 36% in the United States, and 25% in the United Kingdom. In developing regions, the annual incidence is estimated at approximately 165 cases per 100,000 women [6]. Nearly 90% of hysterectomies are performed for benign conditions, including uterine fibroids, refractory abnormal uterine bleeding, and pelvic organ prolapse [7-12].
Bilateral oophorectomy, frequently performed concomitantly with hysterectomy even in the absence of malignancy, has substantial long-term implications for women’s health, particularly among younger patients. Between 23% and 45% of women aged 40-49 years undergo bilateral oophorectomy at the time of hysterectomy [13, 14]. Notably, the rate of this procedure has increased significantly since 2011, both among younger women (from 31% to 65%, p < 0.005) and older women (from 44% to 58%, p < 0.005) [15].
Unlike natural menopause, in which the hormonal transition occurs gradually, surgical menopause induces abrupt endocrine deprivation characterized by the immediate cessation of ovarian production of estrogen, progesterone, and testosterone, accompanied by a marked elevation in gonadotropins (luteinizing hormone [LH] and FSH) [13]. This sudden decline in ovarian hormones precipitates the onset of climacteric syndrome, typically manifested by severe vasomotor symptoms (often emerging immediately after surgery and potentially persisting long term) as well as psycho-emotional and somatic disturbances.
Beyond its clinical manifestations, acute hormonal deprivation also exerts significant effects on biochemical pathways by disrupting systemic redox homeostasis. Estrogen deficiency has been associated with reduced activity of key antioxidant enzymes and increased levels of oxidative stress markers, mechanisms that may exacerbate vasomotor and psycho-emotional symptoms and contribute to heightened susceptibility to metabolic and cardiovascular complications. In this context, the present study aims to evaluate the impact of surgical menopause on the severity of climacteric syndrome and on selected oxidative stress biomarkers.
Materials and methods
Between 2019 and 2024, an analytical observational cohort study was conducted to assess the severity of climacteric syndrome and the degree of redox imbalance in women of reproductive age undergoing surgical menopause. The research project and study protocol were approved by the Research Ethics Committee of the Nicolae Testemițanu State University of Medicine and Pharmacy (Protocol No. 17, April 12, 2019). The study was performed at the Gheorghe Paladi Municipal Clinical Hospital in Chișinău, Republic of Moldova.
Participants were allocated into three cohorts: two study groups — G1A (women who underwent hysterectomy with bilateral oophorectomy) and G1B (women who underwent hysterectomy with ovarian preservation) — and a control group (G0), comprising healthy women. A 1:1 allocation ratio was maintained between the study subgroups and the control group. The representative sample size was calculated using the formula recommended by the Centers for Disease Control and Prevention (CDC, Atlanta, USA), based on the estimated prevalence and desired statistical power,
[16], where:
P0 = proportion of patients with surgical menopause expected to develop climacteric syndrome. Based on the literature, the prevalence of this syndrome is approximately 60%[17], hence P0 = 0.60.
P1 = proportion of subjects in the study cohort expected to develop the outcome, assumed to be 90%, hence P1 = 0.90.
P = (P₀ + P₁)/2 = 0.75
Zα – tabulated value = 1.96
Zβ – tabulated value = 1.28
f = the proportion of subjects expected to withdraw from the study for various reasons, f =10% (0.1). By substituting these values into the formula, the required representative sample size was calculated to be 49 participants per cohort.
Eligible participants were consecutively recruited from the daily surgical schedule for elective gynecological procedures. Surgical indications were determined according to standard clinical judgment and were independent of study participation. Preoperative assessment included a standardized interview, a comprehensive medical examination, evaluation of climacteric symptoms, and measurement of oxidative stress biomarkers. Postoperatively, participants were assigned to study groups based on the type of surgical procedure, and those undergoing unilateral oophorectomy were excluded from the analysis. Follow-up assessments were conducted at 10 - 12 days, 6 months, and 12 months after surgery.
To ensure the integrity of the longitudinal dataset and minimize bias related to missing data, a complete-case analysis approach was applied. For the clinical assessment using the Greene Climacteric Scale, 50 women were included in each study group, all of whom completed the questionnaires at every study time point. Participant recruitment was discontinued once the predefined sample size had been achieved. Within this cohort, biochemical analyses were performed on a sub-sample of 25 women per group. The reduced sample size resulted from non-adherence to the standardized protocol for blood collection and immediate sample processing, and only participants with complete biochemical data across all four study visits were retained for analysis.
Participants included in the study were selected according to well-defined eligibility criteria. Inclusion criteria were as follows: reproductive age ≤49 years, consistent with the World Health Organization definition (15 - 49 years); scheduled for hysterectomy, with or without oophorectomy, for benign uterine pathology; and provision of written informed consent for study participation. Participants in the control cohort were randomly selected from women presenting for their routine annual preventive clinical examination.
The exclusion criteria were as follows: age ≥50 years; hysterectomy with unilateral oophorectomy; use of combined oral contraceptives or other hormonal preparations within the last three menstrual cycles; presence of decompensated extragenital pathology (including renal, hepatic, or cardiac disease, diabetes mellitus, oncological, or psychiatric disorders); hysterectomy performed for malignant disease or obstetric indications; and refusal to provide informed consent for study participation.
Climacteric symptoms were assessed using the Greene Climacteric Scale, which comprises 21 items: items 1–6 for anxiety, 7-11 for depression, 12-18 for somatic symptoms, 19-20 for vasomotor symptoms, and 21 for sexual dysfunction. Each item was rated on a 4-point scale ranging from 0 (not at all) to 3 (extremely). Mean scores were calculated for each symptom domain as well as for the total scale score [18].
Oxidative stress was evaluated through the determination of pro-oxidant and antioxidant biomarkers using spectrophotometric and fluorometric methods adapted for Synergy H1 and Power Wave HT microplate spectrophotometers (BioTek Instruments, USA). Malondialdehyde (MDA) was quantified using the thiobarbituric acid reaction and expressed in μM/L, while advanced protein oxidation products (PPOA) were measured spectrophotometrically at 340 nm and expressed in μmol/L. Nitrite and nitrate derivatives (NO₂⁻, NO₃⁻) were assessed using the Griess method, with results expressed in μM/L of serum. Superoxide dismutase (SOD) activity was determined based on the inhibition of NBT reduction and expressed in U/mL, whereas catalase (CAT) activity was measured by the decomposition of hydrogen peroxide (H₂O₂) and expressed in μM/L. Total antioxidant capacity (AAT) was assessed using the ABTS method and expressed in μM/L. Blood collection and processing were performed according to standardized protocols, with serum samples stored at –20°C until analysis. All biomarker measurements were conducted at the Biochemistry Laboratory of the Nicolae Testemițanu State University of Medicine and Pharmacy.
Primary data were recorded in Microsoft Excel and subsequently exported to IBM SPSS (version 27.0.1) and GraphPad Prism (version 10.4.0) for statistical analysis. Continuous variables were expressed as mean ± standard deviation (SD). Between-group differences were evaluated using one-way analysis of variance (ANOVA). When a statistically significant overall effect was observed, Tukey’s honestly significant difference (HSD) post hoc test was performed to identify pairwise differences.
For the longitudinal assessment of study parameters and adjustment for potential confounding factors, repeated-measures analysis of covariance (RM-ANCOVA) was employed. In this general linear model, time was specified as the within-subject factor, study group as the between-subject factor, and age was included as a covariate. The assumption of sphericity was assessed using Mauchly’s test; when violated, the Greenhouse–Geisser correction was applied to adjust the degrees of freedom. Pairwise comparisons of estimated marginal means were adjusted using the Bonferroni correction. Statistical significance was defined as p < 0.05.
Results
The study included women aged 27-49 years. The mean age was significantly higher in the hysterectomy with bilateral oophorectomy group (46.1 ± 2.8 years; p < 0.001) compared with the hysterectomy without oophorectomy group (41.9 ± 4.8 years) and the control group (43.8 ± 3.3 years; p < 0.001). Most participants were from urban areas (56–66%) and were married (80–84%), with no significant between-group differences. Gynecological and obstetric characteristics were comparable across groups, except for the total number of pregnancies, which was higher in the G1A group (p = 0.006), suggesting a more complex obstetric history. Comorbidities, primarily cardiovascular, digestive, and endocrine disorders, were infrequent and similarly distributed among groups (p > 0.05). Although the duration of surgery was longer in G1A, the difference did not reach statistical significance; however, the observed trend may reflect greater surgical complexity, which could be associated with increased oxidative stress.
Analysis of climacteric symptoms using the Greene questionnaire demonstrated a significant increase in total scores in the surgically treated groups. Preoperatively, patients in the G1B group had higher scores (13.34 ± 6.09) compared with G1A (9.06 ± 6.26) and the control group (3.38 ± 2.98) (F = 43.734; p < 0.001). Postoperatively, total scores increased in both surgical groups, reaching 12.30 ± 6.41 in G1A and 13.86 ± 8.76 in G1B, remaining significantly higher than in the control group (F = 37.790; p < 0.001). In G1A, an immediate postoperative increase was observed, consistent with the rapid onset of symptoms following surgical menopause. The highest mean values were recorded at 6 months postoperatively (14.46 ± 5.72 in G1A and 16.46 ± 7.71 in G1B). At 12 months, scores stabilized without significant further changes, suggesting persistence of climacteric symptoms throughout the postoperative period. Mean total Greene scores are presented in Figure 1, illustrating the sustained increase in symptom burden in the surgical groups.
RM-ANCOVA demonstrated that age did not significantly influence the longitudinal evolution of the total Greene climacteric score (F (2.56, 248.81) = 0.104, p = 0.939, ηp² = 0.001), indicating that age-related differences between groups did not affect symptom progression. Similarly, the time × group interaction was not significant (F = 0.957, p = 0.403, ηp² = 0.010), suggesting a comparable temporal pattern of symptom evolution in both groups.
In contrast, a significant main effect of group was observed for the total Greene score (F (1, 97) = 10.380, p = 0.002, ηp² = 0.097), indicating significant differences between groups after adjustment for age. Analysis of estimated marginal means, adjusted for the mean age of 44.03 years, showed consistently higher Greene scores in the G1B group than in the G1A group, both preoperatively (13.72 ± 0.93 vs. 8.66 ± 0.93) and at the 12-month postoperative assessment (16.04 ± 1.03 vs. 13.46 ± 1.03).
Bonferroni-adjusted post hoc comparisons revealed significantly higher Greene scores at both 6 and 12 months postoperatively compared with baseline values (p < 0.001). Symptoms emerged early, within 10–12 days after surgery, and no significant differences were observed between subsequent postoperative assessments (p > 0.05), suggesting stabilization of symptom severity following their initial onset.
These findings support a more detailed analysis of the Greene Climacteric Scale subdomains to characterize the predominant symptom profile and inform subsequent clinical management.
The psychological domain of climacteric symptoms, presented in Figure 2, was consistently higher in G1B compared with G1A across all assessment time points. Preoperatively, the total psychological score was significantly higher in G1B (8.34 ± 4.14) than in G1A (5.42 ± 4.20) and the control group (1.64 ± 1.80) (F = 44.424; p < 0.001). This pattern persisted postoperatively, with peak values observed at 6 months (G1A: 7.14 ± 3.58; G1B: 9.56 ± 5.70). Intergroup differences remained significant at 12 months (F = 40.172; p < 0.001).
The RM-ANCOVA model demonstrated a significant main effect of group (F (1, 97) = 18.416, p < 0.001, ηp² = 0.160), indicating significant between-group differences after adjustment for age. Age was not a significant covariate in the model (p = 0.731). Consistently higher estimated marginal mean scores (± SE) were observed in the G1B group than in the G1A group, both preoperatively (8.37 ± 0.63 vs. 5.39 ± 0.63) and at 12 months postoperatively (8.67 ± 0.70 vs. 6.18 ± 0.70).
The main effect of time was not significant (F (2.73, 264.98) = 0.220, p = 0.866, ηp² = 0.002). Likewise, neither the time × group interaction (F = 0.269, p = 0.829, ηp² = 0.003) nor the time × age interaction (F = 0.140, p = 0.923, ηp² = 0.001) reached statistical significance, indicating similar temporal trajectories across groups and confirming that age did not influence the longitudinal pattern of change. Bonferroni-adjusted post hoc comparisons revealed no significant differences between the evaluated time points (p > 0.05). The estimated marginal means, adjusted for the mean age of 44.03 years, were 6.88 ± 0.42 preoperatively, 6.83 ± 0.48 at 10–12 days postoperatively, 8.35 ± 0.48 at 6 months, and 7.42 ± 0.46 at 12 months postoperatively.
Somatic symptoms (Figure 2) were more pronounced in G1B preoperatively (3.88 ± 2.52) compared with G1A (2.64 ± 2.43; p = 0.012) and the control group (F = 23.258; p < 0.001). Postoperatively, scores increased transiently before stabilizing, without significant between-group differences (p > 0.05), but remained significantly higher than in the control group (F = 25.741; p < 0.001).
RM-ANCOVA confirmed that the between-group difference was independent of the age covariate (p = 0.238), with the type of surgical intervention exerting a significant main effect on the severity of somatic manifestations (F (1, 97) = 6.302, p = 0.014, ηp² = 0.061), as reflected by consistently higher adjusted values in the G1B group. In contrast, the main effect of time was not significant (F (2.72, 263.40) = 0.900, p = 0.434, ηp² = 0.009). Bonferroni-adjusted post hoc comparisons revealed no significant longitudinal fluctuations across time points (p > 0.05).
Vasomotor symptoms (Figure 2) followed a distinct course depending on the type of surgery. Postoperatively, scores increased significantly, particularly in G1A (2.32 ± 0.99 at 10–12 days; 2.88 ± 1.17 at 6 months), with significant between-group differences (p < 0.05).
RM-ANCOVA demonstrated distinct temporal trajectories between the two groups throughout the follow-up period, with a statistically significant time × group interaction (F (2.55, 247.28) = 2.919, p = 0.043, ηp² = 0.029). After adjustment for age (44.03 years), the model indicated a greater magnitude of postoperative increase in the G1A group compared with G1B, with higher adjusted values at 6 months (2.80 ± 0.21 vs. 2.03 ± 0.21) and at 12 months postoperatively (2.71 ± 0.20 vs. 2.33 ± 0.20), despite comparable preoperative baseline levels between groups.
Regarding overall temporal evolution, Bonferroni-adjusted post hoc comparisons confirmed a significant increase in scores from baseline (0.75 ± 0.11) to all postoperative time points (p < 0.001), indicating a rapid onset and persistence of symptomatology. Age was not a significant covariate in the model (p = 0.080).
Sexual dysfunction, assessed using a single item on the Greene Climacteric Scale (Figure 2), gradually increased throughout the postoperative period, reaching peak values at 12 months (G1A: 1.14 ± 0.96; G1B: 0.96 ± 0.98) (F = 17.271; p < 0.001). Although the difference between G1A and G1B was not statistically significant, both surgical groups had higher scores than the control group.
Table 1. Dynamics of pro-oxidant markers of oxidative stress during follow-up | |||||
Group G1A (n=25) | Group G1B (n=25) | Group G0 (n=25) | F | P | |
MDA, µM/L | |||||
T1 | 18,94 ± 1,76 | 21,10 ± 5,20 | 14,95 ± 1,39 | 22,762 | <0,001 |
Longitudinal assessment adjusted for age revealed a significant late increase in sexual dysfunction scores across the entire sample (F = 21.894, p < 0.001, ηp² = 0.409). Bonferroni-adjusted post hoc comparisons showed no significant difference between the preoperative assessment (0.30 ± 0.05) and the 10–12-day follow-up (0.27 ± 0.06, p = 1.000), followed by a marked increase at 6 months (0.86 ± 0.08) and further elevation at 12 months postoperatively (1.05 ± 0.10); both late postoperative time points were significantly higher than baseline (p < 0.001).
MDA levels were elevated in both surgical groups compared with the control group (G0) throughout the study period, with relative stability in G1A (T1: 18.94 ± 1.76; T4: 19.54 ± 2.42 µM/L) and more variable values in G1B (T1: 21.10 ± 5.20; T3: 23.62 ± 8.90 µM/L). NO₂⁻ levels were slightly higher in the surgical groups than in G0 (T1: G1A 58.92 ± 4.37; G1B 58.09 ± 4.75; G0 53.01 ± 3.30 µM/L) and remained stable up to 12 months postoperatively. NO₃⁻ levels were lower overall, with a slight increase in G1B and moderate fluctuations in G1A (T4: G1A 11.36 ± 4.11; G1B 13.15 ± 7.47 µM/L). The data are presented in Table 1.
These findings indicate persistent postoperative oxidative stress. RM-ANCOVA showed that age did not exert a statistically significant effect on the levels or temporal dynamics of these markers (p > 0.05). Evaluation of the age-adjusted model (mean age = 44.72 years) confirmed temporal stability for MDA, NO₂⁻, and NO₃⁻, as both the main effects of time and the time × group interactions were not statistically significant (p > 0.05). Nevertheless, a significant between-group effect was observed for NO₂⁻ (F (1, 47) = 5.719, p = 0.021, ηp² = 0.108), with consistently higher adjusted values in the G1A group across all time points.
Table 2. Dynamics of antioxidant markers of oxidative stress during follow-up | |||||
Group G1A (n=25) | Group G1B (n=25) | Group G0 (n=25) | F | p | |
SOD, U/ml | |||||
T1 | 121,94 ± 34,20 | 156,54 ± 31,07 | 177,22 ± 11,24 | 25,866 | <0,001 |
Regarding protein oxidative stress, AOPP levels were elevated in both surgical groups compared with the control group. RM-ANCOVA revealed a significant main effect of group (F (1, 47) = 7.403, p = 0.009, ηp² = 0.136), with higher estimated marginal means in the G1B group. In contrast to the other markers, AOPP showed a significant time × group interaction (F(2.63, 123.36) = 4.066, p = 0.012, ηp² = 0.080), indicating different temporal patterns between groups: at 12 months postoperatively (T4), AOPP levels decreased in the G1A group (25.74 ± 13.46 µM/L), whereas they remained elevated in the G1B group (34.68 ± 8.08 µM/L).
Data on antioxidant markers of oxidative stress are presented in Table 2. SOD activity were higher in the G1B group compared with G1A throughout the study period, although both surgical groups remained below those observed in the control group (G0). Total antioxidant capacity was also higher in G1B than in G1A, with values stabilizing by T4 (G1A: 224.72 ± 36.26; G1B: 406.50 ±58.82 µM/L), consistent with a potential protective effect of ovarian preservation on antioxidant capacity. Catalase activity exhibited a similar pattern, with lower values in G1A and higher values in G1B, indicating superior antioxidant defense in patients with preserved ovaries.
RM-ANCOVA showed that age did not significantly influence either overall antioxidant status or its temporal evolution (p > 0.05). For SOD, a significant main effect of group was observed (F (1, 47) = 17.008, p = 0.001, ηp² = 0.266), along with a significant time × group interaction (F (3, 141) = 5.323, p = 0.002, ηp² = 0.102), indicating different temporal patterns between groups. A marked decrease in SOD levels at 12 months (T4) was observed in the G1A group (113.28 ± 6.05 U/ml), whereas levels remained stable and higher in the G1B group (169.12 ± 6.05 U/ml).
AAT showed a similar pattern, with a significant main effect of group (F (1, 47) = 70.235, p = 0.001, ηp² = 0.599) and a significant time × group interaction (F (3, 141) = 9.396, p = 0.001, ηp² = 0.167). Age-adjusted estimates (mean = 44.72 years) indicated a progressive decline in endogenous antioxidant capacity in the G1A group (from 318.07 ± 15.85 preoperatively to 222.40 ± 10.62 µM/L at 12 months), in contrast to a gradual increase in the G1B group (from 369.39 ± 74.63 to 408.83 ± 10.61 µM/L at 12 months).
Catalase (CAT) activity followed a similar pattern, with a significant between-group effect (F(1, 47) = 21.045, p = 0.001, ηp² = 0.309) and a significant time × group interaction (F(2.01, 94.62) = 3.624, p = 0.030, ηp² = 0.072), driven by a reduction in catalase activity at 12 months postoperatively in the G1A group.
At 12 months postoperatively, Pearson correlation analysis between oxidative stress biomarkers (MDA, SOD, AAT, NO₂⁻, NO₃⁻, PPOA, CAT) and the total Greene Climacteric Scale score revealed distinct patterns across groups. In G1A (hysterectomy with bilateral oophorectomy), none of the markers showed statistically significant correlations with symptom severity, although NO₂⁻ (r = 0.307, p = 0.135) and NO₃⁻ (r = -0.345, p = 0.091) exhibited trends toward association, without reaching statistical significance, suggesting a potential link between nitric oxide metabolites and clinical manifestations. In G1B (hysterectomy without oophorectomy), correlations between oxidative stress markers and the total climacteric score were also nonsignificant. However, a significant positive correlation was observed between MDA and NO₃⁻ (r = 0.45; p = 0.024), indicating an association between lipid peroxidation and nitric oxide metabolism (Figure 3).
Discussion
In surgical menopause, the decline in hormone levels occurs early and abruptly, in contrast to natural menopause, where hormonal changes are gradual [19]. This accelerated endocrine transition results in the rapid onset of climacteric symptoms, comprising a complex constellation of neurovegetative, psycho-emotional, and endocrine-metabolic manifestations [20].
Hot flashes are the most common vasomotor symptoms and are primarily driven by decreased serum estrogen levels. They tend to be more intense and persistent in surgically induced menopause than in natural menopause [21]. Although interindividual variation exists, hot flashes are typically described as transient episodes of sudden warmth, initially affecting the face and upper chest, often accompanied by sweating, palpitations, and anxiety [21-24].
In surgical menopause, symptom onset is immediate postoperatively, with higher severity and longer duration. Bachmann G.A. demonstrated that women undergoing surgical menopause experience more intense and prolonged hot flashes compared with those in natural menopause, and that early symptom onset predicts persistence [25]. Farquhar et al. demonstrated that the prevalence of hot flashes increases from 20% to 43% when hysterectomy is combined with bilateral oophorectomy [26, 27], while Golbasi et al. confirmed a higher incidence of vasomotor symptoms in women undergoing bilateral salpingo-oophorectomy compared with simple hysterectomy [19]. Hickey et al. observed in a prospective study that 92% of women without hormone replacement therapy developed hot flashes within the first three postoperative months, which persisted for up to 24 months [28]. Analyses of Australian cohorts revealed that the prevalence of hot flashes and night sweats was nearly double in women undergoing hysterectomy, even in the absence of oophorectomy [29]. However, not all studies support this association. Collaris et al. reported improvements in vasomotor symptoms, as well as in anxiety and depression scores, following total hysterectomy with bilateral oophorectomy, suggesting a potential enhancement in quality of life among previously symptomatic patients [30].
Our study results corroborate these observations, demonstrating a significant increase in vasomotor symptom scores, particularly in patients undergoing hysterectomy with bilateral oophorectomy (G1A). In this group, symptoms were pronounced immediately postoperatively, whereas in patients with ovarian preservation (G1B), symptom severity was moderate but persistent, suggesting a partially protective role of residual ovarian function.
The pathogenesis of vasomotor symptoms remains incompletely understood. These symptoms arise from a complex interplay between the central nervous system, the endocrine system, and the peripheral vascular system [23]. Although hot flashes have been linked to decreased E₂ levels and elevated LH and FSH, this relationship is not consistently observed. Recent studies emphasize the role of hypothalamic KNDy neurons (kisspeptin–neurokinin B–dynorphin) in thermoregulation. Estrogen normally suppresses the activity of these neurons, and in menopause, the loss of this inhibitory effect leads to neuronal hyperactivity and dysregulation of the thermoregulatory center [22, 23, 31].
Vasomotor symptoms have a substantial impact on quality of life, being associated with anxiety, depression, and sleep disturbances [31]. Golbasi et al. reported a 34.5% prevalence of insomnia in women undergoing bilateral oophorectomy, compared with 7.8% in those undergoing salpingectomy [19]. These findings support the concept that acute estrogen deprivation exerts immediate and persistent neuropsychological effects, underscoring the need for careful postoperative monitoring.
Our data highlight an important phenomenon: although vasomotor symptoms were more frequent and severe in women undergoing bilateral oophorectomy, the total climacteric score was significantly higher in the group with ovarian preservation, a difference primarily attributable to the psycho-emotional component, including anxiety and depression. This observation is consistent with the literature but should be interpreted with caution.
Meta-analyses and relevant longitudinal studies indicate that the psychological effects of hysterectomy are complex and influenced by both temporal and preoperative factors. A meta-analysis of 22 studies reported a significant reduction in depressive symptoms following hysterectomy, while emphasizing that preoperative depression remains the strongest predictor of postoperative depressive outcomes [32]. In contrast, long-term follow-up studies spanning 5–29 years demonstrated an increased risk of affective disorders after surgery, suggesting delayed effects not captured in short-term assessments [32, 33].
Several large cohort studies have suggested that hysterectomy, even in the absence of oophorectomy, may be associated with an increased long-term risk of depression and anxiety [34]. Yang et al. (2023) reported that hysterectomy itself constitutes a risk factor for depression, with the addition of oophorectomy potentially amplifying this risk [35].
The underlying mechanisms are multifactorial and complementary. On the one hand, evidence indicates that the uterus exerts a neuroendocrine role influencing the hypothalamic-pituitary-ovarian axis, and its removal can disrupt FSH and E₂ levels, processes associated with negative emotional states [35]. On the other hand, the psychosocial consequences of uterine loss, including effects on identity, perceived fertility, and self-esteem, may explain why some women experience significant emotional distress even when residual ovarian function is preserved [36].
In the context of our study, patients in G1B exhibited a preoperative psycho-emotional vulnerability profile, characterized by higher anxiety and depression scores, which contributed to an amplified total climacteric score postoperatively. Despite this, the absence of complete hormonal deprivation appeared to relatively protect these patients from severe hot flashes. The literature supports the notion that preoperative psychopathology is a strong predictor of postoperative psychological outcomes, and the absence of preoperative psychological assessment and intervention may allow affective symptoms to persist or worsen. Furthermore, social support factors, including the presence or absence of supportive partners and environment, modulate postoperative adaptation and recovery.
The relationship between oxidative stress and climacteric symptoms remains complex and controversial. Although several studies have suggested a role for oxidative stress in the pathogenesis of vasomotor and neurovegetative disturbances, the evidence remains inconclusive. Some studies reported no significant differences between women with and without hot flashes, highlighting a more intricate interplay between estrogen, oxidative metabolism, and menopausal symptomatology [37].
The in vivo antioxidant efficacy of endogenous estradiol (E₂), often cited as the theoretical basis for this relationship, remains incompletely demonstrated. Some studies have reported elevated markers of oxidative DNA damage (8-OHdG) in postmenopausal women, whereas others observed no significant changes in lipid oxidation markers, such as 8-isoPGF₂α and PPOA. These discrepancies may be attributed to methodological differences, the limited sensitivity of colorimetric assays, lack of adjustment for potential confounders (e.g., BMI, diet, lipid profile), and small sample sizes [37].
The absence of significant linear correlations between redox biomarkers and Greene scores suggests a dissociation between systemic biochemical alterations and the subjective perception of symptoms, indicating that isolated biomarkers should be interpreted with caution as direct clinical predictors. Rather than a direct association, this finding may reflect adaptive mechanisms or metabolic compensation, which appear particularly relevant in the presence of residual ovarian function (as evidenced by the MDA–NO₃⁻ correlation, p = 0.024).
Profile analysis revealed distinct, marker-specific post-hysterectomy redox patterns depending on ovarian status. The G1A group (bilateral oophorectomy) was characterized by pronounced antioxidant impairment, reflected by reduced SOD, CAT, and AAT activities, alongside sustained serum NO₂⁻ levels. In contrast, the G1B group (ovarian preservation) showed increased SOD, CAT, and AAT activities approaching control values.
In addition, among pro-oxidant markers, only AOPP exhibited differential temporal dynamics between groups (p = 0.012). At 12 months postoperatively, PPOA levels decreased exclusively in the G1A group, whereas they remained elevated in the G1B group.
The results of this study should be interpreted in light of several limitations. The absence of data on BMI, smoking status, diet, alcohol consumption, physical activity, and overall metabolic profile warrants caution when extrapolating the findings, although the homogeneity of surgical indications may partially mitigate this limitation. Furthermore, redox biomarker analysis was performed in a subset of 25 patients per surgical group due to exclusion of cases with incomplete data. While this complete-case analysis approach ensured a consistent dataset for RM-ANCOVA modelling, the reduced sample size may have limited statistical power. Another limitation is that consecutive recruitment was strictly determined by surgical indications for the underlying benign pathology, resulting in a clinical asymmetry that may explain the higher preoperative psycho-emotional vulnerability observed in the G1B group. Finally, the baseline age difference between cohorts represents an important methodological limitation; however, the use of RM-ANCOVA with age included as a covariate allowed adjustment for this imbalance, suggesting that postoperative trajectories of both symptom scores and oxidative stress markers were not significantly influenced by chronological age.
Conclusions
Hysterectomy, with or without bilateral oophorectomy, appears to induce immediate and sustained clinical manifestations with distinct temporal patterns. Ovarian preservation (G1B) was associated with a higher overall climacteric symptom burden, characterized predominantly by psycho-emotional and somatic symptoms persisting throughout the first postoperative year. In contrast, bilateral oophorectomy (G1A) was associated with an early, acute predominance of vasomotor symptoms.
Oxidative stress dynamics exhibited marker-specific patterns that were not linearly correlated with subjective symptom burden, as shown by the absence of significant associations between redox biomarkers and clinical scores. Ovarian preservation was associated with better maintenance of antioxidant defenses (SOD, CAT, AAT), whereas bilateral oophorectomy was associated with a marked decline in these parameters.
These findings highlight the clinical relevance of integrated perioperative management. The combination of psychological screening and targeted monitoring of oxidative status may facilitate individualized therapeutic strategies, including hormonal, antioxidant, and psychological interventions, aimed at improving long-term quality of life and reducing systemic complications.
Competing interests
None declared.
Contribution of authors
EV conceived the study, contributed to the design and case selection, participated in data analysis, and drafted the initial version of the manuscript. OC served as the scientific coordinator of the study, critically contributed to data interpretation, ensured scientific validation, and participated in drawing the final conclusions. Both authors reviewed and approved the final version of the manuscript.
Acknowledgements and funding
The authors declare no external funding.
Ethics approval
Favorable approvals were obtained from the Research Ethics Committee of the Nicolae Testemițanu State University of Medicine and Pharmacy (Protocol No. 17, April 12, 2019).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Authors’ ORCID IDs
Elena Vataman – https://orcid.org/0009-0006-3959-2308
Olga Cernețchi – https://orcid.org/0000-0002-9229-8080
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