Correlation analysis of hysterectomy and ovarian preservation with depression

1: Establishment of a propensity score model (PSM). The propensity score model (PSM) is a non-parsimonious multivariate logistic regression model26, and pro- pensity score covariates can be found in Table 1. The data of the two groups were matched with propensity score, nearest neighbor matching method was adopted, caliper value was set as 0.2, and the two groups were matched according to 1:127. After PSM, the distribution of covariates reached equilibrium among groups (P > 0.05). The PSM model was built using the statistical software IBM SPSS Statistics 25.0.

2 was logistic regression analysis of hysterectomy and depression. Table 1. Characteristics of participants including general characteristics and past medical histories (n%). Significance at P < 0.05. Q1: Non-hysterectomy, Q2: Hysterectomy. Characteristics Propensity overlap weighting Propensity 1:1 matching Propensity overlap weighting after psm Q1 Q2 P value Q1 Q2 P value Q1 Q2 P value Age (years)% < 0.00001 < 0.001 < 0.00001  < 30 4.457 0.103 5.832 0.216 6.87 0.213  30–44 6.399 1.878 15.695 1.944 19.045 2.209  45–54 4.085 4.506 11.663 4.968 15.371 6.121  55–64 2.45 4.685 14.039 5.112 13.822 4.179  ≥ 65 2.154 7.897 19.366 9.503 13.293 6.803  Missing 80.455 80.932 33.405 78.258 31.6 80.475 BMI 28.007 ± 7.077 29.271 ± 6.676 < 0.00001 29.558 ± 7.284 29.831 ± 6.843 0.31 29.065 ± 7.158 29.291 ± 6.638 0.38887 Race (%) < 0.00001 0.439 0.93634  Hispanic and others 21.464 12.292 28.15 28.078 14.632 14.854  Non-hispanic White 66.924 75.622 46.436 44.492 70.935 70.325  Non-hispanic Black 11.611 12.087 25.414 27.430 14.433 14.821 Education level (%) < 0.00001 0.002 0.00102   College graduate 32.488 20.102 15.839 15.407 22.744 18.208  Missing 0.03 0.057 0.000 0.072 0.00 0.018 PIR (%) < 0.00001 0.207 0.00337  < 1.0 15.891 11.916 22.606 20.662 13.745 13.691  1.0–2.0 20.031 23.704 26.782 29.518 18.996 24.16  ≥ 2.0 60.733 60.479 50.612 49.820 67.258 62.15  Missing 3.344 3.902 0.00 0.00 Marital status (%) 0.73867 < 0.001 < 0.00001  Married or living with partner 39.691 40.052 40.461 50.468 30.511 40.692  Widowed or divorced or separated 60.309 59.948 59.539 49.532 69.489 59.308 Smoked at least 100 cigarettes in a lifetime 37.375 45.518 < 0.00001 39.021 43.053 0.031 41.254 45.239 0.03399 Alcohol consumption (%) 70.823 62.816 < 0.00001 55.22 56.587 0.468 61.969 63.775 0.3247 Ovariectomy (%) 0.339 53.4 < 0.00001 2.448 7.127 < 0.001 2.466 7.207 < 0.00001 Hormone use (%) 7.121 5.695 < 0.00001 4.68 3.528 < 0.001 6.863 4.293 < 0.00001 Hypertension (%) 26.499 56.308 < 0.00001 59.467 58.459 0.503 53.664 53.173 0.9665 Hypercholesterolemia (%) 26.974 51.81 < 0.00001 39.813 49.028 < 0.001 39.354 46.668 < 0.00001 Diabetes (%) 7.339 16.278 < 0.00001 18.143 21.598 0.029 12.748 15.331 0.14522 Weak or failing Kidneys (%) 2.15 4.86 < 0.00001 2.880 4.752 0.01 2.452 3.361 0.15389 Trouble sleeping (%) 28.283 43.959 < 0.00001 31.030 39.597 < 0.001 31.504 41.775 < 0.00001 Depression PHQ ≥ 5 25.934 33.825 < 0.00001 31.102 36.645 0.002 27.861 35.537 0.00001 4 Vol:.(1234567890)Scientific Reports | (2023) 13:9744 | https://doi.org/10.1038/s41598-023-36838-2 www.nature.com/scientificreports/ After obtaining PSM data, we used logistic regression to analyze the relationship between hysterectomy and the dichotomous depression measure25 and each depressive symptom28, respectively, as well as to analyze the effect on depression with or without ovariectomy. First, regression analysis was performed for depression posi- tive or negative (Table  2). Second, to explore the relationship between independent variables and depressive symptoms, three models were designed (Table 3). Model 1 represents unadjusted outcomes. Model 2 is a coarsely adjusted logistic regression after propensity score matching, adjusting for age, marital status, poverty-income ratio, education level, smoking history, ovariectomy status, female hormone use, hypercholesterolemia and sleep disturbance. Model 3 is an adjustment for all covariables. Finally, in order to evaluate the correlation between the preservation of the fallopian tube ovary and depres- sion, logistic regression was used to analyze the relationship between different surgical methods and depression (Table 4). Odds ratios were obtained by adjusting for covariates. Forest plots were drawn to visualize the data (Fig. 2). All logistic analyses were performed with R software, V 0.4.0.3 [R: a language and statistical computing environment (program). Vienna, Austria: R Foundation for Statistical Computing, 2016], and EmpowerStats (http:// www. empow ersta ts. com). The figures were generated using Adobe Photoshop (https:// www. adobe. com/ produ cts/ photo shop. html) or Origin 2021 (https:// www. origi nlab. com/). Finally, we confirm that all methods were carried out in accordance with relevant guidelines and regulations. Table 2. Unadjusted, crude and adjusted odds ratios (95% confidence intervals) for positivity of depression after hysterectomy. a. Crude: Adjusted for marital status, PIR, education level, smoking history, oophorectomy, female hormone use, hypercholesterolemia, and sleep disorders. b. Adjusted: Adjusted for all the covariates. N Odds ratios (95% CI) Unadjusted P value Crude P value Adjusted P value Propensity overlap weighting before psm 12,097 1.307 (1.194, 1.431) < 0.001 1.145 (1.004, 1.306) 0.04 1.128 (0.987,1.289) 0.08 Propensity overlap weighting after psm 2778 1.281 (1.095, 1.500) 0.002 1.236 (1.016, 1.505) 0.03 1.234 (1.007, 1.512) 0.04 Table 3. β (95% CIs) of hysterectomy associated with depressive symptoms. Model 1 represents the unadjusted outcome. Model 2 was adjusted for marital status, PIR, education level, smoking history, oophorectomy, female hormone use, hypercholesterolemia, and sleep disorders. Model 3 refers to the adjustment for all covariates. A: Hysterectomy without Oophorectomy. B: Oophorectomy without Hysterectomy. C: Non-hysterectomy without Oophorectomy. D: Hysterectomy with Oophorectomy. Model 1 β (95% CI) Model 2 β (95% CI) Model 3 β (95% CI) Little interest 0.128 (0.071, 0.185) 0.076 (0.010, 0.142) 0.084 (0.018, 0.150) Feeling down 0.074 (0.016, 0.133) 0.062 (− 0.005, 0.129) 0.069 (0.002, 0.136) Trouble sleeping 0.028 (− 0.048, 0.103) 0.031 (− 0.053, 0.116) 0.034 (− 0.050, 0.119) Feeling tired 0.082 (0.009, 0.155) 0.018 (− 0.065, 0.100) 0.038 (− 0.044, 0.120) Poor appetite 0.082 (0.018, 0.146) 0.036 (− 0.039, 0.111) 0.048 (− 0.026, 0.123) Feeling bad − 0.005 (− 0.056, 0.047) 0.016 (− 0.044, 0.076) 0.018 (− 0.042, 0.079) Trouble concentrating 0.093 (0.040, 0.145) 0.080 (0.020, 0.140) 0.087 (0.026, 0.147) Moving/speaking slowly 0.044 (0.003, 0.086) 0.039 (− 0.009, 0.087) 0.040 (− 0.008, 0.088) Better off dead 0.019 (− 0.003, 0.041) 0.009 (− 0.017, 0.035) 0.009 (− 0.018, 0.035) Table 4. The distribution of patients with depression by four different surgical procedures. Subgroup A: Hysterectomy without Oophorectomy. Subgroup B: Oophorectomy without Hysterectomy. Subgroup C: Non- hysterectomy without Oophorectomy. Subgroup D: Hysterectomy with Oophorectomy. Subgroup A Subgroup B Subgroup C Subgroup D Y es (N = 1290) No (N = 1488) Y es (N = 34) No (N = 2744) Y es (N = 1355) No (N = 1423) Y es (N = 99) No (N = 2679) Depression PHQ ≥ 5 (N%) 464 (35.97%) 477 (32.06%) 9 (26.47%) 932 (33.97%) 423 (31.22%) 518 (36.40%) 54 (54.55%) 896 (33.45%) Depression PHQ < 5 (N%) 826 (64.03) 1011 (67.94%) 25 (73.53%) 1812 (66.03%) 932 (68.78%) 905 (63.60%) 45 45.45%) 1783 (66.55%) P value 0.030 0.359 0.004 0.013 5 Vol.:(0123456789)Scientific Reports | (2023) 13:9744 | https://doi.org/10.1038/s41598-023-36838-2 www.nature.com/scientificreports/

Descriptive statistical analysis. Prior to propensity score matching, 2763 of 12,097 women underwent hysterectomy, of whom 952 were positive for depression, accounting for 34.455% of the sample (P < 0.001). The sample was weighted so that patients with PHQ ≥ 5 points accounted for 33.825% of the total sample (P < 0.001). By adjusting for covariates for propensity matching, a total of 2778 women in the database were successfully matched to the hysterectomized and non-hysterectomized population of 1389 each, with 35.537% of the sample in the hysterectomized group experiencing depression (P < 0.001). And 35.537% were positive for depression in the hysterectomy group. Logistic regression. A PHQ score of 5 was used as the cut-off point for the presence or absence of depres- sion. Before propensity score matching, the OR for PHQ score of 5 or more was 1.145 (95%CI 1.004, 1.306) after crude adjustment of covariates, and 1.128 (95%CI 0.987, 1.289) after exact adjustment. In 2778 subjects after propensity 1:1 matching, the OR for PHQ ≥ 5 was 1.236 (95%CI 1.016, 1.505) after crude adjustment of covari- ates and 1.234 (95%CI 1.007, 1.512) after exact adjustment. This suggests that hysterectomy is associated with positivity for depression. To further explore the key to hysterectomy and depression, we performed a regression analysis for each depressive symptom. The results showed that positive depression was related to little interest and trouble con - centrating. It was not associated with trouble sleeping, feeling tired, poor appetite, feeling bad, slow moving or speaking, and suicidal thoughts. Oophorectomy alone is not associated with depression. In addition, we distinguish in detail between four different types of surgery, including Hysterectomy without Oophorectomy, Oophorectomy without Hysterectomy, Non-hysterectomy without Oophorectomy, and Hyster- ectomy with Oophorectomy. The number of depressed patients in each group was 464,9,423, and 54, respectively. Visualizations were plotted with adjusted covariates. Hysterectomy alone is a risk factor for depression, but hysterectomy combined with oophorectomy has a stronger correlation with depression than hysterectomy alone.

At present, gynecological malignancies29, endometrial hyperplasia with dysplasia30,31, intractable postpartum hemorrhage32,33, or prophylactic resection with a family history of tumors are suitable diseases for hysterectomy. Due to the differences in individualization between patients, surgeons need to perform hysterectomy according to professional knowledge, indications for surgery, nature of the disease34, patient characteristics and patient willingness. However, psychosocial problems after hysterectomy should not be ignored. Post-hysterectomy syn- drome makes researchers raise the concern about postoperative complications. Gupte and Nagabhirava found that 9% of women had post-operative depression35, of which 2% were post-operative new-onset depression. The latest research in modern medicine also provides strong evidence for the correlation between hysterectomy and depression36. Hyo37 extracted data from the Korean Health Insurance from 2002 to 2013, and they found that women who underwent hysterectomy had higher rates of depression than those who did not undergo hysterec- tomy. We conducted a multimodal observational study using data from the National Health and Nutrition Exami- nation Survey (NHANES) from 2007 to 2020 and found consistent findings across patterns. The risk of depression was significantly increased after hysterectomy compared with those who did not undergo hysterectomy. Women are twice as likely to be diagnosed with depression as men, because hormone levels are different in women at different times. Current studies have shown that estrogen can play an antidepressant role by regulating neurotransmitters through estrogen receptors, which affect the hypothalamic–pituitary–adrenal axis, and that the ovaries are the organ that secretes estrogen. It follows that the risk of depression should decrease when hys- terectomy is performed but ovaries are preserved. However, Wilson38 and Laughlin Tomaso39 found that women who underwent hysterectomy with preservation of the ovaries were at higher risk for depression than women who underwent both hysterectomy and bilateral oophorectomy. These are two completely opposite conclusions. Based on the above, the current study explored the effect of four different surgical procedures on depression through regression analysis. We found an interesting result that oophorectomy was not associated with positive depression, but hysterectomy was a risk factor for postoperative depression, and the risk of depression was also increased when both the uterus and ovaries were removed. Figure 2. Logistics regression analysis of different surgical methods on positive depression. 6 Vol:.(1234567890)Scientific Reports | (2023) 13:9744 | https://doi.org/10.1038/s41598-023-36838-2 www.nature.com/scientificreports/ The uterus is an endocrine organ. In addition to its local endocrine function, it may also regulate the hypo- thalamic-pituitary-ovarian (HPO) axis which refers to the complete and coordinated neuroendocrine system composing of the hypothalamus, pituitary gland, and ovary. Each of its links has unique neuroendocrine func- tions, and they regulate and influence each other to maintain a relatively stable dynamic balance40. The pituitary secretes follicle stimulating hormone (FSH), prolactin, and luteinizing hormone (LH) under the regulation of Gonadotropin-releasing hormone (GnRH) secreted by the hypothalamus. FSH, prolactin, and LH can act on the ovary and all three participate in the negative feedback regulation of the HPO axis. Studies have shown a tendency to increase FSH levels after Oophorectomy and the opposite for E2 levels41. FSH levels are associated with negative emotions such as perimenopausal depression42, and women with rapidly rising FSH levels are more likely to experience depressive symptoms43, while lower FSH levels are associated with reduced depressive symptoms44. Disruption of LH and estrogen regulation after Hysterectomymay be the main mechanism contrib- uting to the increased risk of depression. Similarly, because of estrogen’s role in regulating mood and cognitive function, the sudden drop in estrogen levelsdue to Oophorectomy would presumably increase the incidence of depression. But the study had found that postmenopausal oophorectomy did not affect the incidence of depres- sion. This is consistent with the results of the present study that Oophorectomy-alone was not associated with depression. This may be due to the fact that the age of the sample with Oophorectomy-alone in this study was basically close to menopause. The most significant change around menopause is the decline in ovarian func- tion, which is no longer able to affect hormone levels. In addition, removal of the uterus can cause them to stop believing that they are fully female. This affects their self-confidence and self-worth level45, leading to mental health problems. Oophorectomy may exacerbate this psychological burden, which is consistent with the results of this study. Hysterectomy alone is a risk factor for depression, but simultaneous hysterectomy of the ovaries further increases the risk of depression. The study also found that women after hysterectomy had more depressive symptoms, mainly including little interest, feeling down and trouble concentrating, but not more severe symptoms such as self-denial, slow move- ment or speech, suicidal tendencies and behaviors. That is, it is associated with depressed mood and somatic symptoms. However, it was not related to slow thinking, decreased volitional activity and cognitive impairment. Pay attention to female mood and somatic symptoms, and positive psychological intervention will improve the rehabilitation effect after hysterectomy46. Therefore, when hysterectomy has become an established fact, but in the case of opportunistic adnexectomy, it is necessary to retain the patient’s adnexa as much as possible to reduce the risk of depression. Opportunistic adnexectomy refers to the implementation of oophorectomy and salpingectomy without known indications, such as ovarian lesions, hereditary ovarian cancer syndrome, etc.47. Reviewing our study, there are still some limitations. First, because of its cross-sectional design, it was not possible to determine whether depression was present before the hysterectomy occurred. Second, although this study used a control group matched for demographic factors and several medical histories, even though propensity score methods were used, residual and unmeasured confounding is still possible in this study. The development of depression may be affected by the differences in personality and mentality of each respondent, including preoperative psychosocial status, perioperative pain and postoperative infection. This study has several strengths. The NHANES data provide us with a unique opportunity to examine the association between hysterectomy and depressive symptoms in this multi-ethnic, representative sample of the population in the United States. Second, to explore the association, we specifically considered the association of hysterectomy with each depressive symptom. Most importantly, we explored the effect of different types of surgical procedures on depression positivity.

Women who have had a hysterectomy are at higher risk of depression than women who have not had a hyster- ectomy, and this risk may be exacerbated if the uterus and ovaries are removed. When clinically appropriate, surgeons should try to preserve the patient’s ovaries. Data availability The data that support the findings of this study are available, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors via the email address [email protected] upon reasonable request and with permission of us. Received: 25 August 2022; Accepted: 11 June 2023

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