Endometriosis and sexual disorders: the effect of surgical and medical treatment, a multicentre cross-sectional study

Background Sexual health is a major concern in women with endometriosis, however only a few controlled studies have examined this with validated instruments. The effect of hormonal treatments on sexual function in endometriosis is also an underrated topic. The aim of this study was to investigate sexual function of patients with endometriosis by a specific tool to better evaluate their sexual function (including different domains), and the influence of hormonal treatment or surgery on these parameters. Methods An observational, cross-sectional, multicentre study was conducted in a group (n=194) of sexually active, women aged 25–45 years old, with surgical or ultrasonographic diagnosis of endometriosis, referred to the Endometriosis Center of Careggi University Hospital or Negrar di Valpolicella. Sexual function was assessed by administering the Female Sexual Function Index (FSFI), which assesses the domains of desire, arousal, lubrication, orgasm, satisfaction and pain. FSFI scores were compared to those of a control group (n=58) and according to the treatment received by patients with endometriosis. Results Ovarian endometriosis was present in 50 patients (25.8%), deep infiltrating endometriosis in 65 patients (33.5%) and both in 79 patients (40.7%). Adenomyosis coexisted in 102 patients (52.6%). Women with endometriosis reported a mean total FSFI score of 18.3 [4.2-25.8] (< 26.55), indicating female sexual dysfunction (FSD) in all patients. At multivariate analysis, after adjusting for confounders (BMI and hormonal therapy), women with endometriosis presented significantly lower scores than controls in all the FSFI (p<0.001). Patients with endometriosis under hormonal treatments (n=124; 64%), regardless of the type, had significantly lower scores in all FSFI subscales and total score, even after adjusting for confounders—age, BMI and history of surgery. Conclusions Patients with endometriosis are at risk for FSD, encompassing not only dyspareunia, but all domains of sexual function. Hormonal treatments do not result in improvement in sexual symptoms.

Female Sexual Function Index (FSFI), which assesses the domains of desire, arousal, lubrication, orgasm, satisfaction and pain.FSFI scores were compared to those of a control group (n=58) and according to the treatment received by patients with endometriosis.

Results
Ovarian endometriosis was present in 50 patients (25.8%), deep infiltrating endometriosis in 65 patients (33.5%) and both in 79 patients (40.7%).Adenomyosis coexisted in 102 patients (52.6%).Women with endometriosis reported a mean total FSFI score of 18.3  [4.2-25.8](< 26.55), indicating female sexual dysfunction (FSD) in all patients.At multivariate analysis, after adjusting for confounders (BMI and hormonal therapy), women with endometriosis presented significantly lower scores than controls in all the FSFI (p<0.001).Patients with endometriosis under hormonal treatments (n=124; 64%), regardless of the type, had significantly lower scores in all FSFI subscales and total score, even after adjusting for confounders-age, BMI and history of surgery.

Conclusions
Patients with endometriosis are at risk for FSD, encompassing not only dyspareunia, but all domains of sexual function.Hormonal treatments do not result in improvement in sexual symptoms.

Introduction
[4][5] Considering that patients with endometriosis are young and sexually active, sexual health is a major concern and should be carefully evaluated. 6In fact, endometriosis is associated with reduced psychological well-being, and impaired sexual life and relationships.][10][11] Besides, the coexistence of adenomyosis is associated with a worse quality of sexual life than only endometriosis. 12,13reover, multiple surgery and long-term hormonal treatments may represent additional contributing factors to negative sexual function in endometriosis.Induced transient menopausal state associated with some hormonal treatments, such as gonadotropin releasing hormone analogues (GnRHa), affects brain areas involved in sexual response.Also combined oral contraceptives (COCs) 14 and progestin treatment may induce a change in sexual functioning. 15In fact, despite medical treatment having a role in endometriosis management given its efficacy on painful symptoms (e.g., dyspareunia) and prevention of disease recurrence and progression, it may influence the sexual well-being. 7e aim of the present study was to investigate sexual function of patients with endometriosis by a specific tool to better evaluate their sexual function (including different domains, i.e., desire, arousal, lubrification, orgasm, satisfaction and pain), and the influence of hormonal treatment or surgery on these parameters.

Ethical considerations
The study was approved by the local Institutional Review Board (Comitato Etico Regione Toscana-Area Vasta Centro-CEAVC, n. 14558_oss approved on 28 May 2019), and all participants provided written informed consent to be included in the series.

Study design
An observational cross-sectional multicentre study was conducted in a group (n=194) of fertile age women (25-45 years old) with endometriosis, consecutively referred to two different hospitals, both reference Centres for Endometriosis (Careggi University Hospital, Florence and Negrar di Valpolicella, Verona, Italy) and recruited between January 2022 and February 2023.
A group of women without endometriosis attending the two Women's Endocrinology outpatient clinics were enrolled as the control group (n= 58) (mean age was 34.55 AE 8.76 years).Controls were consulting for contraceptive needs, or for follow-up for thyroid or metabolic disorders.The abovementioned endocrinologic conditions were clinically stable since at least six months, respondent to treatment and presenting laboratory or imaging parameters within the normal ranges.These were the criteria to be eligible as controls in the study.Data were collected by an extensive review of clinical records of patients in the follow-up of these outpatient clinics.
Exclusion criteria were: menopausal status, pregnancy, desire of pregnancy when the survey was conducted or previously attempts to conceive, both naturally or through assisted reproductive technologies, breastfeeding, systemic diseasesincluding previous or active cancer, polycystic ovary syndrome, hyperandrogenism, hyperprolactinemia, uncontrolled psychiatric diseases, alcohol or drug abuse, and use of medications with a possible influence on sexual function except for hormonal contraception (i.e., antidepressant and anxiolytic drugs).The ability to provide written informed consent and having engaged in sexual activity in the previous month were considered as inclusion criteria.
During the follow-up visit, patients were interviewed through: (i) a structured questionnaire containing all clinical information regarding the history of the patient (in particular age, body mass index (BMI), parity and current use of hormonal treatment).The hormonal treatments used were: progestins, GnRHa or continuous COCs, for a minimum of 12 months; (ii) a structured questionnaire containing all clinical information about female sexual function.Sexual symptoms were investigated by using the gold standard tool for the screening of Female Sexual Dysfunction (FSD), the Female Sexual Function Index (FSFI).This self-administered questionnaire analyses overall levels of sexual function and its primary components: sexual desire, arousal, lubrication, orgasm, pain, and satisfaction. 16The FSFI is composed by items with answers codified on a 5-point Likert scale ranging from 1 to 5, with higher scores indicating greater levels of sexual functioning for each item.The total score, resulting from the sum of the five domains, ranges from 2 to 36; a total score of 26.55 has been found to provide an excellent cut-off to distinguish women with and without FSD. 17l participants filled out the answers to the FSFI questionnaire themselves, whereas baseline and medical data were asked by a healthcare professional.

Statistical analysis
Data were reported as mean AE SD when normally distributed, as median (quartiles) when non-normally distributed and as percentage and number when categorical.At multivariate analysis, after adjusting for confounding factors (BMI and use of hormonal therapy), all the reported differences between the two groups retained statistical significance (p<0.001 for all the scores; Table 1).In a second step, sexual function in patients with endometriosis was further investigated, exploring the differences between those taking (64%, n=124) and not taking (36%, n=70) hormonal treatment (GnRHa, progestins, oral contraceptives) and the potential influence of previous surgery for endometriosis.Hormonal therapies, regardless of the type, were associated with significantly lower scores in all FSFI subscales and in total score, indicating worse sexual functioning.After adjusting for confounders-age, BMI and history of surgery-all the differences retained statistical significance (Table 2).

Discussion
The present study confirmed that patients with endometriosis have worse sexual function compared to healthy controls in all FSFI domains (desire, arousal, lubrification, orgasm, satisfaction and pain) and FSFI total score.
Our results confirmed those of a recent meta-analysis 18 showing that patients with endometriosis have lower scores of FSFI total score with poor sexual function.Considering that endometriosis is a disease that affects sexually active young women, the evaluation of sexual function in the context of patient's global management is crucial in order to improve the global QoL. 7In fact, endometriosis is not only characterized by sexual pain, but they also present an important impairment in several domains of sexuality (desire, arousal, lubrification, orgasm, satisfaction).A recent study showed patients with endometriosis have a worse score in the short-form of McGill Pain Questionnaire (SF-MPQ), pain subscale of FSFI, and Sexual Distress Scale (FSDS). 19Furthermore, they reported more negative emotions toward sexuality and seem to be characterized by an impairment in body image, 20 depressive symptoms, 21 worse health related QoL (HRQoL) and unemployed work status. 22veral mechanisms play a role in increasing the risk of FSD in women with endometriosis.First, in women with dyspareunia, fear and anticipation of pain strongly affect the global sexual response, thus increasing sexual inhibition and reducing spontaneous desire and sexual fantasy.In addition, psychological and interpersonal correlates of endometriosis, including fertility issues, low self-esteem, and body image concerns, contribute to negatively affect sexual function in its different areas. 7In recent years, evidence is accumulating that indicates a relevant overlap between endometriosis and superficial dyspareunia, and a high prevalence of Genito-pelvic pain and penetration disorder (GPPPD) in endometriosis. 23These comorbidities are also likely to play a role in compromising the sexual experience of affected women.
Considering that endometriosis is a chronic condition, medical treatment is the primary choice for improving symptoms, preventing or treating recurrences and planning surgery or ART.GnRH analogues or antagonists, progestins, combined oral contraceptives block cyclic menstruation and reduce endometriosis-related pain. 1,5The present study showed that hormonal treatment, regardless of the type, is not associated with an improvement in sexual function, showing lower scores in all FSFI subscales and total score.After adjusting for confounders-age, BMI and history of surgery-all the differences retained statistical significance.
The strong hypoestrogenic effect of GnRH agonists seems to be associated with a significant decline in libido and vaginal lubrication. 6Despite the use oral contraceptives and progestins in healthy women was previously described to be associated with negative sexual side effects (sexual activity, arousal, pleasure and orgasm and more difficulty with lubrication), 6,14 a recent observational study detected an improvement of sexual quality of life in patients with DIE with or without adenomyosis after 12 months of treatment with a combined oral contraceptive (2 mg dienogest/30 μg ethinyl oestradiol). 13nsidering the effect of surgical treatment, it is an option that works on pain relief and improvement of quality of sex life in symptomatic women with endometriosis. 24,25On the other hand, persistent or recurrent endometriosis after unsuccessful first-line conservative surgery is associated with severe deep dyspareunia and low FSFI score, below the cut-off for normal sexual function. 6,26Furthermore, the comparison between surgical treatment versus low-dose progestin therapy among patients with deep dyspareunia shows an immediate significant improvement of pain after surgery, but recurrent over time; on the contrary, those on low dose of NETA have a slight decrease in dyspareunia, though progressively declining. 26Medical and surgical treatment should be carefully evaluated because they often do not consistently allow for the global improvement of sexual function, despite their strong effect on painful symptoms of affected patients.
8][29] Adenomyosis determines further a high rate of altered sexual function in patients with endometriosis. 12,13Autoimmune, inflammatory, psychiatric and neurological disorders are commonly described in patients with endometriosis 30,31 and have a strong effect on global QoL and also sexuality.Therefore, the evaluation of eventual gynaecological and systemic comorbidities is mandatory in patients with endometriosis.
The present study has some limitations.First, sexual-related distress was not assessed, and this is a relevant aspect of sexual dysfunction.Second, all women were sexually active, but the relational component (i.e., the presence of a stable relationship, couple conflicts, sexual dysfunction in the male partner) was not evaluated.Furthermore, our study population is a selected sample of patients with severe endometriosis referred to highly specialized centres and most likely include cases with recurrent symptoms after either surgical or hormonal treatment.
In conclusion, sexual dysfunction is a common finding in patients with endometriosis and a multidisciplinary approach, including a psychological support and the contribution of other specialists for systemic comorbidities, is warranted. 7In fact, the traditional hormonal or surgical management do not significantly improve such as an important aspect as sexual function, and a multimodal approach is required.

Maria Grazia Porpora
Department of Maternal and Child Health and Urology, "Sapienza" University,, Rome, Italy I have carefully read the manuscript entitled Endometriosis and sexual disorders: the effect of surgical and medical treatment, a multicentre cross-sectional study, by Tommaso Capezzuoli, Elisa Maseroli, Fabio Barra, Silvia Vannuccini, Linda Vignozzi, Paola De Mitri, Silvia Baggio, Marcello Ceccaroni and Felice Petraglia.
The study aimed to analyze del sexual functioning in women with endometriosis and /or adenomyosis.In this multicentric study, all women with surgical or sonographic diagnosis of endometriosis or adenomyosis answered to a structured questionnaire containing all clinical information on their medical history and to the FSFI questionnaire which is validated for the evaluation of the sexual function.Results were compared with those of a control group.The authors found that all affected women, independently from the type of lesions, had a lower FSFI score than controls, indicating FSD in all patients.Women taking hormonal therapies had worse results in terms of FSD.
The paper is interesting and well written, but I have a few comments for the Authors: 1. Surgery, particularly when involving the bowel and its function, can worsen the self-body image perception and the presence of bowel problems significantly affects sexual functioning (Boyd T, et al 2022.)[Ref 1]; did you find any difference between those who had undergone surgery and those who received only medical treatments?In addition, did you find differences in sexual function according to the type of surgery?
2. Surprisingly, in this study, all kinds of medical therapy worsened the sexual functioning of patients.These results can be easily justified in women taking GnRh analogues or even oral progestins but the detrimental effects on sexual functions are less clear in women taking oral contraceptives.Do you think that the lack of difference between treatments could be related to the small number of patients in each group?Could it be possible that a long history of disease may have affected the quality of and have determined psychological problems, thus influencing the results?
3. Psychological factors and mood disorders were not evaluated in this paper, but they may have influenced the results.Please make a comment about this.

Table 1 .
Differences between women with endometriosis and controls.
Multivariate analysis was adjusted for age, BMI and use of hormonal therapy.The symbol * indicates statistically significant difference.BMI = body mass index.FSFI = Female Sexual Function Index.HT = hormonal therapy.Data were reported as mean AE SD when normally distributed, as median (quartiles) when non-normally distributed and as percentage and number when categorical.Multivariate models, with adjustment for relevant clinical confounders, were conducted by means of analysis of covariance.

Table 2 .
Differences in FSFI scores between women with endometriosis taking and not taking hormonal therapy.Multivariate analysis was adjusted for age, body mass index, and a history of previous surgery for endometriosis.The symbol * indicates statistically significant difference.indicates statistically significant difference.FSFI = Female Sexual Function Index.Multivariate models, with adjustment for relevant clinical confounders, were conducted by means of analysis of covariance.

If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Reviewer Report 21 February 2024 https://doi.org/10.5256/f1000research.154993.r231806© 2024 Porpora M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
4. It is also possible that marital status and a stable affective relationship can improve the patient's sexual life as observed by Giuliani et al. in 2016 (Giuliani et al. 2016)[Ref2].Could you please make a comment on this aspect?"