Genital Graft-Versus-Host-Disease Predicts Decreased Sexual Function in Female Survivors of Allogeneic Hematopoietic Stem Cell Transplant

Sixty-four females, including 20 healthy volunteers, and 44 post-transplant patients of whom 23 (52%) were using systemic immunosuppressive therapy, were included in the analysis. Participant characteristics are shown in Table 1 . Thirty-nine females (60%) reported being sexually active in the year prior to study enrollment. The time from transplant and age were similar between those off or on immunosuppressive therapy (p=0.09 and p=0.4, respectively; Table 2 ). Twenty-seven of 44 (61.4%) of posttransplant survivors had undergone transplant for malignancy with 14 of 44 (31.8%) receiving a myeloablative conditioning regimen. At baseline, two transplant survivors were using topical estrogen cream and four others were using an ultralow dose estrogen vaginal ring to treat genital chronic GvHD. No one was using vaginal estrogen to manage recurrent urinary tract infection. Rates of sexual activity in the past year were compared by cohort and the reasons for no sexual activity described. At baseline, whether participants were not currently sexually active, had low sexual function or had high sexual function significantly differed between transplant survivors (20, 13, and 9, respectively of 44 women) and volunteers (4, 3, and 13, respectively of 20 women, p=0.003; Table 1 ). Exploratory analyses revealed that more HSCT survivors on immunosuppression were not sexually active in the prior year (14 women) (p=0.01) as compared to survivors off immunosuppression (six women) and healthy volunteers (four women). Of those transplant survivors who were not sexually active at study entry, many had sexual partners but reported not having sex because of their own physical problems, lack of interest, and/or feeling tired (eight of 14 [57%] on immunosuppression versus four of six [67%] off immunosuppression). In contrast, only one of four (25%) healthy volunteers who were not sexually active had a partner. Their partner was reported as being “too tired” and uninterested in sex. The occurrence of systemic and genital chronic GvHD did not differ at baseline between those on and off immunosuppression ( Table 2 ). Seventy percent of transplant survivors had either no (19/44 survivors, 43%) or limited (12/44 survivors, 27%) systemic chronic GvHD. Of 11 survivors with skin chronic GvHD, only two had grade 2 or 3, one of whom had extensive sclerotic disease. Four subjects had fascia/joint GvHD and all of those had skin GvHD. Genital chronic GvHD was observed only in those who had either limited or extensive systemic chronic GvHD. The occurrence of genital chronic GvHD in those with limited or extensive systemic chronic GvHD did not differ between transplant survivors on and off immunosuppression ( Table 2 ). At baseline, female transplant survivors had significantly lower SFQ overall scores compared to healthy females (1.59±1.17 vs 3.00±0.90; p<0.001). HSCT survivors had significantly lower interest (1.10±1.21 versus 2.80±1.66; p<0.001), desire (1.91±1.64 versus 3.63±1.07; p<0.001), arousal (1.35±1.59 versus 2.48±1.52; p=0.01), orgasm (1.25±1.57 versus 3.03±1.71; p<0.001), satisfaction (1.51±1.69 versus 3.56±1.73; p<0.001), relationship (3.07±1.50 versus 3.96±1.00; p=0.03), and masturbation (0.72±1.38 versus 1.93±1.62; p=0.003) scores and a higher problems score (2.68±1.32 versus 3.8±0.43; p<0.001) than healthy female volunteers ( Figure 1 ). Baseline overall SFQ scores did not significantly differ between post-transplant females on or off immunosuppression (p=0.43). These significant differences between the transplant survivors and healthy females persisted over time ( Figure 2A – D ). One year following enrollment, HSCT survivors had significantly higher SFQ overall and health impact scores (1.53±0.16 versus 1.87±0.16, p=0.05 and 2.87±0.16 versus 2.16±0.16, p<0.001, respectively) and a lower problems score (2.69±0.15 versus 3.14±0.15, p=0.04) compared to baseline, but the other subscale scores did not change. The comparisons among the transplant survivors revealed important associations between sexual function and current sexual activity, current genital chronic GvHD, and current antidepressant use but not current immunosuppression, current systemic chronic GvHD, or current ovarian function/current hormone use. HSCT survivors who had been sexually active in the year prior to study participation consistently had higher overall SFQ scores than those survivors who were not sexually active (p<0.001) and those differences persisted without any significant changes in overall SFQ scores (p=0.56, Table 3 ). At each timepoint, patients with genital chronic GvHD had lower SFQ overall scores than the patients without genital GvHD (p=0.04). Use of vaginal estrogen to treat genital GvHD was individualized based on findings and increased over time from 6 transplant survivors at baseline to 8 at 7 months and 11 transplant survivors at 12 months. In contrast, overall SFQ scores did not differ among those with no, limited or extensive systemic chronic GvHD. Those transplant survivors who were taking antidepressants at baseline had significantly lower SFQ overall scores than those not on antidepressants (p=0.005). Transplant survivors taking antidepressants had improved SFQ overall scores over time while those not on antidepressants had stable, higher scores (p=0.02). Having ovarian function or currently using hormones at any timepoint did not significantly impact the SFQ overall scores (p=0.89).

We observed that clinically stable transplant survivors on average 2 or more years post-transplant consistently had impaired sexual function compared to healthy volunteers and this difference persisted over time, a finding confirmed by others. 6 , 7 Importantly, sexual function in HSCT survivors improved over time, albeit gradually in this cohort who received whole-person gynecologic post-transplant care. In this relatively small study, the only factor associated with impaired sexual function was current genital chronic GvHD. At baseline but not later, antidepressant use was associated with lower SFQ overall scores. The systematic assessment of female genital chronic GvHD and generalized chronic GvHD alongside sexual function enabled additional comparisons. In this clinically stable cohort, sexual function in HSCT survivors did not significantly differ between those on and off immunosuppression or between those with or without systemic chronic GvHD. The lack of association was due, in part, to some receiving immunosuppression as part of their routine prophylaxis rather than treatment of systemic chronic GvHD and to immunosuppression successfully treating systemic chronic GvHD in others. Thus, in contrast with other studies, systemic chronic GvHD was not associated with lower SFQ overall scores in this cohort of clinically stable transplant survivors. The co-occurrence of genital chronic GvHD in some of those with limited or with extensive systemic chronic GvHD at baseline is not surprising. Our observation that genital GvHD was associated with lower SFQ overall scores is expected as it is associated with higher rates of dyspareunia, avoiding sexual intercourse, and lower libido, all features of sexual dysfunction. 23 , 34 Genital GvHD is not effectively treated by systemic GvHD therapies nor does treatment of vulvar GvHD protect against development of vaginal GvHD. In case series, others have reported that treatment of genital chronic GvHD improved intimacy, lessened genital tract symptoms and enabled intercourse. 21 , 26 In this study, a standardized assessment of genital GvHD was paired with individualized treatment. As expected, those with evidence of genital GvHD continued to have lower SFQ scores than those without genital GvHD. Those currently using antidepressants had significantly lower SFQ overall scores at baseline, but not later in the year. It is important to evaluate the relationship between antidepressants and sexual function as antidepressants are among the medications known to impact sexual function and are frequently prescribed in oncology and following allogeneic transplantation. 23 There likely is significant protocol-related heterogeneity regarding antidepressant use in the post-transplant cohort as the reason antidepressants were prescribed was not obtained. Antidepressants can treat a variety of conditions including mood disorders or pain or be administered prophylactically. 35 Other studies have not shown lower rates of depression with antidepressants given prophylactically. 36 Further, since all antidepressant types do not impact sexual function to the same degree, stratifying by antidepressant class was beyond the scope of the study and is a limitation. Not surprisingly, more transplant survivors than healthy volunteers reported not being sexually active over the last year at study entry and of these survivors, over half were partnered. As a year prior to study participation may have been within a year of transplant, it might be expected that some HSCT survivors had not been sexually active. At baseline, these survivors reported lack of interest, physical issues, and being tired, each known reasons for impaired sexual function after transplant, as reasons for no sexual activity. By contrast, healthy volunteers who were not sexually active either had no sexual partner or a sexual partner uninterested in sex. Sociodemographic factors associated with impaired sexual function in both healthy females and transplant survivors include older age, single marital status, lower education level, and lower income. 3 , 37 These social determinants of health represent structural inequity, and can lead to less access to care, or hamper resilience. Study participants received study and transplant care at the NIH Clinical Center as part of their research participation. Thus, while general health care was provided as part of research studies, many traveled for study participation resulting in some financial burden and likely geographic distance from social supports including perhaps sexual partners. Assessing and/or addressing the sexual health of patients after transplant is often neglected. Many patients report difficulty having discussions about sex with transplant physicians even when sexual concerns exist. 38 More than one-half of females say they want to talk about potential impact of treatment on sexual health, yet only 18% reported actually having this discussion. 38 This lack of discussion between physicians and their patients may be because transplant physicians are focused on medical concerns related to routine transplant care or lack time, interest or knowledge about sexuality and reproductive health. Early discussion of potential effects of stem cell transplant on intimacy and sexuality also may improve sexual function. 17 Including providers trained and tasked with assessing and diagnosing and treating sexual dysfunction as part of multidisciplinary transplant team may help patients better address sexual concerns that can greatly impact their quality of life. 23 A strength of our study is that the post-transplant cohort were all clinically stable females on their way to becoming long-term transplant survivors, a group with the greatest likelihood of recovered sexual function. This study included the standard approach to care of a multidisciplinary collaboration between the transplant team and gynecologists, who all provided directed post-transplant care and management. 21 The general assessment of post-transplant health included assessment for genital and systemic chronic GvHD by the study team. The whole-person gynecology care provided by the gynecologists assessed for and treated genital chronic GvHD including providing individualized therapy, provided recommendations about contraception and ovarian hormone treatments considering ovarian function, and discussed sexual function in the context of transplant and these various therapies. As part of the clinical trial participation, subjects received focused gynecological attention or counseling from the study team that could potentially impact outcomes such as improvement in SFQ over time. This analysis was a planned secondary objective of a study examining immunogenicity of quadrivalent HPV vaccine but has several limitations. First, the study was not specifically powered to assess improvements in sexual health. As recruitment was limited to transplant survivors who were clinically stable, we were unable to determine whether sexual function was impaired in the year before transplant for the nearly two-thirds who underwent transplant for malignancy. Also, we were unable to ascertain whether pre-transplant discussion of the potential effects of hematopoietic stem cell transplantation on intimacy occurred or whether a discussion could have improved overall posttransplant sexual function. Second, while the NIH GvHD scoring system and the NIH genital GvHD scoring system aided in defining the affected organs and extent of GvHD, the transplant team underreported the occurrence of genital GvHD suggesting that they were unaware of the gynecologists’ findings. Further, while the NIH scoring system provides an impression of disease burden, tabulating the scores did not readily translate to extent of disease. Thus, we utilized the categorization of limited versus extensive to convey the extent of disease. Third, this clinically stable, younger population limits generalizability to older or more comorbid patients. Fourth, the contact with transplant survivors was limited to study visits where directed interventions could occur to discuss or improve sexual function. While others have studied the relationship between gonadal hormone alterations and sexual dysfunction, we did not find this relationship. The limited sample size precluded consideration of the varied routes of hormonal delivery (vaginal versus systemic via transdermal or oral formulations), specifically, vaginal GvHD treatment, that often included topical hormonal delivery. Additionally, there is inherent complexity in characterizing the relationship among ovarian failure, hormonal contraception, hormone replacement therapy and hormonal therapies for genital tract symptoms, and their effects on libido, dryness, and sexuality. 39 This year-long assessment of the sexual health of clinically stable female transplant survivors provides insight into the multiple intersectional reasons females continue to have impaired sexual function after transplant compared to males. Our study showed that females after transplant have lower sexual function than their healthy counterparts, and identification of risk factors, such as genital GvHD and antidepressant use, may help identify those most at risk. Developing a standardized approach to assessing sexual health while addressing genital GvHD in transplant survivors is challenging. However, post-transplant gynecologic care that routinely incorporates management of genital GvHD and assessment of sexual function may detect factors contributing to sexual dysfunction and identify women who would benefit from counseling and other targeted interventions. Additional research is needed to help determine prevalence, causes and optimal treatment regimens for sexual dysfunction in women after HSCT.

Survivors of hematopoietic stem cell transplant (HSCT) often face a decline in sexual health as one of their long-term survivorship issues. Sexual health includes both sexual activity and sexual function, with the later encompassing sexual problems and sexual wellbeing. 1 The decline in sexual function generally begins within the first few months after transplant in both males and females and is associated with their medical status. 2 Unlike males, the decline in function in females continues, reaching a nadir at one year and does not recover to pretransplant levels over time 3 – 5 . Compared to healthy females, sexual dysfunction continues among a higher proportion of females up to ten years after transplant. 6 , 7 Physical changes in female transplant survivors resulting from either systemic or genital chronic graft-versus-host disease (GvHD) may contribute to sexual dysfunction. In fact, lower sexual arousal has been reported in females with systemic chronic GvHD. 3 By contrast, the association between genital chronic GvHD and sexual function is understudied despite its reported incidence ranging from 19–52% in women. 8 , 9 Genital GvHD causes mucosal inflammation resulting in tenderness to touch. As it progresses, genital GvHD can lead to vulvar or vaginal scarring. Either mucosal changes or scarring cause pain during intercourse and thus impair sexual function. 9 , 10 However, symptoms of vulvovaginal GvHD continue to be underreported by patients, unsolicited by providers, and may not be addressed with regards to their impact on intimacy and sexual function. Further, both patients and clinicians fail to recognize or differentiate genital GvHD from other vulvar conditions. 11 – 13 Research to evaluate the effectiveness of various treatments for genital chronic GvHD and their relationship to sexual function is limited. Premature ovarian failure resulting in decreased estrogen and testosterone production is another concern for HSCT survivors, the vast majority of whom have received gonadotoxic therapies. 14 – 16 Lowered estrogen levels can result in vaginal dryness and atrophy, leading to dyspareunia, while decreased testosterone is associated with decreased libido. 14 , 17 – 19 Oral or topical hormone replacement therapy may be helpful for preventing some sequelae from a hypoestrogenic state or as part of treatment for genital GvHD, 20 , 21 but their resultant impact on sexual function in HSCT survivors is largely uncharacterized. While the decrease in sexual function can be attributed to physical and physiological limitations, psychosocial factors such as negative body image, feelings of decreased femininity, concurrent life stress, relationship conflicts, anxiety, and depression also contribute. 4 , 6 , 22 – 24 Furthermore, some antidepressants and other medications prescribed to transplant survivors are known to alter sexual response having an impact on sexual function. 22 Discussion about the potential impact of transplantation on sexual function may improve post-transplant sexual health. 25 However, issues relating to sexuality and intimacy are infrequently mentioned, and most often occur only if brought up by the patient. 26 – 28 Diagnosing and treating sexual dysfunction after transplant can be difficult, since the cause is complex and multifactorial, spanning physical, social, psychological and physiological factors. 22 This study aims to compare sexual function in a cohort of clinically stable females after transplant to age-matched healthy female volunteers over time and to explore the contribution of key post-transplant factors on sexual function.

We conducted a prospective study of sexual function, systemic and genital GvHD among clinically stable female transplant survivors who were on and off immunosuppressive therapy compared to healthy female volunteers as part of a year-long prospective clinical trial of the immunogenicity and side-effects of HPV vaccination. 29 In this study, quadrivalent HPV vaccine (HPV-6, HPV-11, HPV-16, HPV-18, Gardasil, Merck, NJ) was administered using the FDA-approved regimen of 3 separate 0.5ml intramuscular injections at 0, 2, and 6 months. Transplant recipients who were at least 90 days post–allogeneic stem cell transplant and age matched healthy volunteers were recruited across the Intramural Research Program at the National Institutes of Health Clinical Center from May 2010 to March 2016. All females were cisgender women aged 18 to 50 years. The study was approved by the Eunice Kennedy Shriver National Institute of Child Health and Human Development institutional review board ( NCT01092195 ). At enrollment, all female survivors were clinically stable without significant infection, worsening GvHD, or disease recurrence. The general assessment of post-transplant health included assessment for genital and systemic chronic GvHD by the study team. The gynecologists assessed for and treated genital chronic GvHD providing individualized management of findings, assessed ovarian function, performed cervical cancer screening, provided recommendations about contraception and ovarian hormone treatments, and discussed sexual function in the context of transplant and various hormonal and other therapies. The transplant team assessed for and treated systemic chronic GvHD and managed general medical conditions. At each visit, a medical history and current medications including use of immunosuppressant therapy and antidepressants were obtained. Whether subjects had ovarian function, used medications containing estrogen via a systemic, topical, or transvaginal route, or had ovarian failure without hormone use was determined. At enrollment, 7 and 12 months, all subjects completed the Sexual Functioning Questionnaire (SFQ). 30 Transplant survivors underwent a pelvic exam by a gynecologist to assess for genital GvHD at enrollment, 7 and 12 months and a physical exam by a transplant clinician to assess for systemic GvHD at enrollment and 12 months, and at 7 months, if their health condition changed. GvHD findings were categorized using recognized scoring systems. 9 , 31 Individualized management of genital tract findings such as use of estrogen vaginal rings or topical steroids followed prior recommendations. 32 The SFQ is composed of 2 multi-item scales: Sexual Functioning and Health Impact. Descriptive information, defining whether a person has “been sexually active in the past year (alone or with a partner)” and “in the past month,” and if not, reason(s) why, was collected. The Sexual Functioning scale is a 23-item measure that assesses sexual activity and the phases of sexual response and sexual problems. The reason for sexual problems was recorded in the participant’s own words indicating whether the problem arose from them such as ‘too tired’, “not interested” or their partner such as “partner not interested” or “husband unable to step out of caregiver role”. A higher SFQ overall mean score indicates better sexual function. Nine subscale scores assess Interest, Desire, Arousal, Satisfaction, Activity, Orgasm, Masturbation, Relationship, and Problems (including vaginal dryness, genital pain or irritation, difficulty with orgasm [climax] and lack of sexual interest or desire). The Health Impact scale is a 5-item measure with higher score indicating more health impact from their disease or treatment. The SFQ has strong validity and reliability in clinical and research populations. SFQ scoring was calculated using an updated, recently validated version of the scoring system in which SFQ overall score was classified as low or high sexual function ≤2.59 versus ≥2.6, respectively. 4 Systemic chronic GvHD scoring was classified as none, limited or extensive and genital chronic GvHD was classified as none or any. 9 , 33 Ovarian function and hormone use was classified as ovarian function and/or using any estrogen containing medication versus ovarian failure without hormone replacement. Descriptive statistics (mean and standard deviation for normally distributed continuous data, median and interquartile range for ordinal and non-parametric data, frequencies, and percentages for categorical data) were used to describe the demographics, transplant characteristics, and SFQ scores among the participants. Independent t-tests were used to compare healthy volunteers and transplant survivors, and to compare transplant survivors on and off immunosuppression. Linear mixed models were used to examine SFQ score differences between healthy volunteers and transplant survivors over time. Linear mixed models were also used to test whether other patient’s characteristics (sexual activity in the last year, current immunosuppression, current genital GvHD, current systemic chronic GvHD, current antidepressant use, and ovarian function/current hormone use) affected the SFQ scores at different timepoints. Linear mixed model results are presented as model estimated means with standard errors. All statistical analyses were conducted using IBM SPSS statistics software, version 29. P value <0.05 was considered significant.