Female sexual dysfunction (FSD) is age-related,

Journal of Andrology, Vol. 28, No. 5, September/October 2007 Copyright E American Society of Andrology Female Sexual Dysfunction and Hormonal Status in Spinal Cord Injured (SCI) Patients GIUSEPPE LOMBARDI,* NICOLA MONDAINI,{ ANGELO MACCHIARELLA,* AND GIULIO DEL POPOLO* From the *Spinal Unit, Neurourology, University of Florence, Italy; and ÀDepartment of Urology, S. Maria Annunziata Hospital, University of Florence, Italy. ABSTRACT: To investigate a possible correlation between sexual hormonal status and the presence of female sexual dysfunction (FSD) using the Female Sexual Function Index (FSFI) in females with spinal cord injuries (SCI), we selected 39 SCI fertile-aged women. At visit 1, we assessed the presence of FSD using the FSFI, and all individuals were submitted to a blood hormone evaluation on the third day of their menstrual cycle. The levels of serum folliclestimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid-stimulating hormone (TSH), cortisol, dehydroepiandrosterone sulphate (DHEA-S), androstenedione, 17[a]-hydroxyprogesterone; total and free testosterone, 17b-estradiol, inhibin, sex hormone-binding globulin (SHBG), and thyroid hormones (ft3 and ft4) were checked. Progesterone was measured on the 20th to 21st day after the menstrual cycle. In patients with amenorrhea, we tested all the hormones using 1 random blood test. After a 3-month period, the tests were repeated. Overall, 23/39 (58.9%) patients continued to manifest at least one sexual dysfunction. These patients reached a median score of 19.52. All but 6 patients (15.3%) consistently showed hormonal values within the normal range. Of the 6 patients with abnormal hormonal alterations, 5 showed at least one sexual dysfunction, 2 had low levels of total testosterone, 1 had a low level of free testosterone, 1 suffered from hypothyroidism, 1 presented with low levels of cortisol, and 1 showed hypoprogesterone. There was no significant correlation between abnormal hormonal status and the presence of a specific sexual dysfunction, as assessed with the FSFI. Key words: Spinal cord injury, blood sexual hormones, Female Sexual Function Index. J Androl 2007;28:722 726 Female sexual dysfunction (FSD) is age-related, progressive, and highly prevalent, affecting 30% 50% of women (Bermann et al, 1999). Hormones influence all phases of the sexual response cycle and act both genitally and neurogenically. Various endogenous hormones, including 17b-estradiol, testosterone, progesterone, and prolactin affect female sexual function, and endocrine disorders may underlie such sexual complaints as: decreased desire and libido, lack of sexual arousal, vaginal dryness, decreased frequency of sexual activity, painful intercourse, diminished sexual responsiveness, difficulty achieving orgasm, and decreased genital sensation (Anastasiadis et al, 2002; Davis et al, 2004). Spinal cord injury (SCI) affects the endocrine system in several ways. However, in SCI females, only Campagnolo et al (1999) have reported increases in both cortisol and dehydroepiandrosterone sulphate, mainly in tetraplegics, without assessing any correlation between the blood levels of sex hormones and sexual Correspondence to: Giuseppe Lombardi, Spinal Unit, Neurourology, University of Florence, Largo Palagi 1, Florence 50100, Italy (email: giuseppelombardi@interfree.it). Received for publication November 6, 2006; accepted for publication May 3, 2007. DOI: 10.2164/jandrol.106.002113 dysfunction. Sexual dysfunction is a common complaint in women after SCI (Sipski et al, 2006). The majority of females affected are young and in their reproductive years, although the relatively lower number of women with SCI is part of the reason that the effects of hormonal alterations in SCI females on sexuality have been studied less in women than in men. Another possible reason is that the majority of paraplegic or tetraplegic women will continue to menstruate, ovulate, and even have babies (Baker, 1996). Therefore, less attention has been given to their potential problems with sexuality due to possible hormonal alterations. Currently, there are several potential therapeutic solutions for the treatment of FSD, including hormonal therapies with estrogen, progesterone, testosterone, or a combination of drugs. Estrogen replacement probably benefits women with SCI more than it does nonneurological patients, since estrogen improves the lipid profile by lowering the LDL cholesterol and raising the HDL cholesterol, which may be decreased in SCI patients. Estrogen also prevents osteoporosis, which is accelerated in the paralyzed areas (Maïmoun et al, 2006). However, at present the possible indications for hormonal therapies for sexual impairment in SCI females remain unexplored. Although it is 722

Lombardi et al N Female Sexual Dysfunction and Hormonal Status 723 natural to look for medical diseases or hormonal deficiencies as the sole cause, most types of sexual dysfunction in SCI females are a combination of physiological and psychological factors, such as poor body image, and even include complaints that partners do not engage in sufficient foreplay for the female to be adequately aroused (Kreuter, 2000). The aims of the present study were to investigate the blood sex hormone alterations in a sample of fertileaged SCI patients, and to examine, using the Female Sexual Function Index (FSFI), the possible correlation between hormonal status and the presence of specific sexual dysfunctions. Materials and Methods Subjects The participants in our study were women with SCI. The criteria for inclusion were as follows: spinal cord injury of any aetiology, excluding suicide attempts, between 18 and 48 years of age at the time of the study, a minimum of a 6-month relationship, and having had sexual intercourse at least once during the previous 4 weeks. We excluded those patients with a history of major psychiatric conditions and those hospitalized for psychiatric pathologies, individuals with drug addiction or alcohol abuse, subjects who reported any pre-sci sexual dysfunction at visit 1, and individuals in iatrogenic menopause. Females who refused any of our tests or did not return for visit 2 were excluded from the study. Moreover, we excluded patients if they had used any sex hormones 1 year before inclusion in the study or if they were using sex hormones during the entire phase of the study. For visit 1, all of the women were interviewed by the same doctors in our spinal cord unit using a predetermined, semistructured set of questions on their pre-sci sexuality. The clinical assessment included detailed medical, gynecological, sexual, and physical examinations. All patients filled out the FSFI questionnaire, which was used to detect the presence and degree of sexual dysfunction (Rosen et al, 2000; Matzaroglu et al, 2005). We used the total score of 26.55 as the cutoff value that divided the subjects with FSD from those without FSD. All patients were submitted to a blood hormone evaluation on the third day of their menstrual cycle. The levels of follicle-stimulating hormone, luteinizing hormone, prolactin, 17[a]-hydroxyprogesterone, estradiol, cortisol, sex hormone-binding globulin, and thyroid-stimulating hormone (TSH), free triiodotyronine (T3), free tetraiodothyronine (T4), dehydroepiandrosterone sulphate (DHEA-S), free and total testosterone, and androstenedione were measured. According to the Princeton consensus meeting, the lower quartile of the normal range was considered as abnormal androgen levels (Princeton Conference, 2001). In addition, progesterone levels (P4) were noted on the 20th to 21st day of the cycle. In patients with amenorrhea, all of the hormones were assayed with only one random blood drawing. After a 3-month period, the evaluations of the patients were repeated, including the Table 1. Stratification of patients with reference to the ASIA/ IMPSOP impairment scale A B C D Cervical lesion 2 2 1 3 Dorsal lesion up to D6 7 1 0 0 Dorsal lesion below D6 6 2 3 3 Lumbosacral lesions 3 1 2 3 hormonal evaluations, and all of the females filled out the FSFI questionnaire once again. The investigators used consensus validation to complete the data analysis, and all of the research findings were reviewed by the study participants for validation. In the statistical analysis of the data, we considered significant only those values with P,.05. Results From January to July 2006, 48 women were surveyed and 9 women were excluded from the study (18.7%); 2 women did not have partners at the start of the study, so they could not fill out the FSFI completely or correctly. Four women declared pre-sci sexual dysfunction for a minimum of 1 year (range, 1 4 years); 2 of these women had histories of major depression and had been hospitalized many times for their pathologies. Three females were excluded because they did not return for the final visit, including the hormonal evaluation. In all, 39 SCI females (79.8%) completed our study. The median age was 33.5 years (range, 21 46) with the median time elapsed since patient injury averaging 6.3 years (range, 1 17 years). In Table 1, we report the levels and degrees of lesions with reference to the criteria of the American Spinal Injury Association (1996). Details of Injuries Traffic accidents were the most common cause of injury, affecting 25/39 subjects (64.1%), whereas myelitis was the cause for 10 subjects (25.6%), posthernia surgery for 3 (7.7%), and vascular disease due to dissecting aneurysm for 1 (2.6%). The main data on sexuality pre-sci are reported in Table 2. Relevant Data from Visit 1 and Visit 2 Menstrual Cycle and Sexual Function Overall, 26/39 (66.6%) women had regular menstrual cycles, 9 (23.1%) reported irregular menstrual cycles, and 3 (7.7%) were in amenorrhea post-sci; 23/39 patients (58.9%) consistently reported at least one sexual dysfunction. Female Sexual Function Index For the FSFI questionnaire, no significant variation was observed for any

724 Journal of Andrology N September ÙOctober 2007 Table 2. Pre-SCI sexuality backgrounds of the patients Children 11 out of 39 women (28.2%) had given birth to a child Negative physical factors for sexuality 2 females (5.1%) presented with type II diabetes 3 females (7.7%) had been using antihypertension drugs 1 female (2.6%) showed hypercolesterolomy and chronic obesity Menstrual cycle and hormonal therapies 32/39 (82%) individuals had regular menstrual cycles 7 (18%) females reported irregular menstrual cycles 8 (20.5%) females had used hormonal therapies for contraception Negative lifestyle 7 (18%) females were chronic smokers of more than 10 cigarettes per day patient between the first and second visits. The score variation regarding each of the 6 domains and the total FSFI score was approximately 10%. Twenty-three out of 39 patients (58.9%) with sexual dysfunction reached a median score at visit 2 of 19.52 (range, 16.5 25.2). Of the 23 patients with sexual dysfunction, desire impairment represented the most common FSD in 16 females (61.5%) associated with another sexual dysfunction (Table 3). In females with sexual dysfunction, we evaluated the type of sexual impairments, the median score, and the range reached for each domain (Table 4). In the other domains, subjects with FSD obtained a minimum score of 4.4. Females with no FSD scored a minimum of 27 (range, 27.3 33.4). Comparing the sexual satisfaction domain in SCI females with and without FSD (questions 14, 15, and 16 of the FSFI; questions 14 and 15 regard the relationship with their partners), we noted that SCI subjects with FSD had remarkably lower scores in the satisfaction domain. The median score of the satisfaction domain for females with sexual deficiencies was 2.26 (range, 0.8 3.2), compared to 4.26 (range, 3.2 6.0) for subjects without sexual impairment. In the Figure, we show the median score of the two groups for each question concerning the satisfaction domain of the FSFI. Hormonal Status Table 5 shows the normal hormone values assessed in our laboratory. All but 6 SCI female patients (15.3%) consistently showed hormonal Table 4. Median values and FSFI range for each sexual impairment Sexual Dysfunction Patients Median FSFI Score Range Arousal 8 0.94 0.3 1.5 Desire 16 1.28 0.6 1.8 Lubrication 8 1.05 0.6 1.5 Orgasm 8 1.00 0.8 1.2 Pain 3 1.20 0.8 1.6 values in the normal range. Of the 6 patients with abnormal hormonal alterations, 5 showed at least one FSD (Table 6). Moreover, comparing SCI patients with and without FSD using the x 2 test, the females with sexual dysfunction did not show increases in the abnormal sexual hormonal values (P 5.386). Discussion To date, there has been no report of an increased risk of sexual hormonal deficiencies in SCI women, even though they present a higher percentage of FSDs, particularly if they have had an SCI prior to reaching 18 years of age (Ferreiro-Velasco et al, 2005). The percentage of sexual dysfunctions in our sample was 63.3%, while the presence of sexual hormone blood alterations in women with sexual impairment was just 21.7%. Even though we studied a low number of patients, we did not observe any significant correlation between hormonal status and presence of a specific sexual dysfunction using the FSFI questionnaire. In 78.3% of females with FSD who presented with 2 sexual impairments concurrently, we did not observe any blood sex hormone impairment, and a statistical analysis for correlating hormonal status and specific sexual deficit was not applicable. Moreover, comparing SCI subjects Table 3. Females with sexual dysfunctions according to the FSFI Sexual Dysfunctions Patients (N) Desire and arousal deficiencies 6 Desire and orgasm disorders 6 Desire and lubrication impairments 4 Arousal and lubrication impairments 2 Lubrication and orgasm disorders 2 Pain and spasticity during intercourse 3 FSFI median scores for satisfaction domain questions in females with and without sexual dysfunction (SD).

Lombardi et al N Female Sexual Dysfunction and Hormonal Status 725 Table 5. Normal values measured in our laboratory for sex hormones in the blood Hormone Our Laboratory Values FSH (U/L) 3.0 9.0 LH (U/L) 0.5 9.0 PRL (mu/l) 72 504 TSH (mu/l) 0.25 3.5 Cortisol (nmol/l) 160 690 DHEA-S (mmol/l) 1.8 10.3 Hydroprogesterone (nmol/l) 1.2 8.0 Androstenedione (nmol/l) 1.4 9.4 Total testosterone (nmol/l) 0.5 3.0 Free testosterone (pmol/l) 0.15 13.2 17 beta estradiol 0.1 0.6 Inhibin (pgram/ml) 5 200 SHBG (nmol/l) 26.7 57.8 FT3 (pmol/l) 3.5 6.4 FT4 (pmol/l) 10.3 19.4 Progesterone (nmol/l).25 with and without FSD, the females with FSD did not show a significant increase in abnormal sexual hormone levels. Our sample showed a relevant gap in satisfaction between patients having and lacking FSDs with regard to their relationships with their partners, which may explain most of the cases of desire impairment. No predictive factors associated with abnormal sexual hormonal status, such as level of spinal cord injury, injury period, and patient age, were observed. According to our present results, the evaluation of blood levels of sex hormones does not appear to be a valid first-line screen for detecting FSD in SCI females. Overall, hormone therapies are the most utilized therapies for sexual dysfunction, especially those that involve androgen, even if the clinical diagnosis and management associated with these therapies for healthy patients remain controversial (Turna et al, 2005; Arlt, 2006). In our sample, 5/6 females with hormonal levels that were out of range showed at least one FSD. Of these, 1 woman was in amenorrhea post-sci. It is appropriate to evaluate the sex hormone profile within 12 months of SCI for fertile-aged patients if they have not recovered their menstrual cycle. Although at this time there is a lack of standardized international protocols for the management of sexual issues in SCI females, clinicians should emphasize as a first-line treatment the removal of all possible physical discomforts during intercourse, including urinary and fecal incontinence, spasticity of the lower limbs, neuropathic pain, and autonomic dysreflexia. Included in first-line treatment is curing concomitant medical pathologies that may worsen or lead to sexual dysfunctions and informing patients that chronic smoking or abuse of alcohol poses a potential threat to sexuality. Moreover, psychological factors may affect sexuality more than physical impairments, so it is important to help these women to recover self-esteem and self-image by involving their partners in this project (Forsythe et al, 2006). A result of the Basson female sexual response is that in order to optimize the sexual adjustment of SCI patients, it is fundamental to involve their partners in order to help the women to trust another person and to open up by sharing personal thoughts and feelings (Basson, 2002). It is necessary that these patients be enrolled in a specific program of sexual rehabilitation with a multidisciplinary spinal cord unit team, including the use of peer and support groups as essential adjuncts to professional intervention. The interaction between the central nervous system and hormones in regard to female sexual function and their etiological roles in dysfunction is complex. Future prospective studies of the effects of estrogen/testosterone on neurologic recovery are recommended. Research findings have supported the hypothesis that the sympathetic nervous system regulates psychogenic genital vasocongestion and that orgasm is a reflex response of the autonomic nervous system, although there is no strict correlation between the level and degree of lesions and specific sexual impairment (Marson et al, 2004). Based on our results, hormonal therapies may be used in restricted cases. Before starting therapy, a preevaluation of blood steroid hormones is useful. Furthermore, it is necessary to evaluate possible medical contraindications in SCI patients. Estrogen treatments may cause a higher risk of thromboembolism than in healthy women due to the absence or reduction of lower Table 6. Types of hormonal alterations correlated with sexual dysfunctions Hormonal Status Patients (N) Sexual Dysfunction Hormone Value 1 Desire and lubrication deficiencies Total testosterone 0.3 nmol/l 1 Desire and orgasm impairment Total testosterone 0.1 nmol/l 1* Arousal and orgasm impairment Free testosterone 0.18 pmol/l 1 Desire and arousal disturbance Hypothyroidism (TSH) 5.21 mu/l 1 Arousal and lubrication deficiencies Cortisol 72 nmol/l 1 - Progesterone 18 nmol/l * This patient showed an abnormal value according to the Princeton Conference criteria.

726 Journal of Andrology N September ÙOctober 2007 limb motility in SCI females. Finally, we must ensure that we have achieved maximum benefits with first-line strategies. Hormonal therapies will not resolve sexual problems that have other causes beyond those factors related to hormones. Sex steroid insufficiency is associated with urogenital atrophy and may also adversely affect central sexual thought processes; even complaints of lack of subjective arousal despite apparently normal genital vasocongestion are common. The same contradictory results in SCI subjects have been reported with the use of 5-phosphodiesterase inhibitors, which cause genital vasocongestion (Sipski et al, 2000). Consequently, there is little to be gained from trying to determine whether a disorder is either biological or psychological, thereby causing a difficulty in predicting when pharmacological effects on sexual response will be beneficial. The relationship between SCI sexual function and blood sex hormone status remains a matter of debate, so obviously further investigation with a higher number of SCI patients is needed. An interesting future investigation would be to compare SCI females with a control group of healthy women, even if these 2 groups are very different due to the fact that the neurologic condition often amplifies negative aspects on sexuality, such as bladder and bowel management and spasticity-pain. References American Spinal Injury Association. International Standards for Neurological and Functional Classification of Spinal Cord Injury Revised 1996. Chicago, Ill: American Spinal Injury Association; 1996. Anastasiadis AG, Davis AR, Salomon L, Burchardt M, Shabsigh R. Hormonal factors in female sexual dysfunction. Curr Opin Urol. 2002;12:503 507. Arlt W. Androgen therapy in women. Eur J Endocrinol. 2006;154:1 11. Bachmann G, Bancroft J, Braunstein G, Burger H, Davis S, Dennerstein L, Goldstein I, Guay A, Leiblum S, Lobo R, Notelovitz M, Rosen R, Sarrel P, Sherwin B, Simon J, Simpson E, Shifren J, Spark R, Traish A, Princeton. Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment. Fertil Steril. 2002;77:660 665. Baker ER, Cardenas DD. Pregnancy in spinal cord injured women. Arch Phys Med Rehabil. 1996;77:501 507. Basson R. A new model of female sexual response. Sexual Dysf Med. 2002;2:72 77. Bermann JR, Bermann L, Goldstein. Female sexual dysfunction: incidence, pathophysiology, evaluation and treatment options. Urology. 1999;54:385 391. Campagnolo DI, Bartlett JA, Chatterton R Jr, Keller SE. Adrenal and pituitary hormone patterns after spinal cord injury Am J Phys Med Rehabil. 1999;78:361 366. Davis SR, Guay AT, Shifren JL, Mazer NA. Endocrine aspects of female sexual dysfunction. Sex Med. 2004;1:82 86. Ferreiro-Velasco ME, Barca-Buyoa de la Barrera SS, Montoto- Marquez A, Vazquez XM, Rodriguez-Sotillo A. Sexual issues in a sample of women with spinal cord injury. Spinal Cord. 2005;43:51 55. Forsythe E, Horsewell JE. Sexual rehabilitation of women with a spinal cord injury. Spinal Cord. 2006;44:234 241. Kreuter M. Spinal cord injury and partner relationships. Spinal Cord. 2000;38:2 6. Maïmoun LC, Fattal C, Micallef JP, Peruchon E, Rabischong P. Bone loss in spinal cord-injured patients: from physiopathology to therapy. Spinal Cord. 2006;44:203 210. Marson L, Foley KA. Identification of neural pathways involved in genital reflexes in the female: A combined anterograde and retrograde tracing study. Neuroscience. 2004;127:723 736. Matzaroglu C, Assimakopoulos K, Panagiotopoulos E, Kasimatis G, Dimakopoulos P, Lambiris E. Sexual function in females with severe cervical spinal cord injuries: a controlled study with the Female Sexual Function Index. Int J Rehabil. 2005;28:375 377. Rosen RC, Brown C, Heiman J, Leiblum S, Meston C, Shabisighr R, Ferguson D, D Agostino R Jr. The Female Sexual Function Index (FSFI): A multidimensional self-report instrument for the assessment of female sexual dysfunction. J Sex Marital Ther. 2000;26:191 208. Sipski ML, Arenas A. Female sexual function after spinal cord injury. Prog Brain Res. 2006;152:441 447. Sipski ML, Rosen RC, Alexander CJ, Hamer RM. Sildenafil effects on sexual and cardiovascular responses in women with spinal cord injury. Urology. 2000;55:812 815. Turna B, Apaydin E, Semerci B, Altay B, Cikili N, Nazli O. Women with low libido: correlation of decreased androgen levels with female sexual function index. Int J Impot Res. 2005;17:148 153.