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Genitourinary Imaging |
1 From the Departments of Radiology (A.V.D., K.R.M., P.A.G., Y.C.) and Psychiatry and Behavioral Sciences (J.R.H., L.H.), University of Washington, 1959 NE Pacific St, Box 357115, Seattle, WA 98195-7115; Pfizer, Groton, Conn (W.O.C., B.T.P.); and EPIX Medical, Cambridge, Mass (R.M.W.). From the 1999 RSNA scientific assembly. Received July 9, 2001; revision requested August 2; final revision received May 20, 2002; accepted June 18. Supported in part by Pfizer and EPIX Medical. Address correspondence to K.R.M. (e-mail: kmarav@u.washington.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Serial MR imaging of the external genitalia was performed in 12 healthy sexually functional women before and after administration of MS-325. MR images were obtained every 3 minutes during a 45-minute examination. During the examination, the subjects viewed neutral and erotic video material while they were in the magnet bore. MR image analysis at each interval consisted of vaginal wall, vaginal mucosa, and clitoris assessments; femoral vein signal intensity measurements; relative regional blood volume (rRBV) calculations; and clitoral volume measurements. Statistical analysis of the results was performed with a t test.
RESULTS: On subjective questionnaires, all subjects in the test group reported being sexually aroused. MS-325–enhanced MR images showed strong contrast enhancement of the external genitalia. The rRBV in the glans clitoris of seven of 10 subjects and in the clitoral body of eight of these subjects increased significantly (P < .05) during erotic visual stimulation. All 10 subjects had a significant (P < .05) increase in clitoral size. There were no significant differences in any measures between the pre- and postmenopausal study groups.
CONCLUSION: The sexual arousal response in healthy women can be monitored at serial MR imaging with MS-325. This examination holds promise for future studies of sexual arousal dysfunction in women.
© RSNA, 2002
Index terms: Gadolinium • Magnetic resonance (MR), contrast media, 855.12143 • Magnetic resonance (MR), volume measurement, 855.12144 • Vagina, 855.91 • Vagina, MR, 855.121412, 855.121416, 855.12143, 855.12144
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Female sexual dysfunction is believed to be the result of a broad range of medical and/or psychological conditions, in which one or more diseases combined or a single disease may be the cause of the dysfunction. More specifically, female sexual dysfunction may be attributed to a spectrum of medical conditions, including vascular insufficiency caused by atherosclerosis, smoking, trauma, or surgical disruption (4). Other medical factors may be neurologic impairment caused by spinal cord injury, diabetes, or multiple sclerosis (5,6). Hormonal or endocrine disturbances or urologic diseases also may be factors. Clinical depression, clinical anxiety, and history of coerced sexual behavior are among the psychogenic factors that have been implicated in sexual dysfunction (1,3). In addition, the use of psychotropic drugs in general and selective serotonin reuptake inhibitors in particular, owing to their side effects of delayed orgasm and decreased libido, has been identified as a major contributor to female sexual dysfunction (7–11). Many of these possible causes may contribute to inadequate vascular response to sexual stimulation, which is an important and common precursor to sexual dysfunction.
The most widely reported method of assessing the vascular component of sexual arousal in women is vaginal photoplethysmography, which involves the use of an intravaginal probe to measure vascular mucosal changes. The limitations with vaginal photoplethysmography can be substantial, however. Vaginal photoplethysmography is affected by movement artifact, and it yields only a relative measurement of vaginal blood flow and no anatomic information (12,13). In addition, it requires vaginal insertion of the photoplethysmography probe, which has the potential to confound the observed arousal response. Duplex Doppler ultrasonography (US) also has been used to measure arterial blood flow in the perineum, but this examination also is sensitive to movement and does not yield anatomic information (9).
Given the difficulty in viewing the underlying anatomy and the complex physiologic response simultaneously, it is essential to the study of female sexual dysfunction that a simple, objective, and less intrusive technique for monitoring changes that occur during sexual arousal be developed.
MS-325 (EPIX Medical, Cambridge, Mass) is a small (molecular weight, 957) gadolinium chelate that binds reversibly to albumin. While bound to albumin, MS-325 increases in relaxivity four- to tenfold, depending on the field strength (14). The clearance of this agent is biexponential, and it has a terminal clearance phase half-life of 10–14 hours (15). MS-325 is currently the subject of phase 3 clinical trials for possible use with magnetic resonance (MR) angiography.
The purpose of this study was to determine whether MR imaging with MS-325, a new blood pool contrast agent, can be used to evaluate the sexual arousal responses in healthy women.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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All subjects underwent a complete physical examination, including a pelvic examination and a Papanicolaou smear test. In all subjects, blood samples to assess baseline chemistry, hematologic, coagulation, iron, and endocrinologic values and urine samples for microscopic urinalysis were obtained. All results showed no substantial abnormalities. Pregnancy was excluded in the premenopausal group both at screening and on the day of MR imaging. Premenopausal women underwent MR imaging between days 7 and 21 of their menstrual cycle. The postmenopausal subjects underwent additional hormonal examinations, including tests to measure estradiol, serum luteinizing hormone, and follicle stimulating hormone levels, which had to be within a specified laboratory range that is typical of postmenopausal women. Subjects with a history of previous vaginal surgery, hysterectomy, or abnormal menstrual cycles, and/or who had received hormone replacement therapy or taken birth control pills within the preceding 6 months were excluded from the study.
A total of 16 healthy sexually functional female volunteers were enrolled in the study. To optimize study methods, the first four subjects were randomly assigned to receive two different doses of MS-325 and were examined with slightly different imaging protocols. Subsequently, 12 additional subjects were examined with a uniform MR imaging protocol and the same dose of MS-325. Of the latter group, six were premenopausal women between the ages of 23 and 38 years (mean, 30.3 years) and six were postmenopausal women between the ages of 53 and 66 (mean, 57.6 years). Women in the premenopausal group weighed between 47.7 and 90.0 kg (mean, 66.8 kg), whereas women in the postmenopausal group weighed between 50.0 and 84.5 kg (mean, 70.2 kg). The height of women in the premenopausal group ranged from 157.5 to 180.3 cm (mean, 166.7 cm), whereas the height of women in the postmenopausal group ranged from 157.5 to 177.8 cm (mean, 165.3 cm).
Safety assessment results, including vital sign, 12-lead electrocardiogram, blood sample, urine test, and physical examination measurements, were documented at specified intervals up to 96 hours after injection of MS-325. Vital signs were measured immediately before MR imaging and at 1 minute, 15 minutes, 30 minutes, 60 minutes, 3 hours, 24 hours, and 72–96 hours after injection of MS-325. A 12-lead electrocardiogram was obtained immediately before MR imaging, within 60 minutes after MS-325 injection, and at 72–96 hours after MS-325 injection. Blood and urine samples were taken within 2 hours, at 24 hours, and at 72–96 hours after injection of MS-325. A follow-up physical examination was performed at 72–96 hours after injection of MS-325. Adverse events were documented from the screening visit to the last follow-up visit at 72–96 hours after injection of MS-325.
Contrast Agent Doses
MS-325 is formulated at a concentration of 0.25 mmol/mL. Of the first four subjects, two received 0.02 mmol of MS-325 per kilogram of body weight and two received 0.05 mmol/kg for evaluation of dose-related enhancement patterns. All 12 of the remaining women enrolled in this study received 0.05 mmol/kg of MS-325. MS-325 was injected intravenously at a maximum rate of 1.5 mL/sec, and a 30-mL normal saline flush followed.
Video Material
The videotapes contained segments of neutral and erotic—that is, sexually explicit—material. The videotapes consisted of a 21-minute neutral segment, followed by a 15-minute erotic segment, and then a 9-minute neutral segment. Serial MR imaging was performed during the entire 45-minute video presentation. Subjects were able to see and hear the video material through a fiberoptic audiovisual display system (Silent Vision; Avotec, Stuart, Fla) while they were inside the magnet bore. Two subjects (one premenopausal woman and one postmenopausal woman) were injected with MS-325 and underwent the entire 45-minute MR imaging examination while viewing neutral video material only; thus, they served as control subjects.
Subjective Response Measurement
To evaluate the subjects’ responses during the erotic video presentation, all subjects were asked to complete a self-assessment questionnaire (16,17) at three time points: 3 minutes prior to viewing the neutral video material, immediately prior to viewing the erotic video material, and immediately after MR imaging was completed (Fig 1). On each questionnaire, they noted the degree of their sexual arousal and their perceived genital changes.
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One three-dimensional-volume image series was obtained prior to contrast agent administration. Intravenous contrast agent injection was followed by a 3-minute delay to allow contrast agent level equilibration. Postcontrast images were then acquired every 3 minutes while the subjects viewed the video material. Figure 1 is a flow chart that outlines the MR imaging protocol.
Data Analysis
Two independent experienced radiologists (A.V.D., K.R.M.) subjectively evaluated the images for pre- and postcontrast image quality and depiction of the genital tract anatomy; disagreements were resolved by consensus. Signal intensities were measured by means of selection of ROIs in the vaginal wall, vaginal mucosa, common femoral vein, muscle, and clitoris and ROIs in the air outside the subject to provide a measurement of background noise. The size of the ROI varied according to the size of the structure being analyzed. For example, among all subjects, the measured size of the vaginal wall ROI ranged from 4 to 22 mm2, whereas the size of the clitoral body ROI ranged from 7 to 70 mm2. The size of the ROI within each subject was kept consistent at each time point throughout the neutral and erotic video segments. The first four subjects were excluded from the final data analyses because they were imaged with a protocol that was different from that used to image the subsequent 12 study subjects. Image volumes for each time point within a given subject were analyzed in random order to attempt to reduce bias. However, all volumes measured within a given subject were analyzed together.
Changes in Blood Volume
Relative regional blood volume (rRBV) was estimated from time-versus–signal intensity curves derived from ROI measurements of the vaginal wall and clitoris by using the following equation:
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To determine whether viewing erotic video material differentially changed the estimated rRBV, the estimated rRBV changes were fit as a function of time to the following three-variable (variables A, B, and C) model to account for these changes:
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Changes in Clitoral Volume
The various structures that form the clitoris, including the crura, clitoral body, and glans of clitoris, were identified and outlined on each section that depicted clitoral tissue. The volumes of these areas were summed, and the total volume was measured at each time point by using a planimetric method, with volumes reported in cubic centimeters. If difficulty in defining the precise boundary between the clitoris and the adjacent mucosal or glandular tissue was encountered, all of the enhancing tissues were included. This was often the case in the area of the clitoral body, but we do not believe that it caused a problem with comparative measurements within a given subject, because the same anatomic areas were outlined at each time point. However, this measurement method may have resulted in a slight overestimation of the true clitoral volume in some subjects. Data were analyzed and graphs constructed by using a two-tailed t test with commercially available spreadsheet (Excel; Microscoft, Redmond, Wash) and graphing (KaleidaGraph; Synergy Software, Reading, Pa) programs.
Subjective Questionnaires
Responses on the standardized subjective questionnaires were analyzed. The questionnaires instructed subjects to report their degree of sexual arousal on a scale of 1 (none) to 7 (intense). Scores of 2 or greater were interpreted to mean some degree of sexual arousal. For each subject, independent scores for "sexually aroused," "mentally sexually aroused," and "physically sexually aroused" were combined to yield an average score of the subject’s level of sexual arousal.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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The MR images obtained after the administration of MS-325 showed intense contrast enhancement of the genitalia of all 16 subjects. Figure 2 shows the pre- and postcontrast MR image appearances of the clitoris of one subject. Representative postcontrast MR images of the external genitalia obtained with two different MS-325 doses in the first four subjects are shown in Figure 3. Although genital contrast enhancement was visualized with both doses, both readers considered the image quality achieved with the 0.05 mmol/kg dose to be superior. Thus, the higher dose was administered to all 12 subsequent subjects.
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The serial MR images obtained while 10 study subjects viewed the video presentation that consisted of both neutral and erotic material showed an increase in both the degree of contrast enhancement and the overall size of the clitoris during the erotic segment, as compared with the findings during the first neutral segment. This was true according to the subjective reader assessments, as well as the quantitative measurements on serial images. Subsequent images acquired during the second neutral segment showed a decrease in contrast enhancement and clitoral size, as compared with the findings during the erotic segment. However, these postarousal measurements did not completely return to baseline during the 9-minute neutral video segment. Figure 4 shows serial images of the clitoris that were obtained at the three time points after contrast agent administration in one subject. The changes in the clitoris in response to the first neutral segment, the erotic segment, and the second neutral segment are seen.
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rRBV data are summarized in Table 1. Clitoral rRBV measurements were analyzed in two areas: the glans of clitoris and the clitoral body. The rRBV changes in the glans of clitoris in seven of the 10 subjects who viewed erotic material and in the clitoral body in eight of these subjects were significant (P < .05). The rRBV in the glans of clitoris in the two subjects who were shown neutral material only did not change significantly. On average, there were significant differences in rRBV between the neutral segment only (control) and erotic segment (study) groups. In the glans of clitoris, rRBV changed 40% ± 10 (mean ± standard error of mean) in the subjects who viewed erotic material versus -3% ± 5 in the control subjects. In the clitoral body, rRBV increased 24% ± 8 in the subjects who were shown erotic material versus 3% ± 8 in the subjects who were shown neutral material only.
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No significant differences between the pre- and postmenopausal groups were observed. Although mean rRBV increases were slightly greater in the clitoral body in the postmenopausal group (9% ± 4 in premenopausal group vs 39% ± 12 in postmenopausal group), the difference was not statistically significant. We believe that in three premenopausal subjects (subjects 10–12), this difference was due primarily to partial volume measurement effects that resulted from slight movement between the measured time points and produced artificially low or negative rRBV changes. This phenomenon lowered the mean rRBV in the premenopausal study subjects. Nevertheless, it should be stressed that this pilot study consisted of a very small group of subjects, and, thus, the results should be considered to be primarily descriptive rather than to have true statistical power.
The quantitative measurements of clitoral volume obtained over time proved to be more robust than the rRBV measurements. The P value results of a two-tailed t test performed to compare the within-subject clitoral volumes measured between the first neutral segment and the erotic video segment are shown in Table 2. In the study group, the average clitoral volume of all subjects increased from 10.74 cm3 during the viewing of the first neutral segment to 21.17 cm3 during the viewing of the erotic segment, and then it decreased to 15.42 cm3 during the viewing of the second neutral segment. This amounted to a mean volume change of 118% ± 73 (range, 51%–280%) between the first neutral segment and the erotic segment (Fig 5). There was no statistically significant difference in clitoral volume changes between the premenopausal and postmenopausal subjects (Fig 6). The mean clitoral volume, as compared between the first neutral segment and the erotic segment in the premenopausal group, increased 107% ± 26 (range, 51%–181%), whereas that in the postmenopausal group increased 129% ± 43 (range, 55%–280%). No significant change in clitoral volume over time was measured in the subjects who viewed neutral video material only (Fig 7).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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In our study, the sexual arousal caused by a video paradigm was corroborated with the subjects’ responses on questionnaires. The results of nonhuman preclinical studies indicate that the estimated blood half-life of MS-325 is approximately 2–3 hours (14). On the basis of these results, we hypothesized that the prolonged effects of MS-325, when used during MR imaging, would enable the study of normal sexual responses in women for an extended period. The increase in the signal intensity and size of the clitoris while subjects viewed erotic video segments were readily appreciated at visual examination of the MR images, even before quantitative data analysis was performed. When additional neutral material was viewed after the erotic segment, these changes decreased but did not dissipate immediately; these observations suggest that there was prolonged vascular engorgement of the clitoris. Thus, MR imaging may be a diagnostic tool to evaluate female sexual arousal disorder, assuming that an abnormal vascular response is the cause of the disorder.
The blood volume estimation method described herein involves a number of assumptions. Although it cannot be assumed that the contrast agent remains solely in the intravascular space, it can be assumed that the signal intensity changes generated by blood volume changes far exceed any signal intensity changes generated by extracellular volume changes that might occur during stimulation. However, the estimate of blood volume changes is most likely an underestimation of the true blood volume changes, because the variable A in Equation (2) also includes some of the leaked interstitial volume. Given the highly vascular nature of the clitoris, the magnitude of blood volume changes (approximately 40%) measured in this study seems reasonable. The 18 minutes of initial neutral video material was specifically intended to allow the contrast agent to equilibrate before the subject viewed the erotic material. However, most subjects continued to have genital contrast enhancement (expressed as the B variable in Eq [2]) that did not correlate to the video presentation; thus, this variable had to be directly eliminated as a confounding variable, as is done many times with small motion in functional MR imaging data analysis (18).
The anatomic outline of the enhancing external genitalia during the initial phase of arousal might have been adequately imaged during the early enhancement phase after injection of a conventional extracellular MR contrast agent. Because serial MR imaging was used to measure rRBV and clitoral volume changes over an extended period (>30 minutes), however, we believed that it was necessary to use a blood pool contrast agent. MS-325 is a gadolinium-based chelate that reversibly binds to serum albumin and has a half-life that is estimated to be as high as 10–14 hours in humans when it is injected intravenously (15). The long half-life of MS-325 enabled relatively constant blood signal intensity for the duration of the imaging study. Furthermore, although some of the contrast material extravasates, the agent creates a much larger area of enhancement when it is bound to albumin. Because the extracellular concentration of albumin is typically one-fourth that of plasma, albumin tends to create blood pool contrast enhancement even when there is extravasation (20).
Although significant changes were measured during the viewing of erotic videos with both the rRBV and the clitoral volume methods of assessing sexual arousal, the absolute measurement of clitoral volume provided a more robust measure of arousal response and was less susceptible to movement artifact. All subjects who viewed the erotic segments had significant (P < .01) increases in clitoral volume, whereas neither control subject had a measurable response. Because both increased blood volume and increased clitoral volume should be manifestations of the same underlying engorgement process, we believe these results reflect the greater precision and reproducibility of the overall clitoral volume measurement. Even with the small degrees of subject movement between successive image acquisitions during the lengthy imaging period, we were able to reproducibly measure clitoral volume at each time point.
On the other hand, signal intensity increases measured in the glans of clitoris or the clitoral body are focused in an anatomically small ROI. This makes these measurements more sensitive to partial volume effects, with small shifts of the region over time due to patient movement. Thus, the small ROI is averaged to differing degrees with the areas of the surrounding muscle and the glandular tissues, and this has the potential to result in rRBV measurement errors. This may explain the negative values of rRBV changes between the neutral and erotic video segment viewings that we observed in some individuals.
There were two control subjects. The change in rRBV in one of these women (subject 19) appears to have been statistically significant; however, it should be noted that the changes in the clitoral body and glans of clitoris were in opposing directions (one positive and one negative). Because a negative change in rRBV in the clitoris with arousal does not make sense physiologically, this should be considered a nonsubstantial finding. We believe that this positive versus negative change in direction was not related to a change in arousal, but rather it was caused by other factors, such as image noise, partial volume effects, and/or slight patient motion. These findings further support our conclusion that clitoral volume measurements were more reliable than rRBV calculations in this study.
Another limitation to this study was the fact that the review of the images was not strictly blinded with regard to subject identity. All image reviews and analyses were performed at a workstation (part of Signa Horizon Echo Speed). Because the serial dynamic MR images were acquired in a single series, it would have been impractical to attempt to randomize the image order among all the subjects so that the reviewer could be completely blinded. Therefore, only the individual time points selected for analysis with a particular subject were randomized to the investigator performing the measurements. However, the magnitude of changes (>100% clitoral volume increase with arousal) made it unlikely that reviewer bias affected the final conclusions.
Our finding of similar subjective responses and similar measured genital changes in the pre- and postmenopausal subjects was important, because findings of increased sexual dysfunction with age that are possibly due to physical changes in the vaginal mucosa, difficulties with lubrication, and/or tissue fibrosis have been reported (21). In our sample population of sexually functional postmenopausal women, the changes seen with sexual arousal matched or exceeded those seen in the premenopausal women. Thus, according to the results observed with our limited study sample size, it appears that age alone does not necessarily imply a decline in vascular genital responses to sexual stimulation. This finding is corroborated by epidemiologic evidence of declining sexual problems with increasing age—to at least age 59 years (3)—despite clinical sample reports of greater sexual dysfunction in postmenopausal women (1).
In conclusion, serial MR imaging of the external genitalia with the blood pool agent MS-325 enables study of the vascular changes associated with female sexual arousal response. This examination is a potentially powerful tool for the future study of sexual dysfunction in women.
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, all authors; study concepts, K.R.M., W.O.C., R.M.W., J.R.H.; study design, A.V.D., K.R.M., W.O.C., R.M.W.; literature research, A.V.D., K.R.M., R.M.W., J.R.H.; clinical and experimental studies, A.V.D., K.R.M.; data acquisition, A.V.D., K.R.M.; data analysis/interpretation, all authors; statistical analysis, R.M.W., Y.C.; manuscript preparation, A.V.D., K.R.M.; manuscript definition of intellectual content, editing, revision/review, and final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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