DRAFT—PLEASE TO NOT CITE—JUNE 23, 2002
Female Sexual Arousal Response Using Serial MR Imaging with Initial Comparisons to
Vaginal Photoplethysmography: Overview and Evaluation
Julia R. Heiman1, Ph.D, and Kenneth R. Maravilla2, M.D
1
Department of Radiology, University of Washington, Seattle, WA
2
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA
Correspondence and Reprints:
Julia R. Heiman, Ph.D.
University of Washington Outpatient Psychiatry Center
4225 Roosevelt Way, NE, Suite 306
Seattle, WA 98105
Phone: 206-598-7152, Fax: 206-598-7794, Email: jheiman@u.washington.edu
Pfizer, Inc, Groton CT. and EPIX Medical, Inc., Cambridge, MA provided funding for
this research
2
INTRODUCTION
Although the sexual arousal and response of women has been empirically studied
over the past four decades, measurement methods have been minimally available. This is
particularly the case in understanding the physiology and psychophysiology of female
sexual dysfunction (FSD), even though problems of sexual functioning may be as
prevalent as 25-40% (Bancroft, et al, 2003; Laumann et al.1999). Attempts to test and
validate differences between functional and dysfunctional sexual response, as well as
treatments for FSD subtypes have been difficult due in part to the limited availability of
physiological measures that are reliable, reproducible and relatively non-invasive.
Recently we presented a new method for objectively monitoring female sexual arousal
response using serial magnetic resonance imaging (MRI) combined with MS-325 (EPIX
Medical, Inc.) an investigational new gadolinium-based blood pool agent (1). Another
female sexual arousal measurement method, vaginal photoplethysmography (VPP), has
been used as a relative arousal measurement method for over 3 decades (2, 3). VPP has
been shown to be a sensitive and reliable indicator of female sexual arousal, but it
remains limited due to its lack of absolute scaling and thus must be used in within-subject
(crossover) designs. We have conducted initial studies to develop the MRI method and
technique for female genital measurement. The present paper is intended to review these
results and to evaluate the advantages and disadvantages of the MS-325 enhanced serial
MRI technique and provide comments on the comparison of it to VPP. Both techniques
also included subjective measures of arousal.
MATERIALS AND METHODS USED
In order to give specifics on the use of MRI and comparison to VPP, we will
detail the methods used thus far.
Participants
This work will summarize the work on 28 healthy, sexually functional women.
Premenopausal women between the ages of 23 and 38 postmenopausal women were
between the ages of 53 and 66. The university Institutional Review Board approved the
protocol and consent form, and subjects signed a written consent prior to study entry.
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Subjects were recruited by the use of advertising in local newspapers and flyers placed on
the university campus. Potential subjects were initially screened by telephone. Subjects
were invited to the study site if they were healthy and had no sexual disorders.
All subjects underwent a complete physical examination, including a pelvic
examination and a Papanicolaou (Pap) smear.
Blood samples were drawn to assess
baseline chemistry, hematology, coagulation, iron, and endocrinology values; and a urine
sample was obtained for microscopic urinalysis in all subjects. All results showed no
significant abnormalities. Pregnancy was excluded in the premenopausal group at both the
screening visit and on the day of the MR visit. Premenopausal females were scanned (and
for those women in the comparison study, run in the VPP procedure with in 8 days of that
window) between day 7 and day 21 inclusive of their menstrual cycle.
The
postmenopausal subjects had additional hormonal testing performed including estradiol,
serum luteinizing hormone, and follicle stimulating hormone levels, which had to be
within a specified laboratory range typical for postmenopausal women. Subjects with a
history of previous vaginal surgery, hysterectomy, abnormal menstrual cycles, and/or
having taken hormone replacement therapy or birth control pills within the preceding six
months were excluded from the study.
There was some weight limits due to the MRI procedure. Weights ranged between
47 and 90kg and height from 157cm to 180cm.
Safety assessments, including vital signs, 12-lead electrocardiograms (ECG), blood
samples, urine tests, and physical examination were documented at specified intervals up
to 96 hours postinjection of MS-325. These are detailed in the first report on MRI results
(Deliganis et al., 2002).
Measures
MRI Measures
Contrast Dosing. MS-325 is a small (MW 957) gadolinium chelate that binds reversibly to
albumin. While bound to albumin, the agent increases its relaxivity 4-10 fold, depending
on field strength (13).
The agent shows a biexponential clearance, with a terminal
clearance phase half-life of 10 to 14 hours (14). MS-325 is currently in phase III clinical
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trials for use in MR angiography. MS-325 is formulated at a concentration of
0.25mmol/mL. All twelve women received a dose of MS-325 calculated at 0.05mmol/kg
of body weight. Contrast MS-325 was injected intravenously at a maximum rate of
1.5mL/seconds, followed by a 30mL normal saline flush.
Videotaped material. The videotapes (the same videotapes as were used in the VPP when
we compared the 2 methods) contained segments of neutral and erotic (sexually explicit)
material. The videotape format included a 21-minute neutral section, a 15-minute erotic
section, and another 9-minute neutral section. MR imaging was performed during the
entire 45-minute videotape presentation. Subjects were able to see and hear the video
material through a fiberoptic audiovisual display system (Avotec, Inc., Stuart, FL) while
in the magnet bore. (Two subjects (one pre- and one post-menopausal female) were
injected with MS-325 but saw only neutral video material, serving as controls.)
Subjective Measurements. Subjective (self-report) sexual responses were measured using
a 30 item Film Evaluation Scale (FES) that has been found to be a reliable and sensitive
measure of sexual response and affect 4, 5 All subjects were asked to complete the FES at
three time-points: prior to viewing the neutral video material, prior to viewing the erotic
video material, and immediately after the MRI was completed (evaluating their responses
during the erotic videotape).
MR Imaging. MR images were obtained on a GE Signa 1.5 Tesla system (General
Electric Medical Systems, Waukesha, WI). Images of the perineum were acquired using
specially designed phased-array (PA) coils built by scientists at the University of
Washington. A 10cm PA coil (15) was placed anterior to the pubic symphysis and a
larger 2-coil PA receiver was positioned posterior to the pelvis. Subjects were imaged
using a T1-weighted fast, three-dimensional (3D) spoiled gradient recalled echo (SPGR),
acquired in an axial orientation (TR/TE/flip angle = 11/1.7/35°, 256x256, FOV = 24cm,
2.0mm slice thickness, 1 NEX). Thus, voxel size was very small, measuring
approximately 0.9 x 0.9 x 2 mm for a total voxel volume of 1.6 mm3. This voxel size was
felt to be warranted since the clitoral structures are small and require fine detail imaging
for accurate measurement. The use of local PA coils boosted the signal-to-noise ratio to
enable detailed imaging of the external genitalia and to provide both reliable anatomical
structure outlines and measures of signal intensity (SI) within small regions of interest
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(ROI). Shim values, transmitter gain, and receiver gain settings were kept constant for
the entire 45 minute imaging session to provide accurate time versus signal intensity plots
for calculation of regional blood volume changes. One 3D-volume series was obtained
prior to contrast administration. Intravenous contrast injection was followed by a 3minute delay for contrast level equilibration.
MR images were obtained on a GE Signa Horizon Echo Speed 1.5 Tesla system
(General Electric Medical Systems, Waukesha, WI).
Images of the perineum were
acquired using specially designed phased-array (PA) coils built by scientists at the
University of Washington.
A 10cm PA coil (17) was placed anterior to the pubic
symphysis and a larger 2-coil PA receiver was positioned posterior to the pelvis. Subjects
were imaged using a T1-weighted fast, three-dimensional (3D) spoiled gradient recalled
echo (SPGR), acquired in an axial orientation (TR/TE/flip angle = 11/1.7/35°, 256x256,
FOV = 24cm, 2.0mm partitions, 1 NEX). Thus, voxel size was very small, measuring
approximately 0.9 x 0.9 x 2 mm for a total voxel volume of 1.6 mm 3. This voxel size was
selected because the clitoral structures are small and require fine, detailed imaging for
accurate measurement. The use of local PA coils boosted the signal-to-noise ratio to
enable detailed imaging of the external genitalia and to provide both reliable anatomical
structure outlines and measures of signal intensity (SI) within small regions of interest
(ROI). Fat saturation was not used. Shim values, transmitter gain, and receiver gain
settings were kept constant for the entire 45 minute imaging session to provide accurate
time versus signal intensity plots for calculation of regional blood volume changes.
One 3D-volume series was obtained prior to contrast administration. Intravenous
contrast injection was followed by a 3-minute delay for contrast level equilibration.
Postcontrast images were then acquired every three minutes while subjects simultaneously
viewed the video material. (Include flow chart?)
VPP Measures
A vaginal photoplethysmograph (Behavioral Technology Instruments, Salt Lake City,
Utah) was used to measure vaginal pulse amplitude (VPA) and vaginal blood volume
(VBV) responses. The vaginal photoplethysmograph has been shown to be a valid and
reliable measure of sexual arousal in women. The software program AcqKnowledge III,
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version 3.3 (BIOPAC Systems, Inc, Santa Barbara, Calif) and data acquisition unit
(model MP100WS, BIOPAC Systems, Inc) were used with a personal computer (Power
Macintosh 6100/70, Apple, Cupertino, Calif) to collect, convert (from analog to digital)
and transform data.
Subjective Measurements. Subjective (self-report) sexual responses were measured using
the 30 item Film Evaluation Scale (FES). A shortened 7 item of the version of the FES
was given before presentation of a neutral video (after the subject had inserted the
photoplethysmograph) and immediately after the presentation of the neutral videotaped
the material. The full length FES was completed immediately after the termination of
erotic segment (before removal of the photoplethysmograph).
VPP Data Sampling and Reduction
Vaginal responses to neutral and erotic stimuli were measured during the initial
adaptation period and throughout the presentation of the videotaped material.
Physiological responses were sampled at a rate of 60 samples per second throughout the
adaptation (baseline phase), the entire 10 minutes of neutral film, and 14 minutes of
erotic film. The BIOPAC software allowed for an automated transformation of raw data
into VPA and VBV scores that were ultimately used in the statistical analysis.
Data Analysis
The images were subjectively evaluated for pre- and postcontrast image quality and for
visualization of the anatomy of the genital tract by two experienced radiologists. Signal
intensities were measured by selection of ROI's positioned within the vaginal wall, vaginal
mucosa, common femoral vein, muscle, clitoris, and in air outside the subject to provide a
measure of background noise. The size of the ROI varied depending on the size of the
structure being analyzed.
For example, across all subjects the measurements of the
vaginal wall ROI ranged in size between 4 mm2 and 22mm2, while the clitoral body ROI
was between 7 mm2 and 70 mm2. Within each subject, the size of the ROI was kept
consistent at each time point throughout the neutral and erotic segments.
Image volumes
for each time point within a given subject were analyzed in random order to attempt to
reduce bias. However, all volumes with a given subject were analyzed together.
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Changes in Blood Volume
Relative regional blood volume was estimated from signal intensity versus time curves
derived from ROI measurements of the vaginal wall and clitoris using the following
equation:
rRBVstructure = SIstructure(t) - SIstructure (t0)
[Equation 1]
SIfemoral (t) - SIfemoral (t0)
Where rRBV is the relative regional blood volume and SI (t) refers to the signal intensity
measurements from the region of interest taken at the various time points, and t0 refers to
the precontrast scan. The denominator compensates for the slow clearance of MS-325 over
the time of the study. In order to smooth statistical fluctuations in SI measurements of the
femoral vein, the femoral signal intensity data was fit to a bi-exponential clearance, and
then the fit values were used in Equation 1. ROI measurements were taken separately over
the body and glans of the clitoris. From these signal intensity measurements, SI versus
time curves were generated and rRBV measurements over time were calculated using
femoral vein SI's corrected for the bi-exponential decay of MS-325 over time.
To determine whether erotic video material differentially changed estimated rRBV, the
estimated rRBV changes were fit as a function of time to the following three-parameter
model (A, B, and C) to account for these changes:
rRBV(t) = A + B t + C video(t),
[Equation 2]
where (t) is the time, video(t) equals 1 during erotic video and 0 during neutral video
corresponding to the last eleven image data sets acquired. Typically, this represents 18
minutes of neutral video material, followed by 15 minutes of erotic video material and 6
minutes of neutral video material. The "A" coefficient depends on the initial blood volume
and "B" reflects both slow extravasation of the agent over time as well as potential
incomplete return of blood volume to a baseline state after the erotic video. "C" reflects
the video-dependent changes in rRBV.
The presence of a significant influence of the C
term in Equation 2 was tested using the t-statistic in the regression, and the relative change
8
in rRBV associated with the video segments were estimated and tabulated as C/A on a
subject-by-subject basis for clitoral body and glans clitoris measurements.
Changes in Clitoral Volume
The various structures comprising the clitoris, including the crura, body, and glans, were
identified and outlined from each slice containing clitoral tissue. These areas were summed
and the total volume was measured at each time point using a planimetric method, with
volumes reported in cubic centimeters (cc). If there was difficulty defining the precise
boundary between the clitoris and adjacent mucosal or glandular tissue, all of the
enhancing tissues were included. This was often the case in the area of the clitoral body,
but this was not felt to cause a problem with comparative measurements within a given
subject since the same anatomical areas were outlined at each time point. However, this
method may have resulted in a slight over-estimation of the true clitoral volume in some
subjects. Data analysis and graphic presentation was done using a two-tailed t-test with
commercially available spreadsheet and graphing programs.
Design and Procedures
Protocols were carried out at two separate locations at the University of
Washington Medical Center 1) MR imaging at the Imaging Center of the Hospital and 2)
Vaginal photoplethysmography at the Reproductive and Sexual Medicine Clinic of the
outpatient clinics. The same neutral and erotic videos were used at both sites, but were
presented in counterbalanced order. A familiarization visit conducted at each site prior to
the experimental session ensured that women were comfortable with the procedures. The
same FES scale was used at both sites to measure sexual arousal and affect.
VPP. During the VPP experimental sessions, the female participant inserted the vaginal
probe in the privacy of the experimental room. She then watched a 10 minute neutral and
14 minute erotic film segment. The data were collected on a computer located in a
separate room and an intercom allowed for communication between the subject and
experimenter. Subjective data were collected before presentation of neutral video
material but after the subject had inserted the photoplethysmograph, immediately after
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the presentation of the neutral videotaped material, and after the termination of the erotic
segment, but before removal of the photoplethysmograph.
RESULTS
1. From Deliganis et al. 2002
MRI response. There was an increase in both degree of enhancement and overall size of the
clitoris during the erotic video segment as compared to the first neutral segment. However
when ROI measurements of the vaginal wall were analyzed, there was very low contrast
enhancement and no significant trends were observed in the vaginal wall blood volume curves.
Vaginal mucosa was not well visualized as a separate structure and attempts to generate
measurements of this very thin structure proved unfeasible.
rRBV. For the glans clitoris, rRBV changed 40 + 10% (SEM) in the subjects viewing the erotic
video versus -3% + 5% for the control group. In the clitoral body, we found rRBV increased
24% + 8% in the group shown erotic videos versus 3% + 8% for the neutral only control group.
No significant differences were observed for the pre- and post-menopausal groups, although
average rRBV increases were slightly greater in the post-menopausal group in the clitoral body
(pre-menopausal, 9% + 4%, post-menopausal, 39% + 12%).
Clitoral volume. Quantitative changes in clitoral volume over time proved more robust than
rRBV measures. The average clitoral volume increased from 10.74cc at baseline (during the
first neutral segment) to 21.17cc while viewing the erotic material and then decreased to
15.42cc while viewing the second neutral segment. There was no significant difference in
clitoral volume changes between pre-menopausal subjects and post-menopausal subjects.
Clitoral volume measurements compared between the first neutral and erotic segments in the
pre-menopausal group showed an average increase of 107% + 26% (range of 45 - 181%), while
the post-menopausal group averaged 129% + 43% (range of 55 - 280%). No significant change
in clitoral volume was measured in the control subjects that viewed only neutral material.
10
Subjective sexual arousal. A review of the subjective arousal questionnaire showed that all of
the 12 study subjects reported no feelings of sexual arousal on the first two queries
administered prior to viewing the initial neutral and again prior to viewing the erotic videotape
segments (average score = 1.0). After viewing the erotic material, all subjects reported sexual
arousal with an average score for all subjects of 3.87 (range of 2 - 6).
Adverse events. Given the Phase I testing of the MS-325, a review of adverse events was
required and provides additional information on the MRI lab context. Subjects tolerated the
procedure well and there were no serious adverse events reported. A total of 40 adverse events
of mild to moderate severity were noted. Of the adverse events reported, 17 were considered
unlikely related to study drug, while 5 were considered possibly and 18 were considered
probably related to the use of the study drug, MS-325. All of the 23 adverse events considered
possibly or probably related to study drug resolved spontaneously without medical intervention.
A breakdown of those adverse events revealed 14 reports of groin itching, burning, or tingling
in the perineum. There were also 2 reports of nausea, 2 reports of general malaise or fatigue,
and 1 report each of metallic taste, scalp itch, lightheadedness, and a thick, tingling tongue. One
subject demonstrated a transient increase in urine white blood cells.
No other clinically
significant laboratory changes were reported. There were no clinically significant changes seen
in the electrocardiograms, vital signs, or physical examination findings.
2. From Maravilla et al, in press
The purpose of this study was to see if the MRI responses in healthy women could be
replicated across two separate sessions. The two sessions occurred 45 min apart
Subjective sexual arousal. In Session 1, the mean score across all subjects taken after the
sexually-explicit video material was shown was 4.2 (range 2.33 – 5.33); while in Session
2 the same score was 4.3 (range 2.0 – 6.33). Arousal scores were tabulated for each
video to determine if one scored significantly different than the other. Figure 1 shows the
correlation curve of the arousal scores among all subjects between Session 1 and Session
2. The r2-value was 0.52. The average arousal scores were 4.3 (range 2.0 – 5.33) for
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Video A and 4.2 (range 2.0 – 6.33) for Video B.
Thus, there was no significant
difference noted in the arousal response between Session 1 and Session 2, nor was there a
significant difference between the two stimulus videos that were used.
Signal intensity. The average percent change in signal intensity from baseline to arousal
increased approximately 90% in Session 1 and 32% in Session 2, The combined percent
change of both sessions was over 60%, with a range between 13% and 177%. Although
there appears to be a decrease in the percent change in clitoral signal intensity with
arousal in Session 2 versus Session 1, this is likely related to residual engorgement from
the arousal response during the initial imaging session. Due to MR tuning changes
required prior to Session 2, it was felt that baseline signal intensity values could not be
reliably extrapolated from Session 1 to Session 2 in order to normalize signal intensity
measurements for Session 2. For this reason, the SI∆ data was not felt to be as reliable as
the anatomic clitoral volume analysis.
Clitoral volume. Average increase in clitoral volume from baseline to arousal increased
approximately 107% in Session 1 and 110% in Session 2. For all subjects, the combined
percent change of both sessions was over 108%, with a range between 16% and 260%,
There was an increase in baseline volume for Session 2 present in varying degrees in 8
out of 9 subjects and likely represents residual clitoral engorgement following the
sexually-explicit video presentation during Session 1. The remaining subject showed no
change in baseline volume between the two sessions. The best fit line plotting the
percent change in clitoral volumes for all subjects between Session 1 and Session 2 are
shown in Figure xx. There was excellent correlation between the two imaging sessions,
as indicated by the 0.95 r2-value. Analysis of both pre- and postmenopausal subject
groups also showed good correlation for each group with calculated r2-values of 0.94 and
0.98, respectively, in the percent clitoral volume change between Session 1 and Session
2.
3. Heiman et al, submitted
This study compared the use of MRI and VPP in the same women.
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VPP Results. VPA = 61-70% increase during erotic video. VBV = 9-25%)
Subjective sexual arousal. Self-reported arousal to erotic video (7-point scale). Mean
(SD) = 4.1 (1.60) to 4.6 (1.21), depending on the video.
Correlations between subjective and MRI and VPP measures.
Change Change Change Change
During the tape, I felt
VPA
VBV AVW
BVW
(1) SEXUALLY
AROUSED
(2) ANY genital feeling
0.65*
0.47
0.50
0.51
0.73*
0.54
0.45
0.42
(3) GENITAL PULSE
THROB
0.59*
0.47
0.54
0.55
0.10
0.09
0.43
0.34
(4) GENITAL WETNESS/
LUBRICATION
Significant at p<.05
MRI-VPP measurement correlations. There were no significant correlations between
MRI and VPP measures.
DISCUSSION
Data on small sample, thus preliminary
1. MRI reveals important data on clitoral blood volume and anatomical volume. This is
the first time précised images have been available in a less intrusive measurement. Also
the absolute measurement of MRI is an advantage.
2. MRI shows good test-retest reliability.
3. VPP, especially VPA measure, shows good correlations with subjective report.
4. VPP and MRI may be measuring somewhat independent system responses. However,
it is also the case that the MRI method was not scanning the same level of tissue as that
of the VPP recording.
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5. Data on small samples and are thus preliminary and need further replication by other
sites.
More discussion and critique in final draft. Including use of contrast agent
And a number of figures will be included to illustrate findings.
References (very rough, unfinished)
1. Deliganis, A, Maravilla, K, Heiman, J., et al. Dynamic MR imaging of the female
genitalia using MS-325: Initial Experience Evaluating the Female Sexual Response.
Radiology, 2002.
2. Laan E, Everaerd W, Evers A. Assessment of female sexual arousal: Response
specificity and construct validity. Psychophysiology. 1995; 32:476-485.
3. Heiman, J.R. (1998). Psychophysiological models of female sexual response.
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4. Heiman JR & Rowland DL. The effects of instructions on sexually functional and
dysfunctional men. J Psychosom Res. 1983;27:105-116.
5. Heiman JR. A psychophysiological exploration of sexual arousal patterns in females
and males. Psychophysiology. 1977;14:266-274.
6. Maravilla, KR, Cao, Y. Heiman, JR, Garland, PA, Peterson, BT, Carter, WO,
Wieisskoff, RM. Serial MR Imaging with MS-325 for evaluating female sexual
arousal response: Determination of intrasubject reproducibility. Journal of Magnetic
Resonance Imaging, in press.
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