Abstract
Objective: Intravaginal DHEA (dehydroepiandrosterone, prasterone), the exclusive precursor of androgens and estrogens in postmenopausal women, has previously been shown to improve all the domains of sexual function by a strictly local action in the vagina. The well recognized female sexual function index (FSFI) questionnaire was used in the present study.
Design: The long-term effect of 52-week treatment with daily intravaginal 0.50% (6.5 mg) DHEA was evaluated on the various domains of female sexual function using the FSFI questionnaire at baseline, Week 26 and Week 52.
Subjects: One hundred and fifty-four postmenopausal women with at least one mild to severe symptom of vulvovaginal atrophy (VVA) and who have completed the FSFI questionnaire at baseline and at least one post-baseline timepoint were included in the analysis.
Results: The FSFI domains desire, arousal, lubrication, orgasm, satisfaction and pain were increased by 28%, 49%, 115%, 51%, 41% and 108%, respectively (p<0.0001 for all parameters) at 52 weeks vs. baseline, while the total score was increased from 13.4±0.62 at baseline to 21.5±0.82 (+60%, p<0.0001) at 52 weeks.
Conclusion: As the serum levels of DHEA and all its metabolites, including estradiol and testosterone, show no meaningful change, the present clinical data indicate a stimulatory effect of intravaginal DHEA through a strictly local action in agreement with the preclinical data showing that the androgens made locally from DHEA in the vagina induce an increase in local nerve density.
Introduction
The prospective, randomized, placebo-controlled and double-blind study ERC-210 has shown significant positive effects of intravaginal dehydroepiandrosterone (DHEA, prasterone) on the various domains of female sexual dysfunction (FSD) as evaluated by the menopause-specific quality of life (MENQOL) and abbreviated sexual function (ASF) questionnaires [1, 2]. A novel approach for the treatment of FSD then became a possibility, as well supported by the preclinical studies showing a stimulatory effect of testosterone [3] and DHEA through its androgenic component [4, 5] on the density of the vaginal nerve endings.
Such mechanism is in agreement with the new understanding of sex steroid physiology in women where all androgens are exclusively made intracellularly from DHEA by the mechanisms of intracrinology with no release of biologically significant amounts of active sex steroids in the circulation [6–9].
By a strictly local action in the vagina, intravaginal prasterone (DHEA) administered at doses where serum estradiol, testosterone and all derived sex steroids remain well within normal postmenopausal values [10–14] appear to exert relatively potent beneficial effects on sexual function.
It is pertinent to mention that when estrogen secretion by the ovaries stops relatively quickly at time of menopause, women have already been submitted for about 20 years to a progressive decreased exposure to androgens due to the declining rate of DHEA secretion by the adrenals [8]. In fact, at time of menopause, serum DHEA has already decreased by 60% on average, thus resulting in a parallel 60% decrease of the biosynthesis of androgens from DHEA in peripheral tissues [9, 15]. In this context, it is important to mention that normal postmenopausal women produce an amount of androgens equivalent to approximately 50% of the androgens present in men of the same age [9, 15–17]. Consequently, the symptoms secondary to sex steroid deficiency observed at post-menopause are most likely secondary to a lack of DHEA with possible differences in metabolism and sensitivity to androgens between women [8, 16].
Sexual dysfunction in women is a common problem with rates up to 50% as self-reported using questionnaires among women in community studies [18–20]. In the USA, it has been observed that 43% of women have sexual dysfunction of one type or another with 10% expressing distress sufficient to be diagnosed with sexual function disorder. The prevalence of sexual dysfunction increases after ovariectomy and with age [21, 22] with a higher incidence in postmenopausal women [23–29].
Although the women who completed the 52-week safety study (ERC-230) were not recruited on the basis of a required level of sexual dysfunction and the absence of a placebo group, it is of interest to analyse the data obtained following introduction of the FSFI questionnaire when about 150 women could be enrolled and completed the questionnaire at baseline and after 52 weeks of treatment in order to obtain information on sexual dysfunction.
Methods and subjects
Study design
This was a Phase III, open-label study primarily aimed at examining long – term safety of daily intravaginal administration of a 0.50% (6.5 mg) prasterone ovule (suppository) for 12 months (52 weeks) (Study ERC-230, NCT 01256671). The subject population studied was postmenopausal women (non-hysterectomized), between 40 and 75 years of age. A total of 798 women were screened and 530 subjects who met the study entry criteria indicated below were enrolled. Four hundred and thirty-five women have completed the study. The study was conducted at 41 study centers including 31 sites in the US and 10 sites in Canada.
The original and amended protocol versions for study ERC-230 were reviewed and approved by the central IRB “Veritas” on November 10, 2010 and March 16, 2011, respectively, for 31 investigational recruiting sites, and by local IECs/IRBs for 10 investigational recruiting sites, before the start of the study and implementation of the amendment. The FSFI questionnaire was added in the amended version of the protocol which was implemented after about 2/3 of subjects were already enrolled in the study. Therefore, about 1/3 of enrolled subjects have filled the FSFI questionnaire at baseline and post-baseline visits. The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization (ICH) guideline E6: Good Clinical Practice (GCP).
Inclusion criteria
Postmenopausal women (non hysterectomized) were required to satisfy a or b or c:
No menses for at least 1 year for non hysterectomized women, or
Follicle stimulating hormone (FSH) levels >40 IU/L (within 60 days prior to Day 1) in women with no menses >6 months but <12 months, or
Six months (of screening visit) or more following bilateral oophorectomy.
Women between 40 and 75 years of age.
Normal mammogram (American College of Radiology BI-RADS 1 or 2) within 9 months of study enrollment (Day 1).
Normal breast examination.
A normal PAP smear (which includes inflammatory changes) within the last 12 months (of Day 1) (see exclusion criterion 16).
Willing to participate in the study and sign an informed consent.
No former or present narcotic addiction or alcoholism.
Women who have self-identified at least one mild to severe of the following symptoms:
Vaginal dryness (none, mild, moderate or severe),
Vaginal and/or vulvar irritation/itching (none, mild, moderate or severe),
Vaginal pain associated with sexual activity (none, mild, moderate or severe).
Willing to have endometrial biopsy at Screening and end of study.
Exclusion criteria
Undiagnosed abnormal genital bleeding.
Previous diagnosis of cancer, except skin cancer (non melanoma).
Active or history of thromboembolic disease (thromboembolic event following an accident, a surgery or immobilization is acceptable).
Clinically significant metabolic or endocrine disease.
Uncontrolled diabetes mellitus.
Use of estrogen alone injectable drug therapy or progestin implant within 6 months prior to study entry (Screening visit).
Use of estrogen pellet or progestin injectable drug within 6 months prior to study entry (Screening visit).
Oral estrogen, progestin or DHEA exposure or intrauterine progestin therapy in the 8 weeks prior to baseline assessments (Screening visit).
Vaginal hormonal products (rings, creams, gels or tablets) or transdermal estrogen alone or estrogen/progestin products in the 8 weeks prior to baseline assessments (Screening visit).
Subjects could washout as follows, but the questionnaire on vaginal atrophy must be answered and the cell maturation and pH evaluations must be performed after the required washout period:
At least an 8-week washout period for prior oral estrogen, DHEA and/or progestin therapy.
At least an 8-week washout period for prior transdermal estrogen alone or estrogen/progestin products.
At least an 8-week washout period for locally delivered hormone replacement therapy for vaginal dryness (rings, creams, gels or tablets).
Minimum of 8-week for prior intrauterine progestin therapy.
At least 6 months for prior estrogen pellet therapy or progestin injectable drug therapy.
Minimum of 6 months for prior progestin implants and estrogen alone injectable drug therapy.
Cardiac failure or manifest coronary heart disease.
Hypertension equal to or above 140/90 mm Hg.
Confirmed clinically significant depression (not controlled by standard therapy) or confirmed history of severe psychiatric disturbance.
The administration of any investigational drug within 30 days of Screening visit.
Previous treatment with androgens or anabolic steroids within 3 months prior to Screening visit.
Clinically significant abnormal serum biochemistry, urinalysis or hematology.
Baseline cervical cytology showing atypia of squamous cells of undetermined significance (ASC-US) or worse. Since ASC-US can be due to atrophy, a subject with ASC-US without history of abnormal PAP smear within the last 2 years and a negative Human Papillomavirus (HPV) test could be enrolled.
Palpable fibroids, or Grade 2 uterine prolapse (when the cervix reaches labia minora) by gynecologic exam.
Coagulation disorders or on anticoagulant drug therapy.
Endometrial hyperplasia (simple or complex hyperplasia with or without atypia), cancer or endometrial histology showing proliferative, secretory or menstrual type characteristics at histologic evaluation of endometrial biopsy performed at screening.
Subjects who suffer from vulvar lichen sclerosis.
Safety and efficacy parameters
The long-term safety of intravaginal prasterone was evaluated by collecting safety data from adverse events (AEs) , hematology and coagulation, blood chemistry, urinalysis, lipid profile, serum steroids, PAP smear, mammography and endometrial biopsy. Efficacy data related to VVA and sexual dysfunction were collected as secondary objectives. The details on the population studied (demographics), treatment and data processing are reported in Labrie et al. [30] along with efficacy data on the VVA symptoms and signs. Data on serum steroids are reported in Ke et al. [31] while results from endometrial biopsies are available in Portman et al. [32].
Female sexual function index (FSFI)
As indicated above, subjects evaluated under the amended version of the protocol were asked to fill the female sexual function index (FSFI) questionnaire which appears to be the most widely accepted validated measure of sexual dysfunction in women [33–37]. It is a 19-item, multidimensional self-report instrument. The FSFI questionnaire is divided into 6 domains, namely desire (questions 1 and 2), arousal (questions 3, 4, 5 and 6), lubrication (questions 7, 8, 9 and 10), orgasm (questions 11, 12 and 13), satisfaction (questions 14, 15 and 16) and pain (questions 17, 18 and 19) [33]. The six key domains are estimated over 4 weeks. Of a total possible score of 36, 26.55 or less is considered to constitute sexual dysfunction in a population of pre- and postmenopausal women [35].
Statistics
Only subjects in the safety population who have filled the FSFI questionnaire at both baseline and at least one post-baseline time point (Week 26, Week 52 and/or discontinuation) were included in FSFI analyses. For each subject, the score for each domain of the FSFI as well as the full scale score were calculated based on the computational formula outlined in Rosen et al. [33]. Individual domain scores were obtained by adding the scores of the individual items that comprise the domain and multiplying the sum by the domain factor. The full scale score (total score) was obtained by adding the six domain scores. It should be noted that within the individual domains, a domain score of zero indicates that no sexual activity was reported during the past month. If one question (or more) has not been answered by the subject at Day 1, the answer(s) given at Screening was used (if available) for baseline calculation; however, if both Screening and Day 1 answers were missing, the domain score of this subject containing a missing answers(s) as well as the full scale score (total score) of the same subject was not calculated. If there was missing data at one post-baseline timepoint due to the discontinuation of a subject or technical oversight, this subject had the last observation carried forward (LOCF) for analysis. Means and standard error of the means (SEM) were calculated at each timepoint for individual domains and total score. The statistical significance of FSFI domains was determined using a paired t-test for the change from baseline to Week 26 and Week 52.
Results
As mentioned earlier in the introduction, the women were not recruited on the basis of a defined level of sexual dysfunction but on the basis of the requirement for at least one mild to severe symptom of vulvovaginal atrophy, namely dyspareunia, dryness and/or irritation/itching. It was also known that moderate to severe dyspareunia has no influence on the benefits of intravaginal prasterone on sexual dysfunction [2].
Domain desire
From a baseline value of 2.39±0.09 (n=154), the average score of the domain desire increased (p<0.0001) to 3.05±0.10 and 3.06±0.10 at 26 and 52 weeks, respectively, for a +28.0% improvement over baseline at both 26 and 52 weeks (p<0.0001). All subjects completed the questionnaire at baseline and provided at least one post-baseline evaluation. As mentioned earlier, the 26-week value was carried forward when the 52-week evaluation was not completed (Figure 1A).
Effect of intravaginal DHEA (prasterone) on the FSFI domains desire (A) and arousal (B).
Daily intravaginal administration of 0.50% (n=154) dehydroepiandrosterone (DHEA; prasterone) was performed for up to 52 weeks. Data are expressed as means±SEM; the p values are comparison with baseline.
Domain arousal
In the sub population of 154 women who met the above-indicated criteria in relation to the FSFI questionnaire, the mean arousal score measured at 2.22±0.13 at baseline increased to 3.48±0.14 (+56.7%) (p<0.0001) at 26 weeks and 3.32±0.16 (+49.5%) (p<0.0001) at 52 weeks, respectively (Figure 1B).
Domain lubrication
When the mean lubrication score was evaluated, it increased (p<0.0001) from 1.69±0.12 at baseline to 3.83±0.16 (+127%) and 3.63±0.18 (+115%) at 26 and 52 weeks, respectively (Figure 2A).
Effect of intravaginal DHEA (prasterone) on the FSFI domains lubrication (A) and orgasm (B).
Daily intravaginal administration of 0.50% (n=154) dehydroepiandrosterone (DHEA; prasterone) was performed for up to 52 weeks. Data are expressed as means±SEM; the p values are comparison with baseline.
Domain orgasm
The orgasm score, on the other hand, increased (p<0.0001) from 2.33±0.15 at baseline to 3.62±0.17 (+55.4%) and 3.53±0.18 (+51.5%) at 26 and 52 weeks, respectively (Figure 2B).
Domain satisfaction
The satisfaction score increased (p<0.0001) from 2.81±0.12 at baseline to 3.95±0.14 (+40.6%) at both 26 and 52 weeks (Figure 3A).
Effect of intravaginal DHEA (prasterone) on the FSFI domains satisfaction (A; n=148) and pain at sexual activity (B; n=154).
Daily intravaginal administration of 0.50% (n=154) dehydroepiandrosterone (DHEA; prasterone) was performed for up to 52 weeks. Data are expressed as means±SEM; the p values are comparison with baseline. *In satisfaction domain, few women were excluded from the analysis since they have not answered one and/or two questions related to sexual activity with a partner.
Domain pain
The pain score was 1.70±0.15 at baseline and improved over baseline (p<0.0001) to 3.55±0.19 (+109%) at 26 weeks and 3.53±0.20 at 52 weeks (+108%), respectively (Figure 3B).
FSFI total score
For the total score, consistent with Rosen’s paradigm [33], each mean domain score was multiplied by a specific factor, namely 0.6 for desire, 0.3 for arousal and lubrication and 0.4 for orgasm, satisfaction and pain. Following these calculations, the total score of 13.43±0.62 at baseline increased (p<0.0001) to 21.99±0.77 (+63.7%) at 26 weeks and to 21.50±0.82 (+60.1%) at 52 weeks, respectively (Figure 4).
Effect of intravaginal DHEA (prasterone) on the FSFI total score.
Daily intravaginal administration of 0.50% (n=148) dehydroepiandrosterone (DHEA; prasterone) was performed for up to 52 weeks. Data are expressed as means±SEM; the p values are comparison with baseline. Few women were excluded from the total score analysis since they have not answered one and/or two questions in the satisfaction domain.
Discussion
Following the positive effects of intravaginal prasterone observed on the various domains of sexual function assessed by the MENQOL and ASF questionnaires [1, 2], the present data show that the FSFI questionnaire also provides positive results to the same treatment. In fact, highly significant effects of intravaginal DHEA were observed over baseline after 26 and 52 weeks of daily intravaginal administration of 0.50% DHEA (1.3 ml ovule/suppository) on all the six FSFI domains of sexual function, namely desire (+28%), arousal (+49%), lubrication (+115%), orgasm (+51%), satisfaction (+41%) and pain (+108%) as well as on the total FSFI score where a 60% increase was observed from a score of 13.4 at baseline to 21.5 at 52 weeks (p<0.0001). A limitation of the present study is that it does not include a placebo group [38, 39]. Accordingly, while no definitive conclusion can thus be reached, the marked improvements over baseline across all the domains of sexual function are in agreement with the positive data obtained previously from studies including a placebo group [1, 2, 40].
The important clinical health issues facing women at menopause pertain to hot flashes, vulvovaginal atrophy, bone loss, loss of muscle mass and strength, fat accumulation, type 2 diabetes, sexual dysfunction, memory loss, cognition loss and possibly Alzheimer’s disease [41]. It is of particular interest to observe that many of these medical problems have been found to respond positively to androgens and, in most cases, to the administration of DHEA when used at the proper dose and under appropriate experimental conditions [42–45] (see review [41, 46]). Due to the variable sensitivity of each specific parameter to sex steroid deficiency, it appears reasonable to believe that sex steroid deficiency in postmenopausal women can lead to clinically significant symptoms and signs in any the above-mentioned parameters but at various degrees in each woman; in some women, osteoporosis will be the predominant sign with no other clinically significant symptom of sex steroid deficiency while in other women, sexual dysfunction will be more predominant and in others, vulvovaginal atrophy or skin atrophy, or muscle loss will be the predominant symptom or sign of menopause.
While psychological factors are believed to play an important role in the loss of sexual desire/interest and arousal, there is convincing evidence from clinical studies for a beneficial effect of androgens on sexual function in women [44, 47–55]. These observations have resulted in an increased use of testosterone for this indication [56, 57], although some controversy still exists about the efficacy of androgens on sexual dysfunction [58, 59].
There is supporting evidence that low DHEA-S levels negatively correlate with sexual dysfunction in both pre- and postmenopausal women to a greater extent than testosterone levels [60–63]. Low serum DHEA has also been associated with increased sexual dysfunction over the menopausal transition [64].
The validity of the FSFI has been established in a variety of patient populations, including women with hypoactive sexual desire disorder (HSDD) [34, 35]. The FSFI has been translated in many languages and used in more than 200 published studies [65]. The FSFI has previously been shown to have good discriminant validity, test-retest reliability and internal consistency, thus providing a reliable and valid measure of sexual function in women with HSDD [33, 34]. The content validity of the FSFI desire domain has been established in both pre- and postmenopausal women with HSDD [37].
Our baseline total FSFI score of 13.4±0.62 at baseline is low compared to most literature data [35, 66]. There are in fact data suggesting that a “new normal” cut-off point of 20 is more appropriate than the presently suggested 26.55 obtained in 18–74-year-old women (mean age=36.2 years) based upon a bimodal distribution [35]. The cut-off point of 20 is in agreement with the Penn Ovarian Aging cohort (age 40–54 years) [64] and the first Menopause Strategies: Finding Lasting Answers for Symptoms and Health trial (ages 40–62 years) [67]. Chedraui et al. [68] found a mean total score of 20.1±12.4 in 40–59-year-old women.
Some of the studies summarized, however, have a limited size population. In a small group of HSDD postmenopausal women (n=31), the total FSFI score has been measured at 17.2±7.1 [37]. Berra et al. have reported median total FSFI scores of 20.5±9.6 and 26.4±7.7 in menopausal and premenopausal women, respectively [69]. Nappi et al. [70], on the other hand, observed a total FSFI score of 22.8 (n=65) in late perimenopausal/early postmenopausal women. In 135 premenopausal women, the total FSFI score was evaluated at 27.3±5.8 with a decrease to 19.3±7.0 in postmenopausal women [71]. In a recent 8-week randomized controlled trial in non-depressed women aged 40–62 years, the median composite baseline FSFI score was 16.3±11.9 (n=256) [72].
In a study performed in 403 postmenopausal women, the total FSFI score has shown a small increase from 18.6±5.8 at baseline to 19.6±5.9 at 24 weeks (p<0.001) with tibolone treatment while it increased from 18.4±6.1 to 19.4±6.1 at 24 weeks (p<0.001) in women receiving E2/norethisterone acetate (NETA) [73]. In postmenopausal women receiving low dose oral estradiol (0.5 mg), venlafaxine (75 mg) or placebo, the respective increases were not statistically changed at +1.4, +1.1 and –0.3 [72] while the increase at 26 weeks with intravaginal DHEA in the present study is 8.6 from 13.4 to 22.0 (Figure 4). No effect of estrogens on sexual function was found at 12 weeks with low dose oral estrogen [74]. Long-term studies have, however, reported some improvement of sexual function [75], including the Kronos Early Estrogen Prevention Study (KEEPS) [76]. Transdermal but not oral E2 improved desire, arousal and orgasm [77].
In 40 postmenopausal women with FSD aged 45–64 years randomized between 0.625 mg conjugated estrogens plus 1.25 mg of methyltestosterone and placebo, the total FSFI score increased from 17.3±6.2 to 26.5±5.3 in the estrogen+methyltestosterone group while, in the placebo group, it increased from 14.7±4.8 to 16.8±5.3 for an increase of 7.1 units over placebo (+41%) for the estrogen+methyltestosterone group [78].
In the study where postmenopausal women with hypoactive sexual desire disorder (HSDD) received 100 mg/day of flibanserin [79], the total FSFI score went from 15.9±6.6 at baseline to 20.1±7.0 at 24 weeks with a change from 15.9±6.4 at baseline to 18.6±6.8 for placebo, for a 1.5 unit (+55.5%) score improvement over placebo [79]. In the ospemifene study performed in postmenopausal women with vulvovaginal atrophy, 60 mg/day of ospemifene improved the total FSFI score by 6.69 units at 12 weeks compared to 4.14 (+61.5%) for the placebo group (p<0.001) [80].
Of particular relevance to the effect of intravaginal DHEA on sexual dysfunction in women is the observation that treatment with testosterone increases the number and size of the nerve terminals in the rat while estrogens and progesterone have no effect [3, 4]. Treatment with DHEA, on the other hand, through its intravaginal conversion into androgens, has caused an increase in the number and surface area of nerve fibers in the vagina of the rat [4, 5], thus providing a potential explanation for the benefits of treatment with intravaginal DHEA on sexual function in women [1, 2, 40]. Androgens have also been suggested to modulate clitoral and vaginal physiology by influencing the muscular tone of the erectile tissue and vaginal wall while contributing to genital arousal and vaginal lubrication [81].
The morphological changes observed in the vagina after DHEA treatment are due to the local conversion of the precursor steroid DHEA into active sex steroids having androgenic and estrogenic action through intracrine mechanisms specific to each cell type [6, 82, 83]. The changes observed in the rat vagina include epithelial mucification, high compactness of delicate, finely woven lamina propria collagen fibers and moderate muscularis thickness increase. These morphological changes are typical of androgenic effects. In the lamina propria, fine newly synthesized collagen fibers are seen near the epithelium. Labeling of the androgen receptor is increased by about 3-fold in the three vaginal layers (epithelium, lamina propria and muscularis) after DHEA administration [84].
The effects of DHEA on vulvovaginal atrophy symptoms and signs [30, 85–88] as well as on sexual dysfunction [1, 2, 40] by a direct action in the vagina are also well supported by recent data obtained in the macaca fascicularis showing the presence of the intracrine estrogen-forming and androgen-forming enzymes in the different monkey vaginal layers [82, 83]. The above-summarized preclinical data combined with the described effects of androgens in clinical trials in women [44, 47–55] strongly suggest that the action of DHEA on sexual dysfunction is a specific androgenic action secondary to the conversion of DHEA into androgens in the nerve fibers of the vagina.
Conclusion
Increased sensitivity of the vaginal nerve fibers following stimulation by the androgenic activity of DHEA is a reasonable explanation for the beneficial effects observed on sexual dysfunction in women receiving intravaginal DHEA with no systemic exposure [1, 2, 31, 40].
Declaration of Interest: This research was sponsored by EndoCeutics. Lyne Lavoie, Adam Beauregard, Isabelle Côté, Céline Martel and Mario Vaillancourt are employees of EndoCeutics, while Fernand Labrie is chief executive officer. John Balser and Erick Moyneur are consultants. Céline Bouchard, Leonard Derogatis, Ginette Girard, Normand Ayotte, John Gallagher, Leonello Cusan, David Archer and David Portman received financial support from EndoCeutics for that clinical study.
Acknowledgments
We want to thank the participating Members of the VVA Prasterone Group: Aqua, Keith, Boyton Beach, FL, USA; Archer, David F., Norfolk, VA, USA; Ayotte, Normand, Shawinigan, QC, Canada; Bachmann, Gloria, New Brunswick, NJ, USA; Baron, Mira, Cleveland, OH, USA; Bélisle, Serge, Montreal, QC, Canada; Berg, Saul, Pittsburgh, PA, USA; Beyer, Roger, Kalamazoo, MI, USA; Blank, Steven, Sandy Spring, GA, USA; Blouin, François, St-Romuald, QC, Canada; Bouchard, Céline, Quebec City, QC, Canada; Cusan, Leonello, Quebec City, QC, Canada; Derogatis, Leonard, Baltimore, MD, USA; Gallagher, John, Omaha, NE, USA; Gangestad, Angelina, Mayfield Heights, OH, USA; Giguère, Nicole, Drummondville, QC, Canada; Girard, Ginette, Sherbrooke, QC, Canada; Goldberg, Cynthia, Tucson, AZ, USA; Goldstein, Irwin, San Diego, CA, USA; Goldstein, Steven, New York, NY, USA; Hauck, Brian, Calgary, AB, Canada; Kaunitz, Andrew, Jacksonville, FL, USA; Khaled, Abdelmoula, Montreal, QC, Canada; Kirstein, Judith, West Jordan, UT, USA; Koltun, William, San Diego, CA, USA; Levine, Bruce, Moorestown, NJ, USA; Levine, Stephen, Beachwood, OH, USA; Lukes, Andrea S., Durham, NC, USA; Martens, Mark, Neptune, NJ, USA; McClinton, Joe, Montgomery, AL, USA; Pinkerton, Joann, Charlottesville, VA, USA; Portman, David J., Columbus, OH, USA; Rice, James, Renton, WA, USA; Simon, James, Washington, DC, USA; Swanson, Stephen, Lincoln, NE, USA; Turner, Mark, Meridian, ID, USA; Varano, Susann, Milford, CT, USA; Wade, Anthony, Bathurst, NB, Canada; Waldbaum, Arthur S., Denver, CO, USA; Weisz, Alla, West Palm Beach, FL, USA; Wine, Alan, Cleveland, OH, USA; Young, Douglas, Sacramento, CA, USA.
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