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International Journal of Impotence Research (2004) 16, 121–129 & 2004 Nature Publishing Group All rights reserved 0955-9930/04 $25.00 www.nature.com/ijir

Serum androgen levels in healthy premenopausal women with and without sexual dysfunction: Part B: Reduced serum androgen levels in healthy premenopausal women with complaints of sexual dysfunction A Guay1*, J Jacobson1, R Munarriz2, A Traish2 , L Talakoub2, F Quirk3, I Goldstein4, R Spark4 1 Center for Sexual Function, Lahey Clinic, Peabody, USA; 2Institute for Sexual Medicine, Boston University School of Medicine, Boston, Massachusetts, USA; 3Central Research, Pfizer Ltd., Sandwich, UK; and 4Steroid Research Laboratory, Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA

Androgen insufficiency has been associated with decreased libido and arousal in postmenopausal women, but rarely has been evaluated in healthy premenopausal women. In all, 32 healthy premenopausal women were enrolled in this study, 18 with one or more complaints of sexual dysfunction and 14 without. Assays of ovarian and adrenal androgens were measured before and after ACTH stimulation. The women with complaints of sexual dysfunction had significantly lower adrenal androgens than did the control women. There were no differences in the basal ovarian androgens or cortisol levels. After ACTH, both groups stimulated cortisol as well as adrenal and ovarian androgens. In conclusion, premenopausal women with complaints of sexual dysfunction had lower adrenal androgen precursors and testosterone than age-matched control women without such complaints. Further study is required to determine how lower adrenal androgens contribute to female sexual dysfunction. International Journal of Impotence Research (2004) 16, 121–129. doi:10.1038/sj.ijir.3901176 Published online 19 February 2004 Keywords: testosterone; DHEA; adrenal androgens; female sexual dysfunction; female androgen deficiency; premenopause

Introduction The role of sex steroid hormones in regulating reproductive function has been extensively investigated. However, the role of sex steroid hormones in regulating sexual function has been poorly investigated. The paucity of research may have been, until recently, due to the lack of an accepted framework and classification of these disorders. Female sexual dysfunction may be expressed through decreased desire or via peripheral arousal symptoms including reduced lubrication, anorgasmia or painful intercourse. A newer classification recognizes that there are both organic and psychological causes.1 Female sexual dysfunction is more common than previously suspected. This notion is readily

*Correspondence: A Guay, MD, Center For Sexual Function/Endocrinology, Lahey Clinic Northshore, One Essex Center Drive, Peabody, MA 01960, USA. E-mail: [email protected] Received 11 July 2003; revised 12 December 2003; accepted 6 January 2004

apparent when women are interviewed about sexual function in a specialty clinic.2 Laumann et al2 evaluated over 1700 women in a general population and revealed similar findings. Sexual dysfunction was found in 43% of women studied, ranging in age from 18–59 y. Sexual desire disorders were the most common complaints reported. More importantly, the percentage of women with decreased libido varied little between decades (between 27 and 32%). Decreased sexual desire in women has been associated with many psychological causes. In addition, decreased sexual desire has been associated with medical causes, including androgen disorders.4 Serum androgen levels exhibit a normal age-related decline in men and women,5 but it is not clear whether the inevitable age-related androgen decline is an epiphenomenon or a cause of female sexual dysfunction. We have reported a normal agerelated androgen profile in premenopausal women who have been screened for symptoms of sexual deficiency.6 However, the exact level of serum androgens under which symptoms of sexual dysfunction might be considered etiological is not known.

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Because Laumann’s3 data seemed to indicate that a significant number of younger women had sexual dysfunction symptoms, especially decreased sexual desire, we decided to study premenopausal women presenting with symptoms of sexual dysfunction, but with normal menses, and compare them to an age-matched group of women who reported no sexual problems. Specifically, we investigated changes in testosterone levels and related adrenal and ovarian precursors. Target hormone levels were compared among healthy premenopausal women with normal menses and concomitant complaints of sexual dysfunction and age-matched controls with no sexual problems. Our results may shed light on possible pathways of androgen insufficiency in women with sexual dysfunction.

Materials and methods Abbreviated Sexual Function Questionnaire (ASFQ) Because some women may be unaware of what constitutes ‘normal’ sexual functioning, or may seek to provide socially appropriate answers during clinical interview, the ASFQ was used to provide a more objective measure of female sexual dysfunction (FSD).6 The ASFQ is a subset of 15 questions from the original, 34-item SFQ created by Quirk et al.7 The original instrument assesses desire, lubrication, pain/discomfort with intercourse, emotional stress, pleasure, satisfaction, and ability to achieve orgasm. We removed questions concerning fear of pain, perceived emotional intimacy and relationship anxiety from the original questionnaire, thereby shortening the instrument and maintaining focus on physiological sexual response. The AFSQ was first validated in our study of normal ranges of androgens in 60 women without sexual dysfunction.6,7 Factor analysis revealed that questions clustered around four basic constructs or ‘domains’: Desire, Arousal-lubrication, Arousal-sensation and Orgasm. Inter-item correlations ranged from moderate to high (0.47–0.87), consistent with validation of the original FSQ. Reliability analysis also revealed strong internal consistency, with a Cronbach’s alpha coefficient of 0.96. Gutman’s split-half reliability coefficients were 0.89 and 0.98, respectively.

USA), were recruited for study. FSD symptoms noted were diminished libido in all, decreased arousal in 80%, and diminished orgasms in 70%, as determined by clinical interview and responses to the AFSQ. A total of 20 women between the ages of 20 and 49 y, with no complaints of sexual dysfunction, were also recruited and screened for inclusion in the control group. These women responded to flyers placed in our respective medical institutions, and included visitors, paramedical personnel and women undergoing routine health maintenance; none were seeking care for a medical problem. Both study groups were carefully assessed for exclusion criteria, including irregular menstrual cycles, chronic disease (to include diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, arthritis), substance abuse, anxiety, depression, relationship problems, acute or chronic illness and medication use (especially oral contraceptives or cortisone-type drugs). The psychological profiles were carried out by direct screening interviews with qualified medical personnel. Two of the original 20 women with FSD and two of the normal controls were excluded due to improperly processed blood specimens. Among the 18 remaining normal controls, four women claiming to be free of FSD failed the survey questionnaire. Thus, 14 controls and 18 patients with FSD comprised the final sample for study.

Laboratory testing All bloods were drawn when androgens were at their peak (ie in the morning hours)8,9 and during the middle third of the menstrual cycle (between days 8 and 15).10,11 Bloods were centrifuged without delay and frozen at 201C, where they remained until laboratory analysis was performed. Bloods were drawn for AM cortisol and included the following adrenal androgen precursors: pregnenolone, 17-OH pregnenolone, dehydroepiandrosterone-sulfate (DHEA-S); ovarian androgen precursors: progesterone, 17-OH progesterone, androstenedione; the common C19 steroid products: total testosterone (T), analog free testosterone (fT). After the baseline hormones were drawn, 250 mg synthetic (1–24) ACTH was given intramuscularly. Blood was drawn for repeat hormone analysis 1 h after the injection.

Participants Hormone analyses In all, 20 women between the ages of 20 and 49 y, seeking consultation for symptoms of FSD at the Center for Sexual Function, Lahey Clinic (Peabody, MA, USA) and the Institute for Sexual Medicine, Boston University School of Medicine (Boston, MA, International Journal of Impotence Research

Serum samples were coded and maintained frozen at 201C. To avoid intra-assay variability, each hormone was measured in a single continuous hormone assay. Hormone analyses were performed

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using commercially available radioimmunoassay kits. DHEA-S was measured using a kit from by Diagnostic Products Corporation of Los Angeles, CA, USA. Crossreactivity was 100% for DHEA-S and 0.121% with androstenedione, 15% with 9-hydroxyandrostenedione, 0.046% with estrone 3 sulfate, 0.55% with androsterone sulfate, 0.5% with DHEA and negligible for all other steroids tested. The interassay coefficient was 6.3–7.7%. fT was measured using the Coat a Count Kits of Diagnostic Products Corporation (Los Angeles, CA, USA). Crossreactivity was 0.41% for dihydrotestosterone, 0.01% for androstenedione.0.10% for methyl testosterone and o0.01% for all other steroids tested. The interassay coefficient was 8.0–8.5%. Total serum testosterone (T) levels were measured with the Immunochem Serum Testosterone Kit of ICN Biomedicals Inc., Diagnostic Division of Costa Mesa, CA, USA. The crossreactivities of the antiserum used in the T RIA were 7.8% for dihydrotestosterone, 2.0% for 11-oxosterone, 2.20% for 5 alpha androsterone 3 beta, 17 beta diol and less than 0.01% for all other steroids tested. The interassay coefficients were 9.57–10%.

Statistical analysis Diagnostic analyses were first conducted to determine the appropriate statistical tests for use. As subjects were not age-matched to controls 1:1, mean age and cortisol levels (7s.e.m.) were compared, in order to eliminate potentially confounding variables. Individual patient responses were then scored and summed for each of the four ASFQ domains. Descriptive statistics (ie, means and standard errors) were calculated for the two groups of women. Mean survey responses were then compared against criteria for defining normal and abnormal function per domain, based on guidelines provided in the original instrument.7 Independent t-tests (assuming equal variance) were used to assess statistically significant differences in mean domain scores between women with FSD and controls. Descriptive statistics (means and standard errors) were also computed for three adrenal steroid precursors (pregnenolone, 17-OH pregnenolone, and DHEA-S), four ovarian steroid precursors (progesterone, 17-OH progesterone, and androstenedione), and for T and fT, before and after ACTH stimulation. The total change in hormones over the 60-min stimulation period was subsequently calculated. Changes in mean laboratory values within each group before and after intervention were compared via paired t-tests. The total change in means before and after stimulation (depicted as the slope of the linear change over the 60-min interven-

tion) was again compared between groups via independent t-tests (assuming equal variance). 95% confidence intervals were used in conjunction with P-values while making statistical inferences. All P-values reported are two-tailed. Analyses for this study were conducted using SPSS Statistical Software for Windows, Version 10.0 (Chicago, II, USA; 2002).

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Results Questionnaire Responses Figure 1 shows the mean responses ( þ s.e.m.) to each of the four AFSQ domains for the controls and patients. Using criterion from Quirk,7 we determined that a score greater than or equal to 23 was needed to exhibit normal sexual desire. Normal Arousal-sensation was determined by a score of 14 or above. Normal Arousal-Lubrication scores were 8 or higher, while Normal Orgasm scores were greater than or equal to 12. Conversely, Abnormal Desire was defined as a score below 17, while Abnormal Arousal-sensation was below 11, Abnormal Arousallubrication was o6, and Abnormal Orgasm was defined by a score o9. The mean Desire score for the control group was approximately twice as high as that of the FSD patients (28.7 vs 13.1; Po0.001), and was the largest between-group difference in questionnaire scores. Arousal-Lubrication scores also differed greatly (controls: 9.6, FSD patients: 4.7; significant difference where P ¼ 0.008). However, differences in Arousal-Sensation were slightly less pronounced. Normal controls had a mean Arousal-Sensation domain score of 19.9, compared to 13.3 for their FSD counterparts (significant difference where

Figure 1 Significant differences in mean domain scores among 18 women with complaints of sexual dysfunction and 14 control women with no complaints of sexual dysfunction responding to the ASFQ.

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P ¼ 0.04). Finally, women with FSD were just 0.10 above the cutoff for abnormal orgasm, while controls scored well above the threshold for normal orgasmic function (9.1 vs 13.9, respectively; P ¼ 0.05).

Age and hormone levels Table 1 shows descriptive statistics for age, cortisol, and each of the hormone assays according to study group. Groups were not significantly different with respect to age. The mean age for the 18 patients was 37.2 (s.d.75.7; s.e.71.7), compared to 36.7 years (s.d.75.5; s.e.71.5) among the 14 controls. Cortisol was slightly higher among patients (mean: 12.2 mg/dl (s.e.72.1) vs 9.0 mg/dl (s.e.7.93), respectively), but this difference did not achieve statistical significance (P ¼ 0.10). Significantly lower serum androgen levels were noted in all adrenal and C19 steroids within patients. Mean pregnenolone concentration in controls was approximately twice that determined in patients (54.2 vs 25.6 mg/dl; P ¼ 0.04). Between-group differences in 17-OH pregnenolone were also noted, with a mean of 64.2 mg/dl for patients and 96.4 mg/dl for controls (significant where P ¼ 0.04). Similar patterns were observed again with DHEA-S (FSD patients: 101.6 mg/dl; controls: 138.8 mg/dl; P ¼ 0.03) and T assays (50.9 vs 38.0 ng/dl; significant where P ¼ 0.05). Finally, fT was 0.92 pg/ml in the 18 patients, and 1.4 pg/ml in controls (P ¼ 0.04). However, due to both the small size of each cohort and the small lab normal range of this assay, the level of statistical significance must be interpreted with caution.

There were no statistically significant differences between groups in the three ovarian D4 androgen precursor sex steroids. As shown in Table 1, patients had lower mean progesterone scores (2.2 mg/dl) than controls (3.4 mg/dl; P ¼ 0.52). In addition, FSD women had an average 17-OH progesterone level of 1.0 mg/dl, whereas controls had a value of 1.6 mg/ dl (P ¼ 0.07). Androstedione varied even less (FSD women: mean ¼ 1.5 mg/dl; controls: mean ¼ 1.8 mg/ dl; P ¼ 0.07). While the latter two P-values did not achieve statistical significance, they are considered as trends, as they are below 0.10. However, the restricted range of androstedione values obviates the need to interpret P-values with caution.

ACTH stimulation: within-group differences Table 2 shows the statistically significant change in hormones following ACTH stimulation. Cortisol, measured as the baseline adrenal hormone, rose from 12.2 to 32.2 mg/dl within patients, and from 9.0 to 27.8 mg/dl in controls (both changes significant where Po0.001). Ovarian steroids. Ovarian hormones increased similarly in each group following stimulation. This result is most likely attributable to the exclusion of women with irregular menstrual cycles during screening. Among the 18 patients, progesterone rose from 2.2 to 3.4 (not significant where P ¼ 0.46). Controls experienced a similar increase (3.4–4.5; not statistically significant (P ¼ 0.46)). Within-group

Table 1 Comparison of mean hormone levels for 18 patients and 14 controlsa Variables

Age (y) Cortisol (mg/dl) Adrenal Steroids Pregnenolone (mg/dl) 17-OH pregnenolone (mg/dl) DHEA-Sulfate (mg/dl) Ovarian Steroids Progesterone (mg/dl) 17-OH progesterone (mg/dl) Androstenedione (mg/dl) Common C-19 steroids Total testosterone (ng/dl) Free testosterone (pg/ml)

Patients (n ¼ 18)

Controls (n ¼ 14)

Mean (7s.e.)

Mean (7s.e.)

37.2 (1.7) 12.2 (2.1)

36.7 (1.5) 9.0 (0.93)

0.5 (0.48) 3.2 (0.10)

25.6 (5.7) 64.2 (15.6) 101.6 (11.4)

54.2 (10.5) 96.4 (14.9) 138.8 (15.1)

28.6 (0.04)* 32.2 (0.04)* 37.2 (0.03)*

(1.9, 54.7) (22.7, 66.2) (9.3, 71.9)

2.2 (1.2) 1.0 (0.33) 1.5 (0.10)

3.4 (1.7) 1.6 (0.30) 1.8 (0.13)

1.2 (0.52) 0.6 (0.07)t 0.3 (0.07)t

(3.7, 4.6) (.54, 1.3) (0.09, 0.61)

38.0 (4.0) 0.92 (0.13)

50.9 (4.5) 1.4 (0.19)

12.9 (0.05)* 0.48 (0.04)*

Mean Difference P-value

Independent t-tests assuming equal variance was used to assess significant between-group differences. *Statistically significant where Po0.05 (two-tailed test; assumes 80% power, 0.10 Beta). t Denotes trend, approaching but not achieving statistical significance.

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95% CI (LCL, UCL) for between-group difference in means

(6.4, 3.1) (8.5, 2.0)

(0.21, 25.7) (0.28, 1.1)

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Table 2 Comparison of changes in hormone levels before and after ACTH stimulationa Variables

Patients (n ¼ 18) Pre-ACTH

Baseline adrenal Cortisol (mg/dl)

12.1 (2.1)

post-ACTH

2.2 (1.7) 1.0 (.33) 1.5 (.10)

3.4 (2.3) 1.2 (.34) 2.2 (.14)

Adrenal steroids Pregnenolone (mg/dl) 17-OH pregnenolone (mg/dl) DHEA-sulfate (mg/dl)

25.6 (5.7) 64.2 (15.6) 101.6 (11.4)

121.2 (22.4) 697.6 (73.5) 110.6 (15.1)

38.0 (4.0) 0.92 (.13)

48.8 (4.5) 1.5 (.29)

Controls (n ¼ 14) pre-ACTH

32.2 (2.3) o0.001 (9.4, 37.6)**

Ovarian steroids Progesterone (mg/dl) 17-OH progesterone (mg/dl) Androstenedione (mg/dl)

Common C-19 steroids Total testosterone (ng/dl) Free testosterone (pg/ml)

Within-group difference P-value (95% CI)

0.46 (0.37, 4.6) 0.97 (0.33, 2.0) 0.14 (0.02, 0.61)

9.0 (0.93) 3.4 (1.2) 1.6 (0.30) 1.8 (0.13)

0.01 (54.7, 117.7)** 54.2 (10.5) 0.01 (121.1, 647.9)** 96.4 (14.9) 0.01 (6.8, 42.4)** 138.8 (15.1) 0.01 (6.4, 25.7)** 0.01 (0.03, 1.0)**

50.9 (4.5) 1.4 (0.19)

Within-group difference P-value (95% CI)

post-ACTH

27.8 (1.8) 4.5 (2.5) 1.9 (0.39) 2.6 (0.19)

o0.001 (8.6, 23.1)* 0.46 (0.37, 4.8) 0.97 (0.34, 2.6) 0.15 (0.13, 0.84)

236.6 (43.8) o0.001 (25.0, 243.9)* 901.1 (86.6) o0.001 (250.1, 887.0)* 150.8 (15.4) 0.008 (7.2, 12.9)* 61.3 (4.2) 2.0 (0.33)

0.01 (5.6, 23.7)* 0.01 (0.11, 1.0)*

Paired t-tests assuming equal variance was used to assess significant between-group differences. *Statistically significant where Pr0.05. (two-tailed test; assumes 80% power, 0.10 Beta).

changes in 17-OH progesterone were virtually identical. The mean 17-OH progesterone value rose negligibly from 1.0 to 1.2 within patients (P ¼ 0.97), and from 1.6 to 1.9 in controls (P ¼ 0.97). Finally, androstedione did not change significantly, increasing from 1.8 to 2.6 in controls (P ¼ 0.15), and from 1. 5 to 2.2 (P ¼ 0.14) in patients.

in both groups, increasing from 1.4 to 2.0 pg/ml in normal women, and from 0.92 to 1.5 pg/ml in patients (both increases significant where P ¼ 0.01).

ACTH stimulation: between-group differences We were specifically interested in comparing the total change (or delta) in pre-ACTH and post-ACTH lab values between groups. Toward that end, we plotted pre- and post-intervention values and then compared the slope of each line between the two cohorts, as shown in Figures 2–4.

Adrenal steroids. It is noteworthy that changes in adrenal steroids were slightly greater within controls. Controls’ mean pregnenelone scores rose (approximately) four-fold (54.2 to 236.6 mg/dl (Po0.001)), whereas FSD patient scores rose from 25.6 to 121.2 mg/dl (P ¼ 0.01). Mean 17-OH pregnenolone scores also increased significantly (96.4– 901.1 mg/dl (Po0.001)) for controls, with smaller increases observed for the FSD group (64.2– 697.6 mg/dl; P ¼ 0.01). Changes in pre- and postintervention DHEA-S followed similar patterns. The pre- to post-ACTH increase achieved higher statistical significance for controls (pre-ACTH mean: 138.8 mg/dl; post-ACTH mean: 150.8 mg/dl; P ¼ 0.008) than for FSD-afflicted women (pre-ACTH mean: 101.6 mg/dl; post-ACTH mean: 110.6 mg/dl; P ¼ 0.01).

Ovarian steroids after ACTH. Figure 2a–c show the stimulation results for the D4 steroids, progesterone, 17-OH progesterone and androstedione, respectively. No significant differences were observed between groups in the total change in ovarian hormone levels following the intervention. The change in progesterone was the most similar between the patient subgroups (P ¼ 0.80), followed by 17-OH progesterone (P ¼ 0.70) and androstedione (P ¼ 0.57).

Total and FT levels. Finally, small but significant changes in T and fT levels were observed among all women following ACTH stimulation. Controls’ T levels rose from 50.9 to 61.3 ng/dl (significant where P ¼ 0.01), while patient T levels rose from 38.0 to 48.8 ng/dl (P ¼ 0.01). The fT (Figure 4b) rose slightly

Adrenal steroids after ACTH. The change in D5 adrenal hormones was somewhat greater for controls than patients (Figures 3a–b). Pregnenolone levels increased by 182.4 mg/dl for normal women, and by 95.5 mg/dl for FSD women (significant difference where P ¼ 0.04) (Figure 3a). We attribute the strong, International Journal of Impotence Research

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Figure 3 ACTH stimulation of the adrenal D 5 sex steroids: (a) pregnenolone; (b) 17-OH pregnenolone; (c) DHEA-S in 18 women with complaints of sexual dysfunction and 14 control women with no complaints of sexual dysfunction. Figure 2 ACTH stimulation of the ovarian D 4 sex steroids: (a) progesterone; (b) 17-OH progesterone; (c) androstenedione in 18 women with complaints of sexual dysfunction and 14 control women with no complaints of sexual dysfunction.

significant difference to the fact that pregnenolone levels were twice as high for controls compared to patients before stimulation. Significant differences in the change of 17-OH pregnenolone were also noted (Figure 3b), with mean levels rising 804.7 mg/ dl for controls and 633.4 mg/dl for FSD women (P ¼ 0.04). In contrast, changes in pre- and postACTH DHEA-S values did not exhibit significant between-group differences (P ¼ 0.57). Despite differences in the adrenal androgens, there were no differences in cortisol secretion between patients and controls, either in the baseline or poststimulation state (see Tables 1 and 2). Finally, when slopes for pre- and post-stimulation cortisol were comInternational Journal of Impotence Research

pared, no statistically significant differences could be discerned (P ¼ 0.93). Total and FT after ACTH. Figure 4a–b shows the change in T and fT, respectively. Slopes depicting changes in C-19 steroid levels during ACTH stimulation were not significantly different (T P-value: 0.46; fT P-value: 0.43). The results (or the lack thereof) confirm earlier findings suggesting there is no change in sex hormone binding globulin (SHBG) in the years prior to menopause.6

Discussion In this study, we found that serum testosterone and adrenal androgen precursor levels were lower in

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Figure 4 ACTH stimulation of the common androgen products: (a) Tl; (b) ft in 18 women with complaints of sexual dysfunction and 14 control women with no complaints of sexual dysfunction.

healthy women with sexual dysfunction than in agematched women without complaints of sexual dysfunction. No differences were noted in the ovarian androgen precursors between groups. This is not surprising since women in both groups had regular menstrual cycles and did not use oral contraception or other hormones. Mushayandebvu et al,12 however, found that women in the late reproductive years (ages 43–47 y), have decreased midcycle production of androgens despite regular menstrual cycles. This difference is not reflected in our study because we studied women from the ages of 20–49 y, and the steroid levels of the older women were diluted by those of the younger women. This may be why there was a trend towards significance. Women with sexual complaints in this study were similar to the control group in that they were healthy, premenopausal and had no other medical symptoms or conditions (ie diabetes mellitus, hypertension, asthma, arthritis or tobacco abuse) except sexual dysfunction. Confounding clinical factors were ruled out by extensive interview and by examination processes, and the two groups were clearly demarcated by the results of the AFSQ questionnaire. It is noteworthy that domain scores for the control group did not differ significantly

from those previously reported in a population of 60 normal women.6 The decreased level of adrenal androgen precursors (ie pregnenolone, 17-OH pregnenolone and DHEA-S) in women complaining of sexual dysfunction suggests a defect in the steroid biosynthetic pathway at a step immediately after cleavage from cholesterol. A number of reports have indicated that several adrenal androgen precursors, (pregnenolone as well as DHEA-S) decrease with age in men and women.5– 6,13–17 The curves are very similar among the various authors, including our own data.6 This is not surprising as the assays for DHEA-S are quite reproducible and not controversial. DHEA-S is also not subject to change with the various phases of the menstrual cycle, nor is it bound to SHBG. The fact that pregnenolone, as well as DHEA-S, decrease with age suggests a decline of all adrenal steroids with age. Evidence for the activation of the D5 adrenal androgen axis is apparent clinically at adrenarche and may commence biochemical activity at a much earlier age.18 Production is higher in utero, and decreases toward term, but still maintains measurable levels by delivery.19 We speculate that premature inactivation of the enzymes involved in androgen biosynthesis in some women may lead to adrenal-dependent androgen insufficiency. In contrast to the well-defined mechanism by which ACTH regulates adrenal glucocorticoid biosynthesis, regulation of adrenal androgen biosynthesis remains controversial and poorly understood. ACTH has been suggested to play a pivotal role in regulating adrenal androgen biosynthesis. However, while cortisol biosynthesis which is dependent on ACTH remains stable throughout life, DHEA-S levels decrease with age. The decrease suggests that other biochemical factors are involved in regulating androgen biosynthesis in the adrenal. It should be noted that our patient group, although exhibiting decreased serum adrenal androgen levels, had, as did the control group, normal baseline and stimulated cortisol levels. A point of evidence that ACTH may be important physiologically in the control of adrenal androgens is the study by Arvat,20 in which small doses of ACTH were administered to young men and women (0.01–250 mg). After comparing the effect of stimulating cortisol, aldosterone and DHEA, they found that DHEA seemed the most sensitive to corticotropin stimulation. The doses of 0.01 and 1.0 mg ACTH were the minimal and maximal effective doses, respectively, for DHEA. The DHEA response was not modified by pretreatment with 0.01, 0.03, 0.06, and 0.125 mg ACTH doses, but was progressively reduced by pretreatment with 0.5, 1.0, and 25 mg ACTH doses. The dose of ACTH (250 mg) given to our patient population and to our control group was indeed supraphysiological, and smaller doses will have to be attempted

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to see if there might be a differential response in the two groups. We also found that a positive response to ACTH was observed in both groups studied. Although the patient group had decreased baseline serum levels of adrenal androgens, these levels increased with stimulation. The adrenal cells had the capacity to respond, albeit with a supraphysiological challenge. This allows us to speculate as to whether a regulatory enzyme(s) in the steroid synthetic chain might be defective. Our study demonstrates that healthy premenopausal women reporting sexual symptoms have reduced adrenal androgen profiles. Recently, Goldstat et al21 showed in a randomized, placebocontrolled crossover study that premenopausal women with a sexual complaint of decreased libido responded positively to treatment with a testosterone cream. The mean age of the women in this study was 39.7 y, similar to the mean age of our women at 37.2 y. Furthermore, depression was ruled out in the same patient population. Our study offers a possible etiological mechanism for some women but more studies are needed to elucidate this further. Our populations seem to be similar and would confirm the high prevalence of sexual dysfunction symptoms seen in women reported by Laumann.3 Recently, Bancroft et al22 suggested that the prevalence was lower at 24% vs the 43% reported by Laumann et al,3 but the population of women studied by Bancroft was so selective that it has been stated that Laumann’s data would seem to be verified.23 Our study is not without statistical limitations. Because of the small sample size, we did not have sufficient statistical power to perform multivariable analyses. Multivariable analyses would have allowed us to compare the direct and indirect effects of several clinical and demographic covariates, and to explore possible first-order interactions. However, the t-test does provide a robust comparison of mean values for small samples (410 per group) when there is heteroscedasticity of errors, equal group variances and an unknown standard error in the population.24,25 Critical statistical assumptions were thoroughly examined and found intact during diagnostic analyses. Moreover, subjects were selected using multiple, explicit criteria, in order to eliminate confounding variables. We were also concerned that imbalanced group sizes might compromise significance testing. Therefore, we repeated mean comparisons using the Mann–Whitney U and Wilcoxon tests (nonparametric equivalents of the independent and paired t-tests, respectively). These tests make no assumptions about the underlying data distribution and compare ranks rather than raw values. However, nonparametric tests did not yield different significant levels than those reported with t-testing. Results presented herein are therefore deemed reliable, preliminary data. Nevertheless, replication

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of results in a larger, more representative study population is required to confirm our conclusions. We would suggest replication in a double-blind, randomized placebo control study with 1:1 matching of subjects on as many clinical covariates as possible. Our results demonstrate that serum testosterone and adrenal androgen precursors are significantly lower in healthy, premenopausal women with sexual complaints when compared with controls who had no complaints of sexual dysfunction. Moreover, the mechanism of the possible defect needs to be elucidated.

Acknowledgements This research was supported by a private donation from the Ellithorpe family.

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Reduced serum androgen levels - Nature

International Journal of Impotence Research (2004) 16, 121–129 & 2004 Nature Publishing Group All rights reserved 0955-9930/04 $25.00 www.nature.com/i...

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