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Original Studies |
Departments of Endocrinology (H.F.E.-M., J.S.) and Biochemistry (S.A.), Hospital Ramón y Cajal, 28034 Madrid, Spain
Address correspondence and requests for reprints to: Héctor F. Escobar-Morreale, M.D., Ph.D., Department of Endocrinology, Hospital Ramón y Cajal, Carretera de Colmenar km. 9,100, 28034 Madrid, Spain. E-mail: hector.escobar{at}uam.es
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Abstract |
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Sixteen hirsute patients were included in the study. Clinical and biochemical variables, including serum PSA (using an ultrasensitive chemiluminescent immunoassay), total testosterone, sex hormone-binding globulin, androstenedione, dehydroepiandrosterone-sulfate, estradiol, and gonadotropin concentrations were recorded at baseline and after 3 and 6 cycles of treatment with a monophasic contraceptive pill containing ethynylestradiol and desogestrel. Twenty-seven healthy women served as controls for serum PSA level and for the serum androgen profile.
Serum PSA levels were higher in hirsute patients, as compared with healthy women (mean ± SEM: 0.014 ± 0.003 vs. 0.006 ± 0.001 µg/L, P < 0.02). Despite a marked decrease in serum androgens (total testosterone and androstenedione, calculated free testosterone and free androgen index; and dehydroepiandrosterone-sulfate) and in the hirsutism score, and a marked increase in sex hormone-binding globulin levels, serum PSA levels did not change and remained detectable in all the hirsute patients after 3 and 6 cycles of treatment with contraceptive pills.
In conclusion, the increased serum PSA levels present in hirsute patients do not change during treatment with contraceptive pills and do not parallel the amelioration in hirsutism and the decrease in serum androgen concentrations that occur during this treatment. Thus, serum PSA measurements have no apparent role in the management of hirsute patients on oral contraceptive treatment, at least with the ultrasensitive assays currently available.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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PSA has been detected in female serum using ultrasensitive assays (3) and has been proposed as a marker of androgen excess in hirsute women (4). We have recently shown that short-term ovarian stimulation and suppression induced by the administration of the long-acting GnRH analog triptorelin, and adrenal stimulation with 1–24 ACTH have no apparent affect on the increased serum PSA levels found in hirsute patients, despite marked changes on serum androgen concentrations (5). These findings suggest that tissues other than the adrenal and the ovary were the sources of these increased serum PSA concentrations and that the increase in PSA levels results from a chronic and prolonged exposure to androgen excess (5), as occurs with other biological end-points of androgen excess, such as hirsutism.
Therefore, as a marker of androgen excess, serum PSA measurements have a potential usefulness in monitoring the treatment of hirsutism. Recently, Negri et al. (6) have shown that the increased serum PSA concentrations found in hirsute patients decrease during treatment with antiandrogen drugs, finally reaching levels comparable with those of normal women.
For years, oral contraceptive pills have been the first-line drugs for the treatment of hirsutism, especially when menstrual disturbances are also present (7). The main mechanisms of action of oral contraceptives are a decrease in LH and an increase in sex hormone-binding globulin (SHBG), thereby decreasing both total and free androgen serum concentrations (7). Inhibition of binding of androgens to the androgen receptor and inhibition of the conversion of testosterone into dihydrotestosterone are only secondary mechanisms in the beneficial effects of oral contraceptives in hyperandrogenic women (7).
Serum PSA levels may also fulfill a role as a marker of androgen action at the tissue level during treatment of hirsutism with oral contraceptive pills. For that reason, in the present study, we have measured its serum levels in a group of hirsute patients before and after 3 and 6 cycles of treatment with a monophasic contraceptive pill containing ethynylestradiol and desogestrel.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen hirsute patients [mean ± SEM: age, 23.0 ± 1.2 yr; body mass index (BMI), 26.3 ± 2.2 kg/m2] were included in the study. Hirsutism, defined by the presence of excessive body hair in an androgen-dependent pattern, was evaluated using a modification of the Ferriman-Gallwey score (8), quantitating the presence of terminal hairs over nine body areas (i.e. upper lip, chin, chest, upper and lower abdomen, upper and lower back, and upper arms and thighs). All the patients had a hirsutism score of 8 or more (range, 9–22; mean ± SEM, 14.8 ± 1.0). Nonclassic congenital adrenal hyperplasia was ruled out by appropriate testing. None of the patients had evidence of Cushing’s syndrome, acromegaly, hyperprolactinemia, or thyroid disorders. Menstrual cycle intervals were evaluated by recall for every patient. Oligomenorrhea, defined by the presence of 6 or more cycles of more than 35 days in the previous year, was present in 5 hirsute patients, who therefore fulfilled the endocrine criteria for the diagnosis of polycystic ovary syndrome (9).
Twenty-seven BMI-matched, healthy, regular-cycling women (mean ± SEM: age, 30.2 ± 1.7 yr; BMI, 28.3 ± 1.5 kg/m2) who did not have signs or symptoms of hyperandrogenic disorders served as controls for serum PSA concentration and serum androgen profile.
Patients and controls had not taken hormonal medications, including oral contraceptive pills, for the last 6 months. The study was approved by the hospital ethics committee, and informed consent was obtained from every patient and control.
Experimental design
Women were studied during the follicular phase, between days
5–10 of the menstrual cycle. Anthropometric measurements, including
height and weight, and the hirsutism score were determined. An
indwelling iv line was placed in a forearm vein; and, after 15–30 min,
basal blood samples were obtained for the determination of the
concentrations of serum PSA, total testosterone (T), SHBG,
4-androstenedione (A), progesterone (P),
17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone-sulfate
(DHEAS), LH, FSH, and estradiol (E2). Immediately
after, a single 250-µg iv bolus of 1–24 ACTH (Synacthen;
Ciba-Geigy Limited, Basle, Switzerland) was administered,
and samples were obtained, after 60 min, for measurement of 17-OHP and
11-deoxycortisol (S). These measurements served to rule out nonclassic
congenital adrenal hyperplasia secondary to 21-hydroxylase or
11ß-hydroxylase deficiency, because none of the patients presented
17-OHP levels more than 30 nmol/L (10) or S values above the upper 95th
percentile of the control group (22 nmol/L).
In patients, the BMI, hirsutism score, and serum PSA and hormone levels were evaluated again after 3 and 6 cycles of treatment with a monophasic oral contraceptive pill containing 30 µg ethynylestradiol and 150 µg desogestrel (Microdiol; Organon Española S.A., Barcelona, Spain). To avoid a direct acute pharmacologic effect of the medication on serum PSA levels, and to adequately compare its evolution with baseline measurements, serum samples were obtained during the 7-day pill-free interval after the 3rd and 6th cycles of treatment. The hirsutism score was evaluated in all the controls and, in the patients at the three visits, by a single investigator (H. F. Escobar-Morreale).
Assays
Serum PSA concentrations were analyzed by an ultrasensitive chemiluminescent enzyme immunoassay (Immulite Third Generation PSA; Diagnostic Products Corp., Los Angeles, CA). The lower limit of detection, as calculated in our laboratory from replicates of the zero PSA calibrator, is 0.002 µg/L. The same value for the lower limit of detection has been reported by other authors for this assay (11). All the samples were analyzed within a single assay to avoid interassay variations. The intraassay coefficients of variation for 0.0035-, 0.012-, and 0.025-µg/L samples were determined in our laboratory and were found to be 15.2%, 11.6%, and 13.0%, respectively (5). T, SHBG, A, P, S, LH, FSH, and E2 were assayed as previously reported (12, 13). The free testosterone concentration (FT) was calculated from T and SHBG concentrations, assuming a serum albumin concentration of 43 g/L and taking a value of 1 x 109 L/mol for the association constant of SHBG for T and a value of 3.6 x 104 L/mol for that of albumin for T (14). The free androgen index (FAI) was calculated using the formula: T (nmol/L) x 100 ÷ SHBG (nmol/L). Serum DHEAS levels were measured by chemiluminescent enzyme immunoassay (Immulite DHEAS assay; Diagnostic Products Corp.), with mean intra- and interassay coefficients of variation of 6.9% and 10.6%, respectively. Serum 17-OHP was measured by direct RIA using a commercially available kit (ImmuChem; ICN Biomedicals, Inc., Costa Mesa, CA), with mean intra- and interassay coefficients of variation of 9.5% and 11.8%.
Statistical analysis
Results are expressed as mean ± SEM in text,
Table 1
, and Fig. 1. The Kolmogorov-Smirnov statistic, with
a Lilliefors significance level for testing normality, was applied to
continuous variables. Logarithmic transformation was used to ensure a
normal distribution as needed. Repeated-measures multivariate ANOVA was
then used to evaluate the changes in the patients’ hormonal and
clinical variables during treatment, as compared with baseline. Paired
t tests were used to identify these differences only when
the result of the repeated multivariate ANOVA was significant. The
differences among patients and controls were evaluated by the unpaired
t test. P < 0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Patients also presented with increased T, FT, FAI, A and
DHEAS levels, and decreased SHBG concentrations, as compared with
controls (Table 1).
The changes in the clinical and hormonal variables of the group of
patients, during treatment with oral contraceptive pills, are shown in
Fig. 1. The hirsutism score decreased after 3 cycles of contraceptive
pills, with respect to baseline values, and a further decrease was
observed after 6 cycles. No changes were observed in the BMI.
The decrease in the hirsutism score was associated with statistically
significant reductions in T, FT, FAI, DHEAS, and A levels, reaching
values that were not different, or were even lower, than those of the
control group (Table 1). A marked increase in SHBG concentrations was
also observed. All these changes were present after 3 cycles of
treatment, and no further changes in these variables were observed
after 6 cycles of contraceptive pills. Despite the marked decrease
observed in serum androgens, no changes were observed in serum PSA
levels during treatment with oral contraceptive pills, compared with
baseline.
Serum 17-OHP decreased only after 3 cycles of medication, and LH decreased after 3 and 6 cycles of treatment. No statistically significant changes were observed in serum P, E2, and FSH concentrations during oral contraceptive therapy.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum PSA levels showed no significant change during acute adrenal stimulation and short-term gonadal axis stimulation and suppression, despite marked changes in serum androgen and estrogen levels (5).
We then hypothesized that PSA production, as occurs with other biological end-points of androgen action in women, such as hirsutism, may require a chronic and prolonged effect of androgen excess, suggesting that serum PSA levels might serve as a clinically useful marker of androgen excess in the management and treatment of hirsutism.
Especially attractive was the possibility that serum PSA levels could reflect an effect of androgen excess at the tissue level, independently of serum androgen concentrations. Therefore, serum PSA measurement might be the ideal marker for patients with nonhyperandrogenic hirsutism or for monitoring treatment with drugs that block the androgen receptor, such as flutamide.
In conceptual agreement with the above possibility, Negri et al. (6) have recently demonstrated a decrease in serum PSA concentrations during treatment of hirsutism with antiandrogen drugs. Forty hirsute patients were treated with spironolactone, flutamide, or finasteride for 6 months, without the concomitant use of oral contraceptives. In addition to a decrease in hirsutism score and hair shaft diameter, the elevated serum PSA levels decreased, reaching concentrations that were no longer different from those of healthy women. This normalization of serum PSA concentrations occurred despite a lack of change in free testosterone concentrations.
In contrast, our present results show that serum PSA levels have no usefulness in the monitoring of the treatment of hirsutism with contraceptive pills. Serum PSA levels were elevated in hirsute patients at diagnosis, as previously described (4, 5, 6), but showed no decrease despite the marked reduction in serum androgen levels (reaching values of FT and FAI that were lower than those of healthy controls) and despite the considerable reduction in the hirsutism score, found after 3 and 6 cycles of treatment with oral contraceptive pills. Therefore, serum PSA measurement does not provide any information of androgen concentrations in serum, or at the pilosebaceous unit, given that no parallelism was found with the decrease in the hirsutism score.
Several factors might have influenced our results, explaining the
differences with the findings of Negri et al. (6). The
mechanism of action of the drugs employed in both studies is completely
different. As stated above, oral contraceptive pills are effective for
the treatment of hirsutism through a reduction in circulating
androgens. On the contrary, spironolactone and flutamide inhibit the
binding of testosterone to the androgen receptor, and
finasteride inhibits 5
–reductase, preventing the
conversion of testosterone into the more active
dihydrotestosterone.
The lack of decrease in serum PSA levels during oral contraceptive
treatment, in our series, suggests that, although serum androgens
levels and hirsutism scores were significantly reduced, circulating
androgen levels, even in normal or subnormal concentrations, are still
sufficient to maintain PSA secretion. Increased 5-reductase activity
in the skin (16) and increased 5-reductase activity and messenger
RNA expression in the ovary (17) have been found in hyperandrogenic
patients, favoring the conversion of testosterone into its much more
potent metabolite dihydrotestosterone. This increased 5-reductase
activity may maintain increased dihydrotestosterone concentrations in
some tissues, even in the absence of serum androgen excess (17).
On the contrary, antiandrogen drugs are probably more effective than oral contraceptives in blocking androgen action at the tissue level. Thus, the higher potency of antiandrogens may explain the decrease in serum PSA levels found during treatment with these drugs (6).
Another possibility is that oral contraceptive pills have both estrogen and progestin components, and the latter may stimulate PSA production, as has been demonstrated with norethindrone-containing contraceptive pills (18). However, this stimulatory effect may be derived from the androgenic effect of norethindrone (19). We have tried to avoid this stimulatory effect by choosing a progestin with low-androgenicity, such as desogestrel (19), and by measuring serum PSA levels during the 7-day pill-free interval between contraceptive pills cycles. Moreover, the reduction in the hirsutism score (associated with a reduction in serum androgens), and a marked increase in SHBG concentrations, suggests that the androgenicity of the progestin employed here was not the reason for the lack of reduction in serum PSA levels.
Finally, the ultrasensitive PSA assay used here may not be sensitive enough to detect small changes in serum PSA levels. As stated above, the lower limit of detection of our assay is 0.002 µg/L, and the concentrations found at baseline in our hirsute patients ranged from 0.002–0.049 µg/L, with a mean value of 0.014 µg/L. At present, there is evidence supporting the premise that the clinically useful decision threshold is 0.010 µg/L (11). Thus, the assays available at present may not be sensitive enough to detect small changes in serum PSA levels, such as the changes that might occur during treatment of hirsutism with oral contraceptive pills. It should be stated that the decrease in serum PSA levels found by Negri et al. (6), during antiandrogen drug treatment, was more pronounced in the patients with the highest baseline serum PSA concentrations. Close inspection of their data reveal no consistent pattern of change during treatment with antiandrogen drugs when baseline serum PSA values were below 0.010 µg/L (6), possibly reflecting the limitations of the PSA assay for these extremely low concentrations. In the near future, measurement of urinary PSA levels, which apparently result from androgen stimulation of the paraurethral glands, might result in better discrimination of the low concentrations present in women (20).
In conclusion, changes in serum PSA levels were not detected during treatment of hirsutism with oral contraceptive pills despite significant reductions in hirsutism scores and serum androgen concentrations. Therefore, with the assays available at present, serum PSA measurements are not useful for monitoring the treatment with oral contraceptives in hirsute women.
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Acknowledgments |
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Footnotes |
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Received November 17, 1999.
Revised February 25, 2000.
Accepted March 1, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, P <
0.05, or less, as compared with the visit after 3 cycles of treatment
with contraceptive pills.