Efficacy of the combination ethinyl oestradiol and cyproterone acetate on endocrine, clinical and ultrasonographic profile in polycystic ovarian syndrome

Leopoldo Falsetti, Alessandro Gambera1 and Giancarlo Tisi

Department of Gynaecological Endocrinology, University of Brescia, Brescia 25128, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study shows the effect of a long-term treatment (60 cycles) with the ethinyl oestradiol/cyproterone acetate pill, and the follow-up after 6 months from cessation, in polycystic ovarian syndrome. The 140 studied women had polycystic ovaries and moderate or severe acne, 108 also presented hirsutism. The endocrine profile significantly modified after six cycles (P < 0.001), with a further significant decrease of gonadotrophins, oestrogens and androgens after 12 cycles, and a greater increase of sex hormone-binding globulins and insulin-like growth factor-binding globulins. Between the 12th and 60th cycle there was only a significant reduction of dehydroepiandrosterone sulphate (P < 0.05). Acne disappeared in all patients within 12–24 cycles, but hirsutism was still present in 30.6% after 60 cycles. Mild-moderate hirsutism disappeared in 36–60 cycles, whereas severe hirsutism substantially decreased, but persisted. Ovarian volume, microcyst numbers and stroma percentage significantly decreased (P < 0.01). After 6 months from the end of the therapy, endocrine parameters were identical to the starting ones, acne and hirsutism reappeared, whereas ovarian morphology was between the initial and final condition. Ovaries were polycystic in 42 (30%) patients and multifolliculars in 98 (70%). Our results show the effectiveness of this combination on androgenic symptoms, especially on acne, and suggest that acne and hirsutism are induced by different peripheral mechanisms.

Key words: acne/cyproterone acetate/ethinyl oestradiol/hirsutism/ultrasonography


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polycystic ovarian syndrome (PCOS) is an heterogeneous disorder characterized by abnormal gonadotrophin secretion, chronic anovulation, hyperandrogenism and a variety of metabolic effects such as obesity (30–60%) and insulin resistance present in 30–46% of lean and in 57–78% of obese women (Falsetti and Eleftheriou, 1996Go; Prevelic, 1997Go; Acien et al., 1999Go). The alteration of the system insulin/insulin-like growth factor-I (IGF-I)/insulin-like growth factor-binding proteins (IGFBPs), in synergy with LH, promotes the mitotic activity and hyperplasia of the ovary theca/stromal compartment in PCOS and increases androgen production (Duleba et al., 1998Go).

In PCOS, hyperandrogenism is clinically silent in ~30% of European women and 80–90% of Oriental women (Aono et al., 1977Go), or induces hirsutism in 60–83% of the cases and acne in 11–43% of the cases (Goldzieher and Green, 1962Go; Conway et al., 1989Go; Lobo, 1991Go). Clinical expression depends on the events which occur in the pilosebaceous unit, where individual sensitivity to androgens is different (McKenna, 1993Go). Dehydroepiandrosterone (DHEA), androstenedione and testosterone, penetrating the cells of the peripheral sensitive tissues, are converted to the more potent dihydrotestosterone (DHT) by 5{alpha}-reductase (5{alpha}-R). Testosterone and DHT can bind to androgen receptors, but the receptor affinity for DHT is ~10-times that of testosterone (McKenna, 1993Go). DHT is metabolized into 3ß- and 3{alpha}-androstanediol and their glucuronide conjugates (3ß-, 3{alpha}-diolG). Hirsute women with or without hyperandrogenism exhibit a consistently increased 3{alpha}-diolG indicating a 5{alpha}-R hyperactivity and preferential use of the DHT/3{alpha}-diolG route in the hair follicle (Matteri et al., 1989Go; Speroff and Glass, 1994Go). In fact, numerous studies have documented that in hirsute women the 5{alpha}-R activity in the skin was steadily elevated (Paulson et al., 1986Go). In hyperandrogenic patients with acne alone, 3{alpha}-diolG is not as high as in hirsutism (Toscano et al., 1993Go).

Two isoforms of 5{alpha}-R have been identified, called type 1 and 2 (5{alpha}-R1 and 5{alpha}-R2). Studies using specific inhibitors of 5{alpha}-R1 and 5{alpha}-R2 have shown that 5{alpha}-R2 enzymatic activity is predominant in the urogenital sinus, in genital skin, in the adult scalp and in the hair follicles, whereas 5{alpha}-R1 is predominant in the central nervous system, in sebaceous glands, in pubic skin and in the non-sex skin of normal women and hirsute patients (Harris et al., 1992Go; Mestayer et al., 1996Go; Paus and Cotsarelis, 1999Go). However, the distribution and role of the two isoforms are not clear.

Hair follicles and sebaceous glands may use different androgens and metabolic paths or different types of 5{alpha}-R (type 1 or 2) resulting in higher DHT production in hair follicles compared with sebaceous glands (Carmina et al., 1991Go; McKenna, 1993Go; Toscano et al., 1993Go). The bioactive androgens in sebaceous glands would be testosterone or androstenedione and its metabolites which appear to be more effective than testosterone in stimulating sebaceous cell mitosis and sebum production (Ebling et al., 1973Go).

Oral contraceptives have been used to treat androgenic symptoms because of their ability to suppress the secretion of gonadotrophins, ovarian or adrenal androgens, and to stimulate the hepatic synthesis of sex hormone-binding globulins (SHBG) resulting in decreased free testosterone fraction. By increasing the insulin-like growth factor binding protein-1 (IGFBP-l), oral contraceptives decrease the active proportion of IGF-I and thus the stimulus to 5{alpha}-R and hair growth (Suikkari et al., 1991Go).

Cyproterone acetate (CPA) is a synthetic progestogen derived from 17{alpha}-hydroxyprogesterone with antigonadotrophic and antiandrogenic peripheral activity. It inhibits testosterone and DHT action by binding competitively to intracellular receptors and decreases ovarian androgen secretions by inhibiting LH release. Furthermore, this drug decreases 5{alpha}-R activity (Mowszowitcz et al., 1986Go) and increases metabolic testosterone clearance (Marcondes et al., 1990Go).

The aim of this study was to investigate the endocrine, clinical and ultrasonographic modifications induced by a long-term use of the monophasic combination EE/CPA and to quantify the restoration of the starting profiles after 6 months from the end of the treatment, in women with PCOS.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 140 premenopausal women with PCOS and acne, with or without hirsutism, who had been referred to the Department of Gynaecological Endocrinology of the University of Brescia, was selected for the study, after written informed consent had been given. The women, with an average age of 24.1 ± 4.9 years and mean body mass index (BMI) of 23.9 ± 3.1 kg/m2, were treated for 60 consecutive cycles with a monophasic combination containing 0.035 mg of ethinyl oestradiol and 2 mg of cyproterone acetate (EE/CPA, Diane 35; Schering, Milan, Italy). None of the patients wished to become pregnant or had contraindications with the use of oral contraceptives. All patients completed the study.

PCOS was diagnosed by clinical, endocrine and ultrasonographic findings. Obese patients (BMI >30 kg/m2) were excluded from the study because of possible weight gain with the use of the EE/CPA pill. Oligomenorrhoea was present in 100 cases (71.4%), secondary amenorrhoea in 40 (28.6%). All the 140 patients had anovulatory cycles. Only 28 patients (20%) were overweight (BMI 26.9 ± 1.1 kg/m2).

Acne was classified according to our modification of a previously published method (Lookingbill et al., 1988Go) on the basis of the number of lesions (comedones and papules/pustules) and their spread on the face, back and chest: `mild' characterized by the number of comedones <10 for each body area, with either no or only a few (<10) inflammatory papules/pustules; `moderate' if the number of comedones was from 10 to 25 and numerous inflammatory lesions (papules or pustules from 10 to 20 for each body area) but with rare cystic activity; `severe' when there were innumerable comedones (>25) and inflammatory papules/pustules as well as cysts (>20) spread over the entire face, on the chest and back. For this study, we only included patients who had acne: moderate in 91 (65%) and severe in 49 (35%).

Hirsutism, present in 108 (77.1%) women, was always evaluated by the same physician with the modified Ferriman-Gallwey score (Ferriman and Gallwey, 1961Go). In particular, the degree of hirsutism was rated on a scale from 0 to 4 over 11 body regions. Women with a Ferriman-Gallwey score >=7 were considered hirsute. Hirsutism was classified as mild, moderate and severe when the Ferriman-Gallwey score was 7-9, 10-14 and >=15 respectively. Hirsutism was mild (Ferriman-Gallwey score 8.5 ± 0.5) in 37 (34.2%) patients, moderate (Ferriman-Gallwey score 13.1 ± 1.3) in 38 (35.2%) and severe (Ferriman-Gallwey score 21.2 ± 2.1) in 33 (30.6%).

Acne and hirsutism were reassessed after 12, 18, 24, 36, 48, 60 cycles of treatment and after 6 months from cessation of therapy.

Transabdominal or transvaginal pelvic ultrasound was used before, at the end of treatment and after 6 months from cessation of therapy, using an ultrasound system and a 6.5 MHz vaginal transducer with 160° sector angle focused at 3 cm. Ovarian volume was calculated by the simplified formula for ellipsoids: 0.5233xlengthxwidthxdepth (Orsini et al., 1983Go) and the stromal area, expressed as a percentage, was calculated subtracting the cystic area from the total ovarian area. In our department, ovarian volume and stroma percentage in normal women were 5.1 ± 1.2 cm3 and <25% respectively. Echographic diagnosis of polycystic and multifollicular ovaries was carried out according to the published criteria (Adams et al., 1985Go).

All patients underwent SHBG, IGFBP-1 and hormonal assays, including: LH, FSH, 17ß-oestradiol (oestradiol), oestrone, androstenedione, total (testosterone) and free testosterone, dehydroepiandrosterone sulphate (DHEAS), 3{alpha}-diolG, fasting insulin and IGF-I. Assays were assessed in the early follicular phase (5th to 7th day) of a spontaneous menstrual cycle or progestin-induced menstrual bleeding (medroxyprogesterone acetate at the dose of 10 mg/day for 5 days) and at the 6th, 12th and 60th cycle of therapy and after 6 months from the end.

Insulin and glucose were determined in fasting conditions after 2 consecutive days of a diet with >300 g of carbohydrates. Fasting blood glucose was 79 ± 5 mg/dl (conversion factor to SI units 0.0549). All women were assessed for insulin resistance with the measurement of the fasting glucose:fasting insulin ratio. A ratio of <4.5, present in 83 (59.3%) patients, is consistent with insulin resistance (Legro et al., 1998Go).

The control group for SHBG, IGFBP-1 and hormone concentrations was made up of 40 women, mean age 24.5 ± 3.1 years and mean BMI 22.7 ± 2.6 kg/m2, with regular ovulatory menstrual cycles and no androgenic symptoms. Control group women also underwent hormonal assays in the early follicular phase of the menstrual cycle (5th to 7th day).

The study was approved by the Ethical Committee of the University of Brescia.

Statistical analysis and hormonal assays
All values were expressed as mean ± SD. Student's paired t-test with Bonferroni correction was used to compare hormone concentrations and ultrasonographic findings before and after treatment. P < 0.05 was considered statistically significant.

Plasma LH, FSH and SHBG concentrations were determined by an immunoradiometric assay method (Radim; Pomezia, Rome, Italy), while the remaining hormones were tested using radioimmunoassay commercial kits from: Diagnostic Products Corporation, Los Angeles, CA, USA (androstenedione; testosterone; free testosterone; insulin); Ortho-clinical Diagnostics, Amersham, UK (oestrone; oestradiol); Immunotech, Marseille, France (DHEAS); Diagnostic Systems Laboratories, Webster, TX, USA (3{alpha}-diolG; IGFBP-1); plasma IGF-I concentrations were tested by a radioisotopic assay method (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA).

The average intra- and inter-assay coefficients of variation (CV) were: 5.1 and 7.7% for LH, 4.8 and 7.1% for FSH, 8.1 and 7.6% for oestrone, 7.1 and 7.8% for oestradiol, 6.8 and 10.1% for androstenedione, 4.9 and 7.5% for testosterone, 6.2 and 9.7% for free testosterone, 5.2 and 7.7% for DHEAS, 5.1 and 2.7% for 3{alpha}-diolG, 4.3 and 4.8% for insulin, 5.0 and 7.5% for SHBG, 3.3 and 10.3% for IGF-I, 4.6 and 6% for IGFBP-1 respectively.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Hormonal results
Table IGo shows the basal endocrine profile of patients with PCOS and of the control group. In women with PCOS, serum LH, oestrone, androstenedione, testosterone, free testosterone, DHEAS, 3{alpha}-diolG, insulin and IGF-I concentrations were significantly higher than in controls, while SHBG and IGFBP-1 were lower (P < 0.001).


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Table I. Endocrine parameters of patients with polycystic ovarian syndrome (PCOS) and controls (mean ± SD)
 
Table IIGo shows the endocrine profile at the 6th, 12th and 60th cycle of therapy and after 6 months from cessation. The EE/CPA pill caused a progressive and significant decrease of LH, oestrone, oestradiol, androstenedione, testosterone, DHEAS, 3{alpha}-diolG and IGF-I until the 12th cycle of treatment; FSH and free testosterone decreased within six cycles. SHBG significantly increased until the 6th (529%) and IGFBP-1 until the 12th (203.6%) cycle. Between the 12th and 60th cycle there was only a significant decrease of DHEAS. Insulin concentrations and the fasting glucose:insulin ratio never changed significantly during treatment. At the 60th cycle of treatment, the hormone reductions were 83.1% for LH, 59% for FSH, 70.1% for oestrone, 65.6% for oestradiol, 65.7% for androstenedione, 49.2% for testosterone, 65.9% for free testosterone, 58.1% for DHEAS, 43.8% for 3{alpha}-diolG and 42.2% for IGF-I. SHBG and IGFBP-1 increased by 526.8% and 119.2% respectively. After 6 months from the end of the treatment, the endocrine profile showed significant modification compared to the 60th cycle, returning almost exactly to the basal profile.


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Table II. Endocrine parameters (mean ± SD): baseline, after 6, 12, 60 cycles and 6 months after cessation of treatment
 
Clinical results
The treatment with the EE/CPA pill cured acne (Table IIIGo) in all patients within 24 cycles. After 6 months from cessation of therapy, acne reappeared in 30 (21.4%) women: mild in 27 (19.3%) and moderate in three (2.1%).


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Table III. Effects of ethinyl oestradiol/cyproterone acetate treatment on acne (140 patients)
 
Mild hirsutism (Table IVGo) disappeared in all patients within 36 cycles of treatment and reappeared in six (16.2%) after 6 months from the end of therapy (Ferriman-Gallwey score 7.8 ± 0.2). The overall Ferriman-Gallwey score (Figure 1Go) decreased from 8.5 ± 0.5 to <7 (P < 0.001).


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Table IV. Effects of ethinyl oestradiol/cyproterone acetate treatment on mild hirsutism (37 patients)
 


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Figure 1. Modification of the mean Ferriman-Gallwey score during treatment and after 6 months from cessation in mild hirsute women with polycystic ovarian syndrome.

 
Moderate hirsutism (Table VGo) completely disappeared after 60 cycles of the EE/CPA pill and reappeared in a mild form in six (15.8%) women (Ferriman-Gallwey score 8.3 ± 0.5) in the follow-up after cessation of therapy. The overall Ferriman-Gallwey score (Figure 2Go) decreased from 13.1 ± 1.3 to <7 (P < 0.001).


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Table V. Effects of ethinyl oestradiol/cyproterone acetate treatment on moderate hirsutism (38 patients)
 


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Figure 2. Modification of the mean Ferriman-Gallwey score during treatment and 6 months after the end of treatment, in moderate and severe hirsute women with polycystic ovarian syndrome.

 
Table VIGo shows that severe hirsutism persisted in six (18.2%) patients after the 60th cycle of treatment with a Ferriman-Gallwey score of 17.0 ± 0.4, decreased in moderate hirsutism in 14 (42.4%) with a Ferriman-Gallwey score of 12.3 ± 0.7, and decreased in mild hirsutism in 13 (39.4%) with a Ferriman-Gallwey score of 8.6 ± 0.3. The Ferriman-Gallwey score significantly decreased after 60 cycles both in patients with persistent severe hirsutism, and in those with moderate and mild forms. Overall, the Ferriman-Gallwey score (Figure 2Go) decreased from 21.2 ± 2.1 to 12.8 ± 4.5 (P < 0.001). After 6 months from the end of the therapy, severe hirsutism was present in nine (27.3%) women, moderate in 18 (54.5%) and mild in six (18.2%), with a mean Ferriman-Gallwey score of 14.3 ± 4.5, significantly higher than the 60th cycle.


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Table VI. Effects of ethinyl oestradiol/cyproterone acetate treatment on severe hirsutism (33 patients)
 
After the cessation of therapy, the menstrual cycles were apparently regular in 91 (65%) patients for 2 months. After that period, all patients showed menstrual irregularity with oligomenorrhoea and secondary amenorrhoea in 115 (82.1%) and 25 (17.9%) patients respectively. During the treatment period 23 (16.4%) patients reported weight gain (between 2 and 7 kg), 10 (7.1%) weight reduction (3 and 6 kg) and 12 (8.6%) mild occasional headache.

Ultrasonographic findings
Table VIIGo shows the ultrasound parameters. In basal condition, ovaries were polycystic in all patients. After 60 cycles of treatment, the ovarian volume, microcyst numbers and stroma percentage were significantly decreased. After 6 months from the end of therapy, ovarian morphology was polycystic in 42 (30%) and multifollicular in 98 (70%). Altogether, the ovarian volume, microcyst numbers and stoma percentage, although significantly varying from that of the 60th cycle, were lower than the starting condition.


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Table VII. Ultrasound parameters in polycystic ovarian syndrome treated with ethinyl oestradiol/cyproterone acetate (mean ± SD)
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our study demonstrated that in women with PCOS, the EE/CPA pill administered for 60 consecutive cycles resolved acne in all cases and hirsutism in 69.4% of cases. All patients with mild and moderate hirsutism completely recovered, while severe hirsutism improved in the mild-moderate form in 81.8% of cases and persisted as severe in 18.2% with an equally significant reduction of the Ferriman-Gallwey score from 21.2 ± 2.1 to 17.0 ± 0.4.

Resolution time for the two androgenic symptoms was very different. Regardless of its severity, acne disappeared within 12–24 treatment cycles, but hirsutism was still present in 30.6% of patients after 60 cycles. In particular, patients with mild hirsutism recovered after 12–36 cycles, those with a moderate form after 36–60 cycles, whereas the initially severe hirsutism persisted in all patients after 60 cycles. Overall, the effect of the EE/CPA pill started before the 12th cycle on mild hirsutism, compared with after the 24th cycle on moderate-severe (Figure 2Go). Recovery from hirsutism occurred at the 12th cycle (62.2%) in mild hirsutism, and at the 36th (44.7%) in the moderate forms. In severe hirsutism there were no recoveries, and the transformation to mild hirsutism appeared after 48 cycles and only in 27.3% of patients.

The EE/CPA combination is effective on androgenic symptoms for its ability to decrease LH and androgen LH-dependent concentrations. Furthermore, it is able to increase, through its oestrogen component, SHBG and IGFBP-1 concentrations (Suikkari et al., 1989Go), resulting in a reduction of bioavailable and active free testosterone and IGF-I serum concentrations. The insulin/IGF-I system acts, in synergy with LH, in stimulating thecal-stromal androgen production (Hernandez et al., 1988Go). The decreased concentrations of androgen and IGF-I concentrations reduce 5{alpha}-R activity and consequently DHT production in the sensitive tissue, as demonstrated by the significant reduction of 3{alpha}-diolG (43.8%). Furthermore, IGF-I is able to stimulate hair growth per se (Paus and Cotsarelis, 1999Go). Oestrogens in general (Kutten and Mauvais-Jarvis, 1975Go) and progestins in oral contraceptives also inhibit 5{alpha}-R activity in skin (Cassidenti et al., 1991Go), further contributing to the clinical impact of oral contraceptives on hirsutism.

Oral contraceptives are able to decrease adrenal androgen production. In particular, the CPA compound, with a moderate glucocorticoid activity, may significantly reduce DHEAS concentrations, presumably through an inhibitory effect on adrenocorticotrophic hormone secretion (Girard et al., 1978Go), and/or a direct effect on the adrenal cortex (Chapman et al., 1982Go). In our study, DHEAS progressively and significantly decreased until the 60th cycle (58.1%), unlike the other androgens that significantly decreased until the 12th cycle.

This study supports the hypothesis that acne and hirsutism are induced by different peripheral mechanisms. Recent studies on the peripheral metabolism of androgens (Carmina et al., 1991Go; McKenna, 1993Go; Toscano et al., 1993Go) have stressed the possibility of finding different quantities of androstenedione, testosterone or DHT in the sebaceous gland and in the hair follicle. Acne and/or hirsutism could be induced, contemporaneously or in an isolated form, depending on the prevalent androgen and the individual tissue sensitivity. Moreover, sebum production proved to be depressed in subjects who were fully insensitive to androgen but not in those with a congenital absence of 5{alpha}-R (Imperato-McGinley et al., 1993Go). Our data are consistent with the concept that sebaceous glands are sensitive to androstenedione and/or testosterone and that hair follicles are sensitive to DHT. In fact, it has been shown that androstenedione and its metabolites are able selectively to stimulate the sebaceous cell multiplication and sebum production to a greater degree than testosterone (Ebling et al., 1971Go; Ebling et al., 1973Go). Therefore, it is possible that sebaceous glands can directly use androstenedione without converting it into testosterone. In fact, it has been shown that in women with isolated acne, the 3{alpha}-diolG values are not as high as in hirsute patients but are similar to normal women (Toscano et al., 1993Go; Falsetti et al., 1998Go). The EE/CPA pill was effective in treating acne because it inhibited, directly and by increasing SHBG, the androstenedione, testosterone, DHEAS and free testosterone. Due to its marked oestrogen prevalence and presence of the antiandrogen CPA, this pill also exhibited a specific action on sebaceous glands. The lower efficacy of this combination on hirsutism was due to the difficulty of blocking the formation and activity of DHT and its metabolites in hair follicles. In fact, after 60 cycles of therapy, 3{alpha}-diolG concentrations were still significantly higher than the control group. Specifically, 3{alpha}-diolG concentrations correlate with 5{alpha}-R activity and largely reflect DHT production and metabolism in the skin (Duffy et al., 1995Go). In our opinion, only by reducing 5{alpha}-R activity and DHT concentrations for a long time within the range of normality is it possible to inhibit androgen-dependent hair growth. It is possible that the EE/CPA pill, with its mechanism, could greatly inhibit 5{alpha}-R1 (prevalent in sebaceous glands) rather than 5{alpha}-R2 (prevalent in hair follicles).

It is doubtful if low doses of CPA (2 mg), also administered for a long time, may have per se a role in hirsutism by blocking androgen receptors or reducing 5{alpha}-R activity. Numerous authors have demonstrated that higher CPA doses (12.5–150 mg/day) result in a greater and more rapid regression of hirsutism (Marcondes et al., 1990Go; Fruzzetti et al., 1999Go; Venturoli et al., 1999Go).

Finally, the present study shows that after 6 months from the end of the therapy, the endocrine, clinical and ultrasonographic profile of PCOS is restored, supporting the genetic, perhaps family origin of this syndrome.

The efficacy of the EE/CPA pill on acne and hirsutism was related to the duration and continuity of the treatment and to the degree of hirsutism. Willingness to comply with the treatment is enhanced by the absence of significant side-effects and by the high psychological motivation of the patients with acne and hirsutism. Due to its action on androgenic symptoms, the excellent menstrual cycle and endometrial control, and the favourable effect on lipid and carbohydrate metabolism (Prelevic et al., 1990Go; Falsetti and Pasinetti, 1995Go; Dahlgren et al., 1998Go), the EE/CPA pill is an effective treatment for women with PCOS who do not want to become pregnant.


    Notes
 
1 To whom correspondence should be addressed at: Via XXV Aprile 10, 24058 Romano di L. (BG), Italy. Back


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on June 27, 2000; accepted on September 29, 2000.





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