Department of Gynaecological Endocrinology, University of Brescia, Brescia 25128, Italy
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Abstract |
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Key words: acne/cyproterone acetate/ethinyl oestradiol/hirsutism/ultrasonography
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Introduction |
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In PCOS, hyperandrogenism is clinically silent in ~30% of European women and 8090% of Oriental women (Aono et al., 1977), or induces hirsutism in 6083% of the cases and acne in 1143% of the cases (Goldzieher and Green, 1962
; Conway et al., 1989
; Lobo, 1991
). Clinical expression depends on the events which occur in the pilosebaceous unit, where individual sensitivity to androgens is different (McKenna, 1993
). Dehydroepiandrosterone (DHEA), androstenedione and testosterone, penetrating the cells of the peripheral sensitive tissues, are converted to the more potent dihydrotestosterone (DHT) by 5
-reductase (5
-R). Testosterone and DHT can bind to androgen receptors, but the receptor affinity for DHT is ~10-times that of testosterone (McKenna, 1993
). DHT is metabolized into 3ß- and 3
-androstanediol and their glucuronide conjugates (3ß-, 3
-diolG). Hirsute women with or without hyperandrogenism exhibit a consistently increased 3
-diolG indicating a 5
-R hyperactivity and preferential use of the DHT/3
-diolG route in the hair follicle (Matteri et al., 1989
; Speroff and Glass, 1994
). In fact, numerous studies have documented that in hirsute women the 5
-R activity in the skin was steadily elevated (Paulson et al., 1986
). In hyperandrogenic patients with acne alone, 3
-diolG is not as high as in hirsutism (Toscano et al., 1993
).
Two isoforms of 5-R have been identified, called type 1 and 2 (5
-R1 and 5
-R2). Studies using specific inhibitors of 5
-R1 and 5
-R2 have shown that 5
-R2 enzymatic activity is predominant in the urogenital sinus, in genital skin, in the adult scalp and in the hair follicles, whereas 5
-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., 1992
; Mestayer et al., 1996
; Paus and Cotsarelis, 1999
). 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-R (type 1 or 2) resulting in higher DHT production in hair follicles compared with sebaceous glands (Carmina et al., 1991
; McKenna, 1993
; Toscano et al., 1993
). 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., 1973
).
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-R and hair growth (Suikkari et al., 1991
).
Cyproterone acetate (CPA) is a synthetic progestogen derived from 17-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
-R activity (Mowszowitcz et al., 1986
) and increases metabolic testosterone clearance (Marcondes et al., 1990
).
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.
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Materials and methods |
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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., 1988) 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, 1961). 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., 1983) 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., 1985
).
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-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., 1998).
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-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-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.
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Results |
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Ultrasonographic findings
Table VII 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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Discussion |
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Resolution time for the two androgenic symptoms was very different. Regardless of its severity, acne disappeared within 1224 treatment cycles, but hirsutism was still present in 30.6% of patients after 60 cycles. In particular, patients with mild hirsutism recovered after 1236 cycles, those with a moderate form after 3660 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 2). 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., 1989), 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., 1988
). The decreased concentrations of androgen and IGF-I concentrations reduce 5
-R activity and consequently DHT production in the sensitive tissue, as demonstrated by the significant reduction of 3
-diolG (43.8%). Furthermore, IGF-I is able to stimulate hair growth per se (Paus and Cotsarelis, 1999
). Oestrogens in general (Kutten and Mauvais-Jarvis, 1975
) and progestins in oral contraceptives also inhibit 5
-R activity in skin (Cassidenti et al., 1991
), 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., 1978), and/or a direct effect on the adrenal cortex (Chapman et al., 1982
). 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., 1991; McKenna, 1993
; Toscano et al., 1993
) 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
-R (Imperato-McGinley et al., 1993
). 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., 1971
; Ebling et al., 1973
). 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
-diolG values are not as high as in hirsute patients but are similar to normal women (Toscano et al., 1993
; Falsetti et al., 1998
). 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
-diolG concentrations were still significantly higher than the control group. Specifically, 3
-diolG concentrations correlate with 5
-R activity and largely reflect DHT production and metabolism in the skin (Duffy et al., 1995
). In our opinion, only by reducing 5
-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
-R1 (prevalent in sebaceous glands) rather than 5
-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-R activity. Numerous authors have demonstrated that higher CPA doses (12.5150 mg/day) result in a greater and more rapid regression of hirsutism (Marcondes et al., 1990
; Fruzzetti et al., 1999
; Venturoli et al., 1999
).
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., 1990; Falsetti and Pasinetti, 1995
; Dahlgren et al., 1998
), the EE/CPA pill is an effective treatment for women with PCOS who do not want to become pregnant.
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Notes |
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References |
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Submitted on June 27, 2000; accepted on September 29, 2000.