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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 608-612
Copyright © 2001 by The Endocrine Society

Original Studies

Evidence That Cyproterone Acetate Improves Psychological Symptoms and Enhances the Activity of the Dopaminergic System in Postmenopause

Anna Maria Paoletti, Stefano Floris, Marina Mannias, Marisa Orrù, Donatella Crippa, Roberto Orlandi, Maria Del Zompo and Gian Benedetto Melis

Clinica Ginecologica Ostetrica e di Fisiopatologia della Riproduzione Umana del Dipartimento Chirurgico Materno-Infantile e di Scienze delle Immagini, Dipartimento di Neuroscienze, Università degli Studi di Cagliari (M.D.Z.), 09124 Cagliari, Italy; and Direzione Scientifica Schering AG Italia (D.C., R.O.), 20090 Milan, Italy

Address all correspondence and requests for reprints to: Prof. Gian Benedetto Melis, M.D., Clinica Ginecologica Ostetrica e di Fisiopatologia della Riproduzione Umana del Dipartimento Chirurgico Materno-Infantile e di Scienze delle Immagini, Università degli Studi di Cagliari, Via Ospedale 46, 09124 Cagliari, Italy. E-mail: paoletti{at}freemail.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The psychological symptoms assessed with a validated psychometric scale, SCL-90, were significantly higher in postmenopausal women (PMW; 60 subjects) than in premenopausal women (20 subjects). In the same PMW, the activity of the dopaminergic system, assessed with the PRL response to the dopamine-blocking agent sulpiride, was significantly lower than that in premenopausal women. During a period of 12 weeks the 60 PMW were randomly divided into 3 groups: no treatment (group A; n = 20), treatment with estradiol (E2) alone (patches with a E2 release of 50 µg/24 h; group B; n = 20), and treatment with hormonal replacement therapy [estradiol valerate (EV) at a daily dose of 2 mg for 11 days and EV at the same daily doses plus cyproterone acetate (CPA) at a daily dose of 1 mg/day for 10 days; group C; n = 20). At the 12th week of the observation, only in group C women were the psychological symptoms significantly decreased, and the indirect evaluation of the dopaminergic system activity through PRL response to sulpiride showed a significant increase. During the same period, no changes in testosterone levels were observed in any group of PMW, whereas a significant increase in E2 levels was found in both groups B and C. Although it is likely that the improvement in psychological symptoms with EV and CPA was due to progestin, we cannot rule out the possibility that greater estrogen exposure may have played a role.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SEVERAL STUDIES demonstrated that estrogen replacement therapy improves the psychological status and well-being of postmenopausal women (PMW) (1, 2, 3, 4). It has been reported that the incidence of depressive mood is significantly reduced in postmenopause by both transdermal (5) and oral estrogen therapy (6). Preliminary results from our studies (unpublished data) also show that postmenopausal psychological symptoms are similarly influenced by either oral or transdermal estrogen therapy. The addition of progesterone (P) to estrogens is needed to prevent endometrial cancer (7). Some studies of the premenstrual syndrome suggest that P and progestins are detrimental for mood swings (2, 8). Nevertheless, psychotic disturbances occurring after delivery could also be attributed to a postpartum withdrawal of both P and estrogens (9, 10). In addition, administration of P in various mammalian species has revealed analgesic, ansiolytic, and sleep-modulating effects (11). Recently, it has been reported that P has antipsychotic properties, which may be relevant for the treatment of psychotic disturbances (12). Studies performed to clarify the mechanism of the action of estrogens at the central level demonstrate that they are capable of restoring the activity of central neurotransmitters, such as opioids and dopamine, which are significantly reduced after the menopause (13, 14). Estrogen treatment may enhance dopaminergic (DA) activity by a direct stimulation of tuberoinfundibular hypothalamic neurons. It may also act indirectly through the stimulation of PRL release (15). As for P, studies on animals proved that via its genomic mechanism of action it may influence the expression of dopamine (DA) receptors (16, 17) and of enzymes involved in DA synthesis (18, 19). P has also shown to modulate the release of DA (20, 21).

The response of PRL to the specific DA receptor-blocking agents, is considered an indirect way to test hypothalamic DA activity (22, 23, 24). Therefore, the PRL response to administration of the anti-DA agent, sulpiride, can be used as a tool to evaluate DA activity. Sulpiride is a selective DA receptor-blocking agent. The drug does not easily cross the blood-brain barrier. However, the blood-brain barrier is not completely defined at the level of the median eminence. The PRL-enhancing activity of sulpiride can also be explained through an effect at both pituitary and hypothalamic levels (25).

In agreement with this evidence, the first purpose of the study was to verify whether the psychological symptoms and the function of the DA system differ between premenopausal women and PMW. In addition, the aim of the study was to investigate whether in PMW hormonal replacement therapy (HRT) with estrogen alone or with estrogen plus a progestin compound could be capable of differently modifying the psychological status and DA activity of PMW.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Assessment of psychological symptoms

To assess psychological symptoms and their intensity, an Italian psychometric self-report clinical scale validated in postmenopausal women was used (SCL-90) (26). SCL-90, is orientated toward the psychiatric out-patient’s symptomatology (SCL-90) (26). It includes 90 items that focus on the assessment of anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, hostility, psychoticism, somatization, phobic anxiety, and paranoid ideation (26).

HRT

Estrogen alone. Treatment with estrogen alone was performed with transdermal estradiol (E2; patches containing 3.9 mg E2 with a hormone release of 50 µg/24 h, one application every 7 days; Climara, Schering AG, Berlin, Germany).

Estrogen plus progestin compound. Treatment with estrogen plus progestin was performed with the biphasic association of estradiol valerate (EV) at a daily dose of 2 mg for 21 days plus cyproterone acetate (CPA) at a daily dose of 1 mg for the last 10 days (EV+CPA; Climen, Schering AG). CPA is a compound derived from 17-hydroxyprogesterone that exerts a powerful and prolonged progestin action, but is devoid of androgen activity (27, 28, 29). The biphasic association of EV at a daily dose of 2 mg for 21 days plus CPA has demonstrated that it can improve postmenopausal syndrome without negative interferences on endometrium and health (30).

Subjects

The subjects included in the study were 60 healthy women (mean age, 52.3 ± 2.1 yr) who were at least 6 months beyond a 12-month period of hypergonadotropic amenorrhea (PMW) and had never begun HRT. Twenty healthy premenopausal women with regular menstrual cycles (mean age, 29.5 ± 4.2 yr) were the control group. None of the women had any past or present psychological or mood disturbances, thyroid diseases, or PRL disorders. The postmenopausal women were recruited from the Center of Menopause of the Gynecological and Obstetric Department, whereas the premenopausal women were selected from women asking for contraception. They gave consent to participate in the study as volunteers. All PMW participated in the study after a careful evaluation of inclusion criteria to HRT. The study was previously approved by the local ethical committee and the institutional review board. Before inclusion in the study all subjects gave informed consent. However, the physician team did not specifically explain to them that one reason for the study was to evaluate their psychological conditions, but to evaluate only menopausal symptoms and compliance to therapy, with the aim to minimize the placebo-like effect on psychological symptoms.

Methods

Randomly, the PMW were divided into three groups: no treatment (group A; n = 20), treatment with transdermal E2 (group B; n = 20), and treatment with HRT in sequential regimen (EV+CPA; group C; n = 20). The length of the study was 12 weeks. Before and during a day during the last week of the study (in the treated women, during the last week of treatment), each PMW was invited to complete an SCL-90 scale.

At the same time, measurements of blood pressure, weight, and hip/waist ratio were made, and a sulpiride test was performed in each woman. The subjects in the control group completed an SCL-90 scale and underwent a sulpiride test during the early follicular phase of the menstrual cycle (days 4–7 from the onset of menstrual bleeding).

To perform sulpiride tests, at 0730 h a polyethylene catheter was placed in an antecubital vein of the nondominant arm and kept patent by a slow infusion of saline solution. The women were supine in a room with standardized environmental conditions and were not allowed to eat, drink, smoke, or sleep during the sampling session. Blood samples were collected before (-30 and 0 min) and 15, 30, 60, 90, and 120 min after the iv injection of 5 mg sulpiride (Levopraid, Ravizza Farmaceutici SpA, Muggiò, Milan, Italy). The blood samples were collected in tubes containing gel and clot activator. The sera obtained after centrifugation in a refrigerated centrifuge were stored at -20 C until assayed.

Total testosterone (T) and E2 were assayed in the first sample of each endocrine evaluation, whereas PRL concentrations were assayed in all samples. The technical characteristics of each assay are reported in Table 1Go. To avoid interassay interferences, the blood samples from each subject were measured in the same assay. At the end of the study all SCL-90 scales were blindly examined by one of the authors (S.F.). The PRL response to sulpiride was evaluated as integrated area under the curve (AUC) calculated by the method of triangulation and expressed as micrograms per L/120 min.


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  		Table 1. Specific performance characteristics of PRL, E2, and total T assays

 
Statistical analysis of the results was performed using Student’s t test and the paired t test. One- or two-factor ANOVA for repeated measures was also used.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline investigation

At baseline, the global score of the SCL-90 scale and scores of symptoms assessed by SCL-90 were significantly lower in the control group than in all PMW groups (Table 2Go). The global score of SCL-90 and all symptoms assessed by this psychometric scale did not differ among the three groups of PMW (Table 2Go). The levels of E2 and total T did not differ among the PMW, but were significantly lower in every PMW group than in the control group (Table 2Go; P < 0.05). The PRL response to sulpiride was similar among the groups of PMW (Table 2Go), but in all PMW groups it was significantly lower than in the control group of premenopausal women (Table 2Go; P < 0.05).


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  		Table 2. Mean ± SE basal levels of E2, total T, response of PRL to sulpiride (AUC), global score of SCL-90, and scores of SCL-90 in premenopausal women (control group; n = 20) and in postmenopausal women (PMW) evaluated before the study period without any treatment (group A; n = 20), treated with E2 alone (group B; n = 20), and treated with EV and CPA (group C; n = 20)

 
Effect of treatment

In all groups of PMW, blood pressure, weight, and hip/waist ratio did not change during the 12 weeks of the study compared with baseline values. At 12 weeks of treatment, the total scores of SCL-90 did not differ in subjects in groups A and B compared with those in women evaluated before the period of observation (group A, 71.86 ± 10.10 vs. 78.79 ± 9.25; group B, 59.40 ± 12.20 vs. 70.60 ± 13.50). Nevertheless, during the 12th week of treatment, anxiety and depression significantly decreased in group B women (Fig. 1Go; P < 0.05 and P < 0.01), but there was no change in symptoms in group A women (Fig. 1Go). In subjects in group C the total score of SCL-90 was significantly lower during the 12th week of treatment compared with that calculated before treatment (50.50 ± 7.8 vs. 76.50 ± 10.30; P < 0.002). In addition, in group C subjects, six of nine symptoms evaluated by SCL-90 significantly decreased during treatment (Fig. 1Go; P < 0.05 and P < 0.01).



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  		Figure 1. Mean ± SE of nine psychological symptoms assessed with the validated psychometric scale, SCL-90, before ({square}) and during the 12 weeks of the study ({blacksquare}) in PMW who during this period did not receive any treatment (group A; upper graph) or were treated with E2 alone (group B; middle graph) or with EV+CPA (group C; lower graph). *, P < 0.05; **, P < 0.01 (vs. before use). OCD, Obsessive-compulsive symptoms.

 
Total T levels did not change during the 12 weeks of treatment in any groups of PMW (group A, 1.35 ± 0.10 vs. 1.21 ± 0.13 nmol/L; group B, 1.28 ± 0.24 vs. 1.14 ± 0.17 nmol/L; group C, 1.52 ± 0.17 vs. 1.38 ± 0.13 nmol/L). The concentrations of E2 did not change in group A women compared with those evaluated at baseline (68.28 ± 12.84 vs. 53.22 ± 9.54 pmol/L). On the contrary, in group B and C women during the 12th week of treatment E2 levels were significantly higher than those before treatment [group B, 119.30 ± 9.54 vs. 55.43 ± 10.27 pmol/L (P < 0.002); group C, 176.94 ± 29.36 vs. 57.63 ± 10.27 pmol/L (P < 0.002)].

During the 12th week of the study, the AUCs of PRL in group A and B women after sulpiride administration were similar to those calculated at baseline (Fig. 2Go), whereas in the subjects of group C it was significantly higher than that calculated before treatment (Fig. 2Go; P < 0.007).



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  		Figure 2. Mean ± SE of PRL secretion after the sulpiride stimulation test, calculated as the AUC before ({square}) and during ({blacksquare}) the 12 weeks of the study in PMW who during this period did not receive any treatment (group A) or were treated with E2 alone (group B) or with EV+CPA (group C). *, P < 0.007 vs. before use.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
A psychometric validated scale, such as SCL-90, showed that in addition to depression and anxiety (5) other psychological symptoms occur in women after the menopause. Changes in the function of several neuronal systems have been indicated as the primary causes of this condition (13, 14). The findings of the present work suggest that, at least through an indirect test, the DA system is significantly different in pre- and postmenopausal women. Brain DA transmission is strongly modulated by estrogens, as demonstrated in animal studies. The injection of physiological doses of E2 to ovariectomized rats increases the density of striatal binding sites of DA (31). In humans, it is known that the tuberoinfundibular DA system is chronically stimulated by estrogens by a short-loop feedback dependent on estrogen-induced-hyperprolactinemia (15, 32, 33). Nevertheless, the restoration of a physiological estrogen environment, such as that obtained with transdermal E2 (34), is insufficient to completely restore the DA system in PMW. In agreement with this observation, E2 alone was capable of improving anxiety and depression (5), but not other psychological symptoms occurring after the menopause. The association of EV+CPA has been demonstrated to be more effective than E2 alone, because in addition to symptoms effectively treated by estrogen alone, it induced a significant improvement of other parameters considered by SCL-90, such as somatization, obsessive-compulsive symptoms, interpersonal sensitivity, and phobic anxiety. E2 levels were significantly increased during both E2 alone and EV+CPA treatments. Total T levels did not change with either EV+CPA or E2 treatment. This could exclude any effect due to the antiandrogenic activity of CPA if the blood sample paradigm is not frequent enough to permit the assessment to be made with confidence. Further, an androgen receptor-blocking agent may exert its actions without changes in the circulating concentrations of androgens. However, we can assume that the activity of CPA at a central level might depend on its progestin property. Progesterone and progestin compounds alone (35) or in combination with estrogens (36) are capable of enhancing the DA system. The beneficial effect of EV+CPA might be dependent on the enhancement of the DA system, as indirectly demonstrated by the PRL response to the DA-blocking agent sulpiride. Nevertheless, the neuronal activity of P and progestin compounds could be related to other mechanisms. In animal studies, P metabolites interact with the GABAA receptor in the brain (37) with an action similar to that of benzodiazepines and barbiturates. In humans, it has been proposed that P and progestin compounds may be beneficial in anxiety states via an action on the {gamma}-aminobutyric acidA receptors (38). It has also been demonstrated that P may enhance the opioidergic system (39).

All of these data suggest that CPA may improve psychological symptoms evaluated by SCL-90 in PMW and at the same time may induce significant changes in the PRL response to the DA-blocking agent sulpiride. They also confirm that after menopause there is a significant impairment of psychological conditions and a decrease in DA activity. Estrogen alone improves psychological conditions, but the addition of CPA to estrogen can improve more psychological symptoms, as evaluated by the SCL-90 scale. The combination of estrogens and CPA is also capable of significantly affecting the PRL response to the DA-blocking agent sulpiride compared with the effect of estrogen alone. In conclusion, our study seems to give evidence that CPA interferes with both the psychological status and the DA system in PMW. Only further studies could demonstrate whether there is a relationship between these two effects. In fact, even if E2 levels did not differ between E2 alone and EV+CPA treatments, it cannot be excluded that total estrogen exposure differed between these two groups. The E2 levels were slightly higher in the oral estrogen group, and estrone levels, which were not measured, were undoubtedly higher as well. Thus, all of the findings that may be attributed to progestin exposure could just as easily be attributed to the higher estrogen exposure or the oral route of delivery.


   Acknowledgments
 
We thank Ms. Franca Fadda and Ms. Mychaela Hayes for typing and revising the manuscript. Particular thanks must be given to Caterina Chelotti, M.D., and Monica Pilloni, M.D., respectively (Dipartimento di Neuroscienze and Clinica Ginecologica Ostetrica e di Fisiopatologia della Riproduzione Umana del Dipartimento Chirurgico Materno- Infantile e di Scienze delle Immagini, dell’Università degli Studi di Cagliari) for their collaboration in the revision of psychological symptoms.

Received March 4, 2000.

Revised July 18, 2000.

Revised August 29, 2000.

Accepted October 13, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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