1 Department of Obstetrics and Gynecology and 2 Section of Endocrinology, Department of Medicine, St Olavs Hospital, University Hospital of Trondheim, Trondheim, Norway.
3 To whom correspondence should be addressed. e-mail: eszter.vanky{at}medisin.ntnu.no
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Abstract |
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Key words: androgens/dexamethasone/metformin/PCOS
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Introduction |
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The use of the anti-diabetic drug metformin in the treatment of PCOS is quite well established (Nestler and Jakubowicz, 1997; Velazquez et al., 1997
; Morin-Papunen et al., 1998
; Moghetti et al., 2000
; Pasquali et al., 2000
). Metformin reduces insulin resistance in muscle, fat and liver tissue, and thereby reduces circulating insulin levels. By reducing insulin levels, metformin reduces both the insulin-enhanced adrenal and ovarian androgen synthesis and the insulin-mediated inhibition of hepatic sex hormone-binding globulin (SHBG) synthesis (la Marca et al, 1999
).
PCOS women have increased adrenal androgen synthesis in response to adrenocortictrophic hormone, demonstrating increased activity in the pituitaryadrenal axis (Loughlin et al., 1986). The use of corticosteroids to treat ovulatory dysfunction was first reported by Jones et al. (1953
). Ovulatory menses were achieved in 11 out of 14 anovulatory, oligo-amenorrhoeic women treated with cortisone 50 mg daily. Another study reported that 60% of 29 hyperandrogenic women with abnormal menses, receiving dexamethasone 0.251.0 mg daily for 615 months, improved their menstrual pattern (Abraham et al., 1981
). In a study of PCOS women, 10 out of 15 women achieved regular menses after 3 months of treatment with dexamethasone 0.5 mg daily (Loughlin et al., 1986
). To our knowledge, there are no prospective randomized controlled studies of the effect of glucocorticoids in a well-defined population of PCOS women.
We regard diet and lifestyle advice and treatment with metformin as the standard treatment of both lean and obese women with PCOS (Kiddy et al., 1989; Knowler et al., 2002
). However, in most cases, such treatment is not sufficient to relieve all the signs and symptoms of PCOS. In a previous study, we demonstrated that 8-week treatment with dexamethasone 0.5 mg daily reduces androgen levels in metformin-treated PCOS patients (Vanky et al., 2003
). To investigate the long-term effect of low-dose dexamethasone in metformin-treated PCOS women, we performed a 26-week prospective, randomized, double blind, placebo-controlled study.
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Materials and methods |
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Exclusion criteria included pregnancy, breast-feeding, known liver disease, alanine aminotransferase >60 IU/l, creatinine >130 µmol/l, known alcohol abuse, diabetes mellitus and treatment with oral glucocorticoids or hormonal contraceptives. Women who had discontinued hormonal contraception at least 1 month prior to inclusion were allowed to enter the study. Congenital adrenal hyperplasia (CAH) was excluded by 17-hydroxprogesterone measurements, and all participants had normal prolactin levels (<784 mIE/l). One of the authors (E.V.) enrolled and assigned all the participants.
The study design is shown in Figure 1. Fifty patients were included, and 38 patients completed the study. Four patients became pregnant, despite being instructed to use non-hormonal contraception during the study period (three in the dexamethasone group and one in the placebo group). Three patients withdrew because of gastrointestinal side effects of metformin (nausea or frequent diarrhoea lasting >3 weeks). In one woman, early ovarian failure had been overlooked. Two patients withdrew from the study due to lack of motivation and another two patients left the study without giving any reason. Of the 38 women completing the whole study, 18 were randomized to dexamethasone 0.25 mg and 20 to placebo. The randomization and encapsulation of dexamethasone and placebo to identical capsules were performed at the pharmacy of our hospital. Block randomization was performed in groups of six according to three categories of body mass index (BMI) <30 kg/m2, 3037 kg/m2 and >37 kg/m2.
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At randomization, after 8 weeks and at the end of the study (26 weeks after inclusion), venous blood samples were drawn from an antecubital vein, at between 8 and 10 a.m. after an overnight fast. Blood samples were centrifuged at room temperature within 30 min and stored at 70°C until analysis (19 months) as described below. The blood pressure was measured while the patient was in the sitting position after at least 15 min of rest with a digital blood pressure monitor (Fuzzy Logic UA-779, Scan.Med. Norway). The blood pressure was measured three times, at least 2 min apart. The mean of the second and third measurement was calculated.
Study protocol
All participants received individual, written and verbal diet and lifestyle counselling at inclusion. Treatment with metformin 850 mg (metformin hydrochloride, Metformin®, Weifa A/S, Oslo, Norway) was initiated at inclusion. All women used metformin once daily during the first week, twice daily during the second week, and thereafter three times daily for the rest of the study period. At inclusion (week 0), the participants were randomized to additional treatment with either dexamethasone 0.25 mg (dexamethasone natriumphosphate, Decadron®, MSD, Drammen, Norway) or placebo one capsule at bedtime. We hypothesized that dexamethasone would induce a further reduction of androgen levels in PCOS patients treated with metformin, diet and lifestyle counselling.
Primary outcome measures were testosterone, androstenedione, SHBG, free testosterone index (FTI) and dehydroepiandrosterone sulphate (DHEA-S).
Secondary outcome measures were BMI, blood pressure, serum lipids, insulin c-peptide, fasting glucose and menstrual pattern.
The Committee for Medical Research Ethics of Health Region IV, Norway, and The Norwegian Medicines Agency approved the study. A written informed consent was obtained from each patient before inclusion, and the Declaration of Helsinki was followed throughout the study.
Assays
Testosterone and androstenedione were measured by a double antibody technique on an Elecsys 2010 analyser (Roche Diagnostics GmbH, Mannheim, Germany) using reagents and calibrators supplied by the manufacturer. 17-Hydroxyprogesterone was measured using a radioimmunoassay technique with reagents and calibrators supplied by Orion Diagnostica, Espoo, Finland. SHBG and DHEA-S were measured using a competitive immunoassay on an Immulite 2000 analyser using the reagents and calibrators supplied by the manufacturer (Diagnostic Products Corporation, Los Angeles, CA).
The lower detection limits for testosterone, androstenedione, 17-hydroxyprogesterone, SHBG and progesterone were 0.1, 0.1, 0.2, 0.02 and 0.6 nmol/l, respectivly. FTI was calculated as total testosterone divided by SHBG and multiplied by a factor of 10.
Reference values were: testosterone 0.12.9 nmol/l; androstenedione 0.711.0 nmol/l; DHEA-S 0.911.7 µmol/l; and 17-hydroxyprogesterone 1.512.8 nmol/l. Blood glucose, total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides were analysed on the day of the blood sampling. Serum glucose was analysed by the glucose dehydrogenase method after protein precipitation with perchloric acid using the Merck Granutest 250 reagent kit (E. Merck, Darmstadt, Germany). For serum lipid analyses, the routine method of our laboratory was used. Insulin c-peptide was analysed on an Immulite 2000 analyser using reagents, methods and calibrator obtained from the instrument supplier.
Statistical analysis
All statistical procedures were performed using the Statistical Package for the Social Sciences (SPSS) version 10.0 for Windows SPSS Inc., Chicago, IL.
Sample size calculations, assuming 90% power to detect 1.0 nmol/l change in testosterone between groups indicated the need for 23 patients in each group. SDs were estimated to 0.6 nmol/l. As we anticipated a 510% possible drop out, we included 25 patients in each group.
To evaluate treatment effects, the changes from week 0 to week 8 and week 26 were calculated for each participant. The differences in change between the study and control groups were compared with two-tailed t-tests for independent samples. Values are reported as means and SD. Pearsons statistics were used for correlation analyses. P-values <0.05 were considered significant. No adjustments for multiple comparisons were performed. Data were analysed according to the intention to treat principle.
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Results |
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After 8 weeks of dexamethasone treatment, testosterone was reduced by 45%, androstenedione by 34%, DHEA-S by 32% and FTI by 50% (Table II). Compared with the placebo group, the reduction was 35% for testosterone, 28% for androstenedione, 52% for DHEA-S and 45% for FTI.
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In the dexamethasone group, there was a positive correlation between the DHEA-S level at inclusion and the change of testosterone (r = 0.58, P < 0.05), androstenedione (r = 0.70, P < 0.005) and FTI (r = 0.52, P < 0.05) at the end of the study.
Fasting glucose, insulin c-peptide, BMI, serum lipid levels and blood pressure were unaffected by dexamethasone treatment (Table III). In the placebo group, BMI at inclusion correlated negatively with change in FTI, i.e. the higher the BMI, the lower the reduction in FTI from week 0 to week 26. In the dexamethasone group, no such correlation was observed.
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Discussion |
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The dominating view is that hyperandrogenism in PCOS women is caused mainly by ovarian androgen synthesis. The fact that an increased activity in the pituitaryadrenal axis has been reported in PCOS women might be important (Arslanian et al., 2002).
Dexamethasone is not known to exert effects in the ovaries. In the present study, DHEA-S, an androgen precursor produced only by the adrenals, was reduced by 46% in the dexamethasone group. This strongly indicates that dexamethasone suppresses adrenal androgen synthesis and that in metformin-treated patients the adrenals are major contributors to circulating androgen levels. This is in accordance with a study of obese hyperinsulinaemic women (Martikainen et al., 1996). Notably, the suppression of adrenal androgen synthesis achieved by low-dose dexamethasone was only partial, as DHEA-S was within the reference range in all participants throughout the study. Nevertheless, FTI was reduced by 50% compared with the control group.
Dexamethasone is a diabetogenic drug and often promotes weight increase. However, in the present study, no adverse effects of dexamethasone 0.25 mg daily were observed on glucose homeostasis or serum lipid levels. Patients in both groups lost weight during the study, and there was no difference in the reduction of BMI between the groups. Diet, lifestyle advice and metformin might have prevented or counteracted adverse effects of dexamethasone commonly reported in previous studies. We believe, however, that the low dexamethasone dose used (0.25 mg daily) explains why no adverse effects were observed.
By and large, long-term, low-dose treatment with dexamethasone appears to be safe when used in PCOS women.
Unfortunately, we did not measure progesterone levels consecutively to detect ovulations. The frequency of menstruations during the 6-month study period almost doubled, with 7.5 versus 8.6 bleedings per year in the placebo and dexamethasone group, respectively. This difference between the groups did not reach statistical significance. The present study was not designed to and does not clarify whether the major reduction in circulating androgen levels leads to improved menstrual cyclicity. However, in women with CAH, an increased incidence of menstrual irregularities and PCOS was observed. Probably this phenomenon is secondary to increased adrenal androgen synthesis and elevated circulating androgen levels. This indicates that increased adrenal androgen synthesis may have a negative impact on ovarian function (New, 1993).
The reason for improved menstrual pattern with metformin treatment is not clear. In the largest prospective placebo-controlled trial to date, Fleming et al. (2002) showed that metformin improved ovulation in the absence of significant changes in androgen levels and insulin sensitivity. Hence, the improved menstrual pattern induced by metformin may have alternative explanations. In the same study, they showed that the least androgenic women responded best to metformin treatment. It is possible that reduction of androgen levels with dexamethasone may lead to an improved response to metformin in the PCOS women with the highest androgen levels. As could be expected, DHEA-S levels at inclusion correlated with reduction in androgen levels in the dexamethasone group. Hence, PCOS women with the highest adrenal androgen production, manifested by high levels of DHEA-S, achieve the greatest reductions in circulating androgen levels with additional dexamethasone. Both a longer period of observation and a larger study population will be needed to clarify if dexamethasone and metformin act synergistically in improving ovulatory dysfunction in PCOS patients.
To our knowledge, this is the first controlled study of dexamethasone treatment in a well-defined population of PCOS women. Low-dose dexamethasone treatment further decreased androgen levels in PCOS women treated with diet, lifestyle counselling and metformin. The large reduction in bioavailable testosterone and DHEA-S levels in the dexamethasone group indicates a role for adrenal androgen synthesis in the pathogenesis of PCOS. The adverse effects of dexamethasone reported in previous studies were not found in the present study, probably due to lower dosage of the drug. This study suggests that the combination of metformin and low-dose dexamethasone may be beneficial in the treatment of PCOS. Larger controlled studies are needed to address this question.
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Acknowledgements |
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References |
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Submitted on May 28, 2003; resubmitted on September 26, 2003; accepted on October 24, 2003.
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