Hum. Reprod. Advance Access originally published online on March 16, 2006
Human Reproduction 2006 21(7):1805-1808; doi:10.1093/humrep/del053
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Clomiphene citrate and dexamethazone in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective placebo-controlled study
Department of Obstetrics and Gynecology, Benha University Hospital, Benha, Egypt
1 To whom correspondence should be addressed at: 24 Gomhoria St. Mansura, Egypt. E-mail: elnashar53{at}hotmail.com
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Abstract |
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BACKGROUND: The aim of this work was to evaluate the efficacy of adding dexamethazone (DEX) (high dose, short course) to clomiphene citrate (CC) in CC-resistant polycystic ovary syndrome (PCOS) with normal dehydroepiandrosterone sulphate (DHEAS) in induction of ovulation. METHODS: Eighty infertile women with CC-resistant PCOS were randomly assigned into two groups. Group I: Clomiphene citrate 100 mg/day was given from day 3 to day 7 of the cycle and DEX 2 mg/day from day 3 to day 12 of the cycle. Group II: Same protocol of CC combined with placebo (folic acid tablets) was given from day 3 to day 12 of the cycle. The main outcome was ovulation. Secondary measures included number of follicles >18 mm endometrial thickness and pregnancy rate. Ovarian follicular response was monitored by transvaginal ultrasound. HCG 10 000 U was given when at least one follicle measured 18 mm, and timed intercourse was advised. RESULTS: There were no statistically significant differences between groups as regards age, duration of infertility, BMI, waist–hip ratio (WHR), menstrual pattern, hirsutism, serum DHEAS or day of HCG administration. The mean number of follicles >18 mm at the time of HCG administration and the mean endometrial thickness were significantly higher in the DEX group than in the placebo group (P < 0.05). Similarly, there were significantly higher rates of ovulation (75 versus 15%) (P < 0.001) and pregnancy (40 versus 5%) (P < 0.05) in the DEX group. Dexamethazone was very well tolerated as no patients complained of any side effect. There was a significant difference between the responders and non-responders in the presence of oligomenorrhea, amenorrhea or hirsutism. CONCLUSION: Induction of ovulation by adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent on age, period of infertility, BMI or WHR.
Key words: anovulation/clomiphene citrate/dexamethazone/infertility/polycystic ovary syndrome
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Introduction |
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Clomiphene citrate (CC) is the traditional first-line treatment for chronic anovulation that characterizes polycystic ovary syndrome (PCOS) (Lidor et al., 2000
). CC is accumulated in the body with low clearance rate and long half-life (5 days). Significant plasma concentrations of the active zu isomer of CC can be detected up to 6 weeks after administration. However, 20–25% of PCOS women fail to ovulate with incremental doses of CC. In addition, clinical data revealed a discrepancy between ovulation rates (75–80%) and conception rates (30–40%) during CC treatment (Yen, 1991). For these patients who do not respond to CC, there are a few limited adjunctive therapies that can be tried before moving on to gonadotrophin therapy or laparoscopic ovarian drilling including bromocriptine (in the presence of hyperpolactinaemia or galactorrhea), insulin sensitizers (to treat hyperinsulinaemia), oral contraceptives (for pretreatment suppression of LH), pulsatile GnRH (to preserve physiological interactive feedback) and extended doses of CC (Branigan and Estes, 1999). However, their usefulness is limited to specific abnormalities, and many women with CC resistance do not present with any overt signs of a treatable disorder. The use of corticosteroid for the treatment of ovulatory dysfunction was first reported in 1953 by Jones et al. and Greenblatt (Azziz et al., 1999). Parsanezhad et al. (2002) had reported the novel use of the dexamethazone (DEX) (high dose, short course) for inducing ovulation in anovulatory women with PCOS and normal dehydroepiandrosterone sulphate (DHEAS). Dexamethazone therapy during the follicular phase has been described without any side effects or serious sequelae (Trott et al., 1996). Our objective was to evaluate the efficacy of adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS in induction of ovulation. |
Materials and methods |
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Eighty infertile women were included from the patients attending the outpatient clinic of Benha University Hospital between March and December 2004. Institutional Review Board approval was obtained for this study at Benha University Hospital. Patients were diagnosed as having PCOS according to the Rotterdam criteria for diagnosis of PCOS (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004
). No patient showed hyperprolactinaemia, clinical evidence of hypercorticism or thyroid dysfunction. All patients had previously received CC and diagnosed as having CC resistance (failure of ovulation after three cycles of CC reaching the dose of 150 mg daily). Our inclusion criteria were: (i) age between 18 and 39 years; (ii) period of infertility >2 years; (iii) serum DHEAS within normal levels (80–400 µg/dl); and (iv) no treatment was taken during the last 2 months prior to the DEX treatment. Serum DHEAS was measured using ELISA technique. None of the other androgens were measured. Exclusion criteria were history of pelvic surgery or infertility factor other than anovulation. Hirsutism was diagnosed when the Ferriman and Gallwey score was >8. Sample size was calculated by using Graph pad Instate, version 3.01 software. The results of the previous study by Parsanezhad et al. (2002) that reported 88% success rate in 230 PCOS patients were considered. Twenty-four patients in each group were required to give the study a power of 80% and 
of 0.05. Patients were assigned randomly to receive CC and either DEX or placebo using closed dark envelopes. Allocation was done by a third party (nurse). The patient and the physician monitoring the cycles were blinded to the identity of each medication. Patients underwent physical examination. Weight, height and waist and hip circumferences were measured.
Amenorrheic patients began treatment with induction of menses using P-in-oil (100 mg). A transvaginal ultrasound examination was performed to exclude any pelvic pathology before treatment. Ultrasonography was performed using a transvaginal transducer (6.5 MHz, Siemens). On day 3, each patient underwent a baseline ultrasonographic examination. Clomiphene citrate, 100 mg, was given from day 3 until day 7. In addition to the CC, each patient was selected randomly to receive either DEX, 2 mg/day orally, in two divided doses (Dexazone 0.5 mg, Cairo, ARE) (group I), or a placebo (folic acid tablets) from day 3 until day 12 (group II). The dose and duration of DEX were chosen based on the previous study by Parsanezhad et al. (2002). Transvaginal ultrasound examination was done the next day after the end of CC and every other day according to the follicular size. HCG 10 000 U (Pregnyl; Organon, Holland) was given intramuscularly when at least one follicle measured 18 mm. Endometrial thickness was assessed on the day of HCG administration. Timed intercourse was advised 24–36 h after HCG injection. Two days after giving HCG, the patients were assessed for signs of ovulation (disappearance of pre-ovulatory follicle, fluid in the cul-de-sac and/or corpus luteum formation). Clinical pregnancy was diagnosed when a gestational sac was detected on transvaginal ultrasound examination 1 week after the missed period. Each participant had only one treatment cycle.
Outcome measures
The primary outcome was the ovulation rate in the treatment cycle. Secondary outcomes included number of follicles of >18 mm endometrial thickness and pregnancy rate.
Statistical analysis
The proportion of pregnancies that occurred in each group was compared with the Fisher’s exact test. t-Test and chi-squared test were used for other comparisons. A P-level of <0.05 was considered significant.
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Results |
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As summarized in Table I, there were no statistically significant differences between both groups as regards age, duration of infertility, BMI, waist–hip ratio (WHR), menstrual pattern, hirsutism, serum DHEAS or day of HCG administration. The mean number of follicles >18 mm at the time of HCG administration and the mean endometrial thickness were significantly higher in the DEX group than in the placebo group. Similarly, significantly higher rates of ovulation and pregnancy were seen in the DEX group. Dexamethazone was very well tolerated as no patients complained of any side effect. There were no significant differences between responders to DEX and non-responders as regards age, period of infertility, BMI and WHR (Table II). There was a significant difference between the responders and non-responders in the presence of oligomenorrhea, amenorrhea or hirsutism.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussion References |
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Parsanezhad et al. (2002)
had reported the novel use of the DEX (high dose, short course) for inducing ovulation in anovulatory women with PCOS and normal DHEAS. Dexamethazone was very well tolerated as no patients complained of any side effect. DEX therapy during the follicular phase has been described without any side effects or serious sequelae (Trott et al., 1996; Parsanezhad et al., 2002). Azziz et al. (1999) found that there were no differences in ovulatory response to DEX therapy between women with and without DHEAS excess. On the other hand, Daly et al. (1984) reported that the effect of DEX was largest in women with raised DHEAS levels. The recent systematic review of the Cochrane library reported that the use of DEX as an adjunct to CC appears promising (Beck et al., 2005). Clomiphene plus DEX treatment resulted in a significant improvement in the pregnancy rate (fixed OR = 11.3, 95% CI = 5.3–24, NNT = 2.7, 95% CI = 2.1–3.6) when compared to CC alone.
In the present study, significantly higher rate of ovulation was reported in the DEX group. Similarly, the mean number of follicles >18 mm at the time of HCG administration was significantly higher in the DEX group than in the placebo group. These results are in agreement with the results of Parsanezhad et al. (2002). There are a number of potential mechanisms by which DEX may affect ovarian function. Dexamethasone acts directly on the pituitary gland to suppress the action of estradiol, which may be involved in the process of induction of ovulation by glucocorticoid–clomiphene treatment (Terakawa et al., 1985). Dexamethasone may directly influence follicular development (Smith et al., 1994). Dexamethasone may act indirectly by increasing serum GH (Casanueva et al., 1990), serum insulin-like growth factor (IGF-1) (Miell et al., 1993) and consequently follicular fluid IGF-1 concentrations. Dexamethasone enhances the FSH-stimulated follicular steroid production. The synergism of DEX with FSH in follicular progesterone production and its inhibition by transforming growth factor-
(TGF-) indicate that glucocorticoid and TGF- interaction may be necessary for granulosa cell differentiation as follicle matures through pre-antral stages (Roy et al., 2003).
The mean endometrial thickness and the pregnancy rate in the DEX group were significantly higher than in the placebo group. The endometrium was of adequate thickness to allow implantation. The adverse endometrial effect seen with CC, which is augmented by the relatively long half-life of CC (5 days), is not seen with DEX. This result is consistent with the results of other studies (Trott et al., 1996; Parsanezhad et al., 2002). They compared the effects of DEX and CC on the endometrium and found that DEX produced a significantly thicker endometrium on the day of HCG administration than CC alone. The mean endometrial thickness for DEX was 8.8 mm versus 7.0 mm for CC alone. Casterlin et al. (2001) found that the majority of pregnancies (97%) occurred when the endometrial thickness was 7–11 mm, and the miscarriage rate doubles when the endometrial thickness measures <7 mm. Immunosuppression, leading to a favourable endometrial environment, was the rationale behind the administration of high-dose glucocorticoid from embryo transfer onwards, and higher implantation rates have been observed (Polak de Fried et al., 1993). Dexamethasone predominantly influenced ovarian response, and a major endometrial effect is unlikely with the low dose used, although a trend towards higher embryo implantation was observed.
In the present study, high-dose DEX during the follicular phase resulted in a high rate of ovulation (75%) with a pregnancy rate of 40%. All pregnancies were single. Parsanezhad et al. (2002) reported a higher ovulation rate (88%). This may be explained by the higher dose of CC (200 mg/day) given in their study. Compared to other methods of ovulation induction, the multiple pregnancy rate is approximately 10% with CC, almost entirely twins (Kousta et al., 1997), 15–25% with gonadotrophins (March, 1990) and about 2% with laparoscopic ovarian drilling (Felemban et al., 2000). Comparing DEX with other medical methods of ovulation induction in cases of CC-resistant PCOS, it is not as expensive as gonadotrophins and does not need intensive monitoring during and after treatment.
Comparing responders and non-responders to DEX combined with CC, there were no significant differences as regards age, period of infertility, BMI and WHR. Thus, we can give DEX to all patients with CC resistance, as its efficacy is not limited to a specific abnormality, and it can be used whatever the BMI. Achieving weight reduction is extremely difficult, particularly as the metabolic status of patients with PCOS conspires against weight loss (Kim et al., 2000). There was a significant difference between the responders and non-responders in the presence of oligomenorrhea, amenorrhea or hirsutism. Responders were more often amenorrheic than non-responders. About hirsutism, the population sample (n = 11) was too small to allow statistical analysis.
Some authors used low-dose DEX (0.5 mg/day) for 1 month (Diamant and Evron, 1981; Lobo et al., 1982; Daly et al., 1984; Hoffman and Lobo, 1985; Trott et al., 1996; Isaacs et al., 1997). Ovulation rates ranged from 55 to 80%, and pregnancy rates ranged from 8.3 to 49%. The high-dose, short-course regimen is more convenient to the patient with higher ovulation (75–88%) and pregnancy rates (40–40.5%) according to the results of the present study and that of Parsanezhad et al. (2002) respectively. DEX 2.0 mg from day 5 to day 14 of the cycle would seem more appropriate than 0.5 mg until further data on 0.5 mg are available (Beck et al., 2005). Further studies comparing the two regimens are required.
In conclusion, induction of ovulation by adding DEX (high dose, short course) to CC in CC-resistant PCOS with normal DHEAS is associated with no adverse anti-estrogenic effect on the endometrium and higher ovulation and pregnancy rates in a significant number of patients. Induction with DEX appears to be independent on age, period of infertility, BMI or WHR. Addition of DEX to CC is an effective, inexpensive and safe method for stimulating follicular development in CC-resistant PCOS and may be tried before gonadotrophins and laparoscopic ovarian drilling.
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References |
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|
TopAbstractIntroductionMaterials and methodsResultsDiscussion References |
|---|
Azziz R, Black V, Knochenhauer E, Hines G, Boots L. (1999) Ovulation after glucocorticoid suppression of adrenal androgens in the polycystic ovary syndrome is not predicted by the basal dehydroepiandrosterone sulfate level. J Clin Endocrinol Metab 84:946–950.
Beck JI, Boothroyd C, Proctor M, Farquhar C, Hughes E. (2005) Oral anti-oestrogens and medical adjuncts for subfertility associated with anovulation. Cochrane Database Syst Rev 1:CD002249.
Branigan ME and Estes A. (1999) Using oral contraceptives as a treatment for clomid-resistant patients. Fertil Steril 71:544–546.[CrossRef][Web of Science][Medline]
Casanueva FF, Burguera B, Muruais C, Dieguez C. (1990) Acute administration of glucocorticoids: a new and peculiar stimulus to growth hormone secretion in man. J Clin Endocrinol Metab 70:234–237.
Casterlin S, Hide B, Houserman VL, Long CA, Honea KL. (2001) Evaluation of effect of endometrial thickness on pregnancy outcome with clomiphene citrate induced pregnancy. Fertil Steril 76:S185–S186.
Daly DC, Walters CA, Soto-Albors CE, Tohan N, Riddick DH. (1984) A randomized study of dexamethasone in ovulation induction with clomiphene citrate. Fertil Steril 41:844–848.[Web of Science][Medline]
Diamant YZ and Evron S. (1981) Induction of ovulation by combined clomiphene citrate and dexamethasone treatment in clomiphene citrate nonresponders. Eur J Obstet Gynecol Reprod Biol 11:335–340.[CrossRef][Web of Science][Medline]
Felemban A, Tan SL, Tulandi T. (2000) Laparoscopic treatment of polycystic ovary syndrome with insulated needle cautery, a reappraisal. Fertil Steril 73:266–269.[CrossRef][Web of Science][Medline]
Hoffman D and Lobo RA. (1985) Serum dehydroepiandrosterone sulfate and the use of clomiphene citrate in anovulatory women. Fertil Steril 43:196–199.[Medline]
Isaacs JD Jr, Lincoln SR, Cowan BD. (1997) Extended clomiphene citrate (CC) and prednisone for the treatment of chronic anovulation resistant to CC alone. Fertil Steril 67:641–643.[CrossRef][Web of Science][Medline]
Kim LH, Taylor AE, Barbieri RL. (2000) Insulin sensitizers and polycystic ovary syndrome; can a diabetes medication treat infertility? Fertil Steril 73:1097–1098.[CrossRef][Medline]
Kousta E, White DM, Franks S. (1997) Modem use of clomiphene citrate in induction of ovulation. Hum Reprod Update 3:359–362.
Lidor AL, Goldenberg M, Cohen SB, Seidman DS, Mashiach S, Rabinovici J. (2000) Management of women with polycystic ovary syndrome who experienced premature luteinization during clomiphene citrate treatment. Fertil Steril 74:749–752.[CrossRef][Web of Science][Medline]
Lobo RA, Paul W, March CM, Granger L, Kletzky OA. (1982) Clomiphene and dexamethasone in women unresponsive to clomiphene alone. Obstet Gynecol 60:497–501.[Web of Science][Medline]
March CM. (1990) Human menopausal gonadotropins. Infertil Reprod Mod Clin North Am 1:59–78.
Miell JP, Taylor AM, Jones J, et al. (1993) The effects of dexamethasone treatment on immunoreactive and bioactive insulin-like growth factors (IGFs) and IGF-binding proteins in normal male volunteers. J Endocrinol 136:525–533.
Parsanezhad ME, Albozi S, Motazedian S, Gholamhossein S. (2002) Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial. Fertil Steril 78:1001–1004.[CrossRef][Web of Science][Medline]
Polak de Fried E, Blanco L, Lancuba S, et al. (1993) Improvement of clinical pregnancy rate and implantation rate of in-vitro fertilization-embryo transfer patients by using methylprednisolone. Hum Reprod 8:393–395.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. (2004) Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25.[Web of Science][Medline]
Roy S, Wang J, Yang P. (2003) Dexamethasone inhibits transforming growth factor- receptor (T R) mRNA expression in hamster preantral follicles: Possible association with NF-YA. Biol Repod 68:2180–2188.
Smith EP, Boyd J, Frank GR, Howe DM, Hurd WW, Randolph WW Jr., et al. (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 221:1056–1061.
Terakawa N, Shimizu I, Aono T, Tanizawa O, Matsumoto K. (1985) Dexamethasone suppresses estrogen action at the pituitary level without modulating estrogen receptor dynamics. J Steroid Biochem 23:385–388.[Medline]
Trott EA, Plouffe L Jr, Hansen K, Hines R, Brann DW, Mahesh VB. (1996) Ovulation induction in clomiphene resistant anovulatory women with normal dehydroepiandrosterone sulfate levels; beneficial effects of the addition of dexamethasone during the follicular phase. Fertil Steril 66:484–487.[Web of Science][Medline]
Yen SS. (1991) Chronic anovulation caused by peripheral endocrine disorders. In Yen SS and Jaffe RB (Eds.). Reproductive Endocrinology; Physiology, Pathophysiology, and Clinical Management 3rd edn (Saunders, Philadelphia) pp. 576–630.
Submitted on November 17, 2005; resubmitted on December 30, 2005; accepted on January 31, 2006.
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