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Oral contraceptives prior to clomiphene citrate increased ovulation in women with CC-resistant anovulation
ARTICLE IN PRESS REPRODUC TIVE ENDOCRINOLOGY & FERTILIT Y
Oral contraceptives prior to clomiphene citrate increased ovulation in women with CC-resistant anovulation Branigan EF, Estes MA. A randomized clinical trial of treatment of clomiphene citrate-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment. Am J Obstet Gynecol 2003; 188: 1424 ^1430.
OBJECTIVE To determine the e⁄cacy of pretreatment with oral contraceptives (OC) prior to clomiphene citrate (CC) in anovulatory women who previously failed to respond to CC treatment. DESIGN Randomized, non-blinded, controlled trial. Allocation was blocked, using sealed envelopes. SETTING Private fertility clinic in the USA. SUBJECTS A total of 48 women, aged o36 (mean 28) years, with anovulatory infertility, who failed to ovulate with CC treatment of at least 150 mg daily. All women had patent tubes, normal serum insulin, prolactin, thyroid stimulating hormone, and follicle stimulating hormone levels, serum dehydroepiandrosterone sulfate level r200 mg/mL, and a male partner with a normal semen analysis. Mean body mass index was 30 kg/m2. Three additional randomized women did not start treatment and were excluded from the analysis. INTERVENTION Randomization allocated 24 women to receive OC (0.03 mg ethinyl estradiol and 0.15 mg desogestrel) for 42^50 days, then, after withdrawal bleeding, CC 100 mg daily on cycle days 5^9. Another 24 women received the same dose of CC after 1^2 spontaneous cycles without treatment. Follicle growth was monitored and ovulation was con¢rmed with transvaginal ultrasonography. If ultrasound evidence of ovulation was ambiguous, a mid-luteal serum progesterone level was done. Up to ¢ve more cycles of CC treatment at the same dose were permitted, but only if the woman ovulated in the previous cycle.
1361^259X/$ - see front matter r 2003 Published by Elsevier Ltd. doi:10.1016/j.ebobgyn.2004.01.002
MAIN OUTCOME MEASURES Ovulation, cumulative clinical pregnancy, change in serum hormone levels.
MAIN RESULTS In the ¢rst treatment cycle, ovulation occurred in 17/24 women (71%) in the OC^ CC group and 2/24 (8%) in the CC group (o0.0001, relative risk 8, 95% CI 3^31, number needed to treat with OC to achieve ovulation in one additional woman is 2, CI 1^3)*. The women in the OC^CC group attempted a total of 62 treatment cycles, of which 65% were ovulatory, while the women in the CC group attempted 27 cycles, of which 11% were ovulatory. The cumulative pregnancy rate was 13/24 (54%) in the OC^CC group, compared to 1/24 (4%) in the CC group ( p = 0.0001, RR 13, CI 3^75)*. There was one spontaneous abortion in each group (thus no ongoing pregnancy in the CC group) and three twin gestations (25% of ongoing pregnancies) in the OC^ CC group. In the CC group, there was no change in mean serum hormone levels from baseline to day 3 of the ¢rst CC cycle; however, in the OC^CC group, mean serum levels of 17b-estradiol, luteinizing hormone, testosterone, and androstenedione were signi¢cantly lower than baseline after OC treatment.
CONCLUSION Pretreatment with oral contraceptives improved the ovulation rate with clomiphene citrate treatment in anovulatory women who were considered clomiphene citrate resistant. *Calculated from data in article.
Evidence-based Obstetrics and Gynecology (2004) 6, 29^30
29
ARTICLE IN PRESS Commentary Ovulatory dysfunction is present in approximately 15^25% of couples presenting for an infertility evaluation. The great majority of women with anovulation falls into the WHO group II category, which is characterized by evidence of endogenous estrogen activity and a distinctive gonadotropin pattern revealing an elevated luteinizing hormone (LH) and normal or low follicle stimulating hormone (FSH) output. These women present with a variety of menstrual disorders, ranging from an inadequate luteal phase to oligomenorrhea and amenorrhea. However, the presence of estrogen production is demonstrated by the occurrence of spontaneous bleeding or progesterone-induced withdrawal bleeding. Most women with WHO group II anovulatory infertility are diagnosed as having polycystic ovary syndrome (PCOS). In these infertile women, clomiphene citrate (CC) induction of ovulation has been used as the primary mode of therapy. However, a marked discrepancy exists between the high ovulation rate (70 ^ 80%) and the lower conception rate (30 ^ 40%) with CC usage. In addition, about 20 ^25% of women are CC-resistant, i.e., they fail to ovulate.Causes for these phenomena proposed in the early literature included anti-estrogenic e¡ects on the cervical mucus and the endometrium but, more recently, interest has been focused on detrimental e¡ects on the follicle/oocyte and increased early pregnancy loss (including subclinical abortions).1 The latter two conditions have been linked to the excessive LH secretion frequently encountered in women with PCOS. Some studies have reported an association of increased LH during the follicular phase with detrimental e¡ects on reproductive function, such as irregular menstrual cycles, anovulation, infertility, and miscarriage.2 Excessive LH levels may be responsible for the abnormal follicular dynamics encountered in women with PCOS and may also, directly or indirectly, hasten late follicular phase meiotic maturation.This concern should be stressed, considering that the main mode of action of CC is to boost FSH concentrations in the early follicular phase but, unfortunately, it also raises LH levels at this apparently critical stage. For women who already have a high baseline LH level, the additional production of LH may seriously compromise their chances of ovulating and conceiving.2 Interestingly, the present study, using an appropriate study design but a limited sample size, showed excellent rates of ovulation and pregnancy in CC-resistant women when pretreatment with oral contraceptives was given for 2 months prior to CC. Unfortunately, the body mass index of the women investigated was not considered in this study. From their results, the authors stressed that the androgen changes seemed to be
30
Evidence-based Obstetrics and Gynecology (2004) 6, 29^30
the most important of the endocrine profile changes for the determination of whether ovulation would occur. However, this conclusion was based on a small number of samples. Considering the above evidence and the fact that LH stimulates theca cell androgen production, the LH hypothesis seems worthy of consideration. In fact, the administration of a progestogen prior to CC treatment in CC-resistant women has been successful in some cases; the women whose LH levels fell became responsive to CC and those whose LH levels were not suppressed remained unresponsive. This finding notwithstanding, oral contraceptives may also decrease adrenal androgen production and estrogens have a direct effect on the liver to increase sex hormone-binding globulin; the result is a reduction in free testosterone levels. Whatever the mechanism involved, the use of oral contraceptives followed by CC in women who previously were CC-resistant may be a useful tool in clinical practice. However, a better definition of candidates for this approach seems necessary, considering the mechanism of action of CC. CC acts at the level of the hypothalamus, via its capacity as an antiestrogen, by displacing estrogen from estrogen receptor sites and interfering with the presumptive negative feedback of endogenous estrogens. Interestingly, in this study, the decrease in estradiol levels associated with oral contraceptive pretreatment was considered responsible for the improved response; further studies are warranted in this respect. In the meantime, it should not be forgotten that, according to recent reports, high singleton live birth rates are obtained following classical ovulation induction in women with normogonadotropic anovulatory infertility.3 Juan Balasch MD University of Barcelona, Barcelona, Spain
Literature cited 1. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996; 2: 483^506. 2. Homburg R. Adverse effects of luteinizing hormone on fertility: fact or fantasy. Baillie're’s Clin Obstet Gynaecol 1998; 12: 555^563. 3. Eijkemans MJC, Imani B, Mulders AGMGJ et al. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod 2003; 18: 2357^2362.
Oral contraceptives prior to clomiphene citrate increased ovulation in women with CC-resistant anovulation Branigan EF, Estes MA. A randomized clinical trial of treatment of clomiphene citrate-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment. Am J Obstet Gynecol 2003; 188: 1424 ^1430.
OBJECTIVE To determine the e⁄cacy of pretreatment with oral contraceptives (OC) prior to clomiphene citrate (CC) in anovulatory women who previously failed to respond to CC treatment. DESIGN Randomized, non-blinded, controlled trial. Allocation was blocked, using sealed envelopes. SETTING Private fertility clinic in the USA. SUBJECTS A total of 48 women, aged o36 (mean 28) years, with anovulatory infertility, who failed to ovulate with CC treatment of at least 150 mg daily. All women had patent tubes, normal serum insulin, prolactin, thyroid stimulating hormone, and follicle stimulating hormone levels, serum dehydroepiandrosterone sulfate level r200 mg/mL, and a male partner with a normal semen analysis. Mean body mass index was 30 kg/m2. Three additional randomized women did not start treatment and were excluded from the analysis. INTERVENTION Randomization allocated 24 women to receive OC (0.03 mg ethinyl estradiol and 0.15 mg desogestrel) for 42^50 days, then, after withdrawal bleeding, CC 100 mg daily on cycle days 5^9. Another 24 women received the same dose of CC after 1^2 spontaneous cycles without treatment. Follicle growth was monitored and ovulation was con¢rmed with transvaginal ultrasonography. If ultrasound evidence of ovulation was ambiguous, a mid-luteal serum progesterone level was done. Up to ¢ve more cycles of CC treatment at the same dose were permitted, but only if the woman ovulated in the previous cycle.
1361^259X/$ - see front matter r 2003 Published by Elsevier Ltd. doi:10.1016/j.ebobgyn.2004.01.002
MAIN OUTCOME MEASURES Ovulation, cumulative clinical pregnancy, change in serum hormone levels.
MAIN RESULTS In the ¢rst treatment cycle, ovulation occurred in 17/24 women (71%) in the OC^ CC group and 2/24 (8%) in the CC group (o0.0001, relative risk 8, 95% CI 3^31, number needed to treat with OC to achieve ovulation in one additional woman is 2, CI 1^3)*. The women in the OC^CC group attempted a total of 62 treatment cycles, of which 65% were ovulatory, while the women in the CC group attempted 27 cycles, of which 11% were ovulatory. The cumulative pregnancy rate was 13/24 (54%) in the OC^CC group, compared to 1/24 (4%) in the CC group ( p = 0.0001, RR 13, CI 3^75)*. There was one spontaneous abortion in each group (thus no ongoing pregnancy in the CC group) and three twin gestations (25% of ongoing pregnancies) in the OC^ CC group. In the CC group, there was no change in mean serum hormone levels from baseline to day 3 of the ¢rst CC cycle; however, in the OC^CC group, mean serum levels of 17b-estradiol, luteinizing hormone, testosterone, and androstenedione were signi¢cantly lower than baseline after OC treatment.
CONCLUSION Pretreatment with oral contraceptives improved the ovulation rate with clomiphene citrate treatment in anovulatory women who were considered clomiphene citrate resistant. *Calculated from data in article.
Evidence-based Obstetrics and Gynecology (2004) 6, 29^30
29
ARTICLE IN PRESS Commentary Ovulatory dysfunction is present in approximately 15^25% of couples presenting for an infertility evaluation. The great majority of women with anovulation falls into the WHO group II category, which is characterized by evidence of endogenous estrogen activity and a distinctive gonadotropin pattern revealing an elevated luteinizing hormone (LH) and normal or low follicle stimulating hormone (FSH) output. These women present with a variety of menstrual disorders, ranging from an inadequate luteal phase to oligomenorrhea and amenorrhea. However, the presence of estrogen production is demonstrated by the occurrence of spontaneous bleeding or progesterone-induced withdrawal bleeding. Most women with WHO group II anovulatory infertility are diagnosed as having polycystic ovary syndrome (PCOS). In these infertile women, clomiphene citrate (CC) induction of ovulation has been used as the primary mode of therapy. However, a marked discrepancy exists between the high ovulation rate (70 ^ 80%) and the lower conception rate (30 ^ 40%) with CC usage. In addition, about 20 ^25% of women are CC-resistant, i.e., they fail to ovulate.Causes for these phenomena proposed in the early literature included anti-estrogenic e¡ects on the cervical mucus and the endometrium but, more recently, interest has been focused on detrimental e¡ects on the follicle/oocyte and increased early pregnancy loss (including subclinical abortions).1 The latter two conditions have been linked to the excessive LH secretion frequently encountered in women with PCOS. Some studies have reported an association of increased LH during the follicular phase with detrimental e¡ects on reproductive function, such as irregular menstrual cycles, anovulation, infertility, and miscarriage.2 Excessive LH levels may be responsible for the abnormal follicular dynamics encountered in women with PCOS and may also, directly or indirectly, hasten late follicular phase meiotic maturation.This concern should be stressed, considering that the main mode of action of CC is to boost FSH concentrations in the early follicular phase but, unfortunately, it also raises LH levels at this apparently critical stage. For women who already have a high baseline LH level, the additional production of LH may seriously compromise their chances of ovulating and conceiving.2 Interestingly, the present study, using an appropriate study design but a limited sample size, showed excellent rates of ovulation and pregnancy in CC-resistant women when pretreatment with oral contraceptives was given for 2 months prior to CC. Unfortunately, the body mass index of the women investigated was not considered in this study. From their results, the authors stressed that the androgen changes seemed to be
30
Evidence-based Obstetrics and Gynecology (2004) 6, 29^30
the most important of the endocrine profile changes for the determination of whether ovulation would occur. However, this conclusion was based on a small number of samples. Considering the above evidence and the fact that LH stimulates theca cell androgen production, the LH hypothesis seems worthy of consideration. In fact, the administration of a progestogen prior to CC treatment in CC-resistant women has been successful in some cases; the women whose LH levels fell became responsive to CC and those whose LH levels were not suppressed remained unresponsive. This finding notwithstanding, oral contraceptives may also decrease adrenal androgen production and estrogens have a direct effect on the liver to increase sex hormone-binding globulin; the result is a reduction in free testosterone levels. Whatever the mechanism involved, the use of oral contraceptives followed by CC in women who previously were CC-resistant may be a useful tool in clinical practice. However, a better definition of candidates for this approach seems necessary, considering the mechanism of action of CC. CC acts at the level of the hypothalamus, via its capacity as an antiestrogen, by displacing estrogen from estrogen receptor sites and interfering with the presumptive negative feedback of endogenous estrogens. Interestingly, in this study, the decrease in estradiol levels associated with oral contraceptive pretreatment was considered responsible for the improved response; further studies are warranted in this respect. In the meantime, it should not be forgotten that, according to recent reports, high singleton live birth rates are obtained following classical ovulation induction in women with normogonadotropic anovulatory infertility.3 Juan Balasch MD University of Barcelona, Barcelona, Spain
Literature cited 1. Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update 1996; 2: 483^506. 2. Homburg R. Adverse effects of luteinizing hormone on fertility: fact or fantasy. Baillie're’s Clin Obstet Gynaecol 1998; 12: 555^563. 3. Eijkemans MJC, Imani B, Mulders AGMGJ et al. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility (WHO 2). Hum Reprod 2003; 18: 2357^2362.