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Administration of clomiphene citrate in patients with polycystic ovary syndrome, without inducing withdrawal bleeding, achieves comparable treatment characteristics and outcome

2009; Elsevier BV; Volume: 93; Issue: 6 Linguagem: Inglês

10.1016/j.fertnstert.2009.08.019

1556-5653

Jacob Farhi, Raoul Orvieto, Roy Homburg,

Ovarian cancer diagnosis and treatment

In an attempt to evaluate the effect of random timing of the start of clomiphene citrate (CC) treatment in anovulatory patients with polycystic ovary syndrome on treatment characteristics and outcome, with no regard to time of menstruation, we studied 291 women in their first CC treatment cycle. Duration of treatment was shorter by 2 days and number of leading follicles was higher when treatment was started late (7–29 days from starting a bleed, as compared with day 5), but no effect of starting day was observed on response rate to CC, maximal E2 level, endometrial thickness, and pregnancy rate. In an attempt to evaluate the effect of random timing of the start of clomiphene citrate (CC) treatment in anovulatory patients with polycystic ovary syndrome on treatment characteristics and outcome, with no regard to time of menstruation, we studied 291 women in their first CC treatment cycle. Duration of treatment was shorter by 2 days and number of leading follicles was higher when treatment was started late (7–29 days from starting a bleed, as compared with day 5), but no effect of starting day was observed on response rate to CC, maximal E2 level, endometrial thickness, and pregnancy rate. For nearly 50 years clomiphene citrate (CC) has been the established first-line therapy for women with absent or irregular ovulation associated with normal concentrations of endogenous E2 and FSH (World Health Organization group II, hypothalamic–pituitary dysfunction). A very large majority of these cases are associated with polycystic ovary syndrome (PCOS). Clomiphene citrate, an antiestrogenic compound, acts by blocking estrogen (E) receptors, particularly in the anterior hypothalamus, thereby signaling a lack of circulating Es and inducing a change in the pulsatile release of GnRH. This induces a discharge of FSH from the anterior pituitary and is often enough to set in motion the cycle of events leading to ovulation.Traditionally CC is given orally in a dose of 50–150 mg for 5 days starting on day 2, 3, 4, or 5 of a spontaneous or progestin-induced bleeding (1Thessaloniki ASRM/ESHRE-Sponsored PCOS Consensus Workshop GroupConsensus on infertility treatment related to polycystic ovary syndrome.Fertil Steril. 2008; 89: 505-522Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). The starting day of treatment within this range does not seem to influence results (2Wu C.H. Winkel C.A. The effect of therapy initiation day on clomiphene citrate therapy.Fertil Steril. 1989; 52: 564-568Crossref PubMed Scopus (85) Google Scholar). It is also established practice that if CC fails to produce ovulation in a given cycle, the cycle is abandoned, a progestin given, and withdrawal bleeding awaited so that an increased dose may be tried. Similarly, for a new patient for whom CC has been prescribed, before starting treatment, a withdrawal bleeding is induced or a spontaneous period awaited.The question we have examined is whether time can be saved and the process made more efficient, without affecting the outcome of treatment, by starting CC at a time unrelated to the onset of bleeding, on condition that no dominant follicle is present and ovulation has not occurred.Between January 1999 and December 2007, all couples presenting at the fertility clinics of two women's health centers were included in this cohort study. All couples were admitted and treated by the same gynecologist. All couples underwent a basic fertility workup that included past medical history of both partners, followed by a day-3–5 hormonal profile. Semen analysis was performed for all men. The ethics committee of the health insurance service to whom the fertility clinics belong gave the institutional review board approval for this study.Polycystic ovary syndrome was defined according to the Rotterdam criteria for diagnosis of PCOS (3Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar), based on the presence of two of the following three criteria: [1] oligo- and/or anovulation, [2] clinical and/or biochemical signs of hyperandrogenism, and [3] polycystic ovaries on ultrasound. A total of 291 women met the criteria and were assigned as a routine to induction of ovulation with CC as first-line treatment.All patients received the same starting dose of 100 mg/d for 5 days. Patients who were at the time of their menstrual period on the day treatment was assigned were started with CC from the fifth day of their cycle. Patients who came for treatment assignment at a later date in relation to their menstrual period had an evaluation of their ovarian activity on that day. This evaluation consisted of E2 and P blood levels and transvaginal ultrasound assessment of follicular growth and endometrial thickness. If no follicles >13 mm were present, E2 was <350 pmol/L, and P <5 nmol/L, CC treatment was started regardless of the time since their menstrual period. Clomiphene citrate treatment was followed by ultrasound scans and assessment of E2 and P levels starting 3 to 4 days after the last CC dose, and repeated evaluations were performed at 3–4-day intervals. Human chorionic gonadotrophin (Pregnyl [Schering Plough, Hod Hasharon, Israel] 10,000 IU [up to 2003]; Ovitrelle [Merck Serono Ltd., Herzlia, Israel] 250 mU [since 2003]) was administered once a leading follicle reached 18 mm. Cycle was defined as nonresponse if in three follow-up assessments at 3–4-day intervals no follicles reached 18 mm. Clinical pregnancy was diagnosed when a gestational sac was detected on transvaginal ultrasound examination 3 weeks after hCG administration. Each participant had only her first treatment cycle data used in this study.Commercial statistical software (SPSS 10.0 for Windows; SPSS, Chicago, IL) was used for data management and analysis. The results are presented as mean±SD, from Fisher's exact test, t-test, and χ2 test for comparisons. A P level of <.05 was considered significant.Treatment was started on the fifth day of the menstrual cycle in 145 women (group 1) and between days 7 and 29 of the cycle in 146 women (group 2). Patients' demographic and clinical characteristics were similar between groups (Table 1).Table 1Comparison between treatment cycle–related variables according to the CC initiation day.CC initiation dayParameter5≥7P valuePatients/cycles145146Age (y)26 ± 3.725 ± 3.90.3Patients with primary infertility103 (71)106 (73)0.7Duration of infertility (y)1.0 ± 1.01.2 ± 1.00.3Day-3 LH (IU/L)9.0 ± 6.08.3 ± 5.40.3Day-3 FSH (IU/L)5.9 ± 1.85.6 ± 1.90.1Nonresponders46 (31.7)33 (22.6)0.07Duration between CC and hCG (d)10.7 ± 2.98.8 ± 2.6< 0.001Follicles >14 mm on day of hCG1.48 ± 0.81.7 ± 1.00.02E2 level on day of hCG (pmol/L)1,536 ± 1,3801,683 ± 1,6390.5Endometrial thickness on day of hCG (mm)7.1 ± 2.16.8 ± 2.40.3Pregnancies16 (16.1)13 (11.5)0.3Multiple pregnancies10—Abortions12—Note: Values are number (percentage) or mean ± SD. Open table in a new tab Comparison of CC cycle characteristics revealed an increased response rate to CC with a shorter duration between CC and hCG administration and a relatively increased follicular recruitment (Table 1) in the CC responders who were started late (group 2) as compared with group 1. There were no between-group differences in the other treatment variables, including peak E2 level, endometrial thickness, and pregnancy rate per cycle.Since the introduction of CC for ovulation induction more than 40 years ago, little has changed in the dosage regimens, results, and timing of administration. The present study has clearly demonstrated that there is room for flexibility in the timing of administration of CC for patients with anovulatory PCOS. The rigid dogma of starting CC only after a spontaneous or progestin-induced bleeding no longer holds.For CC to be effective, endogenous E production must be present and the hypothalamic–pituitary–ovarian axis intact. In anovulatory PCOS, Es are produced at a steady rate without the undulations in concentrations effected by normal functioning of feedback mechanisms. The hypothalamic–pituitary–ovarian axis is intact, albeit dysfunctional. Hence, in the absence of follicular development a steady state of hormonal concentrations is present. When considering the mode of action of CC to induce a discharge of FSH, by blocking hypothalamic E receptors and invoking the negative feedback mechanism, there is indeed no logical reason why CC should only be given after a spontaneous or progestin-induced uterine bleed. This has proved to be the case in this study, in which there was no effect of starting day on response rate to CC, maximal E2 level, endometrial thickness, and pregnancy rate. Duration of treatment was shorter by 2 days, and the number of leading follicles was higher when treatment was started late.Our findings are in accordance with recent observations in cancer patients undergoing immature oocyte retrieval during the luteal phase for fertility preservation (4Demitras E. Elizur S.E. Holzer H. Gidoni Y. Son W.Y. Chian R.C. et al.Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients.Reprod Biomed Online. 2008; 17: 520-523Abstract Full Text PDF PubMed Scopus (107) Google Scholar). The observed ability to retrieve immature oocyte during the luteal phase and in the immediate follicular phase of the next cycle suggests that a "new" cohort of healthy antral follicles is actually present and ready to respond every 2 weeks and not 4, as was traditionally thought.These findings "legitimize" the starting of CC therapy, in the absence of a developing dominant follicle or proof of ovulation, at any time after a uterine bleed. This allows time saving in the initiation of treatment for newly diagnosed patients and justifies a "stair-step" protocol allowing a step-up in dose after a lack of response to CC, without having to induce a menstrual period (5Hurst B.S. Hickman J.M. Matthews M.L. Usadi R.S. Marshburn P.B. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovary syndrome.Am J Obstet Gynecol. 2009; 200 (510. e1–510.e4)Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). For nearly 50 years clomiphene citrate (CC) has been the established first-line therapy for women with absent or irregular ovulation associated with normal concentrations of endogenous E2 and FSH (World Health Organization group II, hypothalamic–pituitary dysfunction). A very large majority of these cases are associated with polycystic ovary syndrome (PCOS). Clomiphene citrate, an antiestrogenic compound, acts by blocking estrogen (E) receptors, particularly in the anterior hypothalamus, thereby signaling a lack of circulating Es and inducing a change in the pulsatile release of GnRH. This induces a discharge of FSH from the anterior pituitary and is often enough to set in motion the cycle of events leading to ovulation. Traditionally CC is given orally in a dose of 50–150 mg for 5 days starting on day 2, 3, 4, or 5 of a spontaneous or progestin-induced bleeding (1Thessaloniki ASRM/ESHRE-Sponsored PCOS Consensus Workshop GroupConsensus on infertility treatment related to polycystic ovary syndrome.Fertil Steril. 2008; 89: 505-522Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). The starting day of treatment within this range does not seem to influence results (2Wu C.H. Winkel C.A. The effect of therapy initiation day on clomiphene citrate therapy.Fertil Steril. 1989; 52: 564-568Crossref PubMed Scopus (85) Google Scholar). It is also established practice that if CC fails to produce ovulation in a given cycle, the cycle is abandoned, a progestin given, and withdrawal bleeding awaited so that an increased dose may be tried. Similarly, for a new patient for whom CC has been prescribed, before starting treatment, a withdrawal bleeding is induced or a spontaneous period awaited. The question we have examined is whether time can be saved and the process made more efficient, without affecting the outcome of treatment, by starting CC at a time unrelated to the onset of bleeding, on condition that no dominant follicle is present and ovulation has not occurred. Between January 1999 and December 2007, all couples presenting at the fertility clinics of two women's health centers were included in this cohort study. All couples were admitted and treated by the same gynecologist. All couples underwent a basic fertility workup that included past medical history of both partners, followed by a day-3–5 hormonal profile. Semen analysis was performed for all men. The ethics committee of the health insurance service to whom the fertility clinics belong gave the institutional review board approval for this study. Polycystic ovary syndrome was defined according to the Rotterdam criteria for diagnosis of PCOS (3Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop GroupRevised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome.Fertil Steril. 2004; 81: 19-25Scopus (0) Google Scholar), based on the presence of two of the following three criteria: [1] oligo- and/or anovulation, [2] clinical and/or biochemical signs of hyperandrogenism, and [3] polycystic ovaries on ultrasound. A total of 291 women met the criteria and were assigned as a routine to induction of ovulation with CC as first-line treatment. All patients received the same starting dose of 100 mg/d for 5 days. Patients who were at the time of their menstrual period on the day treatment was assigned were started with CC from the fifth day of their cycle. Patients who came for treatment assignment at a later date in relation to their menstrual period had an evaluation of their ovarian activity on that day. This evaluation consisted of E2 and P blood levels and transvaginal ultrasound assessment of follicular growth and endometrial thickness. If no follicles >13 mm were present, E2 was <350 pmol/L, and P <5 nmol/L, CC treatment was started regardless of the time since their menstrual period. Clomiphene citrate treatment was followed by ultrasound scans and assessment of E2 and P levels starting 3 to 4 days after the last CC dose, and repeated evaluations were performed at 3–4-day intervals. Human chorionic gonadotrophin (Pregnyl [Schering Plough, Hod Hasharon, Israel] 10,000 IU [up to 2003]; Ovitrelle [Merck Serono Ltd., Herzlia, Israel] 250 mU [since 2003]) was administered once a leading follicle reached 18 mm. Cycle was defined as nonresponse if in three follow-up assessments at 3–4-day intervals no follicles reached 18 mm. Clinical pregnancy was diagnosed when a gestational sac was detected on transvaginal ultrasound examination 3 weeks after hCG administration. Each participant had only her first treatment cycle data used in this study. Commercial statistical software (SPSS 10.0 for Windows; SPSS, Chicago, IL) was used for data management and analysis. The results are presented as mean±SD, from Fisher's exact test, t-test, and χ2 test for comparisons. A P level of <.05 was considered significant. Treatment was started on the fifth day of the menstrual cycle in 145 women (group 1) and between days 7 and 29 of the cycle in 146 women (group 2). Patients' demographic and clinical characteristics were similar between groups (Table 1). Note: Values are number (percentage) or mean ± SD. Comparison of CC cycle characteristics revealed an increased response rate to CC with a shorter duration between CC and hCG administration and a relatively increased follicular recruitment (Table 1) in the CC responders who were started late (group 2) as compared with group 1. There were no between-group differences in the other treatment variables, including peak E2 level, endometrial thickness, and pregnancy rate per cycle. Since the introduction of CC for ovulation induction more than 40 years ago, little has changed in the dosage regimens, results, and timing of administration. The present study has clearly demonstrated that there is room for flexibility in the timing of administration of CC for patients with anovulatory PCOS. The rigid dogma of starting CC only after a spontaneous or progestin-induced bleeding no longer holds. For CC to be effective, endogenous E production must be present and the hypothalamic–pituitary–ovarian axis intact. In anovulatory PCOS, Es are produced at a steady rate without the undulations in concentrations effected by normal functioning of feedback mechanisms. The hypothalamic–pituitary–ovarian axis is intact, albeit dysfunctional. Hence, in the absence of follicular development a steady state of hormonal concentrations is present. When considering the mode of action of CC to induce a discharge of FSH, by blocking hypothalamic E receptors and invoking the negative feedback mechanism, there is indeed no logical reason why CC should only be given after a spontaneous or progestin-induced uterine bleed. This has proved to be the case in this study, in which there was no effect of starting day on response rate to CC, maximal E2 level, endometrial thickness, and pregnancy rate. Duration of treatment was shorter by 2 days, and the number of leading follicles was higher when treatment was started late. Our findings are in accordance with recent observations in cancer patients undergoing immature oocyte retrieval during the luteal phase for fertility preservation (4Demitras E. Elizur S.E. Holzer H. Gidoni Y. Son W.Y. Chian R.C. et al.Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients.Reprod Biomed Online. 2008; 17: 520-523Abstract Full Text PDF PubMed Scopus (107) Google Scholar). The observed ability to retrieve immature oocyte during the luteal phase and in the immediate follicular phase of the next cycle suggests that a "new" cohort of healthy antral follicles is actually present and ready to respond every 2 weeks and not 4, as was traditionally thought. These findings "legitimize" the starting of CC therapy, in the absence of a developing dominant follicle or proof of ovulation, at any time after a uterine bleed. This allows time saving in the initiation of treatment for newly diagnosed patients and justifies a "stair-step" protocol allowing a step-up in dose after a lack of response to CC, without having to induce a menstrual period (5Hurst B.S. Hickman J.M. Matthews M.L. Usadi R.S. Marshburn P.B. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovary syndrome.Am J Obstet Gynecol. 2009; 200 (510. e1–510.e4)Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar).