Hum. Reprod. Advance Access originally published online on July 10, 2006
Human Reproduction 2006 21(11):2823-2829; doi:10.1093/humrep/del267
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Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study
1 Department of Obstetrics & Gynecology, University ‘Magna Graecia’ of Catanzaro, Catanzaro 2 Department of Molecular & Clinical Endocrinology and Oncology 3 Department of Clinical and Experimental Medicine 4 Department of Obstetrics & Gynecology, University ‘Federico II’ of Naples, Naples and 5 Department of Endocrinology, University of Palermo, Palermo, Italy
6 To whom correspondence should be addressed at: Department of Gynecology & Obstetrics, University ‘Magna Graecia’ of Catanzaro, Via M. Greco 10, 88100 Catanzaro, Italy. E-mail: stefanopalomba{at}tin.it
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Abstract |
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BACKGROUND: Previous data on the efficacy of clomiphene citrate, the most commonly used drug for treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS), have shown a discrepancy between ovulation and pregnancy rates. In the present subanalysis (of a larger previously published randomized controlled trial), the effect of clomiphene citrate on several ultrasonographic markers of uterine receptivity in PCOS patients who ovulated under treatment was studied. METHODS: Thirty-three PCOS women who ovulated under 150 mg daily clomiphene citrate and 33 healthy controls were studied. Uterine, subendometrial and endometrial blood flows, endometrial thickness and pattern were assessed using serial ultrasonographic assessments. The data were analysed before and after grouping the clomiphene citrate-stimulated ovulatory cycles for reproductive outcome [unfavourable (ovulation alone or early pregnancy loss) or favourable outcome (clinical pregnancy and/or live birth)]. RESULTS: Both before and during treatment, uterine vascularity assessed at all sites was significantly lower in the PCOS group than in controls. Endometrial thickness and pattern were impaired in the PCOS group under clomiphene citrate treatment. A significant difference in all ultrasonographic parameters was observed between cycles ending in unfavourable versus those ended in favourable outcome. CONCLUSIONS: Clomiphene citrate administration alters several surrogate ultrasonographic parameters of uterine receptivity, and this effect could be crucial for its efficacy.
Key words: anovulation/clomiphene citrate/Doppler/PCOS/velocimetry
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Introduction |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionAcknowledgementsReferences |
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A recent randomized controlled trial (RCT) compared the effectiveness of clomiphene citrate and metformin for inducing ovulation in anovulatory patients with polycystic ovary syndrome (PCOS) (Palomba et al., 2005
). This clinical trial confirmed that clomiphene citrate is effective in inducing ovulation in 
70% of cases (Palomba et al., 2005). However, despite this high ovulation rate, the treatment was related to a pregnancy rate of only 30–40% (Hughes et al., 2000; Palomba et al., 2005).
The exact explanation for the discrepancy between ovulation and pregnancy rates in anovulatory patients who receive clomiphene citrate is unknown, but several hypotheses have been suggested (Kousta et al., 1997). Various studies have shown that clomiphene citrate exerts an anti-estrogenic action either on endometrial development/receptivity to blastocyst implantation or on the quality of the oocytes/embryos or on the cervical mucus (Kousta et al., 1997). However, to date it is not completely clear the relative impact of each of these effects on human reproduction (Schwartz et al., 1997).
Based on these considerations, the present study was carried out in order to evaluate the uterine effects, if any, of clomiphene citrate in anovulatory women with PCOS using several surrogate ultrasonographic parameters of uterine receptivity.
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Subjects and methods |
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The procedures used were in accordance with the guidelines of the Helsinki Declaration on human experimentation. The study was approved by the Institutional Review Board of the University ‘Magna Graecia’ of Catanzaro. The purpose of the protocol was carefully explained to each woman, and written consent was obtained from them before beginning the study.
Patients and protocol
A total of 41 of 50 non-obese primary infertile anovulatory women with PCOS (Zawadzki and Dunaif, 1992) initially enrolled in a wider RCT (Palomba et al., 2005) agreed to participate in the current subanalysis (PCOS group). Briefly, patients aged <20 or >34 years, with a body mass index (BMI, kg/m2) higher than 30, affected by major medical conditions, and/or current or previous (within the last 6 months) users of same hormonal drugs were excluded. Women who intended to start a diet or a specific physical activity program, with no uterine bleeding after progesterone challenge test, affected by organic pelvic diseases, previous pelvic surgery, suspected peritoneal factor infertility, tubal or male factor infertility were also excluded. All subjects had a normal physical activity, and none drank alcoholic beverages.
Age- and BMI-matched healthy volunteer females with regular menstrual cycles were enrolled as controls (control group). The normal menstrual cycle was diagnosed after a 3-month pre-study period. Every day during this period, each woman recorded characteristics of her menses in a daily diary. A normal menstrual cycle was defined as cyclic uterine bleeding with duration of 4–5 days and a frequency of 26–32 days/month. The quantity of blood flow was defined as ‘normal’ subjectively by each woman and objectively using a serum haemoglobin assay. At entry, the normal ovulatory state was confirmed by transvaginal ultrasonography (TV-USG) and plasma progesterone levels detected during the luteal phase of the cycle. Women with clinical and/or biochemical hyperandrogenism alone were excluded from the control group.
At study entry, in all subjects, a venous blood samples was drawn to evaluate a complete hormonal and metabolic assessment, the modified Ferriman–Gallwey score was calculated, the patients’ daily physical activities and the anthropometric measurements [height, weight, BMI and waist to hip ratio (WHR)] were assessed, and a TV-USG was performed (Palomba et al., 2005).
Women were treated with clomiphene citrate (Serophene, Serono, Rome, Italy) at dosage of 150 mg (3 tablets/day) for 5 days starting from the 3rd day of progesterone-induced withdrawal bleeding. The duration of the treatment was six cycles. The patients were instructed to have intercourses every two days for four times from USG detection of a follicle with a mean diameter of at least 18 mm. During the study, the subjects were instructed to follow their usual diet and physical activity. Ovulation, pregnancy, abortion and live birth rates were evaluated in each woman; these results have been reported elsewhere (Palomba et al., 2005).
Each subject underwent serial TV-USG examinations by the same experienced operator (T.R.) and, as detailed below, uterine blood flow and endometrial thickness, pattern and vascularity were assessed. To study the eventual relationship between uterine effects of clomiphene citrate administration and reproductive outcomes, the data were analysed considering all ovulatory cycles induced by clomiphene citrate treatment and categorizing them according to different outcome, that is unfavourable (cycles ended in ovulation alone or early pregnancy loss) and favourable (clinical pregnancy and/or live birth) outcome.
Ultrasonographic and Doppler assessments
Serial TV-USG examinations were performed using an ultrasonic scanner (Aplio, Toshiba Medical Systems, Rome, Italy) equipped with a 7.5 MHz vaginal probe between 8:00 and 11:00 a.m. thus avoiding the effects of circadian rhythms on uterine blood flow, before or after spontaneous uterine contractions, after a rest of at least 15 min, at empty bladder to minimize any external effects on blood flow. Just before TV-USG examination, systolic and diastolic blood pressures and heart rate were recorded, and, in the cases of abnormal values, the examination was delayed until these parameters were normalized.
In the PCOS group, TV-USG scans were performed before and throughout treatment (Palomba et al., 2005) according to the following protocol. During a pre-study period and before treatment, scans were obtained at the 3rd, 14th and 21st day after the onset of progesterone-induced menses; during treatment, scans were made firstly in the early follicular phase (3rd day after the onset of progesterone-induced menses), then, every 3 days beginning the 7th day after the onset of treatment and daily when a follicle achieved at least 16 mm, and, finally, 7 days before expected menses. The ovulation was retrospectively defined on the basis of follicular dimension decrease and by the presence of liquid in the cul-de-sac and confirmed by plasma progesterone assay. In the control group, scans were also obtained on three different occasions, that is 3rd day of the menstrual cycle, 14 and 7 days before the expected menses.
The endometrium was measured by longitudinal scans including the whole endometrium at the point of its maximum thickness. Both endometrial outer limits were included in the measurement, assuming that the amount of intracavity fluid was not significant. In all cases, a mean of three measurements was used.
The endometrial pattern was studied in periovulatory and mid-luteal phases and subjectively evaluated by the comparison with the echogenicity of the surrounding myometrium. In the periovulatory phase, it was described as ‘homogeneous pattern’ or as ‘triple-line pattern’. The ‘homogeneous pattern’ was defined as a single hyperechoic, hypoechoic or isoechoic layer with absent or poorly defined central echogenic line, whereas the ‘triple-line pattern’ was defined as a multilayered endometrium consisting of a prominent outer and inner hyperechoic line and inner hypoechoic regions. In mid-luteal phase, the endometrial echogenicity pattern was classified in four grades: (i) grade 1, hypoechoic pattern with a minimal hyperechoic component and a distinct lumen; (ii) grade 2, about 50% hypoechoic and 50% hyperechoic pattern with a distinct lumen; (iii) grade 3, predominantly hyperechoic pattern with a minimal central hypoechoic area and a distinct lumen; and (iv) grade 4, a totally hyperechoic pattern. The grade 4 pattern was considered satisfactory for a normal luteal phase, and for this reason, the mid-luteal phase endometrial echogenicity patterns were categorized as ‘high-grade pattern’, corresponding to grade 4, and ‘low-grade pattern’, corresponding to grades 1–3.
Ascending main branches of the uterine arteries on both sides of the cervico-uterine junction, at the level of the internal os in a longitudinal plane, and before entering the uterus were visualized using a colour Doppler system. Uterine flow was studied by positioning a sample volume over the area of maximum colour intensity and by activating the pulsed Doppler. Using a power Doppler system, subendometrial and endometrial blood flows were visualized. Doppler flow indices were studied at random on the subendometrial and endometrial areas with maximum colour intensity; the lowest values concerning flow resistance were recorded. For each examination, the resistance index (RI) was calculated electronically by the machine on three consecutive waveforms of good quality and used as an angle-independent index of blood flow impedance.
For each patient, images with colour signals (from uterine fundus to the cervico-uterine junction at the level of the internal os in a longitudinal plane) were recorded and then acquired using an advanced digital camera and processed. Successively, the extension of vascularity was studied by use of advanced image analysis software (Image-Pro Plus 4.5, Media Cybernetics Inc., Silver Spring, MD, USA). Specifically, an operator not aware of who the images belongs to, calculated the extension of vascularity as a ratio between areas in which blood flows were detected (identified as coloured areas by use of the power Doppler) and the total selected subendometrial and endometrial areas. Endometrial borders were set as the outer limits of the hyperechogenic myometrium–endometrium interface, whereas subendometrial areas were considered arbitrarily 1 cm around the endometrial borders.
The bias because of inter-observer error was avoided because the ultrasonographic assessments were performed by a single operator. The intra-observed error was evaluated in 5 of 30 healthy controls by three consecutive measurements at 15 min intervals and calculated using analysis of variance (ANOVA). The intra-observer coefficients of variation (CVs) for the endometrial thickness and for uterine, subendometrial and endometrial blood flow were, respectively, 4, 8, 10 and 10%.
Statistical analysis
Data were expressed as mean ± SD. The Kolmogorov–Smirnov statistic with a Lilliefors significance level was used for testing normality for continuous variables. These were analysed with the paired and the unpaired t-test and with the ANOVA for repeated measures with Bonferroni test for the post hoc analysis, when appropriate. For categorical variables, the Pearson Chi-square test and the Fisher’s exact test were applied as required.
Data were also analysed with the use of general linear model (GLM) repeated-measures procedure (GLM Repeated Measures, 2003) that provides analysis of groups of related variables that represent different measurements of the same attribute (within-subject factor). The model included between-subjects factors that divided the population into groups on the basis of duration of clomiphene citrate administration to investigate its effect in the variance.
A P-value of 0.05 or less was considered significant. The Statistics Package for Social Science (SPSS 14.0, 5 September 2005; SPSS Inc., Chicago, IL, USA) was used for statistical analyses.
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Results |
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A total of 8 of 41 PCOS patients were excluded for the following reasons: missed first follow-up visit (one patient), precocious treatment suspension (one patient), significant reduction in body weight after the first months of treatment (one patient), inadequate visualization of the endometrium at TV-USG for retroverted uterus (one patient) and grossly irregular ultrasonographic appearance of the myometrium (four patients). Thus, the results included in the present study were obtained from a total of 33 PCOS patients (and 33 controls). Specifically, the PCOS patients were studied at baseline for 33 anovulatory cycles and for 108 clomiphene citrate-stimulated ovulatory cycles, whereas the controls were evaluated for 33 spontaneous ovulatory cycles.
The clinical, hormonal and metabolic parameters detected in PCOS and in control patients are shown in Table I. No enrolled patient and, thus, no healthy BMI-matched control, was lean (BMI less than 18 kg/m2). At TV-USG examination, all PCOS patients had polycystic ovaries and satisfied the Rotterdam ESHRE/ASRM criteria (The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group, 2004). On the contrary, only 3/33 (9%) of the healthy controls showed polycystic ovaries (Balen et al., 2003).
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The clomiphene citrate treatment was generally well tolerated, and only one patient suspended the treatment for drug-related side effects. A detailed description of the data regarding the safety has been already reported (Palomba et al., 2005
). No difference between RI values evaluated on the right and left uterine arteries was observed in PCOS, either before and during treatment, or in control group (data not shown). At baseline, mean RI values were significantly (P < 0.05) higher in the PCOS group than in controls. In clomiphene citrate-stimulated ovulatory cycles, mean RI values were similar to those observed in PCOS patients at baseline and significantly (P < 0.05) higher in comparison with control cycles (Figure 1A).
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In clomiphene citrate-stimulated ovulatory cycles, the detection rate for subendometrial and endometrial blood flow, as well as the blood flow impedance on subendometrial and endometrial vessels, did not change in comparison with non-stimulated anovulatory cycles and was significantly (P < 0.05) reduced in comparison with spontaneous ovulatory cycles, whereas the extension of subendometrial and endometrial vascularity were significantly (P < 0.05) reduced in comparison with both non-stimulated anovulatory cycles and spontaneous ovulatory cycles (Table II). A complete description of the data regarding the detection rate for subendometrial and endometrial blood flows, the extension of vascularity at subendometrial and endometrial areas and the mean RI values on subendometrial and endometrial vessels are given in Table II.
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The endometrial thickness assessed in early follicular phase was not different between PCOS and control cycles. In PCOS patients, a significant (P < 0.05) increase in endometrial thickness was detected in periovulatory (5.84 ± 1.11 versus 11.12 ± 1.90, for anovulatory and clomiphene citrate-stimulated ovulatory cycles, respectively) and luteal phases (5.76 ± 1.16 versus 11.14 ± 2.01, for anovulatory and clomiphene citrate-stimulated ovulatory cycles, respectively) in clomiphene citrate-stimulated ovulatory cycles in comparison with non-stimulated cycles. In any period of the cycle, no difference was detected between clomiphene citrate-stimulated ovulatory cycles and control cycles (follicular phase: 5.97 ± 1.18 versus 6.10 ± 1.27, periovulatory phase: 11.12 ± 1.90 versus 11.37 ± 2.19, luteal phase: 11.14 ± 2.01 versus 11.16 ± 3.12, for PCOS and control group, respectively).
As expected, in no case was a triple-line and a high-grade endometrial pattern observed in PCOS patients at baseline assessment. A significant difference between clomiphene citrate-stimulated ovulatory cycles and control cycles was detected in the percentage of cycles with triple-line [69/108 (63.9%) versus 28/33 (84.8%) for clomiphene citrate-stimulated ovulatory cycles and control cycles, respectively; P = 0.023] and with high-grade [62/108 (57.4%) versus 26/33 (78.8%) for clomiphene citrate-stimulated ovulatory cycles and control cycles, respectively; P = 0.027] endometrial pattern.
A significant (P < 0.05) influence of the duration of clomiphene citrate administration was detected by the GLM analysis. In fact, after repeated clomiphene citrate-stimulated cycles, all parameters of subendometrial and endometrial vascularization were worse, even if not significant (data not shown). On the other hand, a progressive reduction in endometrial thickness was observed throughout clomiphene citrate-stimulated ovulatory cycles (follicular phase: 6.23 ± 1.65, 6.14 ± 1.62, 5.99 ± 1.53, 5.59 ± 1.41, 5.4 ± 1.39, 5.31 ± 1.26; periovulatory phase: 12.07 ± 1.87, 11.63 ± 1.84, 11.59 ± 1.79, 10.91 ± 1.74, 10.80 ± 1.73, 10.62 ± 1.69; and luteal phase: 12.10 ± 1.89, 11.68 ± 1.75, 11.61 ± 1.72, 10.88 ± 1.68, 10.73 ± 1.69, 10.59 ± 1.60, for the six cycles assessment, respectively). Endometrial thickness was statistically (P < 0.05) thinner in periovulatory and luteal phase at the 4th cycle of clomiphene citrate administration in comparison with the previous clomiphene citrate-stimulated cycles.
At the end of the 6-month study, 10 patients had a favourable outcome (clinical pregnancy and/or live birth), whereas 23 patients had unfavourable outcomes. In particular, 18 and 5 PCOS patients had ovulatory cycles alone and early pregnancy loss, respectively.
After grouping the PCOS patients who ovulated under clomiphene citrate for different reproductive outcome, no difference in any clinical, hormonal, and metabolic parameter was detected between subjects with unfavourable and favourable outcomes (data not shown).
Uterine blood impedance and subendometrial and endometrial vascularization (detection rate, extension of vascularity and blood flow impedance) were significantly (P < 0.05) increased in cycles that ended in favourable outcomes in comparison with those that ended in unfavourable outcome (Table III, Figure 1B).
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Even thought no difference was detected at early follicular (6.03 ± 1.09 versus 5.47 ± 1.84), at periovulatory (11.35 ± 1.84 versus 8.91 ± 0.82) and at luteal phase (11.34 ± 1.98 versus 9.12 ± 0.82), the endometrium was significantly (P < 0.05) thicker in clomiphene citrate-stimulated ovulatory cycles that ended in favourable outcome in comparison with those that ended in unfavourable outcome. Similarly, at periovulatory and mid-luteal phase assessments, the percentage of cycles with triple-line [59/98 (60.2%) versus 10/10 (100%)] and with high-grade [53/98 (54.1%) versus 9/10 (90%)] endometrial pattern was significantly (P < 0.05) lower in clomiphene citrate-stimulated ovulatory cycles that ended in unfavourable outcome than in those that ended in favourable outcome.
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Discussion |
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It is generally accepted that clomiphene citrate reduces uterine receptivity and, thus, the chances of conception (Kousta et al., 1997
). Uterine receptivity is primarily maintained by the endometrium that prepares for, and sustains, the embryo nidation. Because of invasive methodology related to the study of the endometrial biopsy specimen for predicting uterine receptivity (Noyes et al., 1995), several surrogate ultrasonographic parameters, including the assessment of uterine vascularization and endometrial characteristics, have been proposed (Friedler et al., 1996). To exclude some confounding factors influencing reproductive outcome, we studied a well-selected population of non-obese anovulatory PCOS patients. It is well known, in fact, that obesity influences human reproduction, so we excluded such patients from our study along with those who intended either to lose weight, start a diet or increase their physical activity; all factors which could possibly influence reproduction.
Our data clearly confirm (Battaglia et al., 1995; Aleem and Predanic, 1996; Zaidi et al., 1998) that anovulatory PCOS women have an alteration in uterine vascularity. In fact, blood impedance of the uterine artery and of subendometrial and endometrial vessels were significantly higher in comparison with healthy controls. In addition, throughout clomiphene citrate treatment, even though PCOS patients ovulated, the vascular impedance appeared unchanged in comparison with pre-treatment values being again significantly higher than in the healthy controls.
Elevated flow impedance in the uterine arteries appears crucial for endometrial receptivity (Goswamy et al., 1988; Kurjak et al., 1991; Steer et al., 1994) being associated with a lower reproductive probability not only in patients affected by PCOS (Chappel and Howles, 1991) but also in patients with unexplained recurrent pregnancy loss (Habara et al., 2002).
Even though uterine arterial resistance changes might reflect uterine receptivity, a more accurate method is the evaluation of the extension of the vascularization in the subendometrial and endometrial regions (Chien et al., 2002). Chien et al. (2002) showed, in fact, that the pregnancy and implantation rates were related to subendometrial flow and vascular penetration, whereas no relationship was detected with vascular impedance indexes. Notably, our data on subendometrial and endometrial vascularity confirm that the extension of the vascularization pattern, detected with the use of power Doppler, is more sensible than the evaluation of vascular impedance. In fact, the blood flow impedance on subendometrial and endometrial vessels were impaired in PCOS patients but unchanged during clomiphene citrate administration. To the contrary, morphologic data on subendometrial/endometrial vascularization worsened after clomiphene citrate administration.
A possible explanation for this figure is that clomiphene citrate does not modify the metabolic alterations in PCOS, for example elevated androgen levels (Ajossa et al., 2002), and exerts a local anti-estrogenic action on the uterus reducing the modulation of sex hormone variations due to ovulation. In fact, uterine blood flow changes in normal and stimulated menstrual cycles are related with sex hormones variations (Battaglia et al., 1995; Habara et al., 2002) and estradiol acts on specific estrogen receptors of the uterine artery walls (Perrot-Applanat et al., 1988) thereby eliciting the release of nitric oxide, whose potent vasodilator action causes vasodilatation and improved blood flow (Gisclard et al., 1988).
Both endometrial thickness and pattern have also been considered markers for uterine receptivity and for pregnancy prediction (Yaman et al., 2000; Habara et al., 2002). In fact, a minimum endometrial thickness is necessary to achieve pregnancy and a triple-line pattern is associated with a significantly higher pregnancy rate (Fanchin et al., 2002).
Even if in PCOS patients ovulating under clomiphene citrate there was a lower percentage in triple-line and high-grade patterns than in controls, a significant reduction in endometrial thickness was observed only after three cycles of clomiphene citrate administration. All parameters of subendometrial and endometrial vascularization were also worsened after repeated clomiphene citrate treatments; furthermore, probably because of the small sample size of the subgroups, these results did not reach statistical significance. These data further corroborate a previous study (Palomba et al., 2005), which showed the decrease in conception rate after the 3rd cycle of clomiphene citrate administration. Endometrial anti-estrogenic effects are frequently viewed as possible explanation for the relatively low pregnancy rates with clomiphene citrate (Nakamura et al., 1997). Clomiphene citrate, in fact, causes dose-related histological endometrial abnormalities (Hosie and Murphy, 1995) and delayed endometrial maturation probably because of cytosolic estrogen receptor depletion and, thus, indirect effect on progesterone receptor expression (Aksel et al., 1986). Furthermore, recent data (Gregory et al., 2002) have demonstrated that the endometrium of PCOS patients treated with clomiphene citrate shows suppression in p160 co-activators amplified in breast cancer-1 and transcriptional intermediary factor-2, supporting the hypothesis that endometrial receptivity in clomiphene citrate users is impaired.
In order to detect specific predictors of efficacy of clomiphene citrate treatment, we analysed our data categorizing all the clomiphene citrate-stimulated ovulatory cycles according to different outcomes, that is ovulation alone/early pregnancy loss or clinical pregnancy/live birth. First, no difference was detected in any clinical and metabolic parameters between patients with different reproductive outcomes. It is possible that the study was underpowered to detect these differences but also that the population enrolled in our protocol and analysed in our study was too homogeneous for each characteristic assessed (as well as BMI, insulin resistance and so on). On the other hand, a significant difference in ultrasonographic parameters was observed between cycles ending in clinical pregnancy/live birth and those ending in ovulation alone/early pregnancy loss. This suggests that clomiphene citrate is effective in terms of fertility only when it exerts poor effects on uterine receptivity.
A pivotal factor in the current study was probably the use of clomiphene citrate at fixed and high dosage. This factor limits our results only to PCOS patients treated with fixed doses of at least 150 mg daily, and thus, they cannot be generalized to all patients who receive clomiphene citrate. In fact, in clinical practice, it seems to be more effective to use an escalation protocol of clomiphene citrate from 50 mg up to 150 mg daily (Imani et al., 2002). Furthermore, the choice to use clomiphene citrate at fixed and high doses was made to simplify our initial prospective double-blind double-dummy controlled design (Palomba et al., 2005) and to minimize the rate of clomiphene citrate-resistant patients, because our PCOS population was composed of a large percentage of over-weight women; and BMI and hyperandrogenemia are predictors for clomiphene citrate failure (Imani et al., 1998).
In conclusion, our results confirm that PCOS patients have an altered uterine vascularization and demonstrate that the administration of 150 mg clomiphene citrate, even if effective for inducing ovulatory cycles in PCOS patients, worsens the subendometrial and endometrial vascularization, as well as, the endometrial thickness and pattern, confirming and extending the knowledge regarding the adverse effects of clomiphene citrate on uterine receptivity.
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Acknowledgements |
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No financial support was provided by any pharmaceutical company to realize the present research. The authors thank all the Gynecological Units of the Calabria and Campania Regions that have given their help in recruiting women for this study.
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References |
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Submitted on April 14, 2006; resubmitted on May 30, 2006; accepted on June 12, 2006.
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