Dose Of Clomiphene Citrate Research Articles

Insulin sensitizing agent (metformin) improves clinical pregnancy rate in clomiphene citrate resistant polycystic ovarian syndrome patients with acanthosis nigricans

ObjectiveThere are several studies that showed a positive correlation between acanthosis nigricans (AN) with hyperinsulinemia and increased insulin resistance. The present study evaluated the effect of adding insulin sensitizing agent (metformin) to clomiphene citrate (CC) on improving insulin resistance parameters and pregnancy rate (PR) in clomiphene-resistant polycystic ovary (PCOS) patients with AN.DesignA double blinded randomized control trialed.Materials and MethodsSixty six CC resistant PCO patients (unsatisfactory ovulation after at least 3 month of CC induction) with AN had been recruited in the study. All study participants had proper clinical evaluation to ensure the diagnosis of AN. Additionally, day 3 follicle stimulating hormone level, fasting insulin, fasting glucose and homeostatic model assessment used to quantify insulin resistance (HOMA–IR) were done. Randomization was done using serial number closed opaque envelopes. Blinding was done using two identical packages for induction (group I) two 50 mg CC tablets taken from day 3 to day 7 of the cycle + placebo tablets taken twice daily all through the cycle (Group II) received the above CC dose + metformin 500 mg twice daily continuously for three cycles. Insulin resistance parameters as well as clinical pregnancy rate had been evaluated in both groups. The statistical analysis was done using Chi-square and Fischer exact tests.ResultsTable 1GI(CC)GII (CC + metformin)P. valueMeanSDMeanSDFasting glucose96.856.8489.766.220.001Fasting insulin12.063.127.832.950.005HOMA_IR2.900.711.720.670.001 Open table in a new tab ConclusionAddition of metformin to CC in PCOS patients with AN, decreases insulin resistance and improve clinical pregnancy rate in patients with previous unsatisfactory response to CC alone. ObjectiveThere are several studies that showed a positive correlation between acanthosis nigricans (AN) with hyperinsulinemia and increased insulin resistance. The present study evaluated the effect of adding insulin sensitizing agent (metformin) to clomiphene citrate (CC) on improving insulin resistance parameters and pregnancy rate (PR) in clomiphene-resistant polycystic ovary (PCOS) patients with AN. There are several studies that showed a positive correlation between acanthosis nigricans (AN) with hyperinsulinemia and increased insulin resistance. The present study evaluated the effect of adding insulin sensitizing agent (metformin) to clomiphene citrate (CC) on improving insulin resistance parameters and pregnancy rate (PR) in clomiphene-resistant polycystic ovary (PCOS) patients with AN. DesignA double blinded randomized control trialed. A double blinded randomized control trialed. Materials and MethodsSixty six CC resistant PCO patients (unsatisfactory ovulation after at least 3 month of CC induction) with AN had been recruited in the study. All study participants had proper clinical evaluation to ensure the diagnosis of AN. Additionally, day 3 follicle stimulating hormone level, fasting insulin, fasting glucose and homeostatic model assessment used to quantify insulin resistance (HOMA–IR) were done. Randomization was done using serial number closed opaque envelopes. Blinding was done using two identical packages for induction (group I) two 50 mg CC tablets taken from day 3 to day 7 of the cycle + placebo tablets taken twice daily all through the cycle (Group II) received the above CC dose + metformin 500 mg twice daily continuously for three cycles. Insulin resistance parameters as well as clinical pregnancy rate had been evaluated in both groups. The statistical analysis was done using Chi-square and Fischer exact tests. Sixty six CC resistant PCO patients (unsatisfactory ovulation after at least 3 month of CC induction) with AN had been recruited in the study. All study participants had proper clinical evaluation to ensure the diagnosis of AN. Additionally, day 3 follicle stimulating hormone level, fasting insulin, fasting glucose and homeostatic model assessment used to quantify insulin resistance (HOMA–IR) were done. Randomization was done using serial number closed opaque envelopes. Blinding was done using two identical packages for induction (group I) two 50 mg CC tablets taken from day 3 to day 7 of the cycle + placebo tablets taken twice daily all through the cycle (Group II) received the above CC dose + metformin 500 mg twice daily continuously for three cycles. Insulin resistance parameters as well as clinical pregnancy rate had been evaluated in both groups. The statistical analysis was done using Chi-square and Fischer exact tests. ResultsTable 1GI(CC)GII (CC + metformin)P. valueMeanSDMeanSDFasting glucose96.856.8489.766.220.001Fasting insulin12.063.127.832.950.005HOMA_IR2.900.711.720.670.001 Open table in a new tab ConclusionAddition of metformin to CC in PCOS patients with AN, decreases insulin resistance and improve clinical pregnancy rate in patients with previous unsatisfactory response to CC alone. Addition of metformin to CC in PCOS patients with AN, decreases insulin resistance and improve clinical pregnancy rate in patients with previous unsatisfactory response to CC alone.

Tamoxifene is better than low dose clomiphene or gonadotropins in women with thin endometrium (

Second line of treatment in patients with thin endometrium following clomiphene (CC) is gonadotropin stimulation, which is associated with higher cost, multiple births and ovarian hyperstimulation syndrome. Tamoxifen, a selective estrogen receptor modulator acts as an estrogen agonist on endometrium. The objective of the present study was to compare the efficacy of low dose CC, tamoxifene, and gonadotropins in women with thin endometrium (<6mm) following CC in IUI cycle.

Evaluation of ultrasonographic and Anti-Müllerian Hormone (AMH) changes as predictors for ovarian reserve after laparoscopic ovarian drilling for women with polycystic ovarian syndrome

Laparoscopic ovarian drilling (LOD) is considered one of the effective tools for treatment of women with polycystic ovarian syndrome. The aim of this work was to evaluate the effects of laparoscopic ovarian drilling on ovarian reserve assessed by Anti-Müllerian hormone assay and ultrasonography. The current prospective controlled study included 70 ( n = 70) primary anovulatory women with PCOS who are allocated to undergo LOD ( n = 40), who are clomiphene citrate (CC) resistant, and another group receiving incremental doses (50–150 mg) of CC ( n = 30) and 20 healthy age-matched women with a regular menstrual cycle and normal ovaries (confirmed with ultrasound examination) as the control group. For the LOD group, standard laparoscopy ovarian drilling was done just after the end of the menstruation using a monopolar electrocautery needle. For the CC group, clomiphene citrate was given in incremental doses (50–150 mg) for up to six cycles from days 2–6 of a menstrual cycle or after a progestin withdrawal bleeding. Evaluation for the ovarian reserve was done using the following tests: (1) AMH level in the third cycle day, (2) antral follicle count (AFC) by TVS, and (3) summed ovarian volume (SOV) by transvaginal ultrasound examination (TVS). In the current study, among the (40) PCOS women having LOD, 30/40 (75%) had regular cycles in the 6-month period after LOD, while the ovulation rate was 24/40 (60%) and the pregnancy rate was 11/40 (27.5%) in the 6-month period after LOD. Those rates were not statistically different in the PCO women group treated with CC. There were statistically significant differences between AMH levels and antral follicle count before and after LOD ( p = 0.001 and 0.009 respectively) and this might indicate a possible diminished ovarian reserve. AMH and AFC are reliable markers for assessment of the ovarian reserve and measuring them for women with anovulatory PCOS undergoing LOD may provide a useful tool in evaluating the outcome of LOD.

Medical management of clomiphene-resistant polycystic ovarian syndrome: an update

Clomiphene citrate is the traditional first-line treatment for chronic anovulation that characterizes polycystic ovary syndrome (PCOS). A gold standard therapy has always been Clomiphene Citrate (CC). However, 20%-25% of PCOS women fail to ovulate with incremental doses of CC. A good body of evidence suggest that alternatives for PCOS women with CC-resistant anovulation include insulin sensitizers like metformin and pioglitazone. Insulin sensitizers improves pregnancy outcome and ovulation rate by and acts by ameliorating insulin sensitivity and hyperandrogenemia. Metformin is preferred in obese women. Gonadotropins induce ovulation and maintain optimal follicle growth via controlled administration of follicle stimulation hormone. Two regimens are used which includes high and low dose regimen. Low dose regimen is preferred but is associated adverse effects like ovarian hyperstimulation syndrome (OHSS) and increased cost. Extending clomiphene therapy reduces cost and improves pregnancy outcome. Glucocorticoids are preferably used when serum Dehydroepiandrosterone levels are > 200µg/dL. Bromocriptine improves ovulation rate by decreasing prolactin levels. Human Chorionic Gonadotropin restores ovulation but its use is limited during intrauterine insemination. Tamoxifen acts in a similar way as CC but has lesser antiestrogenic effect on the endometrium, cervical mucus, and granulosa cells, hence an added advantage of monofollicular ovulation. Aromatase inhibitors block conversion androstenedione and testosterone to estrogen in ovary and improves ovulation rate. Added advantage includes lesser cost, simple to use, no danger of multiple pregnancies and convenient for patient. Combination of GnRH analogues and Gonadotropins are associated with increased risk of OHSS. D- chiro -inositol, N-Acetylcysteine, melatonin and acarbose are tried with little success.

Anti-Müllerian hormone, visceral fat, and ovarian stromal Doppler to predict response to ovulation induction in polycystic ovary syndrome

Objective This study was designed to identify whether visceral adiposity, anti-Mόllerian hormone, and ovarian stromal Doppler assessed during initial screening could predict the response to ovulation induction with clomiphene citrate in patients with polycystic ovary syndrome. Background The first choice of drug in women with polycystic ovary syndrome is clomiphene citrate. Three-quarters of women with polycystic ovary syndrome will ovulate with clomiphene citrate. Patients who do not ovulate on the maximum dose of 150 mg are considered to be clomiphene citrate resistant. Several parameters have been used to predict ovarian response in polycystic ovary syndrome patients. Patients and methods The study was carried out on 150 patients with polycystic ovary syndrome. Initial clomiphene citrate doses were 50 mg daily for 5 days starting on cycle day 3. In the absence of response, doses were increased to 100 and 150 mg daily in subsequent cycles. First ovulation with clomiphene citrate was used as the endpoint. Results At the end of the follow-up period, 110 (73.3%) patients had ovulated. Anti-Mόllerian hormone, visceral fat area assessed with computed tomography, and ovarian stromal pulsatility index were significantly different between responders and nonresponders. The cutoff levels for visceral fat area, anti-Mόllerian hormone, and ovarian stromal pulsatility index for predicting clomiphene citrate resistance were 83.6 cm 2 or more (area under the curve 0.79), 3.2 ng/ml or more (area under the curve 0.79), and 0.92 or less (area under the curve 0.66), respectively. Area under the curve for a multivariate prediction model was 0.87. Conclusion Clomiphene citrate-resistant polycystic ovary syndrome patients can be predicted on the basis of initial characteristics such as visceral fat area, anti-Mόllerian hormone levels, and ovarian stromal pulsatility index. This can help in patient selection and counseling regarding the success of ovulation induction.

Thin endometrial stripe does not affect pregnancy outcome in clomiphene citrate/intrauterine insemination cycles

ObjectiveImpaired endometrial development has been reported in clomiphene citrate (CC)-treated women, but its clinical relevance is uncertain. Our goal was to determine the effect of pre-ovulatory endometrial thickness (ET) on pregnancy outcome in CC /intrauterine insemination (IUI) cycles.DesignRetrospective cohort study.Materials and MethodsWe analyzed patients who underwent transvaginal ultrasound (TVU)-monitored CC/IUI and CC+single dose gonadotropin (MinStim)/IUI cycles at Mayo Clinic, between 1/2005 and 12/2012. Patients with age ≥ 40 yrs, BMI > 40 kg/m2, cycle day 3 FSH > 10 IU/ml or semen analysis with < 5 million total motile sperm (TMS) per ejaculate were excluded. A TVU was performed on CD 10, 11 or 12. The primary outcome is clinical pregnancy (CP). Clinical factors were assessed for an association with CPs using generalized estimating equations to account for correlation between multiple cycles from the same patient. The receiver operating characteristic (ROC) curve was used to assess the suitability of using ET to predict CP. SAS 9.3 was used for the analysis.ResultsTable 1Per cycle CPR according to ETET (mm)nCPR (%)ORAdjusted OR*Adjusted for age, diagnoses, CC dose, number of follicles > 15mm, endometrial pattern and TMS. # Referent group.< 615514.80.89 (0.51, 1.52)0.86 (0.48, 1.54)6 - 934916.3##> 958191.22 (0.61, 2.43)1.16 (0.56, 2.41)* Adjusted for age, diagnoses, CC dose, number of follicles > 15mm, endometrial pattern and TMS. # Referent group. Open table in a new tab ConclusionPre-ovulatory ET in CC/IUI cycles had no significant correlation with pregnancy outcome in our patient population. ObjectiveImpaired endometrial development has been reported in clomiphene citrate (CC)-treated women, but its clinical relevance is uncertain. Our goal was to determine the effect of pre-ovulatory endometrial thickness (ET) on pregnancy outcome in CC /intrauterine insemination (IUI) cycles. Impaired endometrial development has been reported in clomiphene citrate (CC)-treated women, but its clinical relevance is uncertain. Our goal was to determine the effect of pre-ovulatory endometrial thickness (ET) on pregnancy outcome in CC /intrauterine insemination (IUI) cycles. DesignRetrospective cohort study. Retrospective cohort study. Materials and MethodsWe analyzed patients who underwent transvaginal ultrasound (TVU)-monitored CC/IUI and CC+single dose gonadotropin (MinStim)/IUI cycles at Mayo Clinic, between 1/2005 and 12/2012. Patients with age ≥ 40 yrs, BMI > 40 kg/m2, cycle day 3 FSH > 10 IU/ml or semen analysis with < 5 million total motile sperm (TMS) per ejaculate were excluded. A TVU was performed on CD 10, 11 or 12. The primary outcome is clinical pregnancy (CP). Clinical factors were assessed for an association with CPs using generalized estimating equations to account for correlation between multiple cycles from the same patient. The receiver operating characteristic (ROC) curve was used to assess the suitability of using ET to predict CP. SAS 9.3 was used for the analysis. We analyzed patients who underwent transvaginal ultrasound (TVU)-monitored CC/IUI and CC+single dose gonadotropin (MinStim)/IUI cycles at Mayo Clinic, between 1/2005 and 12/2012. Patients with age ≥ 40 yrs, BMI > 40 kg/m2, cycle day 3 FSH > 10 IU/ml or semen analysis with < 5 million total motile sperm (TMS) per ejaculate were excluded. A TVU was performed on CD 10, 11 or 12. The primary outcome is clinical pregnancy (CP). Clinical factors were assessed for an association with CPs using generalized estimating equations to account for correlation between multiple cycles from the same patient. The receiver operating characteristic (ROC) curve was used to assess the suitability of using ET to predict CP. SAS 9.3 was used for the analysis. ResultsTable 1Per cycle CPR according to ETET (mm)nCPR (%)ORAdjusted OR*Adjusted for age, diagnoses, CC dose, number of follicles > 15mm, endometrial pattern and TMS. # Referent group.< 615514.80.89 (0.51, 1.52)0.86 (0.48, 1.54)6 - 934916.3##> 958191.22 (0.61, 2.43)1.16 (0.56, 2.41)* Adjusted for age, diagnoses, CC dose, number of follicles > 15mm, endometrial pattern and TMS. # Referent group. Open table in a new tab ConclusionPre-ovulatory ET in CC/IUI cycles had no significant correlation with pregnancy outcome in our patient population. Pre-ovulatory ET in CC/IUI cycles had no significant correlation with pregnancy outcome in our patient population.

The Predictive Value of Circulating Anti-Müllerian Hormone in Women With Polycystic Ovarian Syndrome Receiving Clomiphene Citrate: A Prospective Observational Study

Elevated serum anti-Müllerian hormone (AMH) concentration in women with polycystic ovarian syndrome (PCOS) is known to lower sensitivity of ovarian follicles to circulating FSH. This effect may compromise the outcome of clomiphene citrate (CC) ovulation induction. The objective of the study was to investigate the impact of high circulating AMH on the outcome of CC ovulation induction in women with PCOS. This was a prospective cohort observational study. The study was conducted at the Fertility Unit, Derby, United Kingdom. Sixty anovulatory women with PCOS participated in the study. Serum AMH concentrations were measured on cycle day 2 during 187 CC cycles. These concentrations were compared between responders and nonresponders. The receiver-operating characteristic curve was used to evaluate the prognostic value of circulating AMH. The success rates of CC were compared between patients with high vs low AMH levels. The dose of CC required to achieve ovulation was correlated with serum AMH concentrations. Ovulation and pregnancy rates were measured. Serum AMH concentrations were significantly (P < .001) lower in responders (achieving ovulation) vs nonresponders (mean ± SEM, 2.5 ± 0.1 vs 5.8 ± 0.7 ng/mL, respectively). Similarly, serum AMH concentrations were significantly (P = .046) lower in pregnant (3.0 ± 0.4 ng/mL) vs nonpregnant patients (4.4 ± 0.5 ng/mL). There was a significant (P = .02) gradient increase of serum AMH levels with the increasing dose of CC required to achieve ovulation. The receiver-operating characteristic curve showed AMH to be a useful predictor of no ovulation (area under the curve, 0.809; P < .001) with a useful cutoff level of 3.4 ng/mL. Ovulation and pregnancy rates were significantly higher (97%, P < .001, and 46%, P = .034) in patients with low AMH (<3.4 ng/mL) vs women with AMH 3.4 ng/mL or greater (48% and 19%). PCOS women with high circulating AMH (≥ 3.4 ng/mL) seem to be resistant to CC and may require a higher starting dose.

The relationship between infertility treatment and cancer including gynaecological cancers

Key content Increasing availability and expanding usage of infertility treatment is a concern with regard to a possible increase in the risk of future malignancy development for women and their offspring. Infertile women are at significantly increased risk of developing ovarian and uterine cancers, especially nulliparous women. Earlier studies pointed to a possible increase in the risk of ovarian cancer following large doses and multiple cycles of clomiphene citrate. Recent studies did not observe any increase in malignancy risk due to infertility medications. Other confounding factors, such as infertility itself, may well be the reason for the increased percentage of cancer cases noted in earlier studies. Uterine cancer risk is possibly increased following multiple cycles and high doses of clomiphene citrate. There is no strong evidence linking infertility treatment with non‐gynaecological or childhood cancers, with the possible exception of melanoma. Learning objectives To highlight the available evidence linking infertility treatment with gynaecological, non‐gynaecological and childhood cancers. How to counsel women about any possible risk of future neoplasia after infertility treatment. Ethical issues Is it ethical to persevere with multiple fertility treatment cycles if it might be associated with increased risk of neoplasia in the future?

1901 DEFINING THE UTILITY OF A CLINICAL CARE PATHWAY FOR CLOMIPHENE CITRATE USE IN MEN WITH HYPOGONADISM

You have accessJournal of UrologyInfertility: Therapy1 Apr 20131901 DEFINING THE UTILITY OF A CLINICAL CARE PATHWAY FOR CLOMIPHENE CITRATE USE IN MEN WITH HYPOGONADISM Clarisse R. Mazzola, Darren J. Katz, and John P. Mulhall Clarisse R. MazzolaClarisse R. Mazzola New York City, NY More articles by this author , Darren J. KatzDarren J. Katz New York City, NY More articles by this author , and John P. MulhallJohn P. Mulhall New York City, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2320AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Clomiphene citrate (CC) is an effective treatment for men with hypogonadism (HG). For fear of tachyphylaxis, many clinicians commence CC at low dose and some dose every other day rather than daily. This analysis was undertaken to define if up-titrating dose in men failing to respond to low dose CC is an effective therapeutic approach. METHODS Men with a diagnosis of HG (defined by having 2 separate early morning total T (TT) levels <300 ng/dl) opting for CC therapy constituted the study population. Demographic, comorbidity data, physical and laboratory characteristics were recorded. All patients were started on CC 25 every other day (QOD) and were up-titrated to 50mgs QOD and then eventually 50 mgs daily (QD) if the original dose strategy failed. Laboratory testing was conducted 4 weeks after commencement, 4 weeks after a dose change and every six months thereafter. Response was defined as an increase of ≥200 ng/dl in TT and a TT level ≥400 ng/dl at ≥6 months after commencing CC. ANOVA was conducted comparing TT and LH levels among the three dosing groups. Multivariable analysis was performed on patients failing to respond to CC25 QOD to define predictors of successful response to higher doses. Parameters included in the multivariable model were: patient age, mean testicular volume, varicocele presence, baseline TT, free T and LH levels. RESULTS 112 patients were included with a mean age = 45±19 years. Mean pre-treatment testicular volume = 16±8 mls. Mean baseline T and LH levels were 222±98 ng/dl and 3.8±1.6 (0.1-5.8) IU/ml. On CC25 QOD, 71/112 (63%) patients met the responder definition (TT = 467±190 ng/dl, LH = 12.4±3.6). Of the 41 who were up-titrated to C50 QOD, 32% (13) met the responder definition (TT = 414±212 ng/dl, LH = 8.2±5.2). Of the 28 moving to CC50 QD, 18% (5) met responder definition (TT = 366±166 ng/dl, LH = 7.0±1.6; ANOVA p=0.033 for TT, p=0.025 for LH). On multivariable analysis, the only factors predictive of response to up-titrating CC were: pre-treatment LH level (r=0.51, p<0.01) and pre-treatment LH level ≤6 IU/ml (RR 2.1, p<0.01). CONCLUSIONS These data confirm that about two thirds of men with HG meet a robust responder definition using CC25mgs QOD. Up-titrating permitted 44% of patients not responding to CC25 QOD to meet the responder definition. We believe these data support starting CC at low dose and up-titrating when appropriate giving patients realistic expectations when the latter is necessary. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e779 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Clarisse R. Mazzola New York City, NY More articles by this author Darren J. Katz New York City, NY More articles by this author John P. Mulhall New York City, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Pretreatment and co‐administration of oral anti‐diabetic agent with clomiphene citrate or rFSH for ovulation induction in clomiphene‐citrate‐resistant polycystic ovary syndrome

The objective of this study was to explore the result of pretreatment and concomitant use of metformin with clomiphene citrate (CC) and rFSH for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome (PCOS). This randomized controlled trial was done in the Dhaka Medical College and Hospital and the Infertility Care and Research Centre, Dhaka, Bangladesh. A total of 165 infertile patients with CC-resistant PCOS who attended for treatment were the target population for this study. Patients were divided into three groups: groups A and B were given metformin and group C was the control. Along with metformin, group A received CC and group B received rFSH. Group C was treated with only rFSH. Metformin was given 1500 mg daily for 4 weeks. Afterwards CC or rFSH were added for induction of ovulation along with metformin. Six ovulatory cycles were assessed. Treatment was terminated when there was no response with maximum dose of CC and rFSH or after six ovulatory cycles without pregnancy or after achieving pregnancy. A P-value of <0.5 was considered as significant. Ovulation (89.09%) and pregnancy (54.55%) rates were higher in group B. Ovulation (74.55%) and pregnancy (29.09%) rates were also satisfactory in group C but a dose of rFSH requirement was significantly higher (P = 0.000). In group A, both ovulation and pregnancy rate were much lower than the other two groups (27.27% and 12.73%, respectively). Use of metformin increases the response of ovulation-inducing agents and can be used safely in PCOS.

Metformin-clomiphene citrate vs. clomiphene citrate alone: Polycystic ovarian syndrome

BACKGROUND:Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women that is associated with reproductive and metabolic disorders.OBJECTIVES:We compared the ovulation and conception rates after the treatment with clomiphene citrate (CC) alone and in combination with metformin in infertile patients presented with polycystic ovarian syndrome (PCOS).MATERIALS AND METHODS:This randomized controlled trial of independent cases and controls was conducted at the Department of Obstetrics and Gynecology, Hera General Hospital, Makkah, Saudi Arabia from February 01 to December 31, 2008. The 42 subjects diagnosed as PCOS were divided into group A and B (21 subjects in each) for management with CC + metformin and CC alone, respectively. Group A received 500 mg three times a day of metformin continuously from the first cycle for 6 months or till pregnancy was confirmed. In both groups CC was started at a dose of 50 mg from day-2 till day-6 of the menstrual cycle. The dose of CC was increased to 100 mg in second and 150 mg in third cycle, and then remained 150 mg for the remaining three cycles. With ovulation the dose of CC was unaltered in both groups. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.RESULTS:More than 50% females in both groups were had body mass index > 25. Group A achieved high rate of regular cycles, ovulation success, and conception than group B (71.4% vs. 38.1%; P = 0.03), (76.2% vs. 38.1%; P = 0.021), and (66.6% vs. 28.6%; P = 0.01), respectively.CONCLUSION:Management with metformin + CC increased the ovulation and conception rates.

Optimization of spermatogenesis‐regulating hormones in patients with non‐obstructive azoospermia and its impact on sperm retrieval: a multicentre study

Study Type - Therapy (outcomes) Level of Evidence 2a What's known on the subject? and What does the study add? Clomiphene citrate, hCG and human menopausal gonadotropin (hMG) are widely used in treatment of oligospermia, because they increase FSH and testosterone which are essential for spermatogenesis. Finding a sperm in non-obstructive azoospermia for intracytoplasmic sperm injection is a challenge and much effort is required to reach the optimum method of sperm retrieval. The study shows that a new protocol of clomiphene citrate, hCG and hMG in the treatment of non-obstructive azoospermia achieves an increase in the levels of FSH, LH and total testosterone to the target levels that we set. Our target level of FSH was 1.5 times its initial level and for serum testosterone it was 600-800 ng/dL. Using our described medical treatment protocol in cases of non-obstructive azoospermia, sperm may be found in patients' ejaculate (~11%) and if they remain azoospermic they will have a greater likelihood of sperms being obtained in testicular sperm extraction. To evaluate the effect of optimizing serum level of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone on sperm retrieval for intracytoplasmic sperm injection. A total of 612 patients with non-obstructive azoospermia were evaluated with routine history, physical examination and hormonal assessment. Of these, 116 patients underwent microsurgical (micro)-testicular sperm extraction (TESE) without any medical treatment and formed the control group and the remaining 496 patients were administered clomiphene citrate in a titrated dose. Patients were classified into four groups according to their response to clomiphene citrate. Group 1: patients with an obvious increase in FSH and total testosterone (n = 372). Group 2: patients showing an increase in FSH with no or little increase in LH and total testosterone (n = 62). For these patients we continued with clomiphene citrate and added human chorionic gonadotrophin (hCG). Group 3: patients with no increase in the levels of the three hormones (n = 46). Group 4: included patients with continuously decreasing serum testosterone levels in response to the increasing dose of clomiphene citrate (n = 16). Accordingly, patients in groups 3 and 4 discontinued clomiphene citrate and started hCG and human menopausal gonadotropin (hMG). Semen analyses were performed periodically and, in patients who remained azoospermic, micro-TESE was performed. Sperm were noted in 54 patients (10.9%) in semen analysis after treatment in all groups (with no significant difference) at a mean (sd) concentration of 2.3 (4.1) million/mL. For the 442 patients who remained azoospermic after treatment, successful sperm retrieval was significantly higher (57%) compared with the control group (33.6%). For patients with non-obstructive azoospermia, clomiphene citrate, hCG and hMG administration, leading to an increased level of FSH and total testosterone, results in an increased rate of sperm in the ejaculate and increased likelihood of successful micro-TESE.

Ovulatory rate in subsequent clomiphene citrate(CC) cycle after ‘stair-step’(SS) clomiphene citrate protocol

The CC-SS protocol has been shown to decrease time to ovulation by increasing the CC dose in an incremental fashion when ovulation does not occur rather than inducing a progesterone withdrawal bleed. It has been suggested that the mechanism of action of the SS protocol is via a cumulative effect of the incremental CC dose. The aim of this study was to determine the ovulatory rate in women undergoing ovulation induction (OI) using the previous effective dose from the CC-SS cycle.

Treatment of ovulatory women with unexplained infertility with clomiphene citrate and intrauterine insemination: does dosage affect clinical pregnancy rate?

Treatment of ovulatory women with unexplained infertility with clomiphene citrate and intrauterine insemination: does dosage affect clinical pregnancy rate?

Recent trends in clomiphene citrate (CC) use

There are no recent studies of CC use; therefore this study sought to determine the average number of cycles and duration of contemporary CC treatment. Retrospective analysis of the PharMetrics Patient-Centric Database between 1999 and 2008. The database is comprised of fully adjudicated medical and pharmaceutical claims for approximately 66 million unique patients from 90 health plans across the United States. Included patients were female, between 18 and 65 years, had a CC claim (index) with no use of fertility medications in the preceding 12 months, and continuous eligibility through 24 months post index. CC cycles were identified using an algorithm incorporating CC dose, quantity dispensed, and dispensation date. Duration of CC administration was calculated as number of days between first and last prescription dates. From all claims, 8,780 patients with 28,935 cycles were identified (means: 32.6 ± 5.2 yrs; 3.3 ± 2.5 cycles/patient; duration of treatment 198 ± 178 days). A total of 4,268 (48.6%) patients received treatment ≤ 2004, and 4,512 (51.4%) >2004. During the analysis period, 28.7% of patients received one, 17.8% two, 17% three, 12.1% four, 8.6% five, and 6% six cycles of CC. Patients receiving ≥7 cycles of CC comprised 9.9% of the sample. Among those receiving >1 cycle, average # of days from first to last day of CC use was: 83 ± 121 for 2 cycles, 134 ± 140 for 3 cycles, 193 ± 152 for 4 cycles, 238 ± 159 for 5 cycles, 261 ± 146 for 6 cycles, and 387 ± 161 for ≥7 cycles. Over time there was an increase in the proportion of patients receiving 1-3 CC cycles (59.5%, ≤2004 vs. 67.2% >2004; P<0.0001). Most patients received between 1 and 6 cycles of CC, which is the maximum recommended by ASRM guidelines. All patients receiving ≤6 cycles received treatment within one year of first CC dose. However, about 10% of patients received >6 cycles. The decrease over time in the proportion of patients receiving >3 cycles of CC warrants further investigation.

Clomiphene ‘Stair-step’ protocol vs traditional protocol in patients with polycystic ovary syndrome (PCOS): a prospective trial

The stair-step protocol is an increment the dosage of clomiphene citrate (CC) without an intervening menses who failed to respond initially CC dose. Although shorter duration of treatment is an advantage of the protocol, an increment of the CC dosage at the same period may have a negative effect on endometrium and also may increase the systemic side effects associated with CC. The aim of this study is to evaluate the efficacy of the stair-step CC protocol in PCOS patients.

Teratogenic and Embryotoxic Effects of Clomiphene Citrate in Developing Mice

The objective of this study was to assess the teratogenic and embryotoxic effects of clomiphene citrate in mice. The pregnant mice were administered a single dose of clomiphene citrate at different concentrations i.e 1.0, 2.0, 4.0 and 6.0 g/g BW on day 8 of gestation. Fetuses recovered on day 18 of gestation were analyzed on morphological, morphometric and histological basis. Morphological observations showed defects like open eyelids, anophthalmia, fore and hindlimb micromelia, meromelia, amelia, sacral hygroma, hydrocephaly, hemorrhagic spots, kyphosis and clubbed feet. Morphometric analysis indicated a significant (p<0.001) reduction in fetal body weight, crown rump length, head circumference, eye circumference, forelimb and hindlimb lengths and tail size against controls. The histological observations showed brain defects like hydrocephaly, enlarged ventricles and undifferentiated neuroglial cells in cerebellum. Cleft palate, underdeveloped pharynx and atrophy of jaw muscles were the common anatomical defects of pharyngeal region. It is concluded that the concentrations of clomiphene citrate used during the present study proved teratogenic in

Infertility: an update for the family practitioner

AbstractThe incidence of infertility is approximately 15–20% (one in every five to six couples). The investigation of the infertile couple begins with a careful history, followed by a physical examination. If any abnormality is observed in the history, the couple must be referred. The principle of evaluation of the infertile couple is to establish if the female is ovulatory or anovulatory. If ovulatory, the couple must be referred for more detailed examinations. If anovulatory and her prolactin and TSH as well as his semen analysis are normal, ovulation induction with a low dose of clomiphene citrate can be offered. On the other hand, if her prolactin and TSH as well as his semen analysis are abnormal, it is best to refer the patient.

Clomiphene Citrate Causes Aberrant Tubal Apoptosis and Estrogen Receptor Activation in Rat Fallopian Tube: Implications for Tubal Ectopic Pregnancy1

Clomiphene citrate (CC) therapy for disorders of anovulatory infertility has been linked to an increased frequency of tubal ectopic pregnancy. Although CC enhances apoptotic processes in the ovaries, villi, and decidual tissues, its effect on apoptosis in the fallopian tube is unknown. Here, we show that chronic treatment with CC induces tubal apoptosis, but not necrosis, through an intrinsic mitochondria-dependent signaling pathway in vivo. The apoptosis was specific to epithelial cells in the isthmus, and the damage was reversed with 17beta-estradiol (E2); however, pretreatment or concomitant treatment with E2 did not protect against tubal apoptosis induced by chronic treatment with CC. Chronic treatment activated estrogen receptors (ESRs), particularly cilia-localized ESR2A (formerly ERbeta2). In contrast to E2, acute treatment of superovulating rats with a high dose of CC or the ESR2-selective agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) significantly delayed the transport of oocyte-cumulus complexes through the fallopian tube. Our findings suggest that in response to chronic CC therapy, isthmus-specific apoptosis of epithelial cells and activation of cilia-ESR2A act in parallel to block gamete and embryo passage through the fallopian tube, eventually resulting in tubal ectopic pregnancy.

The efficacy of metformin and clomiphene citrate combination compared with clomiphene citrate alone for ovulation induction in infertile patients with PCOS

CONTEXT:Low ovulatory and pregnancy rates with clomiphene citrate (CC) in anovulatory polycystic ovarian syndrome (PCOS).AIM:To find out the ovulatory and pregnancy rates in infertile PCOS subjects who receive CC alone and a combination of metformin and CC.SETTING AND DESIGN:A prospective controlled clinical trial conducted in the outpatient department from August 2003 to August 2005.MATERIALS AND METHODS:Twenty-four infertile PCOS women received CC alone at incremental doses of 50 mg up to 150 mg for three cycles and then at a dose of 150 mg for another three cycles (control group). The study group (16 PCOS) received the same dose of CC along with 1500mg of metformin. Ovulation was monitored by transvaginal sonography up to six cycles or till pregnancy occurred.STATISTICAL ANALYSIS:This was carried out using software SSPS, version 10. Fisher's exact test was used to calculate the ovulatory rates. Nine subjects of the control group who failed to conceive with CC had opted for CC and metformin and their ovulatory rate was calculated using statistical software, namely SPSS 15.0, Stata 8.0, MedCalc 9.0.1 and Systat 11.0 using Fischer's exact test.RESULTS:The metformin and clomiphene combination resulted in a significantly higher rate of ovulation (P = 0.0016). The pregnancy rate was 8% with CC and 24% with metformin and CC. The CC failure group also ovulated at a similar rate as that of the study group.CONCLUSIONS:The ovulatory rate and the pregnancy rate with the metformin–CC combination was found to be higher when compared with CC alone. Metformin increased the ovulatory rate in CC failures, also implying increased sensitivity to CC.