Sequential clomiphene citrate/hMG versus hMG for ovulation induction in clomiphene citrate-resistant women

Objective

This study was designed to compare sequential clomiphene citrate/hMG regimen to hMG regimen for ovulation induction in clomiphene citrate-resistant women.

Study design

A comparative prospective study.

Patients and methods

Ninety infertile women were randomized to receive either sequential CC/hMG regimen (45 women) or low-dose step-up protocol of hMG (45 women). All participants had received at least six consecutive cycles of clomiphene citrate for ovulation induction within the last year before inclusion in this study, but they did not conceive. The CC/hMG regimen group received clomiphene citrate 100 mg/day for 5 days, followed by hMG 75 IU for 4 days. The hMG group received low-dose step-up protocol for 10–14 days. To detect the number and size of the follicles, TVS was done on cycle day 8 and repeated daily or every other day according to follicular development. When one to three follicles reached a diameter ≥18 mm, hCG injection was scheduled. Before hCG injection, the E2 level and endometrial thickness were evaluated. β-hCG levels were measured on cycle day 22.

Results

There was no significant difference between the two studied groups regarding the demographic data, sperm parameters, and day 3 FSH, LH and estradiol. Also, there was no significant difference between the two studied groups regarding endometrial thickness, number of mature follicles, peak of E2 before hCG injection and number of cases that developed ovarian cyst or OHSS. The dose of gonadotropins used was significantly low in the CC/hMG group compared to the hMG group (295.2 ± 75.5 vs. 625.3 ± 65.0, respectively), and the pregnancy rate was significantly high in the CC/hMG group compared to the hMG group [12 (26.7 %) vs. 3 (6.7 %), respectively, p < 0.05].

Conclusion

The sequential CC/hMG regimen is as effective as hMG regimen for ovulation induction, produces satisfactory pregnancy results and reduces the treatment cost.     

Basal ovarian cysts and clomiphene citrate ovulation induction cycles

OBJECTIVE: To evaluate the effect of simple basal ovarian cysts in patients undergoing infertility treatment with clomiphene citrate. To evaluate the effect of clomiphene citrate on pretreatment simple ovarian cysts. METHODS: Prospective cohort trial of 84 infertility patients undergoing ovulation induction with clomiphene citrate. Patients with basal ovarian cysts of 10 mm or greater (n = 42) were compared with patients without ovarian cysts (n = 42). The main outcome measure was ovulation determined by menstrual cycle day 21 progesterone level. Each patients with an ovarian cyst was also evaluated for persistence or resolution of the cyst in association with ovulation and cyst size. Pretreatment and posttreatment transvaginal ultrasound examinations were performed on all patients. RESULTS: Demographic data were similar among the groups. The mean ovarian cyst size was 17.4 +/- 5.8 mm. Patients in the ovarian cyst group were significantly less likely to ovulate (80.9% versus 97.6%, P < .05), but did not differ in pregnancy rate compared with patients without baseline ovarian cysts (4.8% versus 11.9%, P = .43). Persistent ovarian cysts occurred in 36.7% of the patients. The initial size of the cyst did not predict cyst persistence. CONCLUSION: According to these data, basal ovarian cysts significantly reduce ovulatory events in patients treated with clomiphene citrate. LEVEL OF EVIDENCE: II-2.     

Clomiphene citrate plus cabergoline versus clomiphene citrate for induction of ovulation in infertile euprolactinemic patients with polycystic ovary syndrome: A randomized clinical trial

Objective

To compare the effect of adjunctive use of cabergoline with clomiphene citrate (CC) in infertile polycystic ovarian syndrome (PCOS) patients with normal prolactin level.

A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction

OBJECTIVE: To compare the rates of ovulation and pregnancy after tamoxifen citrate (TMX) or clomiphene citrate (CC) among anovulatory women with infertility. DESIGN: Prospective randomized trial. SETTING: Infertility clinic in a university teaching hospital. PATIENT(S): Eighty-six anovulatory women under 40 years of age undergoing ovulation induction. INTERVENTION(S): The women were assigned randomly to receive either TMX or CC on cycle days 5-9. MAIN OUTCOME MEASURE(S): Rates of ovulation and pregnancy for the two treatment modalities. RESULTS(S): The overall rate of ovulation in the TMX group was 50 of 113 (44.2%) and in the CC group, 41 of 91 (45.1%). There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group. The cycle fecundity per ovulatory cycle was 20.0% in the TMX group and 14.6% in the CC group. CONCLUSION(S): The overall rate of ovulation and pregnancy were similar with TMX and CC. TMX is a suitable alternative agent to CC in the management of anovulatory infertility.     

Comparison of metformin and clomiphene citrate therapy for induction of ovulation in the polycystic ovary syndrome

Objective  

To compare the efficacy of metformin and clomiphene citrate (CC) therapies for ovulation induction in anovulatory infertile women with polycystic ovary syndrome (PCOS).     

Follicle tracking of women receiving clomiphene citrate for ovulation induction.

Forty-five cycles of forty subfertile women were monitored with follicle tracking. Thirty women were anovulatory and 10 had unexplained infertility. Thirty women responded to the initial dose of Clomiphene Citrate (CC) and 10 remained anovulatory. Of those who ovulated with the first dose of CC, 25 developed one follicle, 2 developed 2 follicles and 3 developed three follicles. All the women that produced three follicles belonged in the unexplained infertility group. Eight women from the anovulatory group developed 1 follicle, two developed 2 follicles and 8 failed to respond. Provision of universal follicle tracking proved to be time consuming and required significant resources. Our results indicate that if there is a place for selective monitoring that should include women with unexplained infertility. We should also offer the first scan at around day 12 of the cycle as this could detect multiple follicle development. Patients with Polycystic Ovaries that start on 50 mgs of CC may not necessarily need follicle tracking as they usually do not respond to that dose.     

Normoprolactinemic anovulation nonresponsive to clomiphene citrate: ovulation induction with bromocriptine

Ovulation under bromocriptine was studied in 14 women with normoprolactinemic amenorrhea (5 primary, 9 secondary), unresponsive to clomiphene citrate (CC). On bromocriptine alone, ovulation occurred in 4 (28.6%). In the same subjects, bromocriptine was subsequently associated with CC. Seven patients ovulated (50.0%), including 3 that had responded to bromocriptine alone. Ovulation occurred once or twice in 6 of the 9 cases of secondary amenorrhea (66.6%). In several occasions, when ovulation induction failed, luteinized unruptured follicles were found under ultrasonographic monitoring. Four patients who had a negative response to progestin challenge did not ovulate with the treatment. Women with plasma prolactin in the upper normal range had a greater probability of achieving ovulation induction.     

Superfetation secondary to ovulation induction with clomiphene citrate: a case report

In conclusion, CC has been associated with an increased rate of multifetal pregnancy; however, after each induction cycle, pregnancy should be ruled out before start of a new induction cycle. This would prevent misinterpretations of the gestational age at delivery, and hence of maturity, and would also help prevent any potential malformation that may be caused by a yet undetected teratogenic effect of CC.     

Comparison between two clomiphene citrate protocols for induction of ovulation in clomiphene resistant polycystic ovary syndrome

ObjectiveTo compare two protocols of CC therapy for induction of ovulation in a group CC resistant PCOS women.Study designDouble blind randomized controlled trial.Subjects and methods260 nulliparous CC resistant PCOS women randomized between two groups; In the first group each patient received 200 mg/day for 5 days while the second group received 100 mg/day for 10 days, both starting on day 3 of progestin induced withdrawal bleeding.Main outcome measuresOvulation defined as at least one follicle reaching ⩾14 mm diameter, and confirmed by timed serum progesterone. Secondary outcome measures included; number of dominant follicles, endometrial thickness, clinical pregnancy rate, and live birth rate.ResultsThe extended protocol resulted in significantly higher ovulation, pregnancy, and live-birth rates than the high dose protocol (p 0.001). Serum FSH levels on day 6 of treatment were comparable between the two groups while the level on day 11 was significantly higher in the second group (p 0.02). Serum LH levels were comparable both on days 6 and 11. Patients on longer protocol (group II) required a longer time to ovulate (18 ± 4.4 versus 14 ± 3.6 days) but had a significantly higher endometrial thickness at the time of ovulation. (p 0.02) FSH and LH levels were comparable between responders and non-responders in both groups.ConclusionsThe current study reports significantly higher ovulation and pregnancy rates with the longer lower dose protocol probably because of prolonged FSH rise. Study web address: ACTRN12611000639921.     

Relationship of weight to successful induction of ovulation with clomiphene citrate

Over a 6 1/2-year period, 117 patients who were anovulatory, euthyroid, and estrogen-primed were treated with clomiphene citrate. Graduated doses from 50 mg to 250 mg daily for 5 days were used to induce ovulation. Of 62 patients who completed treatment, 50 ovulated and 12 did not. Several factors, including age, duration of infertility, weight, previous menstrual history, previous pregnancy history, and previous use of oral contraceptives, were investigated to determine conditions which might influence response. Only weight was found to be significantly different between responders and nonresponders. Furthermore, there was a linear relationship between body weight and dose of clomiphene required to induce ovulation. The ovulation rate for those completing therapy was 81% with a pregnancy rate of 76% of the total and 94% of those ovulating. Population homogeneity with anovulation as the major cause of infertility appears to be the most plausible explanation for the high pregnancy rate.     

A randomized study of dexamethasone in ovulation induction with clomiphene citrate

Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).     

Sequential clomiphene citrate-menotropin therapy for induction or enhancement of ovulation

Either to induce ovulation in anovulatory infertility patients or to enhance ovulation in patients with mild endometriosis or luteal phase inadequacy, we utilized a sequential regimen of low-dose clomiphene citrate (CC) followed by human menopausal gonadotropin (hMG) injections on alternate days; duration and dosage of menotropin therapy was individualized by using serum estradiol levels for monitoring until the time of administration of human chorionic gonadotropins. Previous therapeutic efforts without menotropins had been unsuccessful in all patients. One third of 70 treated patients conceived during 156 treatment cycles. The pregnancy rate was 44% in anovulatory patients (n = 34), and 26% in patients with ovulation dysfunction (n = 23). Pregnancy rates declined with patient's age. Four of the 23 patients that conceived had a spontaneous abortion (17%). The multiple gestation rate was 10.5%. A relative inhibition of cervical mucus development was noted and shown to be caused by CC. Hyperstimulation occurred in three patients. The discussed CC-hMG regimen approaches the effectiveness of standard hMG therapy; but compared with standard hMG therapy, it has significant economic advantages and seems to have a markedly lower rate of multiple gestation. However, like standard hMG therapy, CC-hMG therapy requires careful monitoring specifically, because hyperstimulation may occur.     

Massive ovarian edema in pregnancy after ovulation induction using clomiphene citrate

Background Massive ovarian edema is a benign enlargement of the ovary caused by accumulation of fluid occurring mainly in young women. Most cases are thought to result from venous and lymphatic obstruction. Case report We treated a 40-year-old multiparous pregnant woman with massive ovarian edema who had been received clomiphene citrate. She was admitted at 13th week of pregnancy for acute pelvic pain. Left oophorectomy was performed, and pathologic examination disclosed massive ovarian edema. Our report is the first case of massive ovarian edema with pregnancy after ovulation induction using clomiphene citrate.     

Luteal phase clomiphene citrate for ovulation induction in women with polycystic ovary syndrome

Purpose

The aim was to test a new protocol of luteal phase administration of clomiphene citrate (CC) for ovulation induction in women with polycystic ovary syndrome (PCOS).

Methods

This was a prospective, randomized, controlled trial. Two hundred and fifty-two women (cycles) with PCOS were utilized to create two groups. Patients in Group 1 (126 patients) received 100 mg of CC daily for 5 days starting on day 5 of menses, and patients in Group 2 (126 patients) received 100 mg of CC daily for 5 days starting the next day after finishing medroxyprogesterone acetate (MPA) (before withdrawal bleeding). The main outcome measures were the number of growing and mature follicles, serum E2 (in pg/mL), serum progesterone (in ng/mL) levels, endometrial thickness (in mm), pregnancy, and miscarriage rates.

Results

The total number of follicles and the number of follicles ≥14 mm during stimulation were significantly greater in Group 2. The endometrial thickness at the time of human chorionic gonadotrophin (hCG) administration was significantly greater in Group 2 as compared to Group 1 (7.84 ± 1.22 and 8.81 ± 0.9, respectively). Serum E2 levels were also significantly higher (p < 0.05) in Group 2 as compared to Group 1 (449.61 ± 243.45 vs. 666.09 ± 153.41 pg/mL). Pregnancy occurred in 13 patients (10.3 %) in Group 2 and in 11 patients (8.7 %) in Group 1. The difference was not statistically significant.

Conclusion

Luteal phase administration of CC in patients with PCOS leads to increased follicular growth and endometrial thickness, which might result in a higher pregnancy rate.     

Combined metformin and clomiphene citrate versus highly purified FSH for ovulation induction in clomiphene-resistant PCOS women: a randomised controlled trial

Aim.?To compare the effect of combined metformin–clomiphene citrate (CC) with highly purified urinary FSH (HP-uFSH) for ovulation induction in CC-resistant women with polycystic ovary syndrome (PCOS).

Methods.?One-hundred fifty-three anovulatory women with CC-resistant PCOS were selected in this randomised controlled trial. Patients received combined metformin–CC (n?=?75, 205 cycles) or HP-uFSH (n?=?78, 186 cycles) for three cycles. Outcome measures were; Ovulation rate, number of growing and mature follicles, serum E2, serum P, endometrial thickness, pregnancy and miscarriage rates.

Results.?The ovulation rate per cycle was significantly higher in the HP-uFSH group (83.8% vs. 62%, p?=?0.01). The number of follicles ≥12?mm ≥14?mm and ≥18?mm on the hCG day was significantly greater in the HP-uFSH group (p?=?0.01, p?=?0.02 and p?=?0.03, respectively). Pregnancy occurred in 23/205 cycles (11.2%) in combined metformin–CC group and 40/186 cycles (21.5%) in the HP-uFSH group; the difference was statistically significant (p?=?0.02). Two patients in the HP-uFSH group suffered mild OHSS.

Conclusions.?Combined metformin–CC resulted in modest ovulation and pregnancy rates without side effects. It is logical to offer this first for CC-resistant PCOS women before resorting to more expensive alternatives especially in developing communities where economic aspects of therapy are important.     

Letrozole usage adjuvant to gonadotropins for ovulation induction for patients with clomiphene citrate failure

Aim

To compare cycle properties of ovulation induction (OI) with gonadotropin alone or combined with letrozole in the patients with previous clomiphene citrate (CC) failure.

Methods

In this prospective study, 40 patients with previous at least three times CC cycle failure were evaluated. Half of them received 2.5 mg letrozole on days 3–7 of the menstrual cycle and recombinant follicle stimulating hormone (rFSH) starting on day 5. The other half of the patients received only rFSH starting on day 3. Groups were compared according to the OI duration, gonadotropin dosage, endometrial thickness, estradiol (E2) levels on day of human chorionic gonadotropin (HCG) administration and follicle count.

Results

Total rFSH dose, the E2 levels on the day of HCG and >18 mm follicle count was significantly lower and OI duration was significantly shorter in rFSH + letrozole group. Mean endometrial thickness was not different between groups.

Conclusion

Adding letrozole to gonadotropin in OI cycles decreases total gonadotropin dose and induction duration without any adverse effects on endometrial thickness. Monoovulation is better achieved by adding letrozole to gonadotropin stimulation without decreasing pregnancy rates.     

Myocardial infarction in pregnancy associated with clomiphene citrate for ovulation induction: a case report

BACKGROUND: Clomiphene citrate (CC) is commonly prescribed for ovulation induction. It is considered safe, with minimal side effects. Thromboembolism is a rare but life-threatening complication that has been reported after ovulation induction with CC. Spontaneous coronary thrombosis or thromboembolism with subsequent clot lysis has been suggested as one of the most common causes of myocardial infarction (MI) during pregnancy, with a subsequently normal coronary angiogram. CASE: A 33-year-old woman with a 5-week gestation had recently received CC for ovulation induction and presented with chest pain. An electrocardiogram showed a lateral and anterior wall myocardial infarction. Cardiac enzymes showed a peak rise in troponin I to 9.10 ng/mL. An initial exercise stress test was normal. At the time of admission, the patient was at high risk of radiation injury to the fetus, so a coronary angiogram was postponed until the second trimester. It showed normal coronary vessels. CONCLUSION: This appears to be the first reported case documenting a possible association between CC and myocardial infarction. Thrombosis might be a rare but hazardous complication of CC. Given this life-threatening complication, appropriate prophylactic measures should be used in high-risk woman undergoing ovarian stimulation.     

Sequential use of clomiphene citrate and human menopausal gonadotropin in ovulation induction.

In an effort to diminish the incidence of multiple pregnancy, ovarian hyper-stimulation syndrome, and the excessive cost of human menopausal gonadotropin (HMG) administration, a sequence of Clomid-HMG-human chorionic gonadotropin (HCG) was used in 80 patients with infertility due to prolonged amenorrhea. Criteria for this therapeutic regimen were: (1) normal seminal fluid analysis and postcoital test; (2) lack of withdrawal bleeding from progesterone following amenorrhea of more than 6 months' duration; (3) normal x-ray of the sella turcica and visual fields; (4) low serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels; (5) normal endoscopic examination; and (6) lack of response to clomiphene in excessive dose (200 mg daily for 5 days) or prolonged dose (100 mg daily for 10 days) with or without HCG, or apparent ovulatory response to the above sequence for five or six consecutive cycles without pregnancy. Clomiphene was administered in a dose of 100 mg daily for 7 days. HMG was then given in the following manner: two ampules daily for 4 days, then one ampule daily for 2 days (75 IU of FSH and 75 IU of LH/ampule). After a 24-hour interval without treatment, 10,000 IU of HCG were given and 2000 IU of HCG 4 days later. Twenty-three pregnancies occurred in 80 patients. However, 15 of the first 25 patients became pregnant--in these patients the only abnormality noted was lack of ovulation. Six additional pregnancies occurred subsequent to one or more unsuccessful cycles. Multiple pregnancies occurred in only two patients (twins delivered at 32 weeks in one and an abortion of five fetuses at 20 weeks in another). However, multiple pregnancy did not occur in any patient whose urinary estrogen level was monitored and in whom the level was 100 mug or less when the HCG was given. The ovarian hyperstimulation syndrome did not occur in any patient.