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PubMed1985

Clomiphene citrate can mimic the augmentative (positive) but not the depressing (negative) effect of estradiol on the LHRH-stimulated release of LH and FSH by the pituitary gland of the long-term ovariectomized rat.

In the long-term ovariectomized rat, both estradiol benzoate (EB) and clomiphene citrate enhance the release of LH induced by luteinizing hormone-releasing hormone (LHRH). EB also enhances the release of FSH. In rats pretreated with LHRH, EB strongly depresses the LHRH-induced LH/FSH release, but clomiphene enhances this release, regardless of the presence of EB.

Animals↗
PubMed1980

Artificial spawning effected in the fresh water teleost, Cyprinus carpio by clomiphene citrate.

Triweekly i.m. injections of clomiphene citrate (group 1, 25 micrograms/0.5 ml and group II, 50 micrograms/1.0 ml) were administered for a period of 3 months during the preparatory period to female fresh water teleosts exhibiting ovarian recrudescence, while a control group received 0.5 ml of physiological saline throughout the period of experimentation i.e., from February through April. 50 micrograms clomiphene citrate treatment brought about a steady increase in ovarian size, and oocytes began to enlarge and mature and finally ovulation took place in April. This is 4 months ahead of their normal occurrence.

Animals↗
PubMed1989

The assessment of a cycle with clomiphene as an indicator for further treatment.

A group of 15 anovulatory women was treated during one single cycle with clomiphene citrate (CC) 100 mg daily, starting on day 5 of the cycle for 5 days, (group A). Eleven ovulatory patients represent a control group (group B). Serum levels of follicular stimulating hormone (FSH) and luteinizing hormone (LH) were determined on day 5 and 9 of the cycle. Follicular growth was assessed by ultrasound from day 9 until presumed ovulation. Estradiol levels and cervical mucus characteristics were measured on day 14 and progesterone assessed on day 23 of the cycle. In the clomiphene induced cycles FSH and LH values on day 9 were significantly above pretreatment levels (p less than 0.001 and p less than 0.0001, respectively), and above those of day 9 of the control group (p less than 0.0001). In comparison to the control group under CC treatment, an excessive production of estradiol was observed (p less than 0.0001) corresponding to significant increase in number of follicles (over 15 mm in diameter), p less than 0.04. Inspite this elevated estradiol, the cervical score was significantly lower (p less than 0.004) than in the control group. Three patients out of the 15 were characterized by a discrepancy between elevated estradiol levels and a poor mucus score. The rational of the CC assessment cycle is to identify those patients who may need an alternative treatment such as HMG/HCG or pulsatile GnRH.

Adult↗
PubMed2006

Heterotopic pregnancy following ovulation induction by clomiphene citrate and timed intercourse: a case report.

We report a combined intra-uterine and unruptured tubal pregnancy following ovulation induction by clomiphene citrate (CC) and timed intercourse. The diagnosis of heterotopic pregnancy (HP) is the major problem until occurrence of tubal rupture. Because HP is a life-threatening condition, the diagnosis should be made as soon as possible. In a spontaneous conception, HP is a rare event. The risk of HP significantly increases after ovulation induction. Clomiphene itself could be associated with a high HP rate. We present a case with normally developing intra-uterine singleton pregnancy successfully managed by salpingectomy of synchronous tubal pregnancy following ovulation induction by CC and a review of the literature.

Adult↗
PubMed1984

The effects of superovulatory doses of clomiphene citrate on spontaneous luteinizing hormone peaks in regularly ovulating women.

The effects of superovulatory doses of clomiphene citrate (150 mg orally every day for 5 days) on normal spontaneous menstrual cycles were studied in 16 women. Eight-eight percent of treatment cycles had clearly defined, timely luteinizing hormone (LH) peaks indistinguishable from those observed in normal cycles. Eight percent of treatment cycles did not have clearly defined LH peaks but were ovulatory. One cycle (4%) was anovulatory. Treated cycles were 2.1 days longer than previous control cycles (p less than 0.005). The follicular phase was significantly longer than control cycles (p less than 0.025) whereas the luteal phase was not (p greater than 0.05). There was a direct positive correlation between previous menstrual cycle length and follicular phase length in the treated cycle (r = 0.730, 0.01 less than p less than 0.05). The conclusion was that 96% of menstrual cycles of normally ovulating women remained ovulatory when the women were given superovulatory doses of clomiphene and that 88% of the cycles had clearly defined LH peaks.

Adult↗
PubMed1985

Recurrent molar pregnancies associated with clomiphene citrate and human gonadotropins.

A 34-year-old patient, gravida 7, para 0, with three consecutive spontaneous abortions followed by four recurrent molar pregnancies is described. The patient conceived only with clomiphene citrate or human gonadotropin treatment. The occurrence of molar pregnancies succeeded spontaneous abortions with one remaining pregnancy progressing to gestational trophoblastic disease. The role of clomiphene citrate and human gonadotropins in the pathogenesis of this disease is discussed.

Adult↗
PubMed1986

Human chorionic gonadotropin reduces aromatizable androgens and aromatase activity in women stimulated by clomiphene citrate and human menopausal gonadotropin.

Periovulatory steroidal dynamics in women undergoing ovulation induction with clomiphene citrate and human menopausal gonadotropin were studied in 31 women with tubal blockage. Serum estradiol levels were significantly reduced 36 hours after human chorionic gonadotropin administration (from 1792 +/- 162 to 926 +/- 132 pg/ml, p less than 0.001). Peripheral levels of testosterone and androstenedione did not change during this periovulatory time. Progesterone and 17 alpha-hydroxyprogesterone, as anticipated, significantly increased with an early rise noted within the first 8 hours of human chorionic gonadotropin administration (p less than 0.001). A significant reduction of the ratios of the steroidal pairs 17 alpha-hydroxyprogesterone-progesterone (17 alpha-hydroxylase) and androstenedione-17 alpha-hydroxyprogesterone (17,20-desmolase) was observed after human chorionic gonadotropin injection (p less than 0.001). Aromatase activity appeared to be inhibited because of a significant reduction in the estradiol/testosterone ratio 34 to 36 hours after human chorionic gonadotropin administration. Thus human chorionic gonadotropin, which triggers ovulation in women treated by clomiphene citrate-human menopausal gonadotropin, appears to partially reduce aromatizable substrate as well as inhibit aromatase activity.

Adult↗
PubMed1979

Clomiphene citrate therapy for male infertility.

We have summarized 697 reported cases of the use of clomiphene citrate for the improvement of semen quality. Basal levels of gonadotropins are useful criteria for the differential diagnosis of hypo- and hypergonadotropic hypogonadism. Patients with an intact hypothalamic-pituitary-gonadal axis are most likely to respond to clomiphene citrate. Twenty-five mg. per day, administered in a cyclic fashion for a period of six to nine months, caused the greatest improvement. A higher dose (50 mg. per day) may be effective in men who do not respond to 25 mg. During the course of therapy gonadotropin levels and semen samples should be analyzed periodically. This drug is not currently approved for use in men; the incidence of side effects, particularly with long-term treatment, is unknown.

Clomiphene↗
PubMed1988

Subacute toxicity of diethylstilboestrol and hexoestrol in the female rat, and the effects of clomiphene pretreatment.

Two groups, each of ten female rats, were orally dosed with the synthetic oestrogens diethylstilboestrol (DES; 6 mg/kg day) and hexoestrol (60 mg/kg/day) for 6 wk. A further group of ten animals received clomiphene citrate (2 mg/kg/day) and DES (6 mg/kg/day), while two groups, each of ten animals, acted as controls. One animal treated with DES died within the 42-day study period. Its death was associated with a bleeding disorder related to severe liver damage. The remaining treated animals showed little overt toxicity. The major haematological finding in the treated animals that survived was a moderate, stable, normocytic, normochromic anaemia. The terminal bone marrows of these animals showed a modest degree of erythroid hypoplasia. There were stimulatory and other changes in the reproductive tract and there were gains in the liver, adrenal and pituitary weights. These effects were more marked in the rats treated with hexoestrol, the gains in the relative organ weights being particularly striking: liver, 51%, adrenals, 210%, uterus, 79% and pituitary, 500%. The oestrogens caused reductions in body weight (18% in both cases) and appetite, a modest degree of fatty change in the liver, and alterations in the serum proteins. The Thrombotest clotting times of the hexoestrol-treated rats were prolonged. Clomiphene citrate decreased the adverse effects of DES on appetite and body weight, and sharply decreased the gains in the pituitary and uterine weights from 243 to 80% and 59 to 14%, respectively. The toxic effects of the oestrogens in the rat were more closely related to the dose administered than to their hormonal potency. Oestrogens are less toxic to the rat than they are to the cat, dog and ferret, and the toxic effects are in many respects qualitatively different.

Anemia↗
PubMed1986

Elevated testosterone level in response to clomiphene in male Anolis carolinensis.

Anolis carolinensis were used as experimental models to study the short-term effects of the fertility drug, clomiphene citrate, on male squamate reproductive function. Daily injections of 10.0 micrograms of clomiphene induced an increase in plasma testosterone over a 5 day period. No change in testis mass or morphology was elicited over this time.

Animals↗
PubMed1993

Simple and rapid determination of clomiphene cis and trans isomers in human plasma by high-performance liquid chromatography using on-line post-column photochemical derivatization and fluorescence detection.

A validated, sensitive and rapid high-performance high-performance liquid chromatographic method has been developed for the analysis of both cis and trans isomers of clomiphene in human plasma. The method involves a new off-line pre-column solid-phase extraction for sample preparation of clomiphene from human plasma in the presence of an internal standard. Analysis was performed by isocratic elution on a LiChrospher 100 RP-18 5-microns column using on-line post-column photochemical derivatization, with fluorescence detection at 247 nm (excitation) and 378 nm (emission). The limit of quantitation was 0.75 ng/ml for the cis isomer and 1.25 ng/ml for the trans isomer. The precision and accuracy of method were between good laboratory practice (GLP) required limits.

Chromatography, High Pressure Liquid↗
PubMed1989

The effect of clomiphene on the synthesis of prostaglandins (PGF2 alpha, PGE2, PGI2) in human endometrial cells in vitro with and without addition of estradiol-17 beta or progesterone.

The production of prostaglandin F2 alpha in monolayer stromal cell cultures of proliferative human endometrium is enhanced by 10(-7) mol/l estradiol-17 beta or 10(-4) mol/l progesterone. Progesterone in high concentration (10(-4) mol/l) also enhanced the synthesis of prostaglandin E2. Clomiphene citrate reduced this increased prostaglandin production dose dependently. The synthesis of prostaglandin I2 was not influenced either by sex steroids or by clomiphene citrate.

Cells, Cultured↗
PubMed2006

Thorough sonographic oocyte retrieval during in vitro fertilization produces results similar to ovarian wedge resection in patients with clomiphene citrate-resistant polycystic ovarian syndrome.

OBJECTIVE: The purpose of this study was to compare the effectiveness of a thorough sonographic oocyte retrieval to a routine in vitro fertilization retrieval to induce ovulation, pregnancy, and endocrine changes in patients with polycystic ovarian syndrome in their post-in vitro fertilization cycles. STUDY DESIGN: Sixty-four patients from a tertiary infertility clinic, with clomiphene citrate-resistant polycystic ovarian syndrome and who were undergoing in vitro fertilization, were assigned randomly into 2 groups. Group 1 (n = 34) had a thorough (every possible follicle punctured) sonographic oocyte retrieval, and group 2 (n = 30) had a routine (only follicles that were likely to contain oocytes) in vitro fertilization retrieval. These patients who did not conceive in their in vitro fertilization cycle were monitored with ultrasound scanning for evidence of ovulation, pregnancy, before and after day 3 gonadotropin, and steroid hormone levels. Analysis of variance and the Student t test were used for statistical significance. RESULTS: Ovulation rates of 53% (18/34) and cumulative pregnancy rate of 44% (8/18) were observed in group 1, with no ovulations in group 2. Significant decreases in luteinizing hormone/FSH ratio (4.1 to 1.7) and testosterone (1.2 to 0.7 ng/mL) occurred after treatment in the thorough sonographic oocyte retrieval group, with no change after routine in vitro fertilization. Operating time was increased significantly in the thorough sonographic oocyte retrieval group (45 vs 24 minutes) in group 2. CONCLUSION: Thorough sonographic oocyte retrieval during in vitro fertilization cycle can produce significant improvements in the endocrinologic abnormalities, ovulation, and pregnancies that are comparable with ovarian wedge resection in patients with clomiphene citrate-resistant polycystic ovarian syndrome.

Clomiphene↗
PubMed2004

The effects of metformin on insulin resistance, clomiphene-induced ovulation and pregnancy rates in women with polycystic ovary syndrome.

OBJECTIVE(S): To evaluate the effects of metformin on insulin resistance, ovarian androgen production, and clomiphene-induced ovulation and pregnancy rates in infertile women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Twenty-one infertile women with PCOS were selected in this prospective randomized clinical study. Basal steroid and gonadotropin levels were measured, and oral glucose tolerance test (OGTT) was performed. The patients were divided randomly into group 1 (n = 11) and group 2 (n = 10). Group 1 patients were treated with 1700 mg per day of metformin for 3 months. The basal tests and OGTT were repeated after metformin therapy. Group 2 patients did not receive metformin. The patients in both groups received 100 mg of clomiphene citrate (CC) daily for 5 days until either a pregnancy occurred, or six CC cycles were reached. Metformin administration continued during CC therapy until the day of hCG in group 1. Serum progesterone (P) level >or=5 ng/ml was considered as confirmatory of ovulation. Ovulation and pregnancy rates after six cycles were determined. RESULTS: Serum androgens and insulin response to OGTT decreased significantly after metformin therapy. Midluteal serum P level was significantly higher in cycles treated with metformin plus CC (P < 0.05). The ovulation (38 of 51 cycles, 74.4% versus 34 of 55 cycles, 61.8%) and pregnancy rates (5 of 11 women, 45.5% versus 3 of 10 women, 30%) were higher, but not significantly, in the metformin plus CC group than in the CC alone group. All the patients who conceived had insulin resistance in group 1 whereas non-insulin resistance in group 2. CONCLUSION(S): Metformin improves insulin resistance and reduces androgen levels. Metformin did not increase significantly the ovulation and pregnancy rates.

Adult↗
PubMed2004

A trial of a new regimen with clomiphene citrate administration to reduce the antiestrogenic effects on reproductive end organs.

OBJECTIVE: To determine the endocrinological and clinical outcomes of a 3-day clomiphene citrate (CC) regimen and compare it with the classical 5-day clomiphene citrate regimen. STUDY DESIGN: 59 patients, diagnosed with Class II ovulatory deficiency according to the criteria defined by WHO, were randomized into two groups. Patients in Group I received 50mg per day of CC for 3 days starting on the first day of the cycle during 72 cycles. Group II received 50mg per day of CC for 5 days starting on the fifth day during 64 cycles. RESULT(S): The ovulation rate was significantly higher in Group II (78.11%) compared to Group I (63.88%) (P < 0.05). However, the implantation rate was higher in Group I than Group II. CONCLUSION: We observed that starting CC on the first day of the cycle for 3 days would lead to higher implantation rates compared to the classical 5-day CC therapy.

Adult↗
PubMed2004

Obstetric implications for and identification of women with a normal clomiphene citrate challenge test result who have a poor response to gonadotropins.

OBJECTIVE: To determine the incidence and obstetric implications and to identify prospectively women with a poor response to hMG with a normal clomiphene citrate challenge test (CCCT) result. DESIGN: Retrospective chart review. SETTING: Tertiary fertility center. PATIENT(S): One hundred sixty-three women who underwent ovulation induction with hMG for IUI, and 266 women who underwent ovulation induction with GnRH analogue and hMG for IVF. All had a CCCT before stimulation. Seventy-five percent of IUI patients (123 of 163) and 89% of IVF patients (238 of 266) had normal CCCT results. A poor response to hMG was defined as a response less than the 90th percentile of women with an abnormal CCCT result (peak E(2) [pg/mL] level per ampule hMG used: 90th percentile </=30). INTERVENTION(S): Clomiphene citrate challenge test and ovulation induction for IUI or IVF. MAIN OUTCOME MEASURE(S): Response to gonadotropins and pregnancy outcome after treatment. RESULT(S): Thirty-five percent of IUI patients (43 of 123) and 52% of IVF patients (123 of 238) with a normal CCCT result had a poor response to hMG. Intrauterine insemination patients with a poor response to hMG had significantly lower delivery rates than IUI patients with a normal response (19% vs. 39%). In vitro fertilization patients with a poor response to hMG had similar delivery rates compared with IVF patients with a normal response (32% vs. 35%). For both groups of patients, an FSH >12 mIU/mL (IMx assay) on either day 3 or day 10 (normal </=14.5 IMx) was highly predictive of a poor response to hMG, the elevated FSH level being a much better predictor than the woman's age. CONCLUSION(S): A poor response to hMG with a normal CCCT result (false negative) is a common event. A day-3 or day-10 FSH >12 mIU/mL (IMx assay) or 20 mIU/mL (converted to the original RIA) will identify approximately 80% (IUI) and approximately 94% (IVF) of the women who will experience a poor response to hMG. When identified, the data suggest that these patients will benefit significantly from the more aggressive IVF.

Adult↗
PubMed2005

Differential expression of endometrial integrins and progesterone receptor during the window of implantation in normo-ovulatory women treated with clomiphene citrate.

OBJECTIVE: To assess the effect of clomiphene citrate (CC) on endometrial epithelial integrins and P receptors (PR) during the window of implantation. DESIGN: Controlled, prospective, clinical study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-one fertile, normo-ovulatory women participated in this trial. Thirteen women exhibited a CC-stimulated cycle with 50 mg on days 5-9, and 18 women with spontaneous menstrual cycles served as controls. INTERVENTION(S): Endometrial biopsies in the midluteal phase. MAIN OUTCOME MEASURE(S): Immunohistochemical determination and endometrial cellular localization of alpha1, alpha v, beta3, and alpha4 epithelial integrins and PR during the window of implantation. The staining intensity was assessed by a semiquantitative index (HSCORE) and compared by nonparametric Mann-Whitney test. RESULT(S): Higher plasma levels of P and E2 and delayed histologic dating of the endometrium (38%) were features of CC-treated women. In addition, a low epithelial beta3 integrin expression and persistent PR were observed in glandular epithelial cells of "out-of-phase" endometrial biopsies from CC-treated women. In contrast, in "in-phase" biopsies, neither epithelial PR nor beta3 integrin were different from spontaneous control cycles. There was no difference in the expression of alpha1, alpha v, and alpha4 between the groups studied. CONCLUSION(S): The administration of clomiphene produces aberrant endometrial beta3 integrin expression in conjunction with a failure in the down-regulation of PR during the window of implantation in a significant number of normo-ovulatory women, notwithstanding the higher plasma P levels. Therefore, CC might affect the expression of endometrial receptivity markers.

Adult↗
PubMed2005

Estradiol protects clomiphene citrate-induced apoptosis in ovarian follicular cells and ovulated cumulus-oocyte complexes.

OBJECTIVE: To determine whether clomiphene citrate (CC) reduces E(2) level in the ovary and circulation and induces apoptosis in ovarian follicular cells and ovulated cumulus-oocyte complexes (COCs). If yes, to determine whether E(2) coadministration could protect against these adverse effects of CC. DESIGN: A controlled prospective study. SETTING: Laboratory research setting. ANIMAL(S): Ninety sexually immature female rats that were 24-25 days of age. INTERVENTION(S): The immature female rats were injected with a single dose of 10 IU of pregnant mare serum gonadotropin. After 48 hours, 10 IU of hCG along with 10 mg of CC per kilogram of body weight, with or without 2.0 mg of E2 per kilogram of body weight were coadministered. After 16 hrs, the rats were killed; COCs were collected from oviduct and ovaries were isolated. MAIN OUTCOME MEASURE(S): Number of superovulated COCs, oocyte morphology, E2 level in ovary and serum, histology of ovary, DNA fragmentation, and bax protein expression in ovary and COCs. RESULT(S): The number of COCs and E2 level in ovary and serum were reduced, whereas membrane blebbing in oocytes, bax protein expression, and DNA fragmentation in ovarian follicular cells and ovulated COCs were induced after CC treatment. These adverse effects of CC were protected against if animals were coadministered with E2. CONCLUSION(S): Clomiphene citrate-induced apoptosis in ovarian follicular cells (probably granulosa cells), thereby reducing E2 level in ovary and circulation that might have resulted in poor development and maturation of oocytes leading to reduced ovulation.

Animals↗