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PubMed1984

Enhanced follicular recruitment in an in vitro fertilization program: clomiphene alone versus a clomiphene/human menopausal gonadotropin combination.

In an attempt to improve the pregnancy rate following in vitro fertilization and embryo transfer by increasing the numbers of embryos available for transfer to each patient, a prospective, randomized comparison of clomiphene citrate alone (50 mg/day, cycle days 5 to 9) with the combination of clomiphene as above plus human menopausal gonadotropin (2 ampules/day, cycle days 6, 8, and 10) was undertaken from January through April 1983, with 17 patients in each group. The combination produced increased follicular development, compared with clomiphene alone, resulting in the retrieval of more fertilizable oocytes. Two clinical pregnancies resulted in each group. These results show that a fixed combination of clomiphene and human menopausal gonadotropin produces a greater degree of enhanced follicular recruitment, resulting in the recovery of an increased number of fertilizable oocytes. The lack of a statistically significant increase in the number of embryos transferred per patient in the combination group as well as the identical number of clinical pregnancies in both groups suggests that this particular combination of clomiphene and human menopausal gonadotropin offers no advantage over the use of clomiphene alone for enhanced follicular recruitment.

Cell Differentiation↗

PubMed1999

Octreotide is not useful for clomiphene citrate resistance in patients with polycystic ovary syndrome but may reduce the likelihood of ovarian hyperstimulation syndrome.

OBJECTIVE: To determine whether octreotide is effective for ovulation induction in patients with polycystic ovary syndrome (PCOS) and clomiphene citrate resistance or for reduction of the risk of ovarian hyperstimulation syndrome (OHSS) with gonadotropin therapy. DESIGN: Prospective, double-blind, placebo-controlled, crossover trial. SETTING: Private infertility practice. PATIENT(S): Twelve patients with PCOS undergoing therapy for infertility. INTERVENTION(S): The patients were assigned randomly to receive either octreotide or placebo. Those with clomiphene citrate-resistant PCOS received clomiphene citrate, 150 mg. Patients at risk for the development of OHSS received urinary FSH for ovulation induction. MAIN OUTCOME MEASURE(S): Ovulation, pregnancy, the development of OHSS, and levels of fasting insulin, insulin-like growth factor 1, insulin-like growth factor binding proteins 1 and 3, testosterone, androstenedione, DHEAS, E2, LH, and FSH. RESULT(S): Octreotide significantly reduced levels of fasting insulin, insulin-like growth factor 1, and LH in both clomiphene citrate- and urinary FSH-stimulated cycles. Levels of insulin-like growth factor binding protein 3 were increased. Two of six clomiphene citrate-stimulated cycles reached ovulation with the use of either octreotide or placebo. In urinary FSH-stimulated cycles, patients who received octreotide had significantly lower E2 levels at the time of hCG administration and fewer mature follicles. No cases of OHSS occurred in either group. One pregnancy occurred in each group. CONCLUSION(S): Octreotide was no more effective than placebo for clomiphene citrate resistance in patients with PCOS, but it did reduce E2 levels and follicle numbers when combined with urinary FSH. Thus, octreotide may reduce the incidence of OHSS in patients with PCOS.

Adult↗

PubMed2004

Ovulation induction in women with polycystic ovary syndrome: randomized trial of clomiphene citrate versus low-dose recombinant FSH as first line therapy.

This single centre randomized controlled trial was undertaken to compare the efficacy and safety of clomiphene citrate and low-dose recombinant FSH as first line pharmacological therapy for anovulatory infertility associated with polycystic ovary syndrome (PCOS). Seventy-six infertile patients with PCOS were randomized to receive clomiphene citrate (50-150 mg/day for 5 days) (clomiphene citrate group, n = 38) or recombinant human FSH (FSH group, n = 38) in a chronic, low-dose, step-up protocol (daily starting dose 75 IU) for up to three consecutive cycles. Ovarian response was monitored by transvaginal ultrasonography and human chorionic gonadotrophin (HCG) was given to trigger ovulation in all cycles with appropriate follicular development. The primary outcome measure was cumulative pregnancy after undergoing up to three treatment cycles. Secondary outcomes were cycle cancellation rate, ovulation rate per cycle, cumulative ovulation rate, pregnancy rate per cycle, incidence of OHSS, cumulative live birth rate, and multiple birth rate. One hundred and four clomiphene citrate cycles and 91 FSH cycles were evaluable. The relative risk and its 95% confidence interval were 1.17 (0.97-1.46) for HCG cycles with ovulation, 1.78 (0.92-3.54) for the pregnancy rate per woman, and 1.83 (0.79-4.40) for live births per woman in favour of FSH. The cumulative pregnancy rate after three treatment cycles was 43% with FSH and 24% with clomiphene citrate (P = 0.06). By logistic regression analysis, the factors predicting ovulation included female age, serum androstenedione and use of FSH. Predictors of pregnancy were duration of infertility and use of FSH. This randomized controlled trial suggests that low-dose recombinant FSH may be an effective alternative to clomiphene citrate in first-line treatment for anovulatory PCOS patients. Thus, further studies, possibly multi-centre, in order to avoid problems with patient recruitment, are warranted to confirm these results.

Adult↗

PubMed1997

In vitro fertilization with low-dose clomiphene citrate stimulation in women who respond poorly to superovulation.

PURPOSE: Our experience with IVF using low-dose clomiphene citrate for stimulation in "non-" and "poor" responders was reviewed and the treatment outcomes with the previous controlled ovarian stimulation cycles in which hMG and GnRH agonist were used were compared. METHODS: The treatment outcome in 11 non- and 20 poor responders having 30 and 53 clomiphene citrate IVF treatment cycles, respectively, were compared with the treatment outcome in the previous long-protocol buserelin/hMG cycles. RESULTS: The clinical pregnancy rates per oocyte collection achieved in the first clomiphene citrate cycle in non (9.1%)- and poor (10%) responders were comparable to those achieved by poor responders (11.9%) who had buserelin/hMG using the long protocol. Although the numbers were small, a similar pregnancy rate could still be achieved in poor responders up to the third attempt using clomiphene citrate. CONCLUSIONS: IVF using long-protocol buserelin/hMG is more successful than using clomiphene citrate stimulation. However, this advantage may not be significant in those women with a previous poor response to buserelin/hMG. It is suggested that for such poor responders, three attempts of IVF in a clomiphene citrate cycle may offer a viable therapeutic alternative before reverting to more stressful, expensive, and time-consuming treatment.

Adult↗

PubMed1988

Effects of a phorbol ester and clomiphene on protein phosphorylation and insulin secretion in rat pancreatic islets.

The potentiation of glucose-stimulated insulin release induced by 100 nM-12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by clomiphene, an inhibitor of protein kinase C (PK C), in a dose-dependent manner. Clomiphene at concentrations up to 50 microM had a modest inhibitory action (27%) on insulin release stimulated by 10 mM-glucose alone, but had no effect on the potentiation of insulin release induced by forskolin. Islet PK C activity, associated with a particulate fraction, was stimulated maximally by 100 nM-TPA. This stimulation was blocked by clomiphene in a dose-dependent manner, with 50% inhibition at 30 microM. Incubation of intact islets with TPA after preincubation with [32P]Pi and 10 mM-glucose to label intracellular ATP resulted primarily in enhanced phosphorylation of a 37 kDa protein (mean value, +/- S.E.M., 36,700 +/- 600 Da; n = 7). This increased phosphorylation was blocked by the simultaneous inclusion of clomiphene. Subcellular fractionation revealed the presence of the 37 kDa phosphoprotein in a 24,000 g particulate fraction of islet homogenates. Neither clomiphene nor TPA affected the rate of glucose oxidation by islets. These results show that the phosphorylation state of a 37 kDa membrane protein parallels the modulation of insulin release induced by TPA and clomiphene and support a role for PK C in the insulin-secretory mechanism.

Animals↗

PubMed2002

Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice.

AIMS: To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic. METHODS: This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day-1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50-100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin. RESULTS: Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59. CONCLUSIONS: Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.

Adult↗

PubMed1984

[Additive therapy in ovulation induction with clomiphene].

Between 1977 and 1981 1319 patients consulted our hospital with the problem of sterility. 763 women became pregnant, 200 were treated with clomiphen . In 69 cases we used a combination with other agents, because ovulation could not be induced with clomiphen alone. 7 times we combined clomiphen with HCG, in 7 other cases with Prednisolon . Ovulation and pregnancy occurred subsequent to a treatment with Estradiolvalerianate -Norgestrel and clomiphen in 15 patients, in 32 patients after administration of a combination of clomiphen and Bromocriptine. The inadequate cervical mucus which may develop in patients during clomiphen therapy was treated with an additional low dose of ethinylestradiol. Our retrospective study confirms the value of a combination therapy in the treatment of anovulation and sterility.

Adult↗

PubMed2001

Clomiphene citrate in the twenty-first century.

Clomiphene citrate is the drug most commonly prescribed for ovulation induction. It is the first choice medication in normogonadotrophic oligo/amenorrhoeic infertility (WHO group 2), essentially associated with polycystic ovaries. Anovulatory women who are responsive to clomiphene citrate should be treated for at least six cycles and the treatment should probably be limited to a maximum of 12 cycles. It is necessary to monitor at least the first cycle with ultrasonography because of the risk of multiple pregnancy and the variable response of patients to different doses of clomiphene. In addition, the risk of ovarian hyperstimulation syndrome should not be underestimated. More triplets and higher order pregnancies result from ovulation induction than from in vitro fertilization, and multiple pregnancy has many risks for both mother and babies. The role of empirical clomiphene in the treatment of unexplained infertility is debatable and the present data are inconclusive. Obesity, hyperandrogenaemia and insulin resistance are important factors in clomiphene-resistant patients. Failure to ovulate in response to clomiphene has been approached by either medical or surgical treatment. An effective alternative medical treatment is gonadotrophin injections. Treatment with metformin and the new generation of insulin-sensitizing drugs is under evaluation. The most widely used surgical treatment today is laparoscopic ovarian drilling, which appears to be as effective as gonadotrophin therapy.

Clomiphene↗

PubMed2005

Uterine cancer after use of clomiphene citrate to induce ovulation.

Clomiphene citrate, a selective estrogen receptor modulator, increases estradiol levels and consequently may increase risk of cancer of the uterine corpus. The authors conducted a retrospective cohort study of 8,431 US women (145,876 woman-years) evaluated for infertility during 1965-1988. Through 1999, 39 uterine cancers were ascertained by questionnaire or cancer and death registries. Poisson regression estimated adjusted rate ratios. Study results suggest that clomiphene may increase uterine cancer risk (rate ratio (RR) = 1.79, 95% confidence interval (CI): 0.9, 3.4) and present evidence of a dose response (p(trend) = 0.07) and latency effect (p(trend) = 0.04). Uterine cancer risk increased with clomiphene dose (RR = 1.93, 95% CI: 0.9, 4.0 for >900 mg), menstrual cycles of use (RR = 2.16, 95% CI: 0.9, 5.2 for >or=6 cycles), and time elapsed since initial use (RR = 2.50, 95% CI: 0.9, 7.2 for women followed for >or=20 years). Risk was more strongly associated with clomiphene among nulligravid (RR = 3.49, 95% CI: 1.3, 9.3) and obese (RR = 6.02, 95% CI: 1.2, 30.0) women, with risk substantially elevated among women who were both obese and nulligravid (RR = 12.52, 95% CI: 1.5, 108.0). Clomiphene may increase uterine cancer risk, with higher doses leading to higher risk. Long-term follow-up of infertility cohorts is necessary to clarify the association between clomiphene use and uterine cancer.

Adult↗

PubMed1997

Relationship of clomiphene dose and patient weight to successful treatment.

Our objective was to examine the relationship between patient weight and the dose of clomiphene required for pregnancy so as to assess the validity of recommendations that the dose of clomiphene be limited to 100 mg. We retrospectively analysed the weight-dose relationship in 1681 clomiphene pregnancies and the relationship between dose and pregnancy, births, multiple births, number of pre-ovulatory follicles and endometrial thickness in 2841 cycles of clomiphene treatment, 25-250 mg, for 5 days before intrauterine insemination (IUI). Doses of clomiphene >100 mg/day were used before pregnancies in 27.4% of patients who weighed >90 kg and in 14.7% of all pregnancies. In IUI cycles, pregnancies and births, but not multiple births or abortions, were related to dose. An increase in dose from 25 to 100 mg resulted in higher pregnancy and birth rates, and in an increase in the average number of pre-ovulatory follicles > or =12 mm in diameter, from 2.0 to 2.8, with no additional increase at higher doses. Endometrial thickness and cycle day of insemination were not related to dose. We conclude that doses of clomiphene may safely be increased beyond 100 mg, and that doses > or =100 mg are required in significant numbers of patients.

Body Weight↗

PubMed2005

Comparison of tamoxifen and clomiphene citrate for ovulation induction: a meta-analysis.

BACKGROUND: Both selective estrogen receptor modulators, tamoxifen and clomiphene have been used for ovulation induction for patients with anovulatory infertility. This meta-analysis sought to compare the effectiveness of tamoxifen to clomiphene for the induction of ovulation and achievement of pregnancy. METHODS: We searched MEDLINE, BIOSIS, PreMEDLINE, CINAHL, International Pharmaceutical Abstracts, DDSR, ACP Journal Club, DARE and CCTR, along with reference lists and national experts. Inclusion criteria were prospective clinical trials, which compared tamoxifen and clomiphene for ovulation induction in infertile couples with isolated anovulatory infertility. Main outcome measures were ovulation rate and clinical pregnancy rate. Pooled odds ratios were obtained using random effects meta-analysis. RESULTS: Four trials were included. After pooling all the trials, the use of tamoxifen or clomiphene citrate resulted in similar ovulation rates [odds ratio (OR) 0.755, 95% confidence interval (CI) 0.513-1.111]. There was no benefit of tamoxifen over clomiphene citrate in achievement of pregnancy per cycle (OR 1.056, 95% CI 0.583-1.912) or per ovulatory cycle (OR 1.162, 95% CI 0.632-2.134). CONCLUSIONS: Clomiphene citrate and tamoxifen are equally effective in inducing ovulation. Although data regarding pregnancy rates and outcome are limited, there does not appear to be a significant benefit of one medication over the other.

Adolescent↗

PubMed2006

Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study.

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.

Adult↗

PubMed1987

The estrogenic responses to clomiphene in the different cell types of the rat uterus: morphometrical evaluation.

The present study was designed to investigate the dose-response of clomiphene on several estrogenic responses in the immature rat uterus and to compare it to available data on estradiol-17 beta. A dissociation was demonstrated among the different estrogenic responses induced by clomiphene. Very high doses of clomiphene were needed to induce the 6-h uterine eosinophilia and deep endometrial edema, and maximal response levels were not reached at any dose studied. On the contrary, many genomic responses were induced with much lower doses of clomiphene, and maximal response levels were reached with at least the two highest doses of clomiphene. This dissociation is in agreement with the existence of separate groups of responses that are mediated by multiple and independent mechanisms of estrogen action involving different kind of receptors. Luminal epithelial, glandular epithelial, and myometrial hypertrophies were also found to differ with regard to the dose needed to induce this response in each cell type. The dissociation between genomic responses of the different uterine cell types supports the hypothesis of different estrogen receptors for each kind of cell. Clomiphene induces mitoses in the different cell types, but the proportion of mitoses in the cell types was different from that described for estradiol. It is suggested that these differences are also due to differences between receptors involved in cell proliferation.

Animals↗

PubMed1992

Inhibition of decidual induction in rats by clomiphene and tamoxifen.

The objective of this study was to characterize the estrogen action that confers endometrial sensitization to nontraumatic deciduogenic stimuli by use of antiestrogens. Tamoxifen, ethamoxytriphetol, and clomiphene and its two component enantiomers inhibited decidual induction in pseudopregnant rats when administered 17 h before pyrathiazine. Unexpectedly, clomiphene (250 micrograms/rat) and tamoxifen (25 micrograms/rat) proved inhibitory at all times up to and including the time of induction. Clomiphene, administered in the hours preceding decidual induction, inhibited the increase of ornithine decarboxylase activity, which normally marks the end of the induction phase. Clomiphene had no inhibitory effect on the availability or receptor binding of progesterone. Clomiphene also inhibited implantation of blastocysts when administered at the time of their adherence to the uterus. The inhibition by antiestrogens of decidual induction could not be explained on the basis of the current understanding of mechanisms of estrogen action. The discrepancies were that no latent period between the time of antiestrogen administration and decidual induction was observed and no difference was observed in the inhibitory activities of the isomers of clomiphene.

Animals↗

PubMedDate not supplied

Gonadotropins, prolactin, testosterone and estradiol in seminal plasma: effect of clomiphene treatment.

To elucidate the mechanism of clomiphene action in the treatment of male infertility, we studied the effect of three-month clomiphene treatment (50 mg daily) on the radioimmunoassayable concentrations of gonadotropins (FSH, LH), prolactin (PRL), estradiol (E2), and testosterone (T) in seminal plasma and peripheral serum in eleven normogonadotropic subfertile men. Clomiphene therapy increased (p less than 0.01) the levels of FSH and LH in seminal plasma, but to a lesser extent (p less than 0.01) than in peripheral serum. PRL did not change is seminal plasma or peripheral serum. The seminal plasma and peripheral serum T concentrations doubled following clomiphene intake without any demonstrable correlation with the sperm count. The concentrations of E2 increased about ten times (p less than 0.005) in seminal plasma, a significantly greater (p less than 0.05) increase than that in the serum. There was a significant correlation (r = 0.804, p less than 0.01) between the sperm counts and seminal plasma E2 levels following clomiphene treatment. These results suggest that Sertoli cell activation may be a key event in clomiphene action in the treatment of male infertility.

Adult↗

PubMed1982

Effects of clomiphene treatment on infertile women with normal menstrual rhythm.

Fourteen infertile women with normal menstrual rhythm were investigated; each provided daily blood samples throughout two menstrual cycles: one control cycle and another on therapy with clomiphene (50 mg/day) given either from days 1 to 5 (n = 7; group I) or from days 5 to 9 (n = 7; group II) of the cycle. The effects of this empirical clomiphene therapy on the menstrual cycles were assessed by reference to the delay from termination of clomiphene therapy to ovulation (day after the LH peak) and by comparing pre-ovulatory oestradiol levels and luteal phase progesterone indices (total progesterone levels from days 4 to 8 post LH peak) in patients' control and treated cycles. No differences were observed in the effects of the treatment on the two groups of women except that the clomiphene to ovulation delay was greater in those treated earlier in the cycle (group I). Clomiphene caused increased follicular development as indicated by elevated pre-ovulatory oestradiol levels but this was not followed by improved progesterone indices. Ovarian ultrasonography indicated that the increased follicular development was in terms of numbers of follicles and not in maturity or oestrogen biosynthetic capacity of individual follicles. The lack of increased luteal progesterone levels thereafter indicated that mean luteal progesterone production per luteinized follicle was reduced. Clomiphene therapy as given in this study was therefore not successful in stimulating increased follicular/luteal hormone production from the dominant follicle/corpus luteum in such patients.

Clomiphene↗

PubMed1976

Effects of Cis- and trans-clomiphene on the uterine blood flow of oophorectomized ewes.

Changes in the left uterine artery blood flow (YBF) after intraarterial administration of estradiol-17beta and cis- and trans-clomiphene citrate to conscious, oophorectomized ewes were monitored by chronically implanted electromagnetic flow probes. Cis-clomiphene produced UBF increases comparable to or greater than those produced by estradiol-17beta but at dose levels 20 times greater. Comparison of UBF response curves for cis-clomiphene with those for estradiol-17beta showed a delayed onset of initial vasodilation and a delayed peak response. The duration of uterine vasodilation produced by cis-clomiphene was dose-dependent and exceeded that produced by estradiol-17beta. Similar reponses were observed with trans-clomiphene but at dose levels at least 1,000 times those of estradiol-17beta. The characteristics of clomiphene-induced UBF responses that differed from those after estradiol-17beta may reflect differences in estrogen receptor activation between the compounds.

Animals↗

PubMed1988

Characterization of the effects of clomiphene citrate on reproductive physiology in male rats of various ages.

Clomiphene citrate (clomiphene) inhibits reproduction in male rats; however, stimulatory effects have been reported at low doses. Male rats were implanted at 60 (adult), 35 (peripubertal) or 10 (prepubertal) days of age with pellets that delivered 0, 0.05, 0.5 or 5.0 mg clomiphene.kg-1.day-1 and were sacrificed after 7 or 14 days of treatment. Testis weight was unaffected by clomiphene in adult and peripubertal rats, but was reduced by all doses in prepubertal rats. Seminal vesicle and prostate gland weights were decreased to varying degrees by clomiphene in all animals, except seminal vesicle weight in peripubertal rats. Serum LH and testosterone were decreased by most doses in all age groups, whereas pituitary LH was decreased in prepubertal rats only. Pituitary GnRH and testicular LH receptor concentrations were reduced in all treated animals. Serum and pituitary FSH were decreased in pre- and peripubertal rats, whereas testicular FSH receptor concentrations were unaffected by treatment. In summary, 1) reproductive function was compromised by clomiphene and many responses were age-dependent, 2) reductions in gonadotropins suggest that clomiphene decreased their synthesis and/or release, and 3) decreased serum LH and testicular LH receptor concentrations were coupled to reduced testosterone secretion.

Age Factors↗