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PubMed2002

A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.

OBJECTIVE: To evaluate the ovarian follicular dynamics of cycle modification with the aromatase inhibitor letrozole compared with clomiphene citrate in normal ovulatory women. DESIGN: Randomized double-blind controlled trial. SETTING: Tertiary care hospital. PATIENT(S): Nineteen ovulatory female volunteers, ages 18-35 years. INTERVENTION(S): Subjects were monitored in one control cycle. Subjects then received either letrozole 2.5 mg daily or clomiphene citrate 50 mg daily on days 5-9 after menses. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness and endometrial pattern at ovulation, and follicular profiles of LH, FSH, and E(2). RESULT(S): The number of mature follicles at the LH surge in natural cycles was 1.0 with an exaggerated response seen for treatment both with clomiphene and letrozole. There was no difference in the endometrial thickness at midcycle during either the natural cycles or the medicated cycles. LH surges and spontaneous ovulation were documented in all natural and medicated cycles. When measured daily, follicular profiles of LH and FSH are similar between the groups in both the natural and medicated cycles. In the medicated cycles, clomiphene results in a significant increase in E(2) levels, while E(2) levels in letrozole-stimulated cycles appeared lower than in natural cycles. CONCLUSION(S): Transient inhibition of aromatase activity in the early follicular phase with the aromatase inhibitor letrozole results in stimulation of ovarian folliculogenesis similar to that seen with clomiphene citrate with no apparent adverse effect on endometrial thickness or pattern at midcycle.

Adolescent↗
PubMed2000

Clomiphene citrate-induced perturbations during meiotic maturation and cytogenetic abnormalities in mouse oocytes in vivo and in vitro.

OBJECTIVE: To determine if clomiphene citrate induces temporal perturbations during meiotic maturation and aneuploidy in mouse oocytes. DESIGN: A controlled dose study involving mouse oocytes in vivo and in vitro. SETTING: Clinical and academic research setting in a university medical center. INTERVENTION(S): Oocytes were obtained after superovulation and from mature follicles. MAIN OUTCOME MEASURE(S): Cytogenetic analysis of oocytes for aneuploidy, premature centromere separation, premature anaphase, and single chromatids, and the frequencies of metaphase I and diploid oocytes. RESULT(S): Clomiphene citrate resulted in a decrease in the number of ovulated oocytes and a significant (P<.05) increase in hyperploidy at 100 mg/kg in vivo. In vitro, 5.0 microg/mL of clomiphene citrate significantly (P<.05) increased hyperploidy and reduced the proportion of metaphase I oocytes. CONCLUSION(S): These findings suggest that clomiphene citrate has the potential for inducing aneuploidy in mouse oocytes both in vivo and in vitro and that the rate of oocyte maturation is altered after clomiphene exposure in vitro. Additional data are needed to support the results of this study.

Aneuploidy↗
PubMed2003

The impact of LH serum concentration on the clinical outcome of IVF cycles in patients receiving two regimens of clomiphene citrate/gonadotrophin/0.25 mg cetrorelix.

Clomiphene citrate treatment with the association of gonadotrophins and the GnRH antagonist cetrorelix 0.25mg was analysed in two different stimulation protocols for IVF. In protocol I, 18 patients were sequentially stimulated with clomiphene citrate and gonadotrophins. In protocol II, 28 patients started the gonadotrophin injections during the clomiphene citrate administration. LH values significantly dropped after the first 0.25 mg cetrorelix injection in both protocols. A total of 22% and 7% of cycles were cancelled in protocols I and II, respectively, because of poor follicular development. The clinical pregnancy rate following embryo transfer was 18.1% in protocol I and 29.1% in protocol II. In two (11.1%) cycles stimulated according to protocol I and in eight (28.5%) cycles from protocol II, premature LH surges occurred. In patients with premature LH surge, significantly fewer metaphase II oocytes were obtained. The clinical pregnancy rate following embryo transfer was 12.5% in patients with surge compared with 29.6% in patients without. LH values were lower before HCG injection in patients who achieved pregnancy in the study cycle. In conclusion, sequential clomiphene citrate and gonadotrophin administration is not recommended for clomiphene citrate/gonadotrophin/cetrorelix 0.25 cycles. Cetrorelix 0.25 mg/day was associated with a high incidence of premature LH surges and premature LH surges were associated with an adverse cycle outcome.

Adult↗
PubMed1998

Studies of protein binding to nonpolar solutes by using zonal elution and high-performance affinity chromatography: interactions of cis- and trans-clomiphene with human serum albumin in the presence of beta-cyclodextrin.

High-performance affinity chromatography and zonal elution studies were used to examine the binding that takes place between the drug clomiphene and the protein human serum albumin (HSA). Equations were derived to describe the behavior of zonal elution experiments in which a solubilizing agent is present in the mobile phase to aid in the dissolution of a competing agent or injected analyte. These equations were then used to determine the association equilibrium constants for the clomiphene/HSA system, with beta-cyclodextrin being used as a complexation agent to improve the water solubility of cis- and trans-clomiphene without affecting the nature of their binding to HSA. It was found in these studies that both cis- and trans-clomiphene have 1:1 interactions at a common binding region on HSA (association constants at pH 7.4 and 37 degrees C: cis, 7.5 x 10(6) M-1; trans, 1.3 x 10(6) M-1). Further competition experiments between cis- or trans-clomiphene and various site-selective probes indicated that the clomiphene-binding region is the same as the proposed tamoxifen site of HSA. The approach and equations used within this report are general ones that can be applied to zonal elution studies of other solute-ligand systems in which one or more of the test components have limited solubility in the desired mobile phase.

Chromatography, Affinity↗
PubMed2001

A randomized study comparing IVF in the unstimulated cycle with IVF following clomiphene citrate.

The efficiency of IVF in unstimulated cycles was compared with that following ovarian stimulation with clomiphene citrate in a simple protocol with ultrasound monitoring only. A total of 132 couples with no previous IVF attempts, selected by female age <35 years, indication for intracytoplasmic sperm injection or infertility caused by tubal factor or unexplained infertility were randomized to the two protocols. Randomization yielded two comparable groups. The clomiphene group (68 couples) performed significantly better than the unstimulated group (64 couples) in terms of number of cycles with oocyte harvest (90/111 or 81% versus 65/114 or 57%; chi(2) = 9.21, P < 0.002), embryo transfers per started cycle (59/111 or 53% versus 29/114 or 25%; chi(2) = 18.14, P < 0.0001), live intrauterine pregnancy rate per started cycle (20/111 or 18% versus 4/114 or 4%; chi(2) = 12.42, P < 0.0001), live intrauterine pregnancy rate per embryo transfer (20/59 or 34% versus 4/29 or 14%; chi(2) = 3.96, P = 0.047), but not in terms of implantation rate (22/85 or 26% versus 4/29 or 14%; chi(2) = 1.65). Only two twin pregnancies occurred. Modest side-effects were recorded following clomiphene. Accordingly, a simple clomiphene citrate protocol, but not IVF in unstimulated cycles, seems compatible with the concept of 'friendly IVF', yielding a fair pregnancy rate both per cycle started and per embryo transfer in selected patients. The results do not substantiate any important negative anti-oestrogenic effects of clomiphene.

Adult↗
PubMed2004

Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome.

BACKGROUND: The aim of this study was to evaluate the effects of metformin and acarbose on insulin resistance, hormone profiles and ovulation rates in patients with clomiphene citrate-resistant polycystic ovary syndrome (PCOS). METHODS: Thirty clomiphene citrate-resistant patients were selected randomly and divided into two groups. Group I was treated with 100 mg/day clomiphene citrate and 300 mg/day acarbose 100 mg/day orally, for 3 months. Group II was treated with clomiphene citrate 100 mg/day and metformin 1700 mg/day orally, for 3 months. Serum fasting insulin and glucose, FSH, LH, estradiol, progesterone, prolactin and total testosterone levels plus body mass index (BMI) were measured before and after treatment. Follicle growth was followed by transvaginal ultrasonography. RESULTS: LH:FSH ratio and total testosterone concentrations decreased (P<0.05) and ovulation rates increased in both groups. Reduction in weight and BMI was only significant in the acarbose group. CONCLUSIONS: Both treatment modalities were effective in the treatment of insulin resistance and improving ovulation rates. Increase in the number of eumenorrhoeic and normoinsulinaemic cases and decrease in the number of insulin-resistant cases were significant in both groups (P<0.05). Ovulation rate was greater in the metformin group in the second month of therapy (P<0.05). Acarbose was found to be a safe and effective agent that could be used in cases with clomiphene-resistant PCOS.

Acarbose↗
PubMed1993

Effect of clomiphene citrate on sperm cell function.

Experiments were performed to determine time and dose-dependent effects of clomiphene citrate on the function of fertile donor spermatozoa. The percentages of acrosome-reacted, motile and live spermatozoa were assessed. Incubation with clomiphene citrate (1-1000 mumol/l; 1-4 h) induced a dose- and time-dependent increase in the percentage of acrosome-reacted spermatozoa (up to 100%). Acrosome reaction was associated with an impairment of both motility and viability. The maximal value for percentage of live reacted spermatozoa (37 +/- 1%) was obtained when cells were incubated for 1 h with 100 mumol/l of clomiphene citrate. Oestradiol neither affected sperm function when used alone nor inhibited clomiphene action. These results show that clomiphene strongly triggers the acrosome reaction, but that this action is not related to its anti-oestrogenic properties.

Acrosome↗
PubMed1986

Ovulation induction with low doses of clomiphene citrate.

Ovulation was induced with one-quarter tablet (12.5 mg) of clomiphene citrate given for five days to three oligoovulatory patients who had consistently formed functional ovarian cysts when given 50 and 25 mg of clomiphene citrate for five days. Two of the patients had polycystic ovary syndrome and the other had hypothalamic dysfunction associated with an eating disorder. On clomiphene citrate 12.5 mg for five days, one patient conceived, another produced inadequate cervical mucus but later conceived after in vitro fertilization and embryo transfer, and the third woman, who had concomitant fallopian tube disease, ovulated but has not conceived. Women oversensitive to clomiphene citrate can be effectively treated with very low doses of the drug. Perhaps other oligoovulatory patients may benefit from lower than currently recommended clomiphene citrate doses.

Adult↗
PubMed1977

Gonadotrophin release in ovariectomized patients. I. Suppression by clomiphene or low doses of ethinyl oestradiol.

Administration of clomiphene citrate (150 mg/day) for 5 days to twenty-four ovariectomized patients and seven normal female patients evoked a significant release of FSH and LH in the normal control group and suppressed the gonadotrophin secretion in the castrated patients. A similar suppressive effect on gonadotrophin secretion was noted in eight ovariectomized patients treated for 10 days with low doses (50 microgram/day) of ethinyl oestradiol. It is suggested that in the ovariectomized hypoestrogenic patients, clomiphene acted as an oestrogen, suppressing by a negative feedback action gonadotrophin release in a way similar to ethinyl oestradiol. In the normal control group with an adequate steroid environment, clomiphene acted (probably at the hypothalamic level) as an oestrogen antagonist and stimulated gonadotrophin secretion. In view of our findings, it seems as if the ability of anovulatory patients to respond to clomiphene treatment by increased gonadotrophin secretion depends upon the absolute concentration of the compound in the different organs and by the quantitative relation of clomiphene to the endogenous oestrogens.

Adult↗
PubMed1979

Oestrogen modulation of gonadotrophin and prolactin release in women with anovulation and their responses to clomiphene.

An LHRH test was performed before and at both 44 and 92 h after the administration of 2.5 mg oestradiol benzoate in eleven patients with hyperprolactinaemia, eight with idiopathic secondary amenorrhoea and seven with oligomenorrhoea. The basal serum hormone concentrations and the responses to LHRH were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Mean basal concentrations of oestradiol in each group of patients and oestrone in those with hyperprolactinaemia were significantly lower than in the normal subjects. The mean concentration of prolactin in women with secondary amenorrhoea remained lower than in the normal women throught the tests (P less than 0.05). The LH and FSH responses to LHRH before oestrogen in patients with hyperprolactinaemia and of FSH in those with secondary amenorrhoea, were greater than in the normal subjects (P less than 0.001). After oestrogen treatment the responses were similar in all groups except in those with oligomenorrhoea where LH and FSH responses at 44 h (P less than 0.05 and P less than 0.01 respectively) and LH responses at 92 h (P less than 0.01) were lower than in normal controls. The responses at 92 h in all groups were greater than at 44 h (amplification) but the amplification at 92 h and at 44 h compared to the pre-treatment responses, tended to be lower in each group of patients compared to the normal controls. In the hyperprolactinaemic group of patients there was a negative correlation between the basal prolactin concentration and the gonadotrophin amplifications at 92 h (P less than 0.01), and a positive correlation between the basal oestrone levels and the amplifications at 92 h (P less than 0.01). The results of the oestrogen amplification test in eleven of the non-hyperprolactinaemic anovular patients were compared with the ovulatory response to 100 mg clomiphene given for 5 days. Six showed a normal oestrogen amplification and they all ovulated. Two patients failed to show greater amplification at 92 than at 44 h and required human chorionic gonadotrophin (HCG) as well as clomiphene to ovulate. The other three showed a diminished LH amplification at 92 h; they required 200 mg clomiphene and showed a prolonged follicular phase. The responses of the hyperprolactinaemic patients to clomiphene were poor and there was a negative correlation between prolactin concentration and oestrogen production (P less than 0.01). All ten hyperprolactinaemic patients treated with bromocriptine ovulated and eight conceived. The oestrogen amplification test appears to have some value in predicting the subsequent response to clomiphene in non-hyperprolactinaemic anovular women.

Adult↗
PubMed1980

The effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: a controlled double-blind cross-over study.

In order to try to clarify the often supposed stimulating effect of clomiphene citrate on spermatogenesis a controlled double-blind cross-over trial was used. 30 pre-selected normogonadotropic infertile men were given 50 mg clomiphene citrate daily or placebo in a double-blind cross-over fashion for three months, each treatment period being separated by three to four months. On clomiphene treatment the median sperm count increased from 13.3 to 28.7 mill/ml (P < 0.001). During the placebo treatment schedules the median sperm count remained unchanged (P < 0.05). The increases of FSH, LH, testosterone, and oestradiol were highly significant (P < 0.001) during the clomiphene treatment but during placebo treatment the median hormone levels did not change (P < 0.05). Three pregnancies occurred due to clomiphene treatment and one occurred during placebo treatment.

Adult↗
PubMed1992

A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. World Health Organization.

A multicentre, randomized double-blind study was performed to assess the effect on male fertility of treatment with low dose clomiphene citrate. One hundred and ninety couples were included in whom the male diagnosis was idiopathic impairment of semen quality, and the female partner had no demonstrable abnormality or was under successful treatment for a minor endocrine problem. A total of 1308 couple-months were studied. Men received either 25 mg clomiphene citrate daily or placebo for 6 months. The cumulative life-table pregnancy rates at 8 months were 11.7% and 8.1% in the placebo and clomiphene groups respectively. There were no significant differences between the changes in semen quality during intake of either clomiphene or placebo. This study provides no evidence for the efficacy of clomiphene citrate for the treatment of idiopathic male infertility.

Adult↗
PubMed1998

A prospective comparative trial of a gonadotropin-releasing hormone analogue with clomiphene citrate for the treatment of oligoasthenozoospermia.

BACKGROUND: We undertook a prospective trial to compare the efficacy and adverse effects of a gonadotropin releasing-hormone analogue (GnRHa) and clomiphene therapy for idiopathic normogonadotropic oligoasthenozoospermia (INOA). METHODS: Between January and December 1995, 44 newly-diagnosed INOA patients were randomly allocated to treatment with GnRHa or clomiphene citrate. Efficacy was assessed by measuring changes in semen parameters prior to and after 3 months of treatment. Twenty-three INOA patients underwent GnRHa therapy with 15 microg of diluted buserelin acetate given once a day intranasally, and 21 INOA patients were treated with 50 mg of clomiphene citrate daily by oral administration. RESULTS: The mean sperm density in the GnRHa group increased from 16.1 x 10(6)/mL to 26.9 x 10(6)/mL (P < 0.05), while the mean sperm density did not change significantly in the group treated with clomiphene. Similarly, the mean sperm motility increased from 35.9% to 43.9% in the GnRHa group (P < 0.05), but did not significantly change in the clomiphene group. No adverse effects were observed in either group. CONCLUSION: This GnRHa treatment protocol can be administered as an outpatient and is hoped to benefit INOA patients.

Administration, Intranasal↗
PubMed1975

Hormonal responses to a first course of clomiphene citrate in women with amenorrhoea.

The hormonal criteria of a "normal" or "ovulatory" response, and three grades of subnormal anovulatory responses, were defined during a first course of treatment with clomiphene citrate in twenty patients with amenorrhoea for which no organic cause could be found. The hormonal responses were estimated by frequent serum measurements and by the menstrual response. Seven patients had a normal or ovulatory response with a late rise of serum progesterone and subsequent menses. Their serum luteinizing hormone (LH) and oestradiol (E2) responses were greater than in spontaneous menstrual cycles. Five patients gave only partial responses, with menstruation and no prior rise of progesterone, Their serum LH and E2 responses were generally lower than in the normal group but had the same pattern except for an absence of the luteal phase rise in E2. Five patients who did not menstruate showed smaller and more variable responses. The remaining five showed no hormonal responses. The second and third groups had ovulatory responses on subsequent clomiphene courses, whereas no improvement was shown by the last group. The serum E2 responses offered the most sensitive index of the responsiveness to clomiphene. Response values in our normal group suggested that higher progesterone levels need to be reached after clomiphene administration than in spontaneous cycles for ovulation to be inferred. The serum prolactin showed no consistent response during the clomiphene test; three patients with moderately raised basal prolactin levels had "normal" responses.

Amenorrhea↗
PubMed1975

Use of clomiphene and luteinizing hormone/follicle stimulating hormone-releasing hormone in investigation of ovulatory failure.

A luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) test was performed in 70 women with amenorrhoea or anovulatory infertility, or both, and a clomiphene stimulation test was also performed in 24 of these patients. Most patients responded to LH/FSH-RH with significant increases in LH and FSH. In women with gonadal dysgenesis or premature ovarian failure exaggerated responses were observed after LH/FSH-RH and there was no change in high basal LH levels after clomiphene. Patients with absent or impaired responses to LH/FSH-RH failed to respond to clomiphene. All patients with anovulatory menstrual cycles responded to both LH/FSH-RH and clomiphene, while seven out of 13 amenorrhoeic patients with a normal LH/FSH-RH response showed an early LH rise during clomiphene treatment and six were unresponsive. These results suggest a difference between the two groups at hypothalamic level with consequent therapeutic implications.

Adolescent↗
PubMed1976

Effects of clomiphene citrate and progesterone on resting and proliferative cell-populations in resting and proliferative cell-populations in mouse uterine epithelium.

Resting cells (GO cells) of the uterine surface epithelium in castrated mice began to synthesize DNA with high synchrony from 10 hr after the injection of 50 ng of estradiol-17beta with or without 5.5 mug of clomiphene citrate. Highly synchronized DNA synthesis in GO cells elicited with estradiol was delayed approximately 5 hr when the simultaneous administration of 0.5 mg of progesterone was given. In GO cells of castrated mice which received 5.5 mug of clomiphene or 55 mug of clomiphene plus 50 ng of estradiol, DNA synthesis with partial synchrony began 15 hr after the injection. The effects of estradiol were completely suppressed by the administration of 55 mug of clomiphene. It is suggested that the inhibitory action of clomiphene may be due to the competitive blocking of estrogen binding, while progesterone suppresses the estrogen-induced DNA synthesis of the surface epithelium and transfers them to the GO cell-compartment.

Animals↗
PubMed1979

Anovulation and oviductal hyperplasia in rats treated with clomiphene citrate 5 days after birth.

Five day old female rats were administered either 500 micrograms clomiphene citrate or propylene glycol. Vaginal opening occurred significantly earlier in the clomiphene treated group as compared with the control group. Clomiphene treated rats showed permanent sterility associated with anovulatory vaginal cycles in which the stage of vaginal cornification predominated. Furthermore, clomiphene treated rats exhibited a high incidence of pyosalpinx (or oviductal abscess). The possible mechanisms responsible for the anovulatory sterility and the pyosalpinx induced by neonatal clomiphene treatment are discussed.

Animals↗
PubMed1989

Prepubertal treatment of rats with clomiphene citrate affects postpubertal testicular development.

A previous study showed that clomiphene citrate (clomiphene) reduced serum and pituitary gonadotropins and impaired testis growth and steroidogenesis in 10-day-old rats treated for up to two weeks. The present study was conducted to assess the effect of prepubertal clomiphene treatment on postpubertal pituitary-testicular function. Rats were implanted with pellets that released 0, 0.05, 0.5 or 5.0 mg clomiphene.kg-1.day-1 between 10-31 days of age and were killed at 90 days of age. Testis and prostate weights in treated rats were reduced (P less than 0.05), whereas serum LH, FSH and testosterone, and pituitary gonadotropin and GnRH receptor concentrations had recovered to levels observed in control rats. Testicular FSH receptor concentrations were not altered; however, FSH receptor content was decreased (P less than 0.05) in clomiphene-treated rats proportional to the reduction in testicular weight. In contrast, testicular LH and GnRH receptor concentrations were increased (P less than 0.05) in treated animals, resulting in similar receptor contents. Daily sperm production per gram of parenchyma was unaffected, while daily sperm production per testis was decreased in treated rats (P less than 0.05). These data show early postnatal treatment with clomiphene does not permanently impair pituitary function. Despite reduced testicular mass, normal serum testosterone concentrations and testis LH receptor content of treated rats suggest recovered Leydig cell function. The decreased content of testicular FSH receptors and reduced sperm production suggest seminiferous tubule function was compromised in the adult rat.

Animals↗