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PubMed1986

Clomiphene and tamoxifen inhibit the cholesterol side-chain cleavage enzyme activity in hen granulosa cells.

A radiochemical assay was utilized to study the inhibitory effects of clomiphene and tamoxifen on the cholesterol side-chain cleavage enzyme activity in a mitochondrial preparation of granulosa cells isolated from mature ovarian follicles of laying hens. At saturating substrate concentrations, both clomiphene and tamoxifen were able to suppress enzyme activity in a dose-related manner (IC50 1.8 X 10(-5) M). Double reciprocal plots of kinetic data show that the inhibition is mixed, exhibiting competitive kinetics at low concentrations, whereas at high concentrations, the inhibition is of a non-competitive nature. The competitive inhibition constants as determined from Dixon plots are 2 X 10(-5) M for clomiphene and 2.3 X 10(-5) M for tamoxifen. It is concluded that, in granulosa cells, clomiphene and tamoxifen directly inhibit the mitochondrial cholesterol side-chain cleavage activity. This inhibition may represent an important aspect of the mode of action of clomiphene and tamoxifen.

Animals↗
PubMedDate not supplied

Hormonal evaluation in idiopathic oligozoospermia: correlation with response to clomiphene citrate therapy and sperm motility.

The reported response of sperm count to clomiphene citrate therapy in subfertile males with idiopathic oligozoospermia has been widely variable. The author postulates that this may be due in part to patient heterogeneity that may be reflected in pretreatment hormonal status. Seventeen patients with idiopathic oligozoospermia (mean +/- SE sperm density of 7.3 +/- 1.2 x 10(6) sperm/mL, mean FSH of 5 +/- 0.5 IU/L) were studied. Pretreatment basal LH, FSH, testosterone, free T4, and prolactin levels as well as LHRH-stimulated LH and FSH levels were examined in relation to pretreatment semen parameters and percent change in sperm count after a mean of 7.2 +/- 0.6 months of clomiphene citrate therapy. The percentage of motile sperm correlated with basal LH (r = .59, p = .02, n = 16) and free T4 levels (r = .62, p = .02, n = 13). Clomiphene citrate therapy was associated with a significant increase in total sperm count (mean percent change 261 +/- 117, p = .02) and in total motile sperm count (mean percent change 370 +/- 216, p = .03). Percent change in total sperm counts and in total motile sperm counts correlated positively with pretreatment prolactin levels (r = .64, p = .007, n = 16, and r = .62, p = .01, n = 15), but not with the levels of other hormones. The results suggest that in patients with idiopathic oligozoospermia (1) clomiphene citrate therapy may be more effective in the subgroup of patients who have relatively higher prolactin levels, (2) basal and stimulated gonadotropin levels may not be helpful in predicting the response to clomiphene citrate therapy, and (3) lower sperm motility is associated with relatively higher free T4 and lower LH levels. The underlying mechanisms and the clinical utility of the current observations deserve further study.

Adult↗
PubMed1990

Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates.

One hundred and eighteen patients with unexplained infertility were treated with clomiphene (Clomid, Merrell) in a randomized placebo-controlled cross-over study lasting up to 3 months with each preparation. Compared with placebo, clomiphene led overall to a 66% increase in mid-luteal serum progesterone levels (from mean 43 nmol/l to 71 nmol/l, p less than 0.001) and a 53% rise in the 3-month cumulative conception rate (from 14.6% to 22.33%, p less than 0.05). The greatest relative increase in conception rates with clomiphene was in women with infertility lasting more than 3 years (3-month rates from 2.9% to 14.4%, p less than 0.05). Differences in conception rates were not related to the rises in progesterone, and there was no carryover effect of clomiphene into the following placebo cycles in terms of progesterone levels or conceptions. The findings suggest that couples with unexplained infertility of less than 3 years duration are essentially normal, but with more than 3 years duration there is often a subtle disorder of ovulation that is corrected by clomiphene therapy.

Adult↗
PubMed1999

Does maternal drug ingestion cause megacystis microcolon intestinal hypoperistalsis syndrome? I. Clomiphene trial.

PURPOSE: Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a congenital and lethal disease, and the etiology of the disease is not clear. It is speculated that maternal ingestion of some drugs during pregnancy may be an etiologic factor. In this study we aimed to investigate the effect of maternal ingestion of clomiphene on fetal bladder and colon in pregnant rats. METHODS: We separated animals into a control group including 14 rats and a clomiphene group with 30 rats. Nothing was given to the control group during pregnancy. Two mg/kg/day clomiphene intraperitoneally was given to the study group from the 6th to 12th day of pregnancy. All of them were sacrificed on the 20th day of pregnancy. Histopathological examination of the fetal colon and bladder was performed. RESULTS: In the clomiphene group a significant decrease in the thickness of the bladder wall, an increase in bladder epithelium, an increase in muscle atrophy of the colon and bladder wall, an increase in vacuoler degeneration of the muscles of the bladder and colon wall, a decrease in ganglion cell numbers in the myenteric plexus of the bladder and a decrease in the thickness of the bladder tunica muscularis were determined. CONCLUSION: In our rat model we found histological structural changes in the rats' colon and bladder walls as a result of using clomiphene on days 6-12 of pregnancy; a similar pathological finding to those found in some of the MMIHS patients' colons and bladders.

Abnormalities, Drug-Induced↗
PubMed1976

Optimization of determination of ovulation after clomiphene therapy.

A total of 131 cycles of 71 sterility patients, who suffered from anovulatory cycles at least previous 6 months, were monitored daily by a rapid radioimmunoassay for LH and by gynecological examinations before we attempted to induce ovulations with Clomiphene. The width of the cervix, spinnbarkeit, transparency of the cervical mucus and karyopycnotic and acidophilic index of the vagina were recorded daily. 18 subjects exhibited hypoplasia of the uterus and 32 husbands of the 71 patients suffered from severe to medium oligospermia. Homologous inseminations were performed in 15 patients. Different patterns of LH serum levels were observed during and after Clomiphene treatment. The response of LH to Clomiphene and preovulatory LH rise was recorded in 73 cycles. No Clomiphene response with preovulatory LH peak was observed in 31 cycles. 11 patients out of 71 subjects failed to ovulate. 12 patients (30.7%) out of 39 subjects with normospermatic husbands became pregnant. 6 patients (18.7%) of 32 subjects whose husbands suffered from oligospermia became pregnant. A total pregnancy rate of 30% calculated, when the 11 patients with negative responses are excluded. The conclusion is reached that sterility patients benefit most, when both gynecological as well as rapid LH estimations by radioimmunoassay are used to time imminent ovulations in Clomiphene treated subjects.

Anovulation↗
PubMedDate not supplied

A short-term comparison of the effects of clomiphene citrate and conjugated equine estrogen in menopausal/castrate women.

An attempt was made to assess the potential role for an antiestrogen in the hormone replacement therapy of menopausal women who have a contraindication to estrogen use. Two groups of menopausal or castrate women were given either conjugated equine estrogen or clomiphene citrate in a cyclic manner for 25 days each month for 3 months. The effects were measured after 3 months and compared with baseline values. Clomiphene lowered FSH slightly, but had no effect on subjective vasomotor symptoms. With respect to bone metabolism, it produced no change in plasma parathyroid hormone level, whereas estrogen lowered it; both compound lowered serum calcium but clomiphene had less effect. The hydroxyproline/creatinine ratio was decreased more by clomiphene than by the estrogen. These findings are consistent with a beneficial effect on bone. Clomiphene had no adverse effects on clotting parameters and showed effects similar to those of conjugated equine estrogens on certain measures of lipid metabolism.

Adult↗
PubMed1981

Incremental clomiphene therapy: a new method for treating persistent anovulation.

Thirty anovulatory patients, previously unresponsive to clomiphene citrate in standard dosage, were treated with a new incremental method of clomiphene therapy. Clomiphene was given continuously with dosage increments every 5 days, up to a maximum dose of 3750 mg, and ovarian response was monitored with urinary estrogen estimation and with ultrasound. Twenty-one patients (70%) ovulated on this regimen and 8 (27%) conceived; 6 patients who ovulated but did not conceive had other infertility factors. Clomiphene response was associated with a progressive rise in follicle-stimulating hormone, luteinizing hormone, and estrogen excretion; these parameters were unchanged in nonresponders. Side effects of treatment were minimal and only 1 case of hyperstimulation occurred. Preliminary testing with estrogen-amplified gonadotropin-releasing hormone did not differentiate responders from nonresponders. Incremental clomiphene treatment appears to be a less complicated alternative for patients who would otherwise require exogenous gonadotropin therapy.

Adult↗
PubMed1982

Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle.

Seventeen patients treated with clomiphene citrate were examined using real-time ultrasound timing 28 ovulatory cycles to determine the pattern of follicular development under clomiphene stimulation. The rate of growth was faster, but the follicular diameter range at ovulation was similar to that during spontaneous cycles. This information was used to time midcycle human chorionic gonadotropin (hCG) administration in over 97 cycles in 21 patients responsive to clomiphene who had not conceived. When hCG was given when the mean follicular diameter reached 18 mm, 92% of these cycles were ovulatory. Fourteen patients (67%) conceived within 6 ovulatory treatment cycles. Five of 7 patients (71%) who did not conceive were found to have endometriosis at laparoscopy. Midcycle cervical scores were significantly lower in clomiphene-treated as compared with spontaneous ovulatory cycles, and additional treatment with ethinyl estradiol did not effect a significant improvement. Timing of midcycle hCG using ultrasound is an effective method of inducing ovulation in patients in whom an estrogenic follicular response without ovulation is obtained with clomiphene treatment.

Cervix Mucus↗
PubMed1982

Comparison between tamoxifen and clomiphene for induction of ovulation.

The effectiveness of tamoxifen and clomiphene in inducing ovulation was compared in 46 women with anovulatory infertility. All the women were given both the drugs in an alternate way. If one cycle was treated by tamoxifen the next was treated by clomiphene and vice versa. Forty-one out of the 46 women (89.1%) ovulated at least once during the study. Similar ovulation rates were achieved by tamoxifen (56.2%) and clomiphene (62.9%). The lengths of the ovulatory cycles and their luteal phases and the mid-luteal phase serum progesterone levels did not differ significantly between the two compounds. Nor did the occurrence of luteal phase defects during the tamoxifen and clomiphene treatment cycles differ. Thirty-seven of the 46 women (80.4%) responded similarly to both drugs. Thus, tamoxifen is just as effective as clomiphene in inducing ovulation in women with anovulation.

Adolescent↗
PubMed1982

Clinical and laboratory predictors of clomiphene response.

A prospective study was carried out on 158 anovulatory women for the purpose of finding parameters that might predict the clomiphene dose at which ovulation would occur. Both body weight and obesity were positively correlated with the dose required to achieve ovulation (P less than 0.05). Once ovulation occurred, obesity did not affect the ability to conceive. Fifty-eight women who ovulated with various doses of clomiphene, including six women who failed to ovulate, had hormonal measurements performed prior to treatment. Compared with normally ovulating controls, serum luteinizing hormone (LH), the ratio of LH to follicle-stimulating hormone (FSH), serum androgens, unbound testosterone, and unbound estradiol were elevated and sex hormone binding globulin-binding capacity (SHBG-BC) significantly lower in women receiving clomiphene. Although the ovulatory dose of clomiphene was positively correlated with both weight and obesity, neither weight nor any laboratory parameter could accurately predict the clomiphene response.

Androgens↗
PubMed1976

Effect of clomiphene citrate on gonadotropin responses to LRH administration in secondary amenorrhea and oligomenorrhea.

Clomiphene citrate was administered to 17 patients with either secondary amenorrhea or oligomenorrhea to study its effect on hypothalamic-pituitary response. Measurement of pulsatile gonadotropin output was accomplished utilizing samples collected every 20 minutes for 6 to 8 hours before and after clomiphene administration. Response to 100 mug synthetic luteinizing hormone releasing hormone (LRH) was measured at the end of the sampling period. Patients with polycystic ovarian disease who ovulated showed increased baseline FSH and LH, decreased peak LH, and a decrease in the percentage increase over baseline for both LH and FSH. On patient wil clinical anorexia nervosa responded to clomiphene as an estrogen, with lowered baseline LH and FSH values. Patients with resolving anorexia responded to clomiphene as an antiestrogen, with increased baseline gonadotropins, and decreased gonadotropin peak values. A patient with a surgically treated chromophobe adenoma showed no change in parameters measured before and after clomiphene administration. Baseline and pulsatile LH output appear to reflect the tonic output of gonadotropin as affected by estrogen acting in a negative feedback system, and the peak response to LRH administration, the response to the positive feedback of estrogen. Thus, LRH stimulation in clomipheneresistent patients may be of value in diagnosing the site and degree of the defect and aid in improving therapy.

Adolescent↗
PubMedDate not supplied

Changes in the endocrinological milieu after clomiphene citrate treatment for oligozoospermia: the clinical significance of the estradiol/testosterone ratio as a prognostic value.

We have already reported that the rate of increase in the estradiol/testosterone ratio (E2/T ratio) following human chorionic gonadotropin (hCG) injection has prognostic value in the treatment of oligozoospermia. It was found that the rate of increase in the E2/T ratio was statistically greater in the therapeutically ineffective cases compared to the therapeutically effective cases. The present study was planned in order to elucidate the relationship between the changes in the endocrinological milieu, especially the change in the E2/T ratio, and the therapeutic efficacy when clomiphene citrate was administered. Thirty-eight oligozoospermic patients were administered 25 mg of clomiphene citrate daily for 3 months. Sixteen of the 38 (42.1%) cases showed improvement of more than 10 x 10(6)/ml in sperm concentration. The rate of increase in the E2/T ratio of the effective cases (0.90 +/- 0.43) during the administration of clomiphene citrate was statistically (P = 0.02) lower than that of the ineffective cases (1.44 +/- 0.80). The rate of increase in the E2/T ratio during clomiphene citrate treatment showed a statistically positive correlation (r = 0.542) with the rate of increase following hCG injection performed before clomiphene citrate treatment. The rate of increase in follicle-stimulating hormone (FSH) in the ineffective cases (2.16 +/- 1.01) was statistically higher than in the effective cases (1.50 +/- 0.43).(ABSTRACT TRUNCATED AT 250 WORDS)

Chorionic Gonadotropin↗
PubMed1977

Plasma hormones in clomiphene citrate therapy.

Daily plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone (E1), estradiol-17beta (E2), progesterone (P), androstenedione (A), and testosterone (T) were measured in six clomiphene citrate (Clomid) treated cycles. Three patients ovulated and 1 of them conceived during the study cycle. Three other patients failed to ovulate in spite of some evidence of ovarian response to clomiphene treatment in 2 of them. Plasma gonadotropin levels, of LH in particular, rose during the clomiphene therapy and reached a peak during Day 5 to Day 7 of therapy. Levels of plasma estrogens, both E1 and E2, gradually rose, reflecting follicular maturation in the ovary. When E2 reached a critical level as in the normal ovulatory cycle, it triggered an LH surge which consequently initiated ovulation. When the E2 level was inadequate or excessive, ovulation failed in spite of an LH surge. Following ovulation, plasma P rose and fell in a manner similar to the normal ovulatory cycle, with occasional values that exceeded the normal range. Levels of androgens, both A and T, rose during clomiphene therapy in some cases and T seemed to fluctuate in correlation with LH level. The possible local inhibitory influence of high E2 and T levels on follicular maturation in the ovary during clomiphene therapy is suspected in some cycles in which ovarian response was evident, but ovulation failed to occur.

Adult↗
PubMed1977

[Comparative clinical studies on clomiphen, cyclofenil and epimestrol (author's transl)].

Report on the treatment of 310 anovulatory woment in 1173 treatment cycles with Clomiphen, Cyclofenil and Epimestrol. 63% of the patients had a biphasic basal body temperature record after treatment in 718 cycles. Patients with secondary amenorrhea of the first or the second degree had a satisfactory ovulation rate in 71% of the cases only by treatment with Clomiphen. In women with anovulatory cycles an overall ovulation rate of 75% was observed with all three medications. In 73 patients 78 pregnancies occurred. Of these, 38 pregnancies followed Cyclofenil, 25 pregnancies followed Clomiphen and 15 pregnancies followed Epimestrol corresponding to a 15%, 17% and 13% rate in the treated patients. 22 of these pregnancies ended in incomplete abortion. The side effects of Clomiphen especially visual and cystic ovarian and vasomotor side effects are more pronounced than the side effects of Cyclofenil and Epimestrol. The statistical analysis of the clinical results showed that Clomiphen and Cyclofenil had a higher rate of ovulation in secondary amenorrhea of the first or second degree than Epimestrol.

Amenorrhea↗
PubMed1976

Selection of patients for clomiphene citrate therapy.

Ninety-three infertile women were treated with clomiphene citrate alone or in combination with human chorionic gonadotropin (hCG) for absent or infrequent ovulation. The patients were divided into eight categories according to the diagnosis obtained: ovarian androgenic hyperplasia, adrenal androgenic hyperplasia, mixed ovarian and adrenal androgenic hyperplasia, hypothalamic anovulation, postpill anovulation, follicular phase defect, luteal phase defect, and amenorrhea-galactorrhea syndrome. Each group was analyzed individually to compare the ovulation and conception rates and the complications involved. A survey of the data presented in this study shows that the best response was noted in patients with ovarian androgenic hyperplasia. Patients with a functional pathologic adrenal component responded favorably when dexamethasone was used as an adjuvant to clomiphene therapy. Those with hypothalamic anovulation responded better when hCG was added to clomiphene therapy. Women with postpill anovulation as well as those with follicular phase defect were found to be good candidates for clomiphene therapy. In properly selected patients with poor luteal phase defect, hCG secured excellent results both in ovulation and conception. Patients with lactation amenorrhea failed to ovulate when treated with clomiphene alone.

17-Ketosteroids↗
PubMed1997

Histopathological changes in the vagina of rats treated neonatally with clomiphene citrate.

Clomiphene citrate is a nonsteroid antiestrogen which is widely used in the therapy of receptor-positive estrogen for the induction of ovulation. Clomiphene citrate was given subcutaneously to newly born rats with daily injections of 100 mg/kg for 5 days. Changes caused by the clomiphene citrate in vaginas of female rats were investigated at 28 and 35 days. Depending upon the effect of the clomiphene citrate, histopathological changes such as papillary development at keratinization, increase in vaginal epithelium, and observation of polygonal shaped nodular cells in stroma were considered as important findings. It should be emphasised that clomiphene citrate used for induction of ovulation caused these abnormalities in the vagina of rats.

Animals↗
PubMed1981

Induction of ovulation in patients with normoprolactinemic amenorrhea by combined therapy with bromocriptine and clomiphene.

Bromocriptine is known to be effective in the treatment of women with hyperprolactinemic anovulation or amenorrhea-galactorrhea. A new schedule of combined treatment with bromocriptine and clomiphene citrate was applied to 23 patients with normoprolactinemic amenorrhea who failed to respond to clomiphene alone. Ovulation was restored by treatment in 14 of these patients (60.9%), resulting in pregnancy in 3 women. Treatment resulted in immediate suppression of serum prolactin levels and a gradual increase in serum luteinizing hormone levels and estradiol levels followed by a luteinizing hormone surge. The present results indicate that bromocriptine/clomiphene combination therapy is effective in the treatment of amenorrheic patients with normoprolactinemia who do not respond to clomiphene alone, and suggest that bromocriptine restores the responsiveness of the hypothalamic-pituitary-ovarian system to clomiphene.

Adult↗
PubMed2006

Clomiphene and hypospadias on a detailed level: signal or chance?

BACKGROUND: Clomiphene, a drug used to induce ovulation, is chemically related to diethylstilbestrol (DES). DES is associated with vaginal cancer and infertility among daughters and with hypospadias among second-generation male offspring. Because clomiphene has a long half-life and metabolites have been found in feces up to 6 weeks after administration, fetal exposure is possible if the mother took this drug prior to becoming pregnant. METHODS: Case-control analyses were performed to investigate the association between clomiphene exposure and hypospadias. Cases were all male subjects registered in the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) Northern Netherlands registry for congenital anomalies with nonsyndromal hypospadias. Controls were all male children born without hypospadias, including those with chromosomal and monogenic defects. Logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 392 cases, 7 (1.8%) were exposed to clomiphene compared with 64 of 4538 controls (1.4%). For penoscrotal hypospadias, we found that the OR was significantly increased (6.08; 95% CI, 1.40-26.33); for the mild and moderate forms of hypospadias, the ORs were not increased. CONCLUSIONS: Because penoscrotal hypospadias is rare, the effect is diluted when all forms of hypospadias are studied as a group. Therefore, our study stresses the importance of studying birth defects on as detailed a level as possible. Other studies should be conducted to confirm our findings.

Abortion, Induced↗