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PubMed1977

Investigation of amenorrhea with a simplified clomiphene test.

To simplify the clinical evaluation of the hypothalamic-pituitary-ovarian function, a 5-day treatment regimen of 100 mg clomiphene administered daily was tested on a group of 30 amenorrheic women (4 with primary amnenorrhea and 26 with secondary amenorrhea). Vaginal smears and serum follicle-stimulating hormone, luteinizing hormone, prolactin, estradiol-17beta and progesterone levels were obtained prior to treatment and 5 and 12 days after treatment ended. According to her response to clomiphene, each patient was assigned to one of the four response categories established by Kjeld et al. (6). Based on clinical findings and changes in serum hormone levels, the patients' responses to clomiphene were categorized as "normal" (the patient ovulated), "partial" (the patient experienced menstrual bleeding without ovulation), "minimal" (rise in estradiol without menses), and "nil". Of the parameters studied, the patient's serum estradiol level was the most sensitive index of her response to clomiphene.

Adolescent↗
PubMed2004

Gonadotropin response to clomiphene and plasma leptin levels in weight recovered but amenorrhoeic patients with anorexia nervosa.

Anorexia nervosa (AN) is a state of leptin and gonadotropin deficiency. Leptin levels are decreased in normal weight women with hypothalamic amenorrhea and leptin may be a sensitive marker of overall nutritional status. The aim of the study is to provide additional information on plasma leptin levels and on gonadotropin responses after clomiphene testing in patients with AN who recovered weight but were still amenorrheic. We evaluated 17 patients with AN, female age 20+/-1.2 yr who reached goal weight [body mass index (BMI) 14.9+/-0.5 to 19.3+/-0.4 kg/m2]. At diagnosis serum leptin levels were 2.2+/-0.1 microg/l while after behavioural therapy and hypercaloric diet for 6-12 months serum leptin levels rose to 6.4+/-1.4 microg/l significantly lower compared with those in the control (no.=10, age 28+/-6.2 yr, BMI 21.1+/-0.3 kg/m2, leptin 9.3+/-0.7 pg/l; p<0.05). None of the patients resumed spontaneous menstrual cycles after weight gain. They were tested with a 10-day administration of clomiphene citrate. All had a significant rise in LH secretion (from 1.7+/-0.3 IU/l to 8.3+/-0.9 IU/l, p<0.01) and serum estradiol levels (from 19.0+/-5.4 to 937.7+/-241.2 pg/ml, p<0.03). Nine out of 17 patients menstruated after clomiphene. Serum leptin levels were not different in those who menstruated from those who did not (6.4+/-1.4 to 6.8+/-1.4 microg/l, p>0.05). Body compositon was studied in 12 additional carefully matched patients with AN who recovered weight. Six of them resumed spontaneous menstrual cycles. Neither BMI, body fat, nor leptin appeared as significant determinants of menstrual status. In conclusion, relative hypoleptinemia persists, independent of fat mass, in weight recovered patients with AN. A normal response to clomiphene in weight-recovered yet still amenorrhoeic patients with AN, offers reassurance that the axis is intact and that the problem lies in the hypothalamus. It is reasonable to believe that nutritional disturbances, fat intake and persisting psychological factors still affect plasma leptin levels and reproductive functions in weight-recovered patients with amenorrhea.

Adolescent↗
PubMedDate not supplied

The mechanism of the effect of combination treatment with clomiphene and bromocriptine in patients with normoprolactinemic anovulation.

The combination treatment with bromocriptine and clomiphene citrate was applied to 11 normoprolactinemic anovulatory patients who did not respond to clomiphene citrate alone. This combination treatment restored ovulation in 8 of these patients (72.7%). Conception was observed in 2 patients (18.1%) out of 11. The patients who responded to combination treatment showed a significant increase in the serum level of estradiol in the preovulatory phase, of progesterone in the mid-luteal phase, and a significant decrease of serum prolactin. They also showed significant increase in the frequency of luteinizing hormone (LH) pulsatility on day 12 of the cycle from 1.38 +/- 0.86 to 3.75 +/- 0.83 pulses/4h. The 3 patients who did not respond to combination treatment showed no increase in the serum level of estradiol or progesterone, but showed increase in the frequency of LH pulsatility in spite of continuous anovulation. These results indicate that the combination treatment with bromocriptine and clomiphene citrate is effective for treatment of patients with normoprolactinemic anovulation who do not respond to clomiphene alone, and suggest that the mechanism of the effect of combination treatment is related to an increase in the frequency of LH pulsatility caused by bromocriptine, which in turn stimulates follicular maturation.

Adolescent↗
PubMed1976

Effect of clomiphene citrate upon amount and duration of human menopausal gonadotropin therapy.

Human menopausal gonadotropin (HMG) was given to 10 patients who failed to ovulate after treatment with clomiphene citrate. Prior to one or more treatment courses, 200 mg. of clomiphene were administered daily for 5 days; at least one other treatment course was not preceded by clomiphene. Before therapy, progesterone in oil was administered and serum FSH, LH, and estrogen were measured. Those patients who had normal serum FSH levels and had withdrawal bleeding following progesterone had a reduction in amount and duration of HMG requirements for those patients with low serum FSH who did not withdraw. Thus, sequential clomiphene-HMG therapy is of benefit only for those women with normal serum FSH levels and is the treatment of choice.

Adult↗
PubMed1983

The in vivo and in vitro effects of clomiphene citrate on ovulation, fertilization, and development of cultured mouse oocytes.

Clinical data indicate a high rate of discrepancy between ovulation and pregnancy rates and a high abortion rate in anovulatory women treated with clomiphene citrate. An animal model was used to examine the in vivo and in vitro effects of the drug on fertilization and preimplantation development. This work indicates that mice treated with clomiphene in the early follicular phase of pregnant mare's serum-induced cycles show a dose-dependent decrease in ovulated oocytes. No effect was seen on the further development of these ova. When the drug was administered in the late follicular phase, a dose-dependent decrease was seen in the rate of successful copulation, ovulation, and embryo development. Concomitant 17 beta-estradiol treatment reversed the copulatory, ovulatory, and developmental effects of clomiphene. A short in vitro treatment of oocytes with clomiphene prior to in vitro fertilization resulted in an increased proportion of degenerated and unfertilized ova. Moreover, this treatment caused a dose-dependent decrease in blastocyst formation.

Animals↗
PubMed1984

The action of clomiphene in stress-induced amenorrhea.

Seven women with stress-induced amenorrhea were challenged with metoclopramide, 10 mg intravenously, before and at the end of a course of clomiphene. Initial testing with luteinizing hormone releasing hormone demonstrated that all subjects had the capacity to release luteinizing hormone (LH), but in response to metoclopramide there was no increase in the levels of LH. This lack of response did not change after 5 days of clomiphene, although basal levels of LH and estradiol increased significantly. The pattern of response of prolactin to metoclopramide did not change after clomiphene. These results suggest that there is no significant dopamine-mediated inhibition of release of luteinizing hormone releasing hormone in women with stress-induced amenorrhea. The administration of clomiphene to these women does not appear primarily to alter hypothalamic dopaminergic activity.

Adult↗
PubMed1983

The estrogenic effects of clomiphene during the neonatal period in the rat.

The ability of clomiphene and its isomers to cause estrogenic responses during the neonatal period in the rat was examined. Rats were injected s.c. with clomiphene (CL), zuclomiphene (ZUC) or enclomiphene (ENC) on days 1,3, and 5 of life and the stimulation of the reproductive tract and estrogen receptor binding was observed. Uterine weight and DNA content were increased significantly by day 7 in animals treated with clomiphene or zuclomiphene. Uterine epithelial hypertrophy was present in all groups by day 10 and hyperplasia was present in the animals treated with ZUC and CL. The time of vaginal opening was greatly accelerated in all drug treated groups with the earliest day of opening occurring on day 7. Ovarian hemorrhage and blood in the periovarian sac occurred between days 12-14 and continued to be present through day 25. Drug treatment caused the estrogen receptor to accumulate in the nuclear fraction of the uterus and to be depleted from the cytosol fraction. We conclude that clomiphene administered to neonatal rats causes estrogenic stimulation of the reproductive tract in a fashion similar to other estrogens. This stimulation may account for the reproductive tract abnormalities which develop in rats treated with those drugs during the neonatal period.

Animals↗
PubMed1985

Inhibition of intestinal smooth muscle function by tamoxifen and clomiphene.

The acute in vitro effects of the oestrogen antagonists clomiphene (a racemic mixture) and tamoxifen were examined upon spasmogen induced contractions of the guinea pig ileum. Both oestrogen antagonists inhibited the contractions produced by acetylcholine, the muscarinic agonist beta-methylcholine, histamine and bradykinin in a manner which suggests non competitive antagonism. Concentration effect curves to each of the spasmogens were unaffected using 0.1 mumoles/litre of either of the oestrogen antagonists. Clomiphene at 1 mumole/litre reduced the maximum response to the spasmogens by 20 to 50%. Tamoxifen at the same concentration also inhibited the contractions but to a much smaller extent. Clomiphene at the highest concentration tested 10 mumoles/litre completely suppressed contractions to all the spasmogens. Tamoxifen at 10 mumoles/litre completely suppressed contractions to beta-methylcholine and bradykinin. A residue of a response to acetylcholine and histamine remained and this was abolished by raising the concentration to 100 mumoles/litre. The data indicated that clomiphene was more potent than tamoxifen upon the inhibition of the contractions of the ileum. The results demonstrate a non specific effect of the oestrogen antagonists upon smooth muscle function and do not substantiate early reports of specific anticholinergic activity. The possibility of these effects contributing to both the side effects and the antitumor activity of the oestrogen antagonists is discussed.

Acetylcholine↗
PubMed1984

Effects of clomiphene citrate, a nonsteroidal antiestrogen, on brain monoaminergic mechanisms in female goldfish, Carassius auratus.

The antiestrogen, clomiphene citrate ( Merrell -National Laboratories) was administered to female goldfish in order to test the hypothesis that this drug may act on brain monoaminergic mechanisms. Brain monoamine oxidase (MAO) activity and hypothalamic serotonin (5-HT) content were measured fluorometrically after i.p. administration of 0, 5 or 25 micrograms clomiphene citrate/g body wt. Brain MAO activity was significantly inhibited by the high dose of clomiphene citrate, whereas hypothalamic 5-HT content was significantly elevated by both low and high doses of the antiestrogen. These data support the idea that brain monoamines in teleost fish are influenced by estrogen feedback mechanisms which can be blocked by clomiphene citrate.

Animals↗
PubMed2004

Monitoring plasma concentrations to individualize treatment with clomiphene citrate.

OBJECTIVE: Recent reports have indicated that a number of individual patient characteristics are responsible for the success or failure of clomiphene citrate treatment. However, a priori individualization of doses in different patients has not been investigated. We examined the thesis that wide variability in the metabolism of the active component (zuclomiphene) contributes to variability in response. METHODS: The dose-response relationship of clomiphene was established from a meta-analysis of data from 13 published reports. Limited data relating plasma drug concentrations to treatment outcome were examined to determine whether insufficient systemic exposure at a fixed dosage might contribute to therapeutic failure. RESULTS: A fixed-dosage regimen of 50 mg clomiphene per day is likely to cause ovulation in only 46% of patients; subsequent increment in dosage increases the number of responders but at the expense of considerable delay in individualization of treatment. Case reports indicated that dosage based on plasma drug concentration monitoring could improve patient management, and an algorithm is proposed to facilitate treatment. CONCLUSIONS: Prospective studies of clomiphene citrate should be performed to confirm the hypothesis that the monitoring of plasma zuclomiphene concentrations can significantly accelerate dose individualization and improve the therapeutic outcome with this "orphan" drug.

Clomiphene↗
PubMed1988

Effect of clomiphene on fatty acids, sterols and membrane fluidity in clavine producing Claviceps purpurea strains.

Clomiphene depressed the growth and enhanced clavine production of Claviceps purpurea strains 129,35 and 59. Mycelial content of 18:2 and 16:0 fatty acids decreased, whereas that of 18:1 and 18:0 acids increased. In the mutant strain 59 clomiphene, triadimefon and ergosterol stimulated the impaired function of chanoclavine cyclase. Their effect was counteracted by plant oil. Clomiphene decreased the content of total lipids (44%), triglycerides (32%), sterols (22%) and sterol/phospholipid molar ratio. The PC/PE ratio was 9X increased. Clomiphene and triadimefon enhanced membrane fluidity of protoplasts, ergosterol and oil reverted their effect.

Claviceps↗
PubMed2003

Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse.

OBJECTIVE: To report a case of symptomatic hypogonadism induced by the abuse of multiple steroid preparations that was subsequently reversed by clomiphene. DESIGN: Case report. SETTING: University-affiliated andrology practice within family practice clinic. PATIENT(S): A 30-year-old male. INTERVENTION(S): Clomiphene citrate, 100-mg challenge for 5 days, followed by treatment at same dose for 2 months. MAIN OUTCOME MEASURE(S): Clinical symptoms, androgen decline in aging male questionnaire, total T, FSH, LH. RESULT(S): Reversal of symptoms, normalization of T levels with LH surge, restoration of pituitary-gonadal axis. CONCLUSION(S): Clomiphene citrate is used typically in helping to restore fertility in females. This represents the first case report of the successful use of clomiphene to restore T levels and the pituitary-gonadal axis in a male patient. The axis was previously shut off with multiple anabolic steroid abuse.

Adult↗
PubMed1977

The use of clomiphene citrate.

Two hundred and fifty-five women received clomiphene citrate during a 10-year period. Fifty-six were treated diagnostically and one hundred and ninty-nine therapeutically for infertility. It is concluded that clomiphene may aid in confirming the diagnosis and establishing a prognosis in patients with primary or secondary amenorrhea. The success of clomiphene therapy in patients with anovulatory infertility is related to the etiologic factor responsible for the anovulation, but results can be improved by adjustment of the therapeutic regimen used. In the present series, 48% of the patients who ovulated became pregnant, and 25.3% of the pregnancies were miscarried. Those patients who ovulated spontaneously and became pregnant after having discontinued clomiphene therapy showed only a 10% abortion rate. A review of the results indicates that both the ovulation rate and the pregnancy rate can be improved if adjustments are made in therapy to ensure normal follicular maturation and corpus luteum function.

Abortion, Spontaneous↗
PubMed1979

Gestational outcome of clomiphene-related conceptions.

The experience of the gynecologic endocrinology and infertility clinic at The Johns Hopkins Hospital has been subjected to a nonconcurrent prospective analysis in an attempt to evaluate the gestational fate of clomiphene-related conceptions (study series, n = 86). This latter series was contrasted with a series of pregnancies following bilateral ovarian wedge resection (BOWR) (n = 51) in a comparative analysis of gestational outcome event rates. Post-therapy follow-up was available for varying time spans of up to 15 years. A 12.8% twinning rate constituted the single most important complication of clomiphene therapy, resulting in measurable increments in perinatal morbidity and mortality rates. The observation of a 26.5% spontaneous abortion rate would seem to suggest that clomiphene-related conceptions are at little or more risk for spontaneous abortion than would have been expected from the infertile population under discussion. A 3.1% incidence of post-clomiphene birth defects was not increased as compared with commonly quoted rates for the population at large. The corresponding incidence rates of twinning, spontaneous abortion, and birth defects for the BOWR series were 0%, 21.6%, and 0%, respectively.

Abortion, Incomplete↗
PubMed1982

A decade's experience with an individualized clomiphene treatment regimen including its effect on the postcoital test.

During a 10-year period, 428 women received clomiphene citrate according to a graduated therapeutic regimen in which the dose of clomiphene and the laboratory studies were individualized according to each patient's history, examination and response. Of the 428 patients, 85.3% ovulated and 42.8% conceived. The great majority of those who conceived did so during the first three ovulatory cycles. There was no evidence that clomiphene therapy was associated with the induction of another cause of infertility. Overall, 88.2% of those with no other causes for infertility who ovulated also conceived. However, only 7.8% of those who had one or more factors in addition to anovulation became pregnant. There was no evidence that clomiphene adversely affected the postcoital test, as only 15% of the patients had poor cervical mucus. The low rate of complications of this treatment, 5.1% cyst formation as well as the 14% abortion rate and the 2.6% congenital anomaly rate and the excellent gestational outcome in those who conceived support the use of this treatment regimen.

17-Ketosteroids↗
PubMed1982

An extended regimen of clomiphene citrate in women unresponsive to standard therapy.

An extended regimen of clomiphene consisting of 250 mg of clomiphene for 8 days followed by the administration of 10,000 IU of human chorionic gonadotropin (hCG) 6 days later was administered to 13 oligomenorrheic women who had previously failed to ovulate when treated with 250 mg of clomiphene for 5 days and hCG. Eight of these 13 women ovulated. Their postovulatory mean progesterone (P) level 7 days after hCG was 16 +/- 2 ng/ml. Three pregnancies occurred during 25 treatment cycles. Posttreatment estrogen levels were higher when women were treated for 8 days than for 5 days. Women ovulating after 8 days of treatment had increased concentrations of luteinizing hormone (LH) and testosterone (T) prior to hCG administration and higher pretreatment levels of estrogen and T, compared with women who did not ovulate. Changes in the timing of hCG administration may induce ovulation in some women who fail to ovulate when hCG is given on day 14. Because this 8-day regimen of clomiphene and hCG was successful in more than 50% of women failing to ovulate after 5 days, this regimen should be used prior to human menopausal gonadotropin (hMG) therapy.

Chorionic Gonadotropin↗
PubMed1995

A dopamine D3 receptor genotype is associated with hyperandrogenic chronic anovulation and resistant to ovulation induction with clomiphene citrate in female Hispanics.

OBJECTIVE: To determine if dopamine (D3) receptor genotypes are associated with anovulation and response to ovulation induction with clomiphene citrate. DESIGN: Clinical and laboratory characteristics of anovulatory patients and ovulatory controls were compared with findings at the DNA level. SETTING: An outpatient clinic at an university medical center. PATIENTS: One hundred eighty human Hispanic female volunteers (130 of these with documented ovulatory status) were studied. INTERVENTIONS: Genomic DNAs were extracted from each patient. Polymerase chain reaction with subsequent restriction digest was performed to analyze the D3 receptor allele status (two possible alleles). MAIN OUTCOME MEASURES: Menstrual history, serum T, and midluteal serum Ps from spontaneous and clomiphene cycles were correlated with D3 receptor genotype. RESULTS: Hispanic females with the 22 genotype compared with the other genotypes (11 and 12) were more likely to have irregular menses, an elevated serum T (> or = 70 ng/dL [conversion factor to SI unit, 3.467]), and hyperandrogenic chronic anovulation. These patients tended to be resistant to ovulation induction requiring a significantly higher dose of clomiphene to achieve an ovulatory response (22 genotype [mean +/- SEM] [140.0 +/- 19.0 mg] versus 11 [77.1 +/- 17.5 mg] or 12 [69.2 +/- 13.1 mg]). This effect was independent of patient age, weight, or serum T level. CONCLUSIONS: Hyperandrogenic chronic anovulation may have a genetic component. Genetic analysis may be useful in predicting resistance to ovulation induction with clomiphene.

Alleles↗
PubMed1999

Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.

OBJECTIVE: To determine the serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate treatment in anovulatory infertile women. DESIGN: Prospective cohort. SETTING: Tertiary institutional infertility clinic. PATIENT(S): Fourteen consenting anovulatory infertile women receiving standardized, cyclic, incremental treatment with clomiphene citrate for ovulation induction. INTERVENTION(S): Clomiphene citrate treatment (50-150 mg/d, cycle days 5-9), titrated to the minimum effective ovulation-inducing dose, was administered for three to six total cycles. Blood samples were obtained on cycle days 3 and 10 in each treatment cycle. MAIN OUTCOME MEASURE(S): Serum concentrations of enclomiphene and zuclomiphene. RESULT(S): Cycle day 3 zuclomiphene levels were below assay limits in all initial cycles, increased progressively across three consecutive cycles, and thereafter plateaued. Cycle day 3 enclomiphene concentrations were uniformly undetectable. Cycle day 10 enclomiphene levels increased with dose administered, but these observations were not statistically significant. CONCLUSION(S): Clomiphene citrate induction of ovulation results in an isomer-specific systemic accumulation of zuclomiphene across consecutive cycles of treatment. The combined maximum concentration of enclomiphene and zuclomiphene attained in practice approximates 100 nmol/L and is generally well below levels previously demonstrated to have adverse effects in vitro.

Adult↗