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PubMed1983

A graduated regimen of clomiphene citrate: its correlation to glycogen content of the endometrium and serum levels of estradiol and progesterone in infertile patients at the midluteal phase.

The glycogen content, glycogen synthetase level, and glycogen phosphorylase level were studied in endometrial samples obtained from 14 infertile patients during the midluteal phase before and after clomiphene citrate (Clomid, Shionogi & Company, Ltd., Osaka, Japan) treatment, simultaneously with measurement of the serum concentrations of estradiol and progesterone. Increase in the endometrial glycogen content in the clomiphene cycle was accompanied by a corresponding increase of the dosage of clomiphene. Also, the midluteal concentrations of estradiol and progesterone in the clomiphene cycle were significantly higher (P less than 0.005 and P less than 0.005, respectively) than those in the nontreatment cycle. Clomiphene therapy at 50 mg/day resulted in pregnancy in three of ten patients, while clomiphene at 100 mg/day resulted in pregnancy in three of six patients. These results suggest a fair correlation between the dosage of clomiphene and the improvement of endometrial function in infertile patients following stimulated ovarian steroidogenesis.

Adult↗

PubMed1999

Expression of glucosamine trisaccharides on the rat uterine surface is altered by clomiphene citrate.

We have studied histochemically the effects of clomiphene citrate on the expression of oligosacchrides on the apical plasma membrane of uterine epithelial cells using the lectin Phytolacca americana. Ovariectomized sexually mature rats were given a single injection of either clomiphene in two concentrations or estradiol 17 beta or progesterone and were killed 24 hr later. Uterine tissue was labeled with Phytolacca americana conjugated with avidin and subsequently labeled with biotinalyted ferritin and prepared for transmission electron microscopy. Our results indicate that clomiphene and to a lesser degree progesterone significantly increased lectin binding. However, the increase was not as large as that observed with a single dose of estrodiol 17 beta. When the proportion of lectin positivity in relation to total membrane length was analyzed, treatment with clomiphene and progesterone did not have significantly different effects. Low dose clomiphene did not have a significant effect as compared with controls. Our data show that clomiphene has a dose-dependent adverse effect on lectin binding as compared with ovarian hormones. We suggest that these effects contribute to low pregnancy rates with clomiphene use.

Acetylglucosamine↗

PubMed2000

Administration of L-thyroxine does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate in functional hypothalamic amenorrhea.

OBJECTIVE: To investigate the hypothalamo-pituitary-ovarian axis in women with functional hypothalamic amenorrhea to determine whether the combination of L-thyroxine and clomiphene citrate produces a qualitative and quantitative increase in induced ovulatory cycles. SETTING: Gynecological Endocrinology Research Center, University of Siena (Italy). PATIENTS: 16 young women with functional hypothalamic amenorrhea and 15 women with normal cycles in early follicular phase. DESIGN: Administration of 50 microgram GnRH and 200 microgram TRH. The women with functional hypothalamic amenorrhea were divided into groups A (n=8) and B (n=8). Both groups were given 100 mg/day clomiphene for 5 days/month for 3 months. Women in group A were also given 75 mcg/day thyroid hormone (L-thyroxine) for 3 months. MAIN OUTCOME MEASURES: Comparison of basal and stimulated levels of gonadotropins, TSH and Prl, in groups A and B. Qualitative and quantitative comparison of ovulatory cycles induced in the groups. RESULTS: Administration of clomiphene and clomiphene plus L-thyroxine was evaluated in the second and third months of treatment and was followed by a total of 11 ovulatory cycles, six in group A and five in group B. No significant difference was found between groups. Mean progesterone concentrations measured 16 days after the last clomiphene tablet were 5.5+/-1.2 ng/ml in group A and 5.1+/-1.3 ngl/ml in group B. CONCLUSIONS: Administration of L-thyroxine with clomiphene does not improve the response of the hypothalamo-pituitary-ovarian axis to clomiphene citrate or the number of ovulatory cycles and does not reduce luteal phase defects.

Adult↗

PubMed2001

Improved responsiveness of PCOS patients to clomiphene after CYP17a inhibitor.

PURPOSE: To study the effect of CYP17a inhibitor, "ketoconazole," on clomiphene responsiveness in PCOS patients. METHODS: Prospective analysis was employed with the setup at Alexandria IVF/ICSI center. Ninety-seven insulin-resistant PCOS patients undergoing ovulation induction using clomiphene citrate were randomly divided, by random number table, into two groups. The first group (n = 49) received ketoconazole (400 mg daily) till correction of metabolic syndrome followed by clomiphene (100 mg/day); the second group (n = 48) receiving clomiphene without ketoconazole pretreatment. Main outcome measures were incidence of clomiphene resistance, monofollicular response, fasting insulin/glucose ratio, serum testosterone, and pregnancy rates. RESULTS: The ketoconazole group showed significantly (p < 0.05) higher incidence of monofollicular response (38%), higher pregnancy rates, and significantly less marked antiestrogenic manifestations than did the control group. They also had significantly lower incidence of clomiphene resistance (11.6%), lower serum testosterone levels, less hyperinsulinaemia, than did the control group. CONCLUSION: Ketoconazole improved clomiphene responsivenss in PCOS patients and attenuated its untoward biological effects.

Clomiphene↗

PubMed1986

[Endocrine fertility-restricting factors in clomiphene therapy].

A marked discrepancy between a high ovulation rate (70-80%) and a low pregnancy rate (30-35%) is generally observed during clomiphene therapy in female infertility. Disturbances in follicular maturation, inadequate secretory transformation of the endometrium and influence on the quality of cervical mucus are discussed as cause for this phenomenon. The purpose of this study was to investigate whether changes in endocrine patterns might lead to these changes thus limiting the success of clomiphene therapy. In 7 patients gonadotropins, prolactin, ovarian and adrenal androgens, sexual hormone binding globuline (SHBG) and plasma levels of clomiphene were measured at short intervals during a stimulated cycle. The increase of testosterone and androstendione promoted by clomiphene during the follicular phase is in accordance with previous observations. The decline in SHBG due to an antioestrogenic effect on its hepatic production leads to an additional increase in free, biologically active androgens. These androgens interfere with follicular maturation, causing atresia and premature luteinisation. As a direct effect of clomiphene on the adrenal gland, we observed an elevation of DHEAS. The significance of this finding remains unclear. During the follicular phase prolactin remained suppressed inspite of supraphysiological oestrogen levels. In the late luteal phase the diminished antioestrogenic influence on lactotrophic cells causes a 80% rise in prolactin that in some cases may impair luteal function. The average plasma half-life of clomiphene was found to be 12 days. This is in accordance with the half-life of the closely related compound tamoxifen. Clomiphene, also present in the luteal phase of the cycle, may cause inadequate secretory transformation of the endometrium by blocking endometrial oestrogen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed2000

Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome.

The induction of ovulation by clomiphene could be the result of interaction of the drug at various levels: hypothalamus, pituitary and ovary. It was demonstrated that administration of clomiphene to women with polycystic ovarian syndrome (PCOS) is accompanied by a reduction in plasma concentrations of insulin-like growth factor-I (IGF-I). IGF-I seems to have an overall negative effect on normal folliculogenesis and ovulation. The aim of the present study was to evaluate the effect of clomiphene on plasma concentrations of IGF-I and IGF binding protein (IGFBP)-1 and on insulin resistance associated with PCOS. Fifteen patients diagnosed with PCOS were recruited. Clinical diagnosis was based on chronic oligomenorrhoea or amenorrhoea and hyperandrogenaemia. Clomiphene citrate was administered at a dose of 100mg/day to all women from day 5 to day 9 of the spontaneous or medroxyprogesterone acetate (MAP)-induced menstrual cycle. Blood sampling and a 2 h oral glucose loading test (75 g) were performed the day before and after the course of clomiphene. Ovulation was confirmed in 13/15 PCOS patients. Plasma concentrations of IGF-I decreased by 31.5% (434 +/- 84 versus 297 +/- 71 ng/ml; P: < 0.05) after 5 days of clomiphene therapy, whereas plasma concentrations of IGFBP-1 increased by approximately 28.1% (26.3 +/- 4 versus 36.6 +/- 7 ng/ml; P: < 0.05). This gave a 56.5% reduction in the IGF-I:IGFBP-1 ratio (21.9 versus 9.53). No significant changes in basal plasma concentrations of fasting insulin or area under the insulin curve were observed in response to oral loading. The present results show that clomiphene does not cause changes in insulin resistance associated with PCOS but reduces plasma concentrations of IGF-I and increases those of IGFBP-1, with a consequent marked reduction in the IGF-I:IGFBP-1 ratio.

Adult↗

PubMed1992

A randomized prospective study comparing pregnancy rates following clomiphene citrate and human menopausal gonadotrophin therapy.

The anti-oestrogenic effect of clomiphene citrate causes an increased rate of associated cervical factor problems. Theoretically, it may also cause an adverse effect on the endometrium. The hostile mucus may be completely or partially corrected by the use of additional oestrogen after stopping clomiphene, or by intrauterine insemination (IUI). The prospective randomized study presented here was designed to determine whether a higher pregnancy rate might be achieved using human menopausal gonadotrophin (HMG) compared to clomiphene citrate. Thirty-seven women treated with clomiphene citrate for 165 cycles were compared to 33 treated with HMG for 179 cycles. A pregnancy was achieved in 81.1% of clomiphene-treated women (18.2%/cycle) versus 72.7% (13.3% per cycle) of HMG-treated women. The abortion rates of 13.3 and 12.5% respectively, were similar. The data suggest no adverse effect of clomiphene compared to HMG as far as pregnancy rates are concerned. IUI seems to be an effective means of treating cervical factor problems induced by clomiphene.

Clomiphene↗

PubMed1978

Ovulation and pregnancy rates with clomiphene citrate.

A review of recent experience with clomiphene citrate at the Yale-New Haven Medical Center yields the following conclusions: 1) Clomiphene citrate administered at high doses (150 mg and 200 mg) is effective in inducing ovulation in women who would otherwise have failed to conceive if treatment were restricted to only lower dosage regimens. 2) Therapy with clomiphene citrate should be initiated with the 50-mg dose. The 100-mg dose should be reserved for those who fail with the lower dose. 3) Children resulting from clomiphene-induced ovulations appear to be developing normally both mentally and physically. Congenital malformations found in children from clomiphene-induced pregnancies are those seen commonly in general obstetric practice resulting in no significant problems for the children. 4) After 3 ovulations with clomiphene citrate approximately 50% of the patients can be expected to conceive. A 50% conception rate after 3 ovulations with clomiphene citrate does not represent a discrepancy between ovulation rates and pregnancy results, for it agrees statistically with the results obtained for the general population.

Abnormalities, Drug-Induced↗

PubMed1992

Luteinizing hormone response to clomiphene citrate in central precocious puberty.

OBJECTIVE: The aim of the present study was to determine the LH response to clomiphene citrate administration in children with central precocious puberty and different bone ages to gain insight into the hypothalamic maturation mechanism. PATIENTS AND METHODS: Twelve children with untreated central precocious puberty were studied. Five had central nervous system lesions and seven had idiopathic central precocious puberty. Their chronological and bone ages ranged from 1.7 to 8.8 years and 3.5 to 13.5 years, respectively. Clomiphene citrate (3 mg/kg/day) was administered orally for 7 days. Blood samples were collected on days 0, 6 and 8. LH and FSH were determined by RIA. The results were compared with GnRH responses or with bone age. RESULTS: No increase over basal LH levels was detected in four patients, but increased LH levels were detected in the remaining eight during clomiphene administration. The shift from negative to positive responses was around 8-9 years bone age. The sum of LH responses (days 6 and 8) to clomiphene citrate, and particularly the 8th-day LH levels, were significantly correlated with their respective bone age (r = 0.83). However, the LH responses to GnRH were not significantly correlated with bone age or with LH responses to clomiphene. CONCLUSIONS: This study shows that the LH responsiveness to clomiphene citrate in central precocious puberty increases with skeletal maturation, indicating that the activation of the hypothalamic pubertal mechanism in central precocious puberty may progress in a gradual sequence. These changes in LH response to clomiphene in central precocious puberty mimic those observed with the development of normal puberty, but occur at a much earlier age.

Bone Development↗

PubMedDate not supplied

Effects of experimental hyperprolactinemia and clomiphene on pituitary responsiveness to LHRH and TRH in men.

The effect of clomiphene citrate during sulpiride-induced hyperprolactinemia on pituitary function was tested in 8 healthy men, who ingested 100 mg of clomiphene, 150 mg of sulpiride or 100 mg of clomiphene + 150 mg of sulpiride daily for 7 days. Clomiphene treatment increased FSH and LH plasma concentrations and this increase was unaffected by sulpiride-induced hyperprolactinemia. Sulpiride intake alone did not alter serum gonadotropin concentrations. A reduced LH response to LHRH during sulpiride intake was seen, whereas the FSH response was unchanged. The prolactin response to TRH was unaffected during the combined sulpiride + clomiphene ingestion. Sulpiride treatment did not change the basal and/or clomiphene-stimulated gonadotropin secretion in healthy men. Thus, oligozoospermic men using psychotropic drugs and/or with hyperprolactinemia may be suitable candidates for clomiphene treatment.

Adult↗

PubMed2002

Inhibitory effects of the antiestrogen agent clomiphene on cardiac sarcolemmal anionic and cationic currents.

The aim of this study was to determine the effects of the antiestrogen agent clomiphene on cardiac anionic and cationic sarcolemmal ion channels. Whole-cell recordings were made from rat and guinea pig ventricular myocytes. Clomiphene inhibited the volume-regulated chloride current [I(Cl,vol), activated by cell swelling after hypotonic shock (approximately 145 mOsM)] with an IC(50) value of approximately 9.4 microM. In contrast, at concentrations up to 100 microM, clomiphene failed to inhibit both the chloride current activated by cyclic AMP (I(Cl,cAMP)) and the anionic background current (I(AB)). At 10 microM, clomiphene blocked the voltage-gated fast sodium current and the L-type calcium current (I(Ca,L)) in both species. The voltage-independent fractional block of I(Ca,L) induced by clomiphene (10 microM) was approximately 82%, this concentration also inhibited the inwardly rectifying K(+) current with a fractional current block of approximately 26% at -90 mV. Fractional block of outward current at +70 mV in rat was approximately 25%, implying that delayed rectifying K(+) channels were also affected by clomiphene. We conclude that clomiphene shows selectivity for I(Cl,vol) over I(Cl,cAMP) and I(AB) and therefore represents a useful tool for studying chloride conductances in isolated ventricular myocytes with interfering currents blocked. However, due to its effects on cation conductances it would be of little value in this regard for other types of in vitro or in vivo experiments.

Animals↗

PubMed1986

Clomiphene citrate induces pituitary GnRH receptors in ovariectomized rats: its possible role in induction of ovulation.

Since our previous studies have shown that clomiphene citrate (clomiphene) acts directly on the pituitary gland and exerts a facilitatory role on oestradiol-17 beta (E2)-induced LH surge in chronically ovariectomized rats, the effect of clomiphene on pituitary GnRH receptors was investigated. A single ip injection of either 5 micrograms E2 or 200 micrograms clomiphene did not induce LH release in adult rats ovariectomized 1-2 weeks before the injection. However, a significant increase in serum LH was noted 24 h after a single injection of E2 in the ovariectomized rats, if clomiphene was pre-injected 48 h before the E2 injection. The content of pituitary GnRH receptors in the ovariectomized rats (62 +/- 9 fmol/pituitary) remained almost unchanged until 24 h after a single injection of clomiphene but significantly increased 48 h after the injection (105 +/- 13 fmol/pituitary) without any alterations in the affinity for GnRH. To determine steroid specificity for the increase in pituitary GnRH receptors, other classes of steroids were injected in the ovariectomized rats. A single dose of E2 increased GnRH receptors, but either progesterone or 5 alpha-dihydrotestosterone failed to show any effect on the level of GnRH receptors. These results suggest that clomiphene may augment oestrogen-induced pre-ovulatory LH surge in anovulatory women, at least in part by increasing the number of pituitary GnRH receptors.

Animals↗

PubMed1981

Agonist and antagonist activity of en-clomiphene upon oestrogen-mediated events in the uterus, pituitary gland and brain of the rat.

The oestrogen agonist and antagonist activity of a single dose of en-clomiphene (0.5--50 mg/kg) was studied in peripheral and brain tissue in the 3 week ovariectomized rat. 17 beta-Oestradiol benzoate (100 microgram/kg) or vehicle was injected 24 h after en-clomiphene administration and data collected at 72 h. En-clomiphene produced a dose-related (agonist) fall in body weight and food intake. Agonist action was not observed upon sexual receptivity and prolactin secretion; oestrogen antagonism of these parameters was only seen at the higher doses. The effects of en-clomiphene upon serum LH and FSH were complex, both agonist and antagonist activity being demonstrated in the absence and presence of oestrogen. En-clomiphene was uterotrophic at all doses tested; however, oestrogen antagonism was only seen at the higher doses. Inhibition of the accumulation of uterine luminal fluid at the higher doses of en-clomiphene was a sensitive index of oestrogen antagonism. The results are discussed in relation to previous studies of the effects of en-clomiphene on oestrogen receptors. With the exception of the antagonism of oestrogen-induced sexual receptivity no correlation could be made between biological activity and the status of oestrogen receptors in tissue.

Animals↗

PubMed1976

Studies on the mode of action of clomiphene citrate.

In order to further investigate the mode of action of clomiphene citrate, 5 oophorectomized women in the age range 28 to 41 years were followed with weekly determinations of serum FSH and LH for 20 weeks after the operation. They received no treatment during the first 4 weeks but during the next 16 weeks they were given estradiol 2 mg X 2 daily orally, and from the 12th to the 16th week in addition clomiphene citrate 50 mgX2 daily. The high level of FSH after the oophorectomy decreased gradually during the treatment with estradiol alone, but this effect was partly neutralized by clomiphene citrate, as we observed a significant increase in FSH within 1 week of initiating treatment with clomiphene citrate. On the other hand, we did not find any significant changes in FSH within 4 weeks after treatment with clomiphene citrate was discontinued. The high level of LH after oophorectomy did not show any significant changes during the whole treatment period. It is concluded that clomiphene citrate primarily stimulated FSH secretion, most probably by a competition with estradiol for the receptor sites in the hypothalamus or the pituitary. In addition, it is concluded that clomiphene citrate has a prolonged effect, probably because of a tight binding to the receptor sites.

Administration, Oral↗

PubMed1989

Effect of clomiphene on nuclear estrogen receptor of the fallopian tube during ovum transport in rabbits.

The effect of clomiphene on nuclear estrogen receptors of the Fallopian tube during ovum transport in the rabbit has been studied. Nuclear binding capacity was observed in ampulla (A), ampullary-isthmic junction (AIJ), isthmus (I), uterine-isthmic junction (UIJ) and uterus (U). Receptor concentration decreased in all segments of the tube after administration of clomiphene in mated animals. The bindings are of high affinity and low capacity. Important alterations were observed during transport when compared to that of 14, 24, 34, 48, 72, 144 and 168 hr post-coitum (p.c). At 24 hr p.c binding increased only in I and decreased in A and AIJ. Retention of eggs at I at 24 hr p.c showed as increase in binding at I. Egg transport was accelerated and eggs reached prematurely in the uterus due to the influence of clomiphene. Binding in I remained constant from 48 hr p.c to 144 hr p.c but concurrently the binding level increased in U from 34 hr p.c. The elevation of nuclear estrogen receptor level was maximum at 24 hr p.c which coincided with increased plasma estrogen level. The result of such study showed that clomiphene depleted nuclear estrogen receptor complex in the fallopian tube before transfer to the uterus. Further, observation indicated that clomiphene acted directly on the rate of egg transport because of the variations in estrogen receptors during different time periods. Thus, clomiphene reduced the quantity of estrogen receptor i.e., insensitiveness to estrogen. The variations in estrogen binding to its receptor and plasma level at different post-coital periods are modulated by clomiphene resulting in the acceleration of egg transport and prevention of pregnancy.

Animals↗

PubMed2001

Clomiphene, an ovulation-inducing agent, causes [Ca2+]i increases in human osteoblast-like cells.

The effect of clomiphene, an ovulation-inducing agent, on cytosolic free Ca2+ levels ([Ca2+]i) in MG63 human osteosarcoma cells was explored by using fura-2 as a Ca2+ indicator. Clomiphene at concentrations between 5-75 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 of 50 microM. The [Ca2+]i signal consisted of an initial rise and a sustained phase. Ca2+ removal reduced the Ca2+ signal by 40+/-10%. The [Ca2+]i increase induced by 50 microM clomiphene was inhibited by 80+/-5% by 10 microM nifedipine, but was insensitive to 50 microM La3+ or 10 microM verapamil. In Ca2+-free medium, pretreatment with 50 microM brefeldin A (to disrupt the Golgi complex Ca2+ store), 1 microM thapsigargin (to inhibit the endoplasmic reticulum Ca2+ pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; to uncouple mitochondria) inhibited 51+/-3% of 50 microM clomiphene-induced Ca2+ release; conversely, pretreatment with 50 microM clomiphene abolished the [Ca2+]i increase induced by thapsigargin, CCCP, and brefeldin A. The Ca2+ release-induced by 50 pM clomiphene was unchanged by inhibition of phospholipase C with 2 microM 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U73122). Collectively, the results suggest that clomiphene increased [Ca2+]i, in osteoblast-like cells, by releasing intracellular Ca2+ in a phospholipase C-independent manner and by causing nifedipine-sensitive Ca2+ influx.

Calcium↗

PubMed1992

[Ovarian stimulation with clomiphene is not a risk factor for extrauterine pregnancy].

In a retrospective cohort study of 252 patients with ectopic pregnancies the possible association between use of clomiphene citrate and the occurrence of an ectopic pregnancy was examined. Seventeen out of 252 patients had been treated with clomiphene. Epidemiologic data and animal experiments suggest, that there may be a role of clomiphene in the etiology of ectopic pregnancy. Marchbanks et al. [6] reported that patients who used clomiphene were found to have a relative risk of 10.0 for ectopic pregnancy. The analysis of our own data show an accumulation of classic risk factors as history of pelvic inflammatory disease or of microsurgery for treatment of tubal disease in the clomiphene group. The higher rate of ectopic pregnancies in patients who have been treated with clomiphene is more likely associated with the diagnosis of infertility than with the use of ovulatory-inducing agents. Clomiphene treatment is no independent risk factor in the etiology of ectopic pregnancy.

Clomiphene↗

PubMed1989

A short course of menotropin after clomiphene failure in infertile women with luteal phase defects.

Twenty-four women with luteal phase defects who were ovulatory on clomiphene therapy with or without human chorionic gonadotropin (hCG) at midcycle for three to eight cycles yet failed to produce a live birth were treated with a short course of menotropin (hMG-S), one to two ampules for five days in the early follicular phase followed or not followed by hCG at midcycle for three to eight cycles. The luteal phase defect was diagnosed with repeat endometrial biopsies with a lag time of three or more days prior to clomiphene therapy. A complete infertility workup revealed only eight patients (33%) with a purely endocrine factor (luteal phase defect). The rest (16 patients, or 67%) had one or two additional infertility factors. Two abortions occurred in this group during clomiphene therapy, while five pregnancies (four live births and one spontaneous abortion) occurred during hMG-S therapy. The ovulation rates were similar for hMG-S (89%) and clomiphene (91%) therapy, but the frequency of a normal ovulatory cycle was significantly greater (P = .026) for hMG-S therapy (71%) than for clomiphene therapy (57%). The midluteal mean serum progesterone level was lower and the mean luteal length shorter in the cycles with less than 130 ng/mL/d of total integrated luteal progesterone. The postcoital test results showed better cervical mucus, with increased mucus volume and better fluidity and spinnbarkeit, in hMG-S cycles than in clomiphene cycles. It appears that hMG-S treatment can improve ovarian function and achieve successful pregnancy in patients with luteal phase defects who fail to produce a live birth during clomiphene treatment.

Adult↗