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PubMed1987

Estrogen receptor binding material in blood of patients after clomiphene citrate administration: determination by a radioreceptor assay.

The aim of the current study was to assess whether clomiphene citrate (CC) and/or active metabolites are present at presumed time of ovulation, nidation, or steroid-sensitive organogenesis, in serum of patients receiving CC for induction of ovulation. A radioreceptor assay, based on competitive replacement of 3H-estradiol on the rat uterus estrogen receptor, by ligands present in serum of patients after CC administration, was developed. Ligands reached maximal concentration 4 to 5 hours after a single dose of CC was administered, and declined with a half-life of 4.5 to 10 hours. In patients receiving CC on day 5 to day 9 in the cycle, ligands are still present on day 14 in the cycle and in some patients on day 22 of the cycle, but no ligands were detected 60 days after CC treatment.

Amenorrhea↗
PubMed1987

Biotransformation of the antiestrogen clomiphene to chemically reactive metabolites in the immature female rat.

Novel metabolites of clomiphene (CLO), an antiestrogen effective in experimental breast cancer models, were characterized in studies using immature female rats. After i.p. administration, CLO was eliminated unchanged in feces and as two components which were chromatographically identical to synthetic CLO analogues bearing a m-methoxy-p-hydroxyphenyl (guaiacol) moiety in place of one or the other of its phenyl rings. These components were also found in liver tissue. In the presence of liver microsomal homogenate, CLO underwent p-hydroxylation of either of its phenyl rings, affording 4-hydroxy-CLO and 4'-hydroxy-CLO. These in turn underwent liver microsomal mediated conversion to the respective guaiacol metabolites. 4'-Hydroxy-CLO and its 3'-methoxy analogue, but not positional isomers of these, had arylating ability as shown by chemical and spectral studies, apparently due to spontaneous conversion to electrophilic allene-quinones. Reproductive tract abnormalities produced in neonatal rats by CLO were suggested not to be mediated via such metabolites, since similar such effects were caused by 4'-fluoro-CLO. However, the latent arylating potential of the 4'-hydroxylated metabolites of CLO suggests that these compounds may be useful in biochemical studies of breast cancer cell growth inhibition.

Age Factors↗
PubMed1987

Estradiol reverses the limiting effects of clomiphene citrate on early embryonic development in the in vitro perfused rabbit ovary.

This study examined whether the addition of estradiol (E2) to the perfused rabbit ovary would reverse the deleterious effects of clomiphene citrate (CC) on early embryonic development. Ovaries were perfused with CC (10(-5) M) or CC + E2 (1 to 1000 ng/ml). Human chorionic gonadotropin (hCG, 50 IU) was added to the perfusate of each ovary. In vitro ovulated ova in cumulus were retrieved and inseminated in vitro. E2 significantly increased the percentage of ovulated ova achieving (1) the 2-cell stage at 36 hours, (2) the morula stage by 84 hours, and (3) the blastocyst stage at 132 hours. The percentage of inseminated ova showing evidence of degeneration was reduced in ovaries treated with E2. These data suggest that CC may exert an antiestrogenic effect on the intrafollicular oocyte, which interferes with postfertilization development.

Animals↗
PubMed1987

Identification and management of clomiphene citrate responses.

Clomiphene citrate (CC) is widely used for induction of ovulation; however, adequate time is rarely used to monitor patients on this form of therapy. Two hundred thirty-one infertility patients qualified for this study in 1155 cycles, during which basal body temperature charts were kept and the quality of cervical mucus was evaluated. Nine types of responses were classified: three ovulatory (O1, O2, O3), three anovulatory (A1, A2, A3), and three miscellaneous (M1, M2, M3). The overall, uncorrected pregnancy rate was 54.9%, and 79.2% showed ovulatory responses. The most common response was O1 (normal responses, 38.5%) with the highest pregnancy rates (92.1%). Poor estrogenic response with poor cervical mucus (CM) (O2) was fairly common (13.4%) and had poor pregnancy rates, even with the addition of estrogens (12.9%). It is suggested that this new classification of CC responses will help to identify and more efficiently manage patients undergoing this form of therapy.

Body Temperature↗
PubMed1986

Luteal phase serum progesterone levels after follicle aspiration with and without clomiphene citrate treatment.

Peripheral serum progesterone (P) levels were studied on random days after the spontaneous luteinizing hormone (LH) surge in women who underwent follicle aspiration. Comparisons were made with ovulatory women treated with clomiphene citrate (CC) undergoing follicle aspiration and women undergoing midcycle general anesthesia and laparoscopy without follicle aspiration. There were no differences in mean P levels in the group of women who underwent follicle aspiration, compared with the group who did not. Women treated with CC showed higher P levels during the first week of the luteal phase. During the second week of the luteal phase P levels were similar, regardless of follicle aspiration alone or in combination with CC use. In the groups not using CC, more individual women had P levels less than 10 ng/ml. Follicle aspiration does not appear to reduce luteal phase P levels in groups of patients in the natural menstrual cycle or receiving CC. Some individual patients, however, appear to be at risk for lower P levels, particularly after follicle aspiration or general anesthesia, in the natural cycle.

Clomiphene↗
PubMed1985

[Clinical and endocrinological studies on anovulatory women treated with two-step administration of clomiphene citrate].

The two step clomiphene citrate (CL) administration therapy was performed in 89 patients with first grade amenorrhea during 1980 through 1983, and clinical data in 89 patients and daily serum hormone levels in 20 patients were investigated. Out of the 89 women, ovulation occurred in 71 (79.8%). As to the treatment cycles, ovulation occurred in 158 cycles (53.4%) out of the total 296 cycles. Pregnancy was achieved in 16 women, among whom 2 women ended in spontaneous abortion and one had a multiple pregnancy. (1) As for 9 women in whom ovulation was induced by this treatment, the serum level of LH in the follicular phase and that of estradiol in the late follicular phase and luteal phase were higher than those of women who had normal ovulatory cycles. (2) No significant differences were observed between the serum levels of FSH and progesterone of the 9 women and those of women with normal ovulatory cycles. (3) As for 11 women in whom ovulation was not induced by this treatment, a transient increase in serum levels of LH and estradiol were observed after the first step administration of CL. This change also appeared soon after completion of the second step administration of CL and became more significant as additional stepwise administration of CL was performed. In view of observations, it was concluded that CL two step administration is effective for anovulatory women who did not respond to one step use of CL. As previously reported, CL exerts its action on the central nervous system to promote ovulation, but it is also strongly suggested that CL has its direct action on the ovary too.

Adult↗
PubMed1985

Potentiation of GnRH response by clomiphene citrate.

The method whereby clomiphene citrate (CC) induces ovulation in anovulatory women is not known. It probably binds to cytoplasmic estrogen receptors throughout the reproductive axis, with a central hypothalamic site postulated as a major center of action. Three patients who had severe hypothalamic amenorrhea and were clinically and biochemically unresponsive to CC alone had ovulation induced with the intermittent intravenous administration of gonadotropin-releasing hormone (GnRH). When CC was added to the GnRH, an enhanced secretory response of estradiol was demonstrated in all the patients. One patient demonstrated hyperstimulation, with large increments of estradiol and the development of multiple follicles, similar to what occurred with a larger dosage of GnRH alone. This finding suggests that CC may potentiate the response to GnRH, indicating that the action of CC is, at least in part, extrahypothalamic.

Adult↗
PubMed1985

[Clomiphene-HMG ovarian stimulation in human in vitro fertilization and embryo transfer].

In a program for in vitro fertilization and embryo transfer, laparoscopies for oocyte aspiration were performed in 40 cycles in 36 normally menstruating women with irreparable tubal diseases (IVF patients) who received clomiphene citrate (CC) and human menopausal gonadotropin (hMG). An intramuscular injection of human chorionic gonadotropin (hCG) was given to all patients after completion of follicular maturation. Fourteen cycles in 13 spontaneously ovulating women (control patients), also stimulated with CC and hMG, were adequately monitored to identify the appearance of the spontaneous luteinizing hormone (LH) surge. The follicular maturation was followed by daily ovarian ultrasonographic examination and serum estradiol estimations. Just before the LH surge the diameter of the leading follicle was 20.2 +/- 0.7 (mean +/- S.E.) mm and the serum estradiol concentration per follicle was 384.1 +/- 16.3pg/ml in the control patients. In the IVF patients the former was 20.6 +/- 0.3mm and the latter was 305.8 +/- 13.3pg/ml prior to hCG administration. When the relationship of follicular size to the rates of oocytes recovery, maturation, fertilization and cleavage was examined, larger follicles (3ml less than or equal to follicular fluid volume) showed good results. Of the 152 oocytes that were recovered from these IVF patients, 96 (63.2%) were fertilized and 79 (52.0%) cleaved. Three pregnancies resulted from 35 embryo transfers.

Adult↗
PubMed1986

Advanced secretory changes in the proliferative human endometrial epithelium following clomiphene citrate treatment.

In an effort to characterize the effect of clomiphene citrate (CC) on the human endometrium, we took biopsy specimens of the endometrium 24 to 48 hours after CC treatment (100 to 250 mg/day for 5 consecutive days). Nineteen biopsy specimens were taken from 19 patients. Fifteen of the patients suffered from anovulatory infertility associated with oligomenorrhea or normal cycle length. The other four patients were amenorrheic, two in association with hypogonadotropic hypogonadism and two with hypergonadotropic hypogonadism. The histopathology of all samples was evaluated with the use of light microscopy, including periodic acid-Schiff (PAS) and PAS-diastase staining for glycogen demonstration. All samples were also examined with the use of scanning electron microscopy (SEM). Serum levels of estradiol (E2), progesterone (P), luteinizing hormone, and follicle-stimulating hormone were determined on the day of biopsy. In 10 of the 19 biopsy specimens, local or diffuse signs of early secretory events were demonstrated by the presence of subnuclear vacuolization and glycogen in the glandular epithelial cells. SEM corroborated these findings of advanced secretory changes by demonstrating apical protrusions at luminal epithelial cells and secretory products within the glands' openings. The E2 levels ranged between 110 and 1500 pg/ml (mean, 371 pg/ml) and P levels were either undetectable or less than 1.1 ng/ml. The two patients with hypogonadotropic hypogonadism both exhibited the same phenomena; those with primary ovarian failure had atrophic endometrium even after high-dose CC treatment. This observation, together with the low P levels detected, indicating the lack of luteinization, suggests a possible direct effect of CC on the endometrium.(ABSTRACT TRUNCATED AT 250 WORDS)

Anovulation↗
PubMed1979

Clomiphene-induced pregnancy in a patient with diabetes insipidus and hypothyroidism.

A patient with diabetes insipidus and hypothyroidism developed anovular menstrual cycles. Ovulation, which was followed by pregnancy, was induced by the administration of clomiphene. In the later stages of pregnancy, an increase in the dosage of vasopressin was necessary to achieve a satisfactory control of the symptoms of diabetes insipidus. Labour was induced before the estimated date of confinement by the intravenous administration of oxytocin and an intra-partum haemorrhage necessitated delivery by the lower-segment caesarean section. The post-partum period was uneventful. Lactation was suppressed on request from the patient.

Adult↗
PubMed1979

[Therapeutic application of clomiphen to women with functional sterility (author's transl)].

Clomiphen citrate doses of 50 mg or 100 mg per die were administered over five days to 150 infertile women with menstrual disorders. The conception rate eventually achieved was 38.7 per cent (58 cases). The most favourable results were obtained from patients with anovulatory oligomenorrhoea (53.9 per cent), secondary infertility (63.3 per cent), and those treated between one and three months (81.2 per cent).

Clomiphene↗
PubMed1982

Clomiphene treatment in male infertility.

After the discovery that Clomiphene-citrate (Clomid) increased the secretion of gonadotropins, it was first used to induce ovulation and later on it was also used in males in certain cases of infertility. The effects of Clomid on the hypothalamic-pituitary level made it also possible to use it for a dynamic evaluation of the hypothalamic-pituitary gonadal axis in both females and males. The results obtained with Clomid are reviewed. The results are widely divergent because of the fact that the selection of the patients, the dosage, and the length of the therapy are not always appropriate. However, the experience with Clomid appears to show sufficient effectiveness in oligozoospermic men, who have a low or normal FSH-level.

Clomiphene↗
PubMed1981

[Influence of synthetic estrogens on experimental Schistosoma mansoni parasitosis in hamsters: cis and trans clomiphene isomers].

Within the framework of previous investigations concerning the protective effect of estrogens during an experimental infection with Schistosoma mansoni in female hamster, the respective actions of the cis and trans forms of clomiphene have been studied. These two forms appear to be unable to assure a protective effect, the mean numbers of parasitic worms and the seric specific antibodies levels which have been observed in the treated animals do not significantly differ from those of the control group.

Animals↗
PubMed1984

Antiestrogenic effect of clomiphene citrate: correlation with serum estradiol concentrations.

The antiestrogenic effect of clomiphene citrate (CC) on cervical mucus was evaluated in women receiving 150 mg CC daily for 5 days. Daily cervical mucus scores and serum estradiol (E2) concentrations were determined in control (n = 25) and CC (n = 24) cycles. E2 concentrations were significantly higher in the CC-treated women (mean +/- standard error of the mean, 1254 +/- 102 pg/ml versus 337 +/- 18 pg/ml, P less than 0.0001). Despite supraphysiologic E2 concentrations, however, cervical mucus scores were significantly reduced in the CC-treated group (P less than 0.01). These data indicate that CC exerts a direct suppressive effect on cervical mucus despite markedly increased E2 concentrations.

Adult↗
PubMed1978

Pregnant mare's serum gonadotropin. IV. Induction of premature labor by pregnant mare's serum gonadotropin and its prevention by using clomiphene or indomethacin.

The administration of pregnant mare's serum gonadotropin (PMSG), 30 IU on day 18 of pregnancy, resulted in premature labor in rats. However, this abortifacient efficacy of PMSG was not demonstrable when a simultaneous injection of progesterone, clomiphene, or indomethacin was scheduled, thus suggesting that the action of PMSG is medicated by the estrogen-stimulated release of prostaglandin. The termination of pseudopregnancy in bilaterally hysterectomized rats by PMSG and its reversal by indomethacin revealed that the inhibition of luteal function by PMSG does not require the presence of a uterus.

Abortifacient Agents↗
PubMed1983

Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation.

During the five years ending on December 31, 1981, 159 anovulatory and oligomenorrheic patients were treated with clomiphene citrate for induction of ovulation. Overall, 86% of these patients ovulated, and 49% of the patients who ovulated conceived. Life table analysis was employed to investigate factors contributing to reduced conception rates, including abnormal semen analysis, pelvic or tubal abnormalities, and poor cervical mucus. Elevated serum testosterone levels did not affect conception rates. The most significant factor contributing to reduced overall pregnancy rates was patient discontinuation of therapy. Cumulative pregnancy rates corrected for discontinuation approach 100% after ten cycles of therapy. During this period, the monthly probability of pregnancy (monthly fecundability) remained constant. Optimal pregnancy rates are attained if other infertility factors are corrected and treatment is continued for ten to 12 ovulatory cycles.

Cervix Mucus↗
PubMed1982

[Effects of subacute treatment with clomiphene, ethamoxytriphetol (Mer-25), and nafoxidine on blood calcium and bone density in rats].

The authors study the effect of clomiphene, ethamoxytriphetol and nafoxidine on calcemia and bone density of the rat. These antiestrogens induce hypercalcemia, reproducing the bone radiologic changes produced after castration. The different effects obtained in normal and ovariectomized rats are probably due to the small estrogenic activity of antiestrogens.

Animals↗