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PubMed1989

Effects of clomiphene citrate on ovarian function in hypophysectomized rats.

On Days 28-30 of age, hypophysectomized rats were treated with oestradiol-17 beta (0.1 mg/day) and/or clomiphene citrate (0.1 mg/day). Subsequent treatment with PMSG (10 i.u., on Day 31) and hCG (10 i.u., on Day 33) was identical for all animals. Rats were killed on Day 34. Treatment with oestradiol-17 beta alone resulted in ovulations of 45.1 +/- 5.5 oocytes/rat (mean +/- s.e.m.). There were no ovulations among animals treated with clomiphene citrate alone but treatment with oestradiol-17 beta and clomiphene citrate resulted in a significant (P less than 0.05) reduction (23.1 +/- 7.6 oocytes/rat) in ovulatory response. Similarly, ovarian weights and serum progesterone concentrations were highest in the oestradiol-17 beta-treated rats, intermediate in those given oestradiol plus clomiphene citrate and the lowest in rats receiving clomiphene citrate alone. We suggest that clomiphene citrate exerts direct ovarian antiovulatory and oestrogen-antagonist actions.

Animals↗

PubMed2000

Cyclic changes in serum levels of insulin-like growth factor binding protein-1 in women treated with clomiphene citrate and tamoxifen.

In order to investigate the cyclic changes of serum insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 levels in menstrual cycles treated with or without antiestrogens (clomiphene citrate and tamoxifen), we treated 24 young women having irregular menstrual cycles with either clomiphene citrate (100 mg/day) (n = 12) or tamoxifen (60 mg/day) (n = 12) from the 5th to the 9th day of the menstrual cycle. Without antiestrogens, 12 women with regular menstrual cycles were recruited as controls. There was a preovulatory (day 13) peak of circulating IGFBP-1 in women treated with or without antiestrogens. A significant concomitant increase in serum estradiol was also observed on day 13 of the menstrual cycle in subjects treated with clomiphene citrate and in controls. However, no significant elevation in preovulatory estradiol was detected in women treated with tamoxifen. In clomiphene citrate and control groups, a significant positive correlation was found between circulating IGFBP-1 and estradiol, and between serum levels of IGFBP-1 and inhibin A at the preovulatory stage (on day 13). In contrast, no such association was observed in the tamoxifen group. Unlike cyclic changes in circulating IGFBP-1, serum concentrations of IGF-I and IGFBP-3 remained unchanged throughout the menstrual cycle in all groups. In conclusion, the preovulatory peak of circulating IGFBP-1 can be induced in cycles treated with both clomiphene citrate and tamoxifen. In addition, a significant positive correlation between estradiol, inhibin A and IGFBP-1 at the preovulatory stage indicates that IGFBP-1 may also reflect follicular development and may further be used as an additional indicator to monitor folliculogenesis under clomiphene citrate treatment.

Adult↗

PubMed1993

The effect of clomiphene citrate isomers on human granulosa-lutein cells in culture.

The effect of racemic clomiphene citrate and its two individual isomeric forms (i.e. en and zu) on corpus luteum function was evaluated. Granulosa-lutein cells were obtained from three normal ovulatory women undergoing oocyte retrieval following ovulation induction with agents other than clomiphene citrate for in vitro fertilization--embryo transfer (IVF-ET). The granulosa cells were cultured in the presence and absence of the three forms of clomiphene citrate, and in the presence and absence of human chorionic gonadotropin (hCG). Patients were recruited from the unit for assisted reproductive technology in a university hospital. The main outcome measured was the production of estradiol and progesterone by cultured human granulosa cells under the various conditions described above. The production of estradiol and progesterone by the cultured granulosa cells was dose-dependently reduced to a similar extent by all three forms of clomiphene citrate. The addition of hCG augmented steroidogenesis in all groups at all concentrations, but this still remained lower in all clomiphene citrate-treated groups compared to controls. The data suggest that all three types of clomiphene citrate (racemic, en, and zu) have inhibitory effects on the production of estradiol and progesterone by cultured human granulosa-lutein cells.

Adult↗

PubMed1999

Clomiphene-induced severe hypertriglyceridemia and pancreatitis.

Clomiphene has been available for clinical use since 1960 and has been successfully used to aid fertility in women with certain anovulatory disorders. It is a synthetic estrogen analog, of the triphenylethylene derivative group, and its biochemical structure is similar to that of tamoxifen. Estrogen and tamoxifen lower total and low-density lipoprotein cholesterol and increase triglyceride and high-density lipoprotein cholesterol levels. In patients with baseline hypertriglyceridemia, these agents can induce severe hypertriglyceridemia and pancreatitis. The actions of clomiphene on lipid metabolism have not been studied, and to our knowledge, no cases of severe hypertriglyceridemia related to the use of clomiphene have been described. We report the case of a woman who developed 2 episodes of clomiphene-induced hypertriglyceridemia and pancreatitis while receiving this drug for treatment of infertility. Given the striking structural similarity between clomiphene and tamoxifen, it is likely that clomiphene is capable of inducing severe hypertriglyceridemia in patients with certain underlying lipid disorders by a mechanism similar to that of tamoxifen.

Adult↗

PubMed1975

[Clomiphene--its use from stimulation test and for treatment of functional sterility].

There is reported on application of clomiphene (Clostilbegyt-EGYT Pharmaceutical Works, Budapest, Hungaria) in 17 patients for a clomiphene-stimulation-test and in 34 patients with functional sterility on 124 cycles. The dosage was between 50 to 150 mg p.d. for 5 to 7 days and was adapted individually. 12 patients responded to clomiphene-stimulation-test positively and in 4 ovarian hypoplasias and one Anorexia nervosa in acute phase, the clomiphene-stimulation-test was negatively. From the 34 patients with functional sterility 18 women were in 21 times gravid, 13 women could be delivered on term; in 8 cases it was an abortion. By reason of the findings after a clomiphene therapy a gravidity can be accepted, if the hyperthermic phase in the BBT existed for more than 25 days. For a repetition - treatment a dosage is recommended with 150 mg p.d. clomiphene for 7 days.

Adult↗

PubMed2002

Basal serum testosterone as an indicator of response to clomiphene treatment in human epididymis, seminal vesicles and prostate.

The present study was designed to determine the response of human epididymis, seminal vesicles and prostate function after a 5-day course of clomiphene citrate in men attending an infertility service. In 45 men, the secretions of the epididymis, seminal vesicles and prostate were assessed by measurements of seminal alpha-glucosidase, fructose and acid phosphatase, respectively. Subjects were classified as normal or abnormal: abnormal men were defined as those who either had history of a sexually transmitted disease (STD), leukocytospermia, hypoandrogenism, or a low response of Leydig cells to clomiphene stimulation; and normal subjects were those who did not have these conditions. Mean serum testosterone luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels were significantly increased after the short course with clomiphene citrate. After clomiphene citrate stimulation, the men in the normal group showed significantly increased marker levels of the seminal vesicles (P < 0.02) and prostate (P < 0.05), but not of the epididymis (P : NS). Men classified as abnormal showed no response according to the markers of the seminal vesicles and epididymis. Men with history of STD and abnormal basal values of acid phosphatase did not respond to the treatment. Men with history of STD but normal basal values of seminal acid phosphatase increased significantly in their levels of seminal acid phosphatase after clomiphene stimulation (P < 0.02). Multivariate analysis showed that the basal serum testosterone level was the only variable in predicting the probability of response to the clomiphene in terms of true-corrected seminal fructose, seminal acid phosphatase and seminal alpha-glucosidase levels. In fact, a high response of the seminal vesicles was observed in men with the highest basal serum testosterone levels (0.45 +/- 0.17; coefficient of regression +/- standard error; P < 0.018). However, a high response in terms of seminal acid phosphatase (P < 0.004) or alpha-glucosidase (P < 0.037) was observed in men with low basal serum testosterone levels. In conclusion, in the normal men, true-corrected fructose and acid phosphatase but not alpha-glucosidase in semen increased after duplicate androgen stimulation. An absence of response was observed in cases with history of STD/leukocytospermia or hypoandrogenism.

Acid Phosphatase↗

PubMedDate not supplied

Empirical therapy of the male with clomiphene in couples with unexplained infertility.

Unexplained infertility may be secondary to a cryptic male or female factor. Although most often empirical therapy of the female partner may be attempted, clomiphene has been claimed, after uncontrolled studies, to improve fertility in men with subnormal spermograms. We chose to determine if clomiphene therapy of the male would improve fertility in couples with unexplained infertility despite normal-appearing semen parameters. One hundred husbands were randomized to treatment with clomiphene citrate, 25 mg daily for 25 days with 5 days' rest each month, if their social security numbers ended in an even number or ascorbic acid, 500 mg daily, if ending in an odd number. All female infertility factors had to be meticulously corrected for at least eight cycles for inclusion in the study, along with a minimum of 1 1/2 years' duration of infertility. Within 8 months, 29 of 50 couples (58%) with clomiphene therapy of the male achieved a pregnancy, but only 8 of 50 (16%) with ascorbic acid treatment of the male. There were no appreciable changes in sperm counts, motility, or morphology after either treatment, nor were there any significant differences in semen parameters in those conceiving versus those who did not. Further, improved fertility could not be accounted for by improvement in the hamster ova penetration test. Possibly, clomiphene improves some quality of the sperm that is defective but not measurable by standard androgenologic methods, or it improves some aspect of the seminal plasma. Perhaps, though, the results might be better explained on a psychogenic basis, i.e., clomiphene is a "better" placebo than ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

The efficacy of every-other-day administration of gonadotropin-releasing hormone in women with hypothalamic amenorrhea: gonadotropin-releasing hormone treatment can induce clomiphene responsiveness.

The efficacy of every-other-day gonadotropin-releasing hormone administration was investigated in clomiphene-human chorionic gonadotropin (hCG) resistant, anovulatory women with hypogonadotropism or normogonadotropism. One hundred micrograms of gonadotropin-releasing hormone was injected intramuscularly three times a week for four weeks (one course). Ten of 11 hypogonadotropic patients responded to clomiphene or clomiphene-hCG after one to three courses of gonadotropin-releasing hormone treatment. Once the patients were converted to clomiphene responsiveness, ovulatory response continued without additional treatment, and all four patients who desired pregnancy conceived. Among eight normogonadotropic women, four with amenorrhea of one year or less became clomiphene-hCG responders after one or two courses of gonadotropin-releasing hormone treatment. They were subsequently treated with gonadotropin-releasing hormone after every one or two ovulatory cycles. One of the four women who desired to be pregnant conceived. We conclude that intramuscular gonadotropin-releasing hormone treatment is effective in inducing responsiveness to clomiphene, especially in hypogonadotropic anovulatory women. In normogonadotropic women, gonadotropin-releasing hormone treatment may be useful in those who have been amenorrheic for less than a year.

Amenorrhea↗

PubMed1987

Effect of clomiphene citrate on the ovary of a wild rat, Bandicota bengalensis.

The effects of clomiphene citrate (0.3 or 3.0 mg/kg body weight/day) for 10 consecutive days on the ovary of a wild rat, Bandicota bengalensis, were studied. The low dose of clomiphene decreased the number of nonatretic follicles larger than 400 microns in diameter, increased atresia in follicles smaller than 200 microns, inhibited granulosal mitosis in follicles less than 200 microns and between 401 and 600 microns in diameter and inhibited thecal mitosis in follicles smaller than 400 microns and larger than 600 microns. The high dose of clomiphene increased the number of follicles between 201 and 400 microns, decreased the number of follicles larger than 600 microns, increased atresia in follicles of 51-400 microns and increased granulosal mitosis in follicles of 201-400 microns diameter. In both the doses, clomiphene inhibited the ovulation rate (p less than 0.005), with 25 and 35% of the rats being anovulatory in low and high doses, respectively. In addition, clomiphene caused irregularity in the estrous cycles associated with increased cycle length. These results suggest that the clomiphene-induced partial inhibition of ovulation is possibly through its action on follicular growth and atresia mainly in nonantral (less than 200 microns) and mature follicles (401-600 microns).

Animals↗

PubMed1999

Intrauterine exposure to clomiphene and neonatal persistent hyperplastic primary vitreous.

A 4-year-and-10-month-old girl was diagnosed shortly after birth with persistent hyperplastic primary vitreous (PHPV). Her mother took clomiphene 100 mg daily for approximately 4 weeks and discontinued the drug once she had a positive pregnancy test. The exact time of gestation was not clear. Clomiphene is an estrogen antagonist effective in the treatment of anovulation. Various ocular side effects have been described in women taking the drug, including decreased vision, mydriasis, flashing lights, central scotoma, photophobia, diplopia, allergic reactions, retinal vasospasms, detachment posterior vitreous, and possibly posterior subcapsular cataracts. These occur in 1.5-10% of patients taking clomiphene. The potential effects of clomiphene on the fetus have been investigated in five animal studies. Cataracts were observed in fetal mice and rats, but not in monkeys. In humans, a case of congenital retinal aplasia was described. The possibility of clomiphene-induced congenital PHPV should be considered, especially in pregnant women who are taking a high and prolonged dose.

Animals↗

PubMed1983

Comparison of megestrol acetate and clomiphene citrate as supplemental medication in postmenopausal oestrogen replacement therapy.

In a prospective clinical trial lasting one year, 35 postmenopausal women with severe climacteric symptoms were cyclically treated with conjugated oestrogens (1.25 mg daily). This oestrogen replacement therapy was randomly supplemented with 10 mg of megestrol acetate daily (18 women) or 50 mg of clomiphene citrate (17 women) for 10 days four times a year. Both treatment regimens significantly alleviated climacteric symptoms. At the end of the oestrogen-megestrol acetate treatment no endometrial proliferation or hyperplasia was seen, while at the end of the oestrogen-clomiphene citrate treatment the endometrium was proliferative or hyperplastic in two women and atrophic in the other 15. Regular uterine bleeding occurred in each woman after megestrol acetate but never after clomiphene citrate administration. Break-through bleeding during the oestrogen treatment periods appeared in the megestrol and clomiphene groups in five and eight women, respectively. There were no clinically adverse hormonal or metabolic changes during megestrol acetate or clomiphene citrate treatment periods. Our results provide further evidence that in addition to progestins postmenopausal oestrogen replacement therapy can safely be supplemented with antioestrogen and thereby avoid the bleeding which occurs regularly after progestin withdrawal.

Climacteric↗

PubMed1986

Effects of clomiphene citrate on cytosolic estradiol and progesterone receptor concentrations in secretory endometrium.

Cytosolic estradiol and progesterone receptor concentrations were measured in luteal phase endometrial biopsy samples obtained from 12 anovulatory or oligoovulatory women on clomiphene citrate therapy and from 40 normal control subjects. Clomiphene citrate treatment (250 to 750 mg per cycle) decreased both endometrial estradiol and progesterone receptor concentrations. Estradiol receptor levels were nondetectable in seven tissue samples and progesterone receptor levels in four samples from the 12 subjects given clomiphene citrate compared to nondetectable estradiol receptor concentrations in one tissue sample and progesterone receptor concentrations in two samples from the 40 normal control subjects. In histologically dated endometrium, mean estradiol receptor concentrations on days 20 to 23 and progesterone receptor levels on days to 24 to 27 were lower than the values observed in the comparable dated endometrium of normal ovulatory women. Steroid receptor concentrations correlated negatively with the duration of clomiphene citrate therapy, which implies a time-dependent suppressive effect of clomiphene citrate on measurable cytosolic estradiol and progesterone receptor concentrations during the luteal phase of the cycle.

Adult↗

PubMed1989

Effects of clomiphene citrate on episodic luteinizing hormone secretion throughout the menstrual cycle.

Pituitary luteinizing hormone secretory dynamics (pulse frequency and amplitude) were evaluated in eight normal women administered clomiphene citrate or placebo. After 5 days of treatment clomiphene citrate was found to increase mean luteinizing hormone secretion by increasing the amount of pituitary luteinizing hormone released per pulse. No change in pituitary luteinizing hormone interpulse interval was found in the follicular phase of the cycle, although a faster pulse frequency in the luteal phase was found after clomiphene citrate when compared with placebo. No differences were found in the luteal phase (pulse frequency, amplitude, and mean luteinizing hormone level) after clomiphene citrate versus placebo in the volunteers. These data suggest that the principal mechanism of action of clomiphene citrate is an increase in the concentration of hypothalamic gonadotropin releasing hormone into the hypothalamic-pituitary portal circulation, with a resultant increase in pituitary luteinizing hormone secretion.

Adult↗

PubMed1990

Luteal insufficiency: correlation between endometrial dating and integrated progesterone output in clomiphene citrate-induced cycles.

Midluteal phase endometrium was histologically dated with midcycle luteinizing hormone surge time in 29 cycles from 10 parous women during untreated cycles (control) and treatment with clomiphene citrate 50 mg and 150 mg daily on days 5 through 9. Integrated progesterone output for 7 days after luteinizing hormone surge calculated from the daily plasma progesterone levels was 66.6 +/- 9.8 ng/ml in the control group compared with 117.5 +/- 18.6 ng/ml for clomiphene citrate 50 mg treatment and 152.1 +/- 11 ng/ml for clomiphene citrate 150 mg treatment (p less than or equal to 0.05). Only one cycle (clomiphene citrate 150 mg) had an out-of-phase endometrium and a significantly reduced integrated progesterone output of 28 ng/ml. All other cycles showed synchronous endometrial maturation. We conclude that luteal insufficiency as a result of clomiphene citrate treatment in ovulatory women is infrequent and is more likely to be a result of functional outcome of a relative lack of luteal phase progesterone output.

Adult↗

PubMed1995

The effect of consecutive cycles of clomiphene citrate therapy on endometrial thickness and echo pattern.

OBJECTIVE: To determine whether successive cycles of clomiphene citrate affect endometrial thickness. METHODS: Thirty-four women presenting for treatment of anovulation, oligoovulation, or follicle maturation defects were given the smallest dose of clomiphene citrate necessary to attain a mature follicle. If no pregnancy ensued, the same dose was continued if a follicle 18-24 mm in diameter and a serum estradiol (E2) level greater than 200 pg/mL were achieved. Ethinyl E2 was supplemented for poor cervical mucus only. Endometrial thickness and echo patterns were measured each cycle at peak follicular maturation. RESULTS: There was no difference in mean endometrial thickness during the first six cycles of therapy, nor was there a trend for thickness to increase or decrease with successive cycles with or without the addition of ethinyl E2. There was no change in the distribution of echo patterns with successive cycles of clomiphene citrate. Post-treatment measures of thickness and echo pattern did not differ from baseline pre-treatment values. The homogeneous hyperechogenic pattern was the rarest. Mean serum E2 and progesterone levels at mid-cycle did not change with successive cycles. CONCLUSION: One proposed mechanism for the dichotomy between ovulation and pregnancy rates after clomiphene citrate therapy is that the drug adversely affects the endometrium. If clomiphene citrate does affect implantation adversely, the mechanism does not seem to be related to thinning the endometrium or causing an echo pattern that indicates a poor prognosis. The data also suggest that estrogen supplementation does not influence endometrial thickness and would best be used exclusively for hostile cervical mucus.

Adult↗

PubMed1985

Embryo toxicity of clomiphene citrate on mouse embryos fertilized in vitro and in vivo.

The effect of the ovulatory agent clomiphene citrate on fertilization and early embryogenesis was investigated with the use of in vitro fertilized mouse oocytes. Alterations in early embryogenesis with clomiphene citrate exposure were further studied with the use of embryos obtained from mouse oocytes fertilized in vivo. In the nontreated group, the fertilization rate was 81%, and 61% of the oocytes reached the blastocyst stage by 96 hours. Both fertilization and blastocyst formation declined in a dose-dependent fashion when clomiphene citrate was added to the culture media in concentrations greater than or equal to 10 micrograms/ml (p less than 0.001). The rate of progressive embryo cleavage was also slower at 48 and 72 hours after drug exposure. Mouse embryos fertilized in vivo demonstrated similar findings, with decreased blastocyst formation and increased degeneration rates, again at clomiphene citrate concentrations greater than or equal to 10 micrograms/ml (p less than 0.01). Exposure to the drug beyond 24 hours had no additional effect. It appears that clomiphene citrate-exposed embryos may undergo subtle changes that later manifest themselves in the form of decreased embryo growth rates and increased embryo degeneration rates.

Animals↗

PubMed1999

Localization and expression of oxytocin receptor and its messenger ribonucleic acid in peri-implantation phase human endometrium during control and clomiphene-treated cycles.

OBJECTIVES: This study was undertaken to determine expression levels of oxytocin receptor and its gene in peri-implantation phase human endometrium during clomiphene-treated cycles compared with control cycles. STUDY DESIGN: Oxytocin receptor and its messenger ribonucleic acid in peri-implantation phase endometrium during control and clomiphene-treated (50 mg days 5 to 9) cycles of 5 healthy fertile women were determined by immunohistochemical methods, Western blot analysis with monoclonal antibody against amino acids 20 through 40 of the extracellular N-terminal human oxytocin receptor, and reverse transcription-polymerase chain reaction with oligonucleotide primers to amplify the 391-base pair fragment of the oxytocin receptor gene. RESULTS: Oxytocin receptor and its messenger ribonucleic acid were expressed in human peri-implantation phase endometrial samples from both control and clomiphene-treated cycles. The receptor was localized predominantly in the epithelial cells and glands, with little or none detected in the stroma. Oxytocin receptor protein was separated out as a single 70-kd band by Western blot analysis; its relative abundance was significantly reduced during clomiphene-treated cycles. The messenger ribonucleic acid was detected in all endometrium during control and clomiphene-treated cycles, with greater expression during control cycles. CONCLUSIONS: The expressions of oxytocin receptor and its gene in luteal phase human endometrium suggest a functional relevance in modulation of biochemical changes for implantation.

Adult↗

PubMed1986

DNA breakage of human leukemia cells by clomiphene, an ovulation-inducing agent.

When HPB-ALL, human lymphoblastic leukemia cells were treated with clomiphene citrate, an ovulation-inducing agent, poly(ADP-ribose) synthesizing activity of the cells increased up to 4 fold. This stimulatory effect was almost comparable to that of bleomycin, a typical DNA strand breaking agent. Since the agents causing DNA breakage stimulate poly(ADP-ribose) synthesis in cells [Berger, N. A., Sikorski, G. W., Petzold, S. J., and Kurohara, K. K. J. Clin. Invest. 63, 1164-1171 (1979)], clomiphene citrate is suggested to damage DNA of the cells. In fact, an increase of single strand breakage of the DNA was detected by using alkaline sucrose density gradient centrifugation when the HPB-ALL cells were treated with increasing concentration of clomiphene. The inhibition of the cell growth by clomiphene citrate (IC50 = 5 micrograms/ml) appeared to be ascribable to its potent DNA-damaging effect. Although bleomycin activated purified poly(ADP-ribose) synthetase by cleaving covalently closed circular plasmid pBR322 DNA in vitro, clomiphene citrate per se did not.

Bleomycin↗