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PubMed1972

Effect on reproductive organs of three clomiphene analogues.

1. The oestrogenic properties of four triphenylethylene compounds were compared. They can be listed as follows in order of their oestrogenic potency: 1-[p-(beta-diethylaminoethoxy)-phenyl]-2-nitro-1,2-diphenylethylene (E.I.P.W. 111) > clomiphene > 1-[p-(beta-dimethylaminoethoxy)-phenyl]-2-nitro-1, 2-diphenylethylene (E.I.P.W. 113)> 1-[p-(beta-diethylaminoethoxy)-phenyl]-1,2-diphenylethylene (E.I.P.W. 103). The oestrogenic potency of compound E.I.P.W. 111 was found to be about 1/10th of that of oestradiol.2. Compound E.I.P.W. 111 is partially antioestrogenic but not progesteronic in nature. It has no androgenic effect.

Animals↗
PubMed1978

Differential depletion of cytoplasmic high affinity oestrogen receptors after the in vivo administration of the antioestrogens, clomiphene, MER-25 and tamoxifen.

1 The in vivo actions of the oestrogen antagonists, MER-25 and tamoxifen upon the cytosol oestrogen receptors prepared from amygdala, hypothalamus, pituitary and uterus of rats were studied 24 h after drug administration. 2 There was a dose-related depletion of cytosol oestrogen receptors. However, the uterine and pituitary receptors were consistently affected at a lower dose than were those from the brain. 3 The ratios of the combined central ED50 to the combined peripheral ED50 were clomiphene 169 greater than MER-25 19.2 greater than tamoxifen 2.13. 4 The receptor changes were not related to biological activity monitored by serum luteinizing hormone levels and uterotrophic response. 5 The possible role of these drug effects in the induction of ovulation and future developments are discussed.

Animals↗
PubMed1982

The outcome of pregnancy resulting from clomiphene-induced ovulation.

The outcome of pregnancy was studied in all women conceiving after ovulation induction with clomiphene at the gynaecological endocrine clinics operating in 2 Tasmanian cities. In 156 pregnancies where details were available, the main findings were: abortion rate 10.3%; multiple pregnancy rate 4.1%; congenital abnormality rate 3.6%; and perinatal mortality rate 3.5%. The results are compared with other reported series.

Abnormalities, Drug-Induced↗
PubMed1990

Hormonal changes related to impairment of cervical mucus in cycles stimulated by clomiphene citrate.

The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), 17-oestradiol (E2), progesterone (P), and testosterone (T) were determined for the early, midfollicular and periovulatory phase of spontaneous and clomiphene citrate (CC) induced cycles in 5 patients who responded with appearance of hostile cervical mucus (Group A) and 5 patients whose cervical mucus remained unchanged during the same treatment (Group B). The patients with hostile mucus were further investigated during a third cycle stimulated by CC and ethinyloestradiol (EE). Patients treated with CC for induction of ovulation who developed hostile cervical mucus showed higher levels of LH and T in the midfollicular phase of the menstrual cycle and significantly higher levels of T in the periovulatory period compared to patients with unchanged mucus. EE treatment induced a drop in the elevated LH and T levels and improved the cervical score. No change in E2 levels was noted. A direct effect of EE on the cervical glands together with the centrally mediated lowering of serum T are suggested to be responsible for improving the cervical mucus.

Cervix Mucus↗
PubMed2004

Case series of a single centre's treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination in 2002.

The present paper reports a single department's retrospective case series of all clomiphene citrate (CC) combined with intrauterine insemination (IUI) treatment cycles for ovulatory infertility performed during 2002. Thirty-eight couples with unexplained, endometriosis, male or unilateral tubal factor infertility had undergone 71 cycles of CC and IUI. The clinical and ongoing cycle pregnancy rates were 20 and 17%, respectively. Seven percent of the clinical pregnancies were multiple pregnancies, with all multiple pregnancies being twin gestations. The current use of CC and IUI is an effective early treatment option in couples with ovulatory infertility presenting to our department.

Adult↗
PubMed2005

Clomiphene citrate as a new treatment for SUNCT: hormonal manipulation for hypothalamic-influenced trigeminal autonomic cephalalgias.

We present a patient with treatment refractory short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) who was found to have low levels of serum testosterone supporting the hypothalamic connection to this trigeminal autonomic cephalalgia. Clomiphene citrate therapy induced a significant elevation of testosterone levels (by its effect on hypothalamic estrogen receptors) and led to a dramatic reduction in SUNCT attacks. Hormonal manipulation may be a treatment strategy for hypothalamic-influenced trigeminal autonomic cephalalgias.

Autonomic Nervous System Diseases↗
PubMedDate not supplied

Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.

We have investigated the comparative effects of estradiol benzoate (EB), the antiestrogen clomiphene citrate (CC), and the progestin medroxyprogesterone acetate (MPA) on seizures induced by systemic injection of kainic acid (15 mg/kg i.p.) in male and female rats. Subcutaneous administration for 10 days of EB (10 micrograms/kg) or high doses of CC (50 mg/kg) significantly potentiated kainate-induced seizures, with this effect being more pronounced in male animals. Doses of 2.5 mg/kg of CC potentiated kainate-induced seizures in male rats but were ineffective in female rats. Low doses of CC (0.5 mg/kg) exhibited a mild anticonvulsant effect in both sexes. Repeated administration of MPA (2.5 mg/kg) partially protected female animals against kainate-induced seizures; in male animals, MPA induced a 30% increase in the seizure severity score, although the difference from the score of control male rats was not significant. These data suggest that sex steroids influence kainate-induced seizures in a sex-dependent manner and that the effects of the antiestrogen CC are dose dependent. This should be taken into account in view of a possible use of CC and MPA in hormonal therapy for seizure disorders.

Animals↗
PubMed1985

Effect of clomiphene on the functional morphology of oviductal and uterine mucosa.

The effect of clomiphene on the functional morphology of the uterine and oviductal mucosa was studied in rabbits by means of light and electron microscopy (SEM and TEM). Tissues were obtained from mature nulliparous animals receiving subcutaneous doses ranging from 0.01-10 mg/kg per day. In all cases the effects were evaluated 2 days after termination of treatment. With 2 and 10 mg, effects were studied up to 12 and 7 days, respectively. Normally appearing oviductal and endometrial tissues, corresponding to various stages of the cycle, were observed with doses up to 5 mg. However, a burst of cellular secretory activity becomes evident with the administration of higher doses. Apical protrusions or cytoplasmic portions seem to be extruded, and draw attention. These cytologic events are concentrated near gland openings in the endometrium and can be seen abundantly among cilia of oviductal cells. Other ultrastructural changes are evident as well. These histologic changes may reflect nonsynchronous cellular activities which in turn interfere with oviductal and endometrial functions before implantation.

Animals↗
PubMed2003

Catamenial haemoptysis and clomiphene citrate therapy.

Case reports of catamenial haemoptysis are uncommon. We report the first case of thoracic endometriosis associated with clomiphene citrate therapy and previously unpublished endobronchial and angiographic findings.

Adult↗
PubMed1981

Disparate effect of clomiphene and tamoxifen on pituitary gonadotropin release in vitro.

The direct effects of clomiphene citrate (Clomid), tamoxifen, and estradiol (E2) on the gonadotropin-releasing hormone (GnRH)-stimulated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in cultured anterior pituitary cells obtained from adult ovariectomized rats. Treatment of pituitary cells with Clomid or enclomid (10(-8) M) in vitro for 2 days resulted in a marked sensitization of the gonadotroph to GnRH as reflected by a 6.5-fold decrease in the ED50 of GnRH in terms of LH release from 2.2 x 10(-9) M in untreated cells to 3.6 x 10(-10) M. Treatment with E2 or Clomid also increased the sensitivity of the gonadotroph to GnRH in terms of FSH release by 4.3- and 3.3-fold respectively. Tamoxifen, a related antiestrogen, comparable to Clomid in terms of its ability to compete with E2 for pituitary estrogen receptors, was without effect on the GnRH-stimulated LH release at a concentration of 10(-7) M. Furthermore, tamoxifen, unlike Clomid, caused an apparent but not statistically significant inhibition of the sensitizing effect of E2 on the GnRH-stimulated release of LH. Our findings suggest that Clomid and its Enclomid isomer, unlike tamoxifen, exert a direct estrogenic rather than an antiestrogenic effect on cultured pituitary cells by enhancing the GnRH-stimulated release of gonadotropin.

Animals↗
PubMed1999

Endometrial development was improved by transdermal estradiol in patients treated with clomiphene citrate.

The objective of this study was to examine the effect of transdermal estrogen therapy on the endometrial thickness and serum hormone levels in anovulatory patients treated with clomiphene citrate (CC). There was a significant difference in endometrial thickness between the CC + transdermal estrogen group and the CC only group from day -2 to day +2. Serum estradiol (E2) levels in the CC + transdermal estrogen group were significantly higher than those in the CC only group on day -2 and day 0. Our results support that addition of transdermal E2 to the treatment protocol of the women treated with CC elicited a favorable response of the endometrium.

Administration, Cutaneous↗
PubMed2001

Low dose of ethinyl estradiol can reverse the antiestrogenic effects of clomiphene citrate on endometrium.

Fifty healthy, voluntary patients aged between 20 and 30 years with regular menstruation and plasmatic progesterone level >10 ng/ml at the midluteal phase have been enrolled in this study. They were randomly treated with clomiphene citrate (CC; group A) or CC + ethinyl estradiol (0.05 mg group B, or 0.02 mg group C). We estimated the difference in uterine artery pulsatily index, endometrial thickness and histological dating and morphometric analysis of endometrium. No significant differences in Pulsatility Index values and in the number of preovulatory follicles were noted. The difference between endometrial thickness, histological dating and morphometric analysis of the endometrium were statistically different between groups B and C vs. A. Our study shows that CC has a deleterious effect on endometrium maturity and that adding ethinyl-E(2) produces a favorable endometrial response even with very low doses.

Adult↗
PubMed2005

Obesity and Clomiphene Challenge Test as predictors of outcome of in vitro fertilization and intracytoplasmic sperm injection.

One hundred and sixty-two consecutive patients undergoing in vitro fertilization (IVF) or IVF/intracytoplasmic sperm injection (ICSI) were studied to determine the effect of obesity on the outcome of this treatment and to evaluate the prognostic value of the Clomiphene Challenge Test (CCT) in controlled ovarian hyperstimulation. In this prospective clinical study, we assessed the mean number of stimulation days, the mean gonadotropin level/day, cancellation rate, the mean thickness of the endometrium, the mean number of oocytes retrieved, the fertilization rate, the clinical pregnancy rate/embryo transfer and the abortion rate. Obese women had a doubled risk of cancellation due to poor response, although this was not statistically significant. Furthermore, they showed up to 45% lower fertilization rates compared to women of normal weight. The CCT was a good predictor of IVF and IVF/ICSI outcome. Women with an abnormal CCT needed more days of stimulation and higher doses of gonadotropins to reach an adequate stimulation, but still overall results were less than in women with a normal CCT. We conclude that obesity negatively affects IVF and IVF/ICSI outcome, and that CCT is a useful prognosticator of response to ovarian stimulation. Obese patients show a tendency to experience more cancellation due to poor response and lower fertilization rates. Obese women should be counseled on their possible poor performance in IVF and IVF/ICSI programs.

Adult↗
PubMed2005

Effect of clomiphene citrate on ovarian, endometrial, and cervical histologies in a rat model.

OBJECTIVE: To examine the effect of clomiphene citrate (CC) on the ovarian, endometrial, and cervical histologies in a rat model. METHODS: The rats (n = 40) were randomly assigned to 4 treatment groups: CC 50 (repetitive doses of 0.2 mg CC); CC 100 (repetitive doses of 0.4 mg CC); CC 200 (repetitive doses of 0.8 mg CC), and control (repetitive doses of normal saline). Each study group received its CC dose intraperitoneally in 2 ml saline for 5 days and the controls received 2 ml saline only. Each treatment cycle was repeated six times. Six months later the rats were euthanized. Their ovaries, uterine horns, and cervices were removed and examined for histologic changes. RESULTS: We found no significant difference in the number of follicles and corpora lutea of the study groups (p > 0.05). The numbers of granulosa, theca, and luteal cells of the CC 100 and CC 200 groups were significantly higher than those of the CC 50 group and controls (p < 0.05). There was no important finding related to pre-malign and malign changes in ovarian, endometrial and cervical samples of the control and CC 50 groups. Focal atypia and atypical mitoses were noted in 2 cases of granulosa cells in the CC 100 and CC 200 groups. CONCLUSION: We did not find an association between the use of CC and ovarian, endometrial, and cervical neoplasms; nevertheless, we noticed an increase in granulosa, theca and luteal cells with high doses of CC, which may be a risk factor for granulosa, theca, and luteal cell tumors.

Animals↗
PubMed2006

In vivo evaluation of the genotoxic effects of clomiphene citrate on rat reticulocytes: a micronucleus genotoxicity.

OBJECTIVE: To determine the genotoxic effects of clomiphene citrate (CC) on rat reticulocytesin vivo. METHODS: In this prospective, randomized, controlled study, rats were each assigned randomly to the CC 50, CC 100, CC 200, or control group and were given repeat doses of 0.16, 0.32 or 0.64 mg CC, or normal saline, respectively. Each study group received its CC dose in 2 ml of saline intraperitoneally for 5 days, while the control group received only 2 ml of saline. Each treatment cycle was repeated six times. Six months later, the rats were euthanized. Bone marrow tissues were removed, and pluripotent reticulocyte cells with micronuclei, nuclear buds, and binuclear abnormalities were analyzed using an in situmicronuclei assay under light microscopy. The proportion of micronucleated erythrocytes was measured. RESULTS: Fewer cells with nuclear buds and binuclear abnormalities were detected in the CC 50 group and controls. The CC 100 and 200 groups had significantly (p < 0.05) more nuclear buds and binuclear abnormalities compared with the CC 50 group and controls in the cytogenetic analysis of bone marrow stem cells. CONCLUSION: In rats, the micronucleus genotoxicity assay suggests a dose-dependent CC effect on genomic instability in bone marrow stem cells in vivo.

Animals↗
PubMed1992

Clomiphene citrate alters vaginal surface morphology in cycling rats.

Cycling virgin female rats were treated with clomiphene citrate (CC) during dioestrus of the reproductive cycle. Animals were sacrificed 2 days after the initial injection and their vaginal tissue was examined by scanning electron microscopy. Animals treated with one dose of CC had an epithelium consistent with a prolonged dioestrus. Treatment with CC for 2 days induced changes in the epithelium that had no resemblance to any normal hormonally controlled event in the vagina. It was found that CC had effects consistent with progesterone alone as well as effects unique to this superovulatory drug.

Animals↗
PubMed1993

Effects of clomiphene citrate on vaginal epithelium of ovariectomised rats.

Scanning electron microscopy and light microscopy have been used to study changes to the vaginal epithelium induced by exogenous hormones and clomiphene citrate (CC) administered to ovariectomised rats. Oestrogen (E2) administration resulted in epithelial cell proliferation and keratinisation. The administration of the E2/anti-E2 CC also resulted in the stimulation of cell proliferation, but not to the extent produced by E2. Lack of keratinisation, a decreased number of epithelial layers and decreased epithelial height were viewed as non-oestrogenic, or retarded oestrogenic, effects of CC. Modifications to the surface of vaginal luminal cells were also apparent following CC treatment. Cell apices were raised and separated by prominent borders; the surface covering consisted of short bulb-tipped microvilli that clumped together to form rosettes. Individual, elongated microvilli were also evident. The results of this study indicate that CC has retarded oestrogenic actions, as well as a unique ability to alter cell and surface morphology to produce characteristics dissimilar to those seen after treatment with E2 and progesterone.

Animals↗