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PubMed1986

Intranuclear crystalloids in arcuate nucleus neurons after clomiphene citrate administration.

The action of high doses of clomiphene citrate on the nuclei of hypothalamic arcuate neurons of male cats has been studied. Clomiphene produces an accumulation of typical crystalloid material in the nuclei. After administration of a protein-synthesis inhibitor, no such material was observed in clomiphene-treated animals. These ultrastructural features could possibly be due to a more intense protein synthesis in the hypothalamic arcuate neurons.

Animals↗
PubMed1979

Comparison between tamoxifen and clomiphene therapy in women with anovulation.

Forty-eight women with various types of menstrual disorder were treated with tamoxifen: 30 of them ovulated as judged by serum progesterone concentrations and the basal body temperature (BBT) record. Serial determinations of serum FSH, LH, prolactin, and estradiol-17 beta showed that tamoxifen acts primarily on the hypothalamic-pituitary axis. Before or after the tamoxifen treatment cycles, 30 women received clomiphene. The ovulation rate in women with primary and secondary amenorrhea was similar, while women with oligomenorrhea tended to be more responsive to tamoxifen than to clomiphene. There was no difference between the drugs in the duration of the luteal phases nor in the pregnancy rate. The side effects during treatment with clomiphene were pronounced than during tamoxifen therapy.

Adolescent↗
PubMed1995

Ovulation triggering in clomiphene citrate-stimulated cycles: human chorionic gonadotropin versus a gonadotropin releasing hormone agonist.

PURPOSE: To compare the use of human chorionic gonadotropin (hCG) to a gonadotropin releasing hormone (GnRH) agonist, nafarelin, in initiating ovulation and supporting the luteal phase after priming with clomiphene. METHODS: In 26 infertile women 50 mg clomiphene citrate produced a preovulatory-size follicle. Then, 11 women were randomized to receive two 400-micrograms doses of nafarelin intranasally 16 h apart, and 15 women were injected intramuscularly with 5000 IU of hCG (luteal day 0 = LD0). Starting on LD6, 7 more 400-micrograms doses of nafarelin were repeated on an every 16-h schedule or a single 2500 IU dose of hCG was given, respectively. Serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P), and hCG were measured. On LD13, endometrium was evaluated with ultrasonography and biopsy in 19 nonpregnant women. RESULTS: As judged by a threefold rise in serum LH, an LH surge was detected on LD1 in all 11 nafarelin patients, but in only 8 hCG patients (P = 0.01). LH and FSH levels were significantly higher on LD1, 7, and 8 and were significantly suppressed on LD13 in the nafarelin group. All patients had mid-luteal P levels greater than 10 ng/ml and luteal phases longer than 13 days. Significantly different luteal E2 or P levels were noted only on LD13, with lower values in the nafarelin group. Pregnancies were achieved in 3 of 11 nafarelin cycles and 2 of 15 hCG cycles. Luteal phase defects were also similar: 4 of 8 nafarelin patients and 7 of 11 hCG patients. CONCLUSION: Nafarelin or hCG in conjunction with clomiphene can result in viable pregnancies, but is associated with low pregnancy rates and a high incidence of luteal phase defects.

Administration, Intranasal↗
PubMed1984

Clomiphene protects against osteoporosis in the mature ovariectomized rat.

Clomiphene citrate, a mixed estrogen agonist-antagonist, protects mature ovariectomized breeder rats from changes in total body calcium and from deterioration of femur structure. Over 6 months, mature ovariectomized rats took up calcium at the rate of 0.7 +/- 0.5 mg/day, while normal controls gained 2.5 +/- 0.7 mg/day (mean +/- SEM) as measured by whole body neutron activation analysis. Injections of clomiphene (20 mg/kg/week) kept ovariectomized rats in positive calcium balance at 2.0 +/- 0.5 mg/day. Reductions in total femur calcium content, cortical thickness, and visible trabeculae of femurs in ovariectomized animals were prevented by chronic clomiphene administration. These results in animals suggest a possible new line of investigation of the use of antiestrogenic drugs as therapeutic agents for hormone-dependent osteoporosis in animals and humans.

Animals↗
PubMed2002

Simultaneous intrauterine and ovarian pregnancy following treatment with clomiphene citrate.

Heterotopic pregnancy is increasingly being diagnosed since the advent of assisted reproductive technology involving the use of superovulatory drugs and/or in-vitro fertilization and the availability of high-resolution ultrasound scans. There are reports of Heterotopic tubal pregnancies following clomiphene use. Heterotopic ovarian pregnancies are however rare. Clomiphene citrate, which is widely used in the primary care setting to treat anovulatory infertility, is felt safe. We present a case of heterotopic ovarian pregnancy following treatment with clomiphene citrate. The diagnosis and management of heterotopic ovarian pregnancy are also discussed.

Adult↗
PubMed1982

Heterotopic columnar epithelium and adenosis in the vagina of the mouse after neonatal treatment with clomiphene citrate.

Physiologically, the epithelium of the mouse vagina undergoes conversion during early postnatal life from columnar to stratified squamous. A similar process in the human occurs in the late first and early second trimesters of pregnancy. The mouse vagina has been identified as a good developmental model of the human. Previous work in the mouse has shown that this process is affected by neonatal administration of diethylstilbestrol. We have administered diethylstilbestrol and clomiphene citrate to parallel groups of BALB/c neonatal mice. They were followed up to 24 weeks. In both groups, persistent columnar or heterotopic columnar epithelium, not seen in the control mice, was identified and associated with adenosis. This effect of diethylstilbestrol and clomiphene citrate appears to be similar to the biologic response to transplacental diethylstilbestrol in the human. After transplacental diethylstilbestrol, malignant vaginal tumors rarely develop. If clomiphene citrate, given to the human prior to pregnancy to induce ovulation or by inadvertence during pregnancy, were to circulate into the critical time of vaginal differentiation, a similar biologic potential may exist. The first situation seems to be unlikely. The second is of more concern.

Animals↗
PubMed1983

The effect of clomiphene citrate on LH release by dispersed rat anterior pituitary cells.

Preincubation of pituitary cells for 48 hours with estrogen or clomiphene citrate did not enhance LH release of dispersed pituitary cells after incubation for 4 hours without the secretagogues. In the presence of GnRH, estrogen increased release, but neither the racemic mixture of clomiphene nor its two trans and cis isomers had any appreciable effect on LH release. It is concluded that contrary to published reports, clomiphene in the rat pituitary may behave differently from estrogen in its effects on gonadotrphin release by dispersed cells.

Animals↗
PubMed1987

Clomiphene citrate response is predictable in corpus luteum insufficiency.

In order to predict the correct dose of clomiphene citrate in corpus luteum insufficiency, the results of the treatment of 117 patients were evaluated. Serum progesterone and prolactin concentrations were determined by RIA. A 3-fold increase in serum progesterone concentration was found following the 100 mg per day clomiphene citrate treatment, independently of the pretreatment progesterone or prolactin values. This means that in a well-selected, hormonally homogeneous group of patients, contrary to earlier observations, the clomiphene citrate sensitivity of the patients is predictable.

Clomiphene↗
PubMed1990

Pituitary-related weight changes affecting the liver, uterus and adrenal glands of rats treated with hexoestrol and clomiphene in high doses.

The synthetic oestrogen hexoestrol, administered at 60 mg/kg/day for 4 days to female rats in 3 studies, caused the following mean changes in the relative weights of some of the principal organs: liver (+37%), spleen (-11%), adrenals (+43%), kidneys (+3%), pituitary (+23%), uterus (+49%), and ovaries (+13%). The heart weights showed no consistent changes. The mean relative organ weights of hypophysectomized, hexoestrol-treated rats did not differ significantly from those of untreated hypophysectomized controls. The latter animals had lower organ weights than sham-operated controls. Pretreatment with clomiphene citrate at dose levels of 20-60 mg/kg/day prevented in a dose-dependent manner most of the organ weight changes induced by hexoestrol. The exception was the adrenal weight, which was increased. Compared with controls, the mean relative organ weights of rats receiving clomiphene alone at 60 mg/kg/day differed as follows: liver (-18%), spleen (-17%), heart (-16%), adrenals (+7%), kidneys (-11%), pituitary (-13%), uterus (-25%), and ovaries (-4%). The changes affecting the liver, spleen, heart, kidneys and uterus were significant. Rats immunised with a monkey antiserum to rat growth hormone and treated with hexoestrol had significantly lower relative liver weights than did animals treated with hexoestrol alone. No other significant differences were observed. It is tentatively concluded that there is a mediating or co-operative pituitary influence involved in the significant hepatic, uterine and adrenal weight gains caused by hexoestrol. Clomiphene may act centrally to affect these organ weight changes and, indeed, may act at this level to (mainly) anti-organotrophic effect even in the absence of exogenous oestrogen. In the case of the hexoestrol-induced liver enlargement, the role of pituitary growth hormone is worth further investigation.

Adrenal Glands↗
PubMed1995

Ovulation induction with clomiphene citrate complicated by deep vein thrombosis.

A case of recurrent deep vein thrombosis following standard clomiphene citrate treatment, in a patient with a history of a previous episode of deep vein thrombosis, is described. This case indicates that deep vein thrombosis might be a rare but hazardous complication of clomiphene citrate treatment in patients with certain risk factors. We recommend that the use of clomiphene citrate in such cases be undertaken with caution and under close surveillance.

Adult↗
PubMedDate not supplied

The long-term effect of clomiphene citrate on vaginal epithelial differentiation in the mouse.

Clomiphene citrate, administered to the neonatal mouse during cervicovaginal epithelial differentiation, is associated with subsequent adenosis. Similar lack of neonatal transformation of columnar to squamous epithelium occurs after diethylstilbestrol. Mouse neonatally exposed to diethylstilbestrol have a high incidence of reproductive tract tumors in later life. In this study Balb/c neonates were exposed to clomiphene citrate, maintained with controls, and killed at 52, 56, and 60 weeks. Cervicovaginal histology was studied by light microscopy. In all control animals only mature squamous epithelium was seen (44/44). After clomiphene citrate, at 52 weeks, 3/10 animals had other than mature squamous epithelium identified. One of these genital tracts contained adenosis. At 56 weeks only mature squamous epithelium was seen (11/11), and at 60 weeks immature squamous epithelium was identified in 1 of 10 animals. In no study animal (0/31) was there any evidence of tumor development. This differs from the high incidence of reproductive tract tumor seen in the mouse after neonatal diethylstilbestrol exposure.

Animals↗
PubMed1994

Prostaglandin inactivation is increased in endometrium after exposure to clomiphene.

Prostaglandin (PG) dehydrogenase inactivates PGs by oxidising the 15-hydroxyl group and thus plays a key role in controlling their effective local concentrations. This enzyme is thought to be under the control of steroid hormones and is found in human endometrium at high levels in the secretory phase of the menstrual cycle but is absent during the proliferative phase. We have examined the PG dehydrogenase activity in human endometrium from women who had been treated with the anti-oestrogen clomiphene at an earlier stage of the cycle and found high levels of the enzyme in the proliferative phase. This data was supported by the culture of endometrium from clomiphene treated women which showed both high PG production and extensive inactivation comparable to that seen in the secretory phase. This effect of clomiphene on the PG inactivating ability of endometrium could be of clinical use in management of disorders where elevated PGs are present.

Adult↗
PubMed2003

Comparison of the effects of letrozole and clomiphene citrate on ovarian follicles, endometrium, and hormone levels in the rat.

OBJECTIVE: To compare the effects of letrozole and clomiphene citrate in the rat in terms of number of ovarian follicles; endometrial thickness; and serum levels of E2, FSH, LH, and T. DESIGN: Controlled prospective study. SETTING: University research laboratory. ANIMAL(S): Thirty sexually mature female Wistar-Albino rats that were 20 weeks of age. INTERVENTION(S): Letrozole, 5 mg/kg of body weight daily (10 rats); clomiphene citrate, 100 microg/kg daily (10 rats); or saline solution, 2 mL/d (10 rats). After 2 days, rats were euthanized and ovariectomized. MAIN OUTCOME MEASURE(S): Number of mature follicles, endometrial thickness, and serum levels of hormones. RESULT(S): Mean levels of FSH, LH, E2, and T; number of mature follicles; and ovary size differed among the groups, whereas the mean endometrial thickness did not differ. CONCLUSION(S): In rats, the effect of letrozole on follicular maturation is similar to that of clomiphene citrate.

Animals↗
PubMed2003

Laparoscopic evaluation following failure to achieve pregnancy after ovulation induction with clomiphene citrate.

OBJECTIVE: To assess the value of laparoscopic evaluation of the pelvis after failure to achieve pregnancy with clomiphene citrate-induced ovulation and to determine whether predictors for significant pelvic pathology can be isolated. DESIGN: Retrospective study. SETTING: Tertiary care academic medical center. PATIENT(S): Ninety-two patients failing to conceive after four ovulatory cycles with clomiphene citrate with a normal hysterosalpingogram who underwent laparoscopic evaluation of the pelvis. INTERVENTION(S): Laparoscopy. MAIN OUTCOME MEASURE(S): Presence of pelvic pathology and predictors of pelvic disease. RESULT(S): Of the 92 patients studied, 32 patients (34.8%) had a "positive" laparoscopy (i.e., stages III and IV endometriosis, an endometrioma, pelvic adhesions, and/or tubal disease), 27 patients (29.3%) had stage I or II endometriosis, and 30 patients (32.6%) had a normal pelvis. The predictors for intrapelvic disease were a history of dyspareunia, no prior use of oral contraceptive pills, and no prior use of any form of contraception. Almost 40% of women with predictors had a "positive" laparoscopy, compared with only 12.5% of patients without predictors; however, the majority of patients (91.3%) had at least one predictor. CONCLUSION(S): More than one third of the patients failing to conceive after four ovulatory cycles of clomiphene citrate had significant intrapelvic pathology. Although predictors for intrapelvic disease were isolated, their high prevalence reduced their predictive value.

Clomiphene↗
PubMed2005

Twin gestation induced by clomiphene citrate and bromocriptine in both horns of a bicornuate uterus.

OBJECTIVE: To describe a case of twin gestation that occurred in both horns of a bicornuate uterus after the administration of clomiphene citrate and bromocriptine. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Korea. PATIENT(S): A 34-year-old woman presented with secondary infertility and hyperprolactinemia. INTERVENTION(S): Bromocriptine, 2.5 mg/day, was administered immediately, and clomiphene citrate, 150 mg/day, was started from menstruation day 5 for 5 days. MAIN OUTCOME MEASURE(S): The establishment of pregnancy and obstetric outcome. RESULT(S): A nonidentical twin pregnancy occurred but ended in preterm delivery at 24 weeks. One baby has survived for over 3 months. CONCLUSION(S): Twin gestation can occur in both horns of a bicornuate uterus after clomiphene citrate administration.

Adult↗
PubMed2006

Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate.

OBJECTIVE: To review the management of male hypogonadotropic hypogonadism (HH) and evaluate the efficacy of clomiphene citrate (CC). DESIGN: Retrospective review. SETTING: Two university-based urology clinics. PATIENT(S): Ten patients referred for male infertility evaluation. INTERVENTION(S): Patients were treated with either clomiphene citrate or injectable gonadotropins. MAIN OUTCOME MEASURE(S): Changes in seminal parameters, gonadotropin levels, serum testosterone, and pregnancy. RESULT(S): Ten men who were evaluated for infertility were diagnosed with HH. Four had Kallmann's syndrome, four idiopathic HH, and two panhypopituitarism. Eight patients were azoospermic, and two were oligospermic on presentation. Three of the four men with adult-onset idiopathic HH responded to CC alone with increases in testosterone, FSH, and LH. Semen parameters in this group also improved, and two of the three men achieved pregnancies with CC alone. Out of the ten men actively attempting conception, four pregnancies were achieved. Three pregnancies (two with CC and one with gonadotropins) were in men diagnosed with adult-onset idiopathic forms of HH. CONCLUSION(S): Select patients with adult-onset idiopathic forms of HH may benefit from a trial of clomiphene citrate.

Adult↗
PubMed2005

Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of ultra-short (12 days) metformin pretreatment in clomiphene-citrate (CC) resistant polycystic ovary syndrome (PCOS). METHOD: Eighty women with CC-resistant PCOS were randomly allocated to metformin pretreatment or usual treatment. Forty women received 1500 mg metformin daily for 12 days, followed by clomiphene 150 mg daily for 5 days along with metformin. Forty women (control group) received the same dose of clomiphene but no metformin pretreatment. RESULTS: In the metformin group, 17 (42.5%) women ovulated, and 6 (15%) conceived. In the control group, 5 (12.5%) women ovulated but none conceived. Compared with the control group, the metformin group had significantly higher ovulation (P = 0.03) and pregnancy rates (P = 0.026). CONCLUSION: Twelve days of metformin pretreatment improves ovulation and pregnancy rates in women with CC-resistant PCOS.

Adult↗
PubMed1998

Clomiphene analogs with activity in vitro and in vivo against human breast cancer cells.

Six hundred triphenylethylenes were assayed for antiproliferative activity against MCF-7, LY2, and MDA-MB-231 breast cancer cells using sulforhodamine B dye to measure proliferation. Here we report on just 63 of the compounds, mostly clomiphene analogs, with substitutions on the alpha' or beta ring, at the vinyl position or in the side chain, of which 23 were active, as defined by antiproliferation IC50 values < or =1 microM. Activity profiles showed that 23 and 11 analogs were active toward MCF-7 and LY2, respectively, but none were active against MDA-MB-231. The IC50 values of tamoxifen were 2.0 microM against MCF-7 and 7.5 microM against LY2 and MDA-MB-231. Estradiol reversed antiproliferative activities of several E isomers but not their Z isomer counterparts. Clomiphene side chain analogs 46 [(E)-1-butanamine, 4-[4-(2-chloro-1,2-diphenylethenyl) phenoxy]-N,N-diethyl-dihydrogen citrate (MDL 103,323)] and 57 [(E)-N-[p-(2-chloro-1,2-diphenylvinyl) phenyl]-N,N-diethylethylenediamine dihydrogen citrate (MDL 101,986)] were 4- to 5-fold more effective than tamoxifen. Methylene additions up to (-CH2-)12 in the clomiphene side chain showed that analog 46 [(-CH2-)4 side chain] had maximal antiproliferative activity, binding affinity, and inhibition of transcription of an estrogen response element luciferase construct in transfected MCF-7 cells. Intraperitoneal administration of 46 or 57 inhibited progression of MCF-7 breast tumor xenografts in nude mice with ED50 values of <0.02 mg/mouse/day. Both analogs may hold promise for treating ER positive breast cancer and are of interest for further development.

Animals↗