Clomiphene

There is little information on serum aminotransferase levels during clomiphene therapy which is typically given in low doses for a short time only. There have been a few reports of mild serum enzyme elevations in patients taking clomiphene, but no convincing instances of idiosyncratic, clinically apparent liver injury with its use.

Some reported adverse effects from using clomiphene include headache, dizziness, exacerbation of psychiatric illnesses, gynecomastia, testicular tumor, vasomotor flushing, gastrointestinal disturbance, and mastalgia. Other common adverse reactions are nausea, vomiting, ovarian enlargement, blurred vision, scintillating scotoma, abnormal uterine bleeding, pelvic pain, and hypertriglyceridemia. Some serious reactions to the use of clomiphene are multiple pregnancies, thrombocytopenia, pancreatitis, risk of ovarian cancer after prolonged use, increased risk of malignant melanoma, severe visual disturbance, and hepatic damage.

There are no reported toxic effects after the acute use of clomiphene citrate. The signs and symptoms of clomiphene citrate therapy overdose include nausea, vomiting, visual disturbance, vasomotor flushes, scotoma, ovarian enlargement, and pelvic and abdominal pain. Clomiphene is also nephrotoxic after prolonged use.

Clomifene has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stumulate the release of gonadotropins, follicle-stimulating hormone (FSH), and leuteinizing hormone (LH), which leads to the development and maturation of ovarian follicle, ovulation, and subsequent development and function of the coprus luteum, thus resulting in pregnancy. Gonadotropin release may result from direct stimulation of the hypothalamic-pituitary axis or from a decreased inhibitory influence of estrogens on the hypothalamic-pituitary axis by competing with the endogenous estrogens of the uterus, pituitary, or hypothalamus. Clomifene has no apparent progestational, androgenic, or antrandrogenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.

...REPORTED A CASE OF GRANULOSA-CELL TUMOR OF THE OVARY IN A 28-YR OLD FEMALE WHO HAD RECEIVED CLOMIPHENE CITRATE THERAPY FOR TWO CYCLES (2 FIVE-DAY COURSES OF 100 MG PER DAY). TWO CASES OF BILATERAL BREAST CANCER WERE REPORTED IN WOMEN AGED 28 AND 29 WHO HAD RECEIVED SUCH THERAPY. MOLAR PREGNANCIES HAVE BEEN OBSERVED FOLLOWING INDUCTION OF OVULATION BY CLOMIPHENE CITRATE...AND RAPID ENLARGEMENT OF UTERINE FIBROIDS HAS ALSO BEEN REPORTED. /CLOMIPHENE CITRATE/

A 28-YEAR OLD MALE WHO HAD RECEIVED 1 MG 'CISCLOMIPHENE CITRATE' (ENCLOMIPHENE, THE TRANS ISOMER) DAILY FOR 10 WK DEVELOPED A GERM-CELL TUMOR WITH ELEMENTS OF SEMINOMA AND MATURE ADULT TERATOMA. /TRANS- ISOMER OF CLOMIPHENE CITRATE/

REPORTED IS A CASE OF BILATERAL OVARIAN DYSPLASIA WITH ONE LARGE OVARIAN CYST IN AN INFANT WHOSE MOTHER WAS GIVEN CLOMIPHENE IMMEDIATELY BEFORE CONCEPTION. IT WAS CONCLUDED THAT TRANSPLACENTAL PASSAGE OF CLOMIPHENE COULD BE ASSOCIATED WITH CYSTIC DYSPLASIA OF THE OVARIES IN THE NEWBORN.

In a study of fifty-eight patients taking clomiphene citrate, four developed visual symptoms of phosphenes, consisting of episodes of flashing lights, or complaints of blurred vision, and two of these patients were found to have reduced visual acuity with central scotomas. In one of these patients the scotomas disappeared while the drug was still being administered. In the other patient the scotomas disappeared when the drug was stopped and reappeared when it was readministered. /Chlomiphene citrate/

For more Human Toxicity Excerpts (Complete) data for CLOMIPHENE (12 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

clomiphene

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

ALTHOUGH THERE IS NO EVIDENCE THAT THE INCIDENCE OF FETAL ANOMALIES IS INCR CLINICALLY, ABERRATIONS HAVE BEEN OBSERVED IN OFFSPRING OF SOME SUBPRIMATE ANIMALS GIVEN CLOMIPHENE DURING PREGNANCY. /CLOMIPHENE CITRATE/

IN RATS GIVEN 40 MG/KG PER DAY GROSSLY VISIBLE OPACITIES WERE REPORTED IN LENSES OF 4 OUT OF 29 ANIMALS BETWEEN 35 & 53 WK OF TREATMENT.

IN DOGS RECEIVING 40 MG/KG PER DAY FOR 53 WK NO OPACITIES WERE OBSERVABLE OPHTHALMOSCOPICALLY IN MEDIA, BUT BY SLIT-LAMP VERY MINUTE OPACITIES OF QUESTIONABLE SIGNIFICANCE WERE SEEN IN SMALL PROPORTION OF EYES. IN ONE DOG "BILATERAL RETINITIS" BELIEVED TO BE DUE TO INCIDENTAL INFECTION RATHER THAN TEST DRUG...

CLOMIPHENE INTERFERES WITH INTERNAL MILIEU OF ENDOMETRIUM WITHOUT DAMAGING BLASTOCYST...& ALSO PREVENTS IMPLANTATION IN MOUSE, RAT, & DOG...

For more Non-Human Toxicity Excerpts (Complete) data for CLOMIPHENE (15 total), please visit the HSDB record page.

Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) evidence in animals: inadequate. Overall summary evaluation of carcinogenic risk to humans is Group 3: The agent is not classifiable as to its carcinogenicity to humans.

The acute oral LD₅₀ of clomifene is 1700 mg/kg in mice and 5750 mg/kg in rats. The toxic dose in humans is not known. Toxic effects accompanying acute overdosage of clomifene have not been reported. Signs and symptoms of overdosage as a result of the use of more than the recommended dose during clomifene therapy include nausea, vomiting, vasomotor flushes, visual blurring, spots or flashes, scotomata, ovarian enlargement with pelvic or abdominal pain.

Hepatic

INCUBATION OF THE NONSTEROIDAL ANTIESTROGEN CLOMIPHENE WITH RAT LIVER MICROSOMES RESULTED IN THE FORMATION OF THE 4-HYDROXY-, N-DESETHYL-, & N-OXIDE METABOLITES, IN QUALITATIVE CONTRAST TO RESULTS PREVIOUSLY OBTAINED ANALOGOUSLY WITH RABBIT MICROSOMES IN WHICH ONLY THE FIRST 2 METABOLITES WERE DETECTED. ORAL ADMIN OF CLOMIPHENE RESULTED IN NO DETECTABLE URINARY ELIMINATION OF THE DRUG OR ITS METABOLITES. 4-HYDROXYCLOMIPHENE WAS THE SOLE DETECTABLE ELIMINATION PRODUCT IN FECAL EXTRACTIONS.

Hepatic

1HRS458QU2

CLOMIPHENE

Established Pharmacologic Class [EPC] - Estrogen Agonist/Antagonist

Mechanisms of Action [MoA] - Selective Estrogen Receptor Modulators

Clomiphene is an Estrogen Agonist/Antagonist. The mechanism of action of clomiphene is as a Selective Estrogen Receptor Modulator.

Compounds which inhibit or antagonize the action or biosynthesis of estrogenic compounds.

Compounds which increase the capacity to conceive in females.

A structurally diverse group of compounds distinguished from ESTROGENS by their ability to bind and activate ESTROGEN RECEPTORS but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the ENDOMETRIUM or second generation based on their patterns of tissue specificity. (Horm Res 1997;48:155-63)

Based on early studies with 14 C-labeled clomifene, the drug was shown to be readily absorbed orally in humans.

Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.

SC DOSE OF (14)C CLOMIPHENE CITRATE...WAS DISTRIBUTED IN TISSUES OF FEMALE GUINEA PIG NEONATES... ESTROGENIC-RESPONSIVE TISSUES SHOWED HIGH AFFINITY FOR (14)C. LEVELS OF (14)C...CONSTANT IN UTERUS...THOSE IN OVARIES & PLASMA DECLINED...IN ADRENALS INCR. /CLOMIPHENE CITRATE/

ABOUT ONE-HALF OF THE INGESTED DOSE IS EXCRETED IN FIVE DAYS; TRACES APPEAR IN THE FECES UP TO SIX WEEKS AFTER ADMIN. /CLOMIPHENE CITRATE/

Clomiphene is well absorbed following oral administration. The drug and its metabolites are eliminated primarily in the feces and to a lesser extent in the urine. The rather long plasma half-life (approximately 5 to 7 days) is due largely to plasma protein binding, enterophepatic circulation, and accumulation in fatty tissues. Active metabolites with long half-lives also may be produced.