Clomiphene Citrate

What is Clomiphene Citrate

Clomiphene Citrate is a fertility agent that is used to induce ovulation in women who do not ovulate periodically and anovulatory women. This includes patients with a polycystic ovulatory syndrome. This medication is very effective in producing ovulation in women who have ovaries that do not function normally, but they should have an intact hypothalamic –pituitary-ovarian axis. Clomiphene is usually prescribed as a first line medication for women suffering from infertility because, apart from its low economic expenses, it induces ovulation in more than 80% of the chosen patients and roughly 40% of them become pregnant within the first six cycles of the treatment.

Clomiphene Structure

Clomiphene Structure

Clomiphene should not be used to increase the rates of ovulation in women who ovulate normally and on a regular cycle. This therapy is associated with slightly higher rates of multiple conceptions which can be by up to 35% of the normal rates. If multiple gestations occur, twins are more likely to be born than triplets or more. Clomiphene exhibits a much lower rate of multiparity when compared to other fertility agents like menotropins and Follicle Stimulating Hormones. In some cases, Clomiphene is usually used as a diagnostic tool to assess a woman’s ovarian reserve and it can also be administered as an effort towards regulating the timing of ovulation in patients receiving donor insemination. To many people’s interest, clomiphene can be used to increase the sperm count in male patients suffering from oligospermia. Clomiphene was approved for clinical use by the FDA in 1976.

Clomiphene’s Mechanism of Action

Clomiphene is classified as a selective estrogen receptor modulator because it has the ability to compete with estradiol for estrogen receptors at the hypothalamus levels. Clomiphene blocks a negative feedback of circulating estradiol in the hypothalamus, which prevents estrogen from reducing the output of the gonadotropin-releasing hormones. During a therapy with clomiphene, the amplitude, and frequency of the GNRH increases which stimulates the pituitary glands to secrete more follicle stimulating hormones and Luteinizing hormones. These hormones then stimulate the ovaries to develop oocyte follicles. Clomiphene may facilitate the development of multiple oocytes to maturity in some patients. The estrogen produced by these follicles leads to the thinning of the cervical mucus and the proliferation of the endometrium. As the levels of estradiol produced by the follicles rise, a positive feedback is facilitated which causes a surge of the LH and the FSH which is followed by the release of mature oocytes/ovulation. Once ovulation occurs, a corpus lutetium forms and the levels of progesterone rise just as they should in a normal ovulatory cycle. The traditional timing of administering this medication is from the follicular phase cycle of day 5 through to day 9. Women are expected to ovulate after 510 days of the final dosage of a cycle, nevertheless, an earlier initiation of treatment and longer courses of up to 10 days or higher doses may be required as per the ovulatory response of an individual.

Clomiphene Structure

Clomiphene Structure

 

Clomiphene is a weak estrogen antagonist which may interact with tissues containing estrogen receptors. These include; the ovaries, the vagina, cervix, and the endometrium. In the cervix, it can interfere with the ability of the cervical mucus glands to produce thin secretions that can favor conception and sperm motility. In some women, this medication can induce the secretion of thick cervical discharges. Studies are being carried out to find out how clomiphene affects breast tissues. On the other hand, it exhibits no anti-androgenic properties, progestational effects, and androgenic effects and it does not affect the normal functioning of the pituitary-adrenal system and the pituitary-thyroid systems.

When a medication using clomiphene is discontinued, its pharmacological effect on the menstrual cycles is also diminished. In some women, spontaneous ovulation can continue.

In a number of selected female patients, clomiphene therapy had to be supported and combined with other drugs so that it could realize the best results and successful outcomes. These medications include; dexamethasone for hyperandrogenism or hirsutism, estradiol to offset the effects od clomiphene on cervical mucus, the human chronic gonadotropin to induce an LH surge to facilitate ovulation and Metformin/Troglitazone to offset the hyperinsulinemia that occurs in patients with polycystic injuries. Octreotide can also be used in combination with clomiphene in these patients because together, they can effectively reduce the secretion of androgens, decrease the levels of the luteinizing hormones and potentially reduce the incidences of ovarian hyperstimulation. All these drugs have mechanisms of action that are different from clomiphene and they do not alter the pharmacokinetics of this medication. The use of these augmenting medications requires careful monitoring and good timing. The administrations should be conducted by a qualified and experienced fertility and endocrinology physician.

Clomiphene can be used to stimulate the release of the sperms in men with a condition of idiopathic oligospermia. It acts by stimulating the hypothalamus to release the GNRH which increases the levels of the LH and the FSH in the serum. These hormones then stimulate the testes to produce testosterone and sperms. This medication can be used to increase the density of sperms but it does not increase sperm maturation or motility.

The Pharmacokinetics of Clomiphene

Clomiphene should be administered orally and because it is a combination of racemic isomers, zuclomifene, and enclomiphene which may have different pharmacokinetics, its specific pharmacokinetics has not been established, but Zuclomiphene is presumed to be the more estrogenic isomer. The point of metabolism of this medication has not also been clearly defined but it seems to undergo hepatic metabolism. After that, its metabolites and its unchanged form are excreted in the feces via the bile. Stereospecific enterohepatic recycling appears to occur with zuclomifene and it accumulates in the body after several cycles of treatment. However, maximum plasma levels never seem to surpass 100mmol/L even with continued cycles of treatment. Clomiphene has a half life of 5 days but some studies have demonstrated that it can be found in feces even after 6 weeks.

Indications for Clomiphene

Clomiphene citrate is prescribed as an option for increasing a woman’s chances of getting pregnant by increasing her ability to produce mature eggs during a menstrual cycle. Its functions are to inhibit the effects of estrogen and to increase its production. In men, this drug can be used as a partial antiestrogen and it can also be used to counter the side effects of aromatizing steroids. These include excessive water retention and gynecomastia. As an antiestrogenic medication, it can be used to facilitate an increased production of the LH and the FSH, which in turn elevated the production of sperms and testosterone.

Contraindications and precautions when using Clomiphene

Your health care provider should be informed if you are suffering from the following health conditions. Blood clots, blood vessel disease, adrenal gland disease, liver disease, ovarian cysts, ovarian cancer, pituitary gland disease, endometriosis, vaginal bleeding that has not been diagnosed and allergic reactions to clomiphene, other medications, dyes, and preservatives. Your healthcare provider should also know if you are pregnant or if you are trying to get a child and if you are breastfeeding.

Clomiphene is only effective at inducing ovulation in women with a normal ovarian function and an intact hypothalamic-pituitary tract. Patients with any untreated pituitary conditions, primary ovarian failure, and thyroid diseases will not respond to treatment using this therapy.

A reduced response to this therapy may occur in females with hirsutism, diabetes mellitus, obesity, hyperinsulinemia and lower levels of endogenous estrogens. In many cases, a combination of clomiphene and other drugs may be necessary to increase the chances of conception.

In men, clomiphene is only effective for the treatment of oligospermia. Men with infertility problems like the primary testicular failure, disruption of hypothalamic-pituitary functions and other associated conditions are not expected to respond to this treatment.

Clomiphene is contraindicated in patients with a dysfunctional uterine/an abnormal uterine bleeding which has not been diagnosed. Before its administration, all possibilities of ovarian carcinomas should be ruled out. This is mainly because clomiphene can stimulate the growth and development of tumors. Clomiphene should be used carefully in patients with fibroids and other associated conditions for the same reason.

Clomiphene is classified under the pregnancy risk category X and it is strongly contraindicated for use once conception has been achieved. There is still inadequate evidence on its effects on a human fetus but animal studies showed adverse fetal effects which include; bowel changes, ocular defects, and congenital structural bladder. Clomiphene does not seem to increase the risks of congenital abnormalities and it cannot be used to induce an abortion. Nevertheless, data suggests that if clomiphene is continued into a pregnancy, teratogenesis can occur.

It is not clear whether clomiphene is excreted over to breast milk but it is advisable to use it with caution or rather avoid using it because of the potential effects that it can have on a fetus. Studies indicate that clomiphene can lactation in women who previously did not want to breastfeed. This mechanism may be due to a reduction in a serum prolactin. If this is experienced by a patient, alternative methods of breastfeeding should be considered but only if the treatment is necessary.

Clomiphene is contraindicated in patients with hepatic dysfunctions and hepatic diseases since it may result in increased risks of some side effects that are associated with these conditions. Additionally, hepatotoxicity can occur in some patients in conjunction with an ovarian hyper-stimulation syndrome. Because of this, normal liver functioning should be established before a treatment using this medicine.

Clomiphene should be used cautiously in patients with psychosis and depression. There is a possibility that it can worsen these conditions. Depression is very common in women who are infertile because they lack some cycles where ovulation should occur.

Clomiphene should also be used cautiously in patients with active thrombophlebitis or other thromboembolic diseases because it exhibits estrogenic characteristics.

Clomiphene should not be taken by people who are driving, performing tasks which require mental alertness and people who operate machinery because it can cause dizziness and blurred vision. In a case of any visual disturbances, contact your healthcare provider immediately.

All patients on this medication should avoid excessive consumption of alcoholic beverages, ethanol intoxication, and tobacco intake. These lifestyle choices can lead to the development of infertility and the effectiveness of fertility drugs.

Interactions of Clomiphene

Androgens can antagonize the effects of fertility treatments. In women, increased levels of prasterone hormones and DHEA have been associated with infertility and hyperandrogenism. It is presumed that a nutritional supplementation of DHEA during a clomiphene treatment can reduce the effectiveness of the medication, so this should be avoided.

Herbal drugs and other alternative therapies for fertility can have various effects on the functions of the hypothalamus and the pituitary. These can affect hormone concentrations which may influence the efficacy of fertility treatments. Some herbs that should be avoided include; chaste tree fruit, chaste berry and vitex agnus castus.

Theoretically, soy isoflavones may compete with drugs that selectively modulate estrogen receptors, so they should be used cautiously in patients undergoing treatment with clomiphene.
Your health care provider should guide you on the adequate methods to ensure the safety and effectiveness of your treatment.

Adverse Reactions and Side Effects of Clomiphene

Clomiphene is associated with increased rates of multiple births. Other side effects that can be experienced by patients on this treatment include; hot flashes, mild pelvic discomfort, mastalgia/breast tenderness, dizziness, fatigue, headaches, nausea/vomiting, abnormal uterine bleeding, bowel pain, menstrual irregularities, diarrhea and weight gain.

Vaginal dryness, enlargement of the ovaries, ovarian hyperstimulation syndrome, and visual impairment are also some possible effects. In some groups, patients can experience skin conditions that are associated with a rash, dermatitis, alopecia, acne, Vulgaris, allergic dermatitis and hypertrichosis.
Adverse symptoms to the central nervous system can include; depression, anxiety, insomnia, restlessness, light-headedness, psychosis, emotional lability, and irritability.

This list may not contain all the possible side effects, so it is very important that you contact your health service provider immediately in case you experience any negative reactions that may include; skin rashes, swelling of the face, dizziness, blue tints on your skin, chest tightness, chest pains, itching and red painful swollen areas on your body.

How is this medication best taken?

This medicine should be administered orally, with a glass of clean water as per the directions on your prescription label or instructions from your physician. You should take this medicine at regular intervals and if you miss a dose, it is advisable to take it as soon as possible but you should never take two doses at a time or at close intervals, if it’s almost time for your next dose, you can skip it. Most women take this medicine for a period of 5 days, but the length of the therapy may be adjusted.

How should this medicine be stored?

This medicine should be stored at room temperature at the range of 15 to 30 degrees Celsius. You should protect it from direct light, heat, and moisture. Keep all medicine from the reach of children and always remember to correctly dispose of any unused medicine after its expiry date.

Conclusion

Clomiphene Citrate is usually indicated for: Increasing the chances of pregnancy by helping women ovulate during their menstrual cycle, it can also Increase the production of testosterone in males by Inhibiting the effects of estrogen in them.

The dosage forms available for Clomiphene Citrate are Tablets and Capsules, Absolute Pharmacy can compound this medication to suit your personal needs. Our drugs are compounded under the stringent USP 795 guidelines. With a process that ensures the potency, consistency, uniformity, and beyond use dating (BUD) of every compound we dispense. For more information on this medication and its administration, feel free to contact us.