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Clomid, also known as Clomiphene, Clomifene, CC, Clomiphene Citrate, Clomifert, Serophene and Milophene is frequently given to women who are sub-fertile to stimulate ovulation.  Since the 1970s, clomiphene citrate has been considered the gold standard treatment for infertiity, however, its use is associated with several negative outcomes, including low pregnancy rates, multiple gestations, unfavourable cervical mucus, and thinning of the endometrium.

It is a non-steroidal ovulatory stimulant, categorised as a SERM or selective estrogen receptor modulator and oestrogen antagonist (though this effect does depend upon the target tissue).  

Clomid increases the body’s production of gonadotrophins like follicle stimulating hormone (FSH) & luteinising hormone (LH) through inhibiting oestrogen receptors in the hypothalamus, which in turn inhibits negative feedback.

Clomiphene (as Clomid, Serophene etc) is given as 50mg tablets and is well absorbed orally, primarily excreted in the faeces (42%) with some urinary excretion (8%) and a half-life of 5-7 days.

Clomiphene initiates a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The first endocrine event, in response to a course of clomifene therapy, is an increase in the release of pituitary gonadotropins. This initiates steroidogenesis and folliculogenesis resulting in growth of the ovarian follicle and an increase in the circulating level of estradiol. Following ovulation, plasma progesterone and estradiol rise and fall as they would in a normal ovulatory cycle.

Clomid has both estrogenic and anti-estrogenic properties, but its precise mechanism of action has not been determined. Clomifene appears to stimulate 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 corpus 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 anti-androgenic effects and does not appear to interfere with pituitary-adrenal or pituitary-thyroid function.  Clomiphene is capable of interacting with estrogen-receptor-containing tissues, including the hypothalamus, pituitary, ovary, endometrium, vagina, and cervix. It may compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of intracellular estrogen receptors.

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.

Side effects of clomiphene treatment include a greater risk of multiple pregnancies as it can stimulate more than one mature ovarian follicle to rupture.  In comparison to purified FSH, the rate of ovarian hyperstimulation syndrome is low, however, there may be an increased risk of ovarian cancer and weight gain.  Other more common side effects of Clomid treatment include:

  • Mood swings, psychological / emotional side effects
  • Hot flashes
  • Abdominal discomfort
  • Visual disturbances
  • Ovarian cyst formation
  • Nausea
  • Thinning of the uterine endometrial lining
  • Reduced production of cervical mucous – this can lower fertility

The available data suggest that clomiphene treatment, especially after several cycles, might be associated with a slightly higher risk of neural tube defects and severe hypospadias in the offspring.

More Information:

Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E: Clomiphene and anti-oestrogens for ovulation induction in PCOS. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD002249. Pubmed
Elizur SE, & Tulandi T. (2008) Drugs in infertility and fetal safety. Fertility and sterility, 89(6), 1595-602. PMID: 18519067

Fritz MA, Holmes RT, Keenan EJ: Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women. Am J Obstet Gynecol. 1991 Jul;165(1):177-85. Pubmed
Hayon T, Atlas L, Levy E, Dvilansky A, Shpilberg O, Nathan I: Multifactorial activities of nonsteroidal antiestrogens against leukemia.  Cancer Detect Prev. 2003;27(5):389-96. Pubmed

Homburg R: Oral agents for ovulation induction—clomiphene citrate versus aromatase inhibitors. Hum Fertil (Camb). 2008 Mar;11(1):17-22. Pubmed

Homburg R: Clomiphene citrate—end of an era? A mini-review. Hum Reprod. 2005 Aug;20(8):2043-51. Epub 2005 May 5. Pubmed

Hughes E, Brown J, Collins JJ, Vanderkerchove P: Clomiphene citrate for unexplained subfertility in women. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000057. Pubmed

Mitwally MF, Biljan MM, Casper RF. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation. Am J Obstet Gynecol. 2005;192(2):381–6. [PubMed]

Purvin VA: Visual disturbance secondary to clomiphene citrate. Arch Ophthalmol. 1995 Apr;113(4):482-4. Pubmed

Use of clomiphene citrate in women. Fertil Steril. 2006 Nov;86(5 Suppl 1):S187-93. Pubmed
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