Ovarian Lifecycle

Normal Events

Ovulation Detection

Ovulation Dysfunction

Clinical Evaluation

Treatment Options
  • Thyroid Treatment
  • Prolactin Treatment
  • Fertility Medications
  • Donor Eggs

A Patient Reviews her Experience
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Treatment Options: Fertility Medication
Introduction  |   Clomiphene Citrate  |   Controlled Ovarian Hyperstimulation

Ovulation induction with fertility medication is appropriate in many clinical situations. Two different goals of fertility medication are:

  1. ovulation induction, where a woman who does not ovulate takes medication to enable her to ovulate (create and release at least one mature egg), and

  2. ovulation enhancement, where a woman who ovulates spontaneously takes medication to optimize the maturation of recruitable follicles (and eggs) for a particular cycle (produce multiple mature eggs).

Ovulation induction may be attempted in any woman who does not ovulate spontaneously as long as there are some eggs within the ovaries that may respond. The cycle day 3 FSH and estradiol concentrations as well as the clomiphene challenge test may help in determining ovarian reserve.

Clomiphene citrate is the usual entry level drug for inducing ovulation since it is easier to use than menotropins. It is

  1. much less expensive,

  2. requires less ongoing monitoring (ultrasounds and blood work), and

  3. the complications are typically much less severe.

Overall, ovulation is initiated or made significantly more regular about 85% of the time in women selected for clomiphene citrate. Regularization of ovulation may allow for a greater degree of predictability in timing intercourse or artificial inseminations. If clomiphene citrate fails to accomplish ovulation or if the woman is intolerant to the side effects, then menotropins should be considered. If a woman is ovulating regularly on her own, it is not clear that clomiphene citrate offers any real fertility advantage.

Common indications for the use of clomiphene citrate include:

  1. polycystic ovary syndrome, and

  2. CNS-hypothalamic dysfunctions when there is adequate estrogen production for at least a withdrawal flow to progesterone

Clomiphene citrate is taken by mouth usually for 5 days soon after the onset of the menstrual flow (I typically recommend cycle days 5-9). The lowest effective dosage of clomiphene citrate to accomplish ovulation is best. The pills are marketed in only the 50 milligram dosage. Common dosages are from 50 mg (1 pill) to 150 mg (3 pills) per day.

Clomiphene citrate was synthesized in 1956. It was introduced into clinical trials in 1960 and FDA approval for clinical use came in 1967. The FDA approval was for a maximum total consumed dose per cycle of 750 mg (a limit that is frequently surpassed).

Clomiphene citrate is composed of a mixture of two compounds that share the same chemical composition but have a subtle difference in shape (stereoisomers), referred to as zuclomiphene and enclomiphene. Each of these stereoisomers of clomiphene has a different half life in the circulation. The more bioactive isomer is more rapidly excreted so it does not accumulate from cycle to cycle. The less active isomer is excreted slowly so it will potentially accumulate over time if clomiphene is given month after month. The biological effect of this accumulated clomiphene is not known.

The action of clomiphene citrate depends upon its ability to bind the cell's nuclear receptors for estrogen for prolonged periods of time. Clomiphene may bind estrogen receptors for weeks while natural estrogens bind the nuclear receptors for only hours. This difference results in a rapid depletion of cellular estrogen receptors, and the body's cells are no longer able to detect circulating estrogen accurately. This "perceived" decrease in circulating estrogen results in an increase in hypothalamic GnRH and pituitary FSH and LH. Increased FSH results in enhanced egg and follicle maturation. Therefore, clomiphene citrate acts indirectly to "trick" the brain into believing there is a lack of estrogen.

The primary site of action of clomiphene citrate in the brain is the hypothalamus. If clomiphene is given to normally ovulating women, there is an increase in the frequency of the FSH and LH pulses but there is no increase in the pulse amplitude. This suggests that clomiphene enhances hypothalamic GnRH pulse frequency. When clomiphene is given to anovulatory women, it results in an increase in the amplitude of the FSH and LH pulses without an increase in frequency. This suggests that the frequency of the pulsatility is maximal in the anovulatory women and the primary mechanism of action of the clomiphene is therefore in terms of increased amplitude of secretion.

In women with low estrogen concentrations clomiphene theoretically is not effective, since its mechanism of action is to "trick" the brain into believing that there is a low circulating estrogen. When there already is a low circulating estrogen, the FSH and LH should be near maximal without medication. However, it has been found clinically that an occasional woman with hypogonadism (especially if the FSH is also low) will ovulate with clomiphene and so it can reasonably be tried.

The optimal duration of treatment for clomiphene has not been clearly established. The literature is conflicting. One classic study used life table analysis (a sophisticated statistical technique that calculates rates per month [or other convenient unit of time] and removes subjects that drop out of the study after a period of time) to follow the results of clomiphene treatment in about 160 women with ovulatory dysfunction and found that the most important factor contributing to reduced pregnancy rates was patient discontinuation of medication. This study suggests that clomiphene treated cycles have high fecundity rates until at least 10 to 12 months. Other studies have suggested that 75% of pregnancies to occur on clomiphene occur within 3 months and that pregnancies are uncommon after 6 months of therapy. To date, there is no really solid information that can resolve these conflicts. I have used between 3 and 12 months of treatment.

It is not clear if human malformations increase when clomiphene is taken in early pregnancy, but it is certainly advisable to carefully avoid its use if there is a chance of pregnancy. In rats and rabbits, clomiphene taken during pregnancy at the time of fetal organ development resulted in a dose dependent increase in malformations. A woman taking clomiphene should always confirm that she is not pregnant prior to taking the medication. There is no increase in miscarriages for pregnancies resulting from clomiphene induced or enhanced ovulation.

The main side effects of clomiphene include (but are not limited to)

  • hot flashes (up to 10%)
  • abdominal distention and discomfort, breast tenderness, and headaches,
  • mood swings (which can reportedly be dramatic), and
  • visual alterations (1-2%).

These side effects generally occur when taking the drug. Relatively long lasting side effects do not usually last for more than a few days after discontinuing the medication.

Complications of clomiphene may include

  • multiple pregnancies (twinning rate of about 8-10%, triplets are rare),
  • ovarian cyst development or ovarian hyperstimulation syndrome (with abdominal bloating, possibly serious dehydration, and tender sore ovaries) and
  • counterproductive alterations in the cervical mucus around ovulation (in about 15% of women on clomiphene the peri ovulatory mucus is less receptive to sperm and may pose a barrier to fertilization).

Ovarian cyst development is rare but should not go unnoticed. This is the basis for a clomiphene-check office visit during the first few days of the menstrual flow that follows the first successful (ovulatory) cycle on this medication. Additionally, the basal body temperatures can be reviewed and treated accordingly. Cervical mucus should be checked for hostility to sperm during a cycle on clomiphene once the woman is successfully ovulating, via a postcoital test.

Controlled Ovarian Hyperstimulation
Ovulation enhancement is an attempt to mature all of the recruitable eggs for a given cycle. Typically, clomiphene citrate is a poor ovulation enhancement medication. However, there is some reasonably convincing literature (predominantly from Europe) that suggests higher doses of this medication starting on cycle day 2 rather than cycle day 5 may result in better ovulation enhancement (with regular development of more than one fully mature egg). The ovulation enhancement medication of choice is the family of menotropins, which includes (in 1999) Pergonal, Humegon, Metrodin (no longer produced), Fertinex and two recombinant forms of FSH (Follistim and Gonal F). Some common indications for the use of menotropins include:

  • ovulation induction for women who fail to ovulate with clomiphene citrate (or are intolerant to clomiphene citrate's side effects),
  • subtle male factor problems,
  • endometriosis,
  • unexplained infertility,
  • some forms of ovarian failure and women with diminished ovarian reserve,
  • tubal factor infertility with patent fallopian tubes
  • ARTs (including IVF)

For a detailed discussion of controlled ovarian hyperstimulation, including general considerations, the medications used, the protocols employed and the complications encountered see the sections on COH within the infertility procedures tutorial.

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