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Treatment of Anovulation

In approximately 40% of patients who visit an infertility clinic, anovulation is diagnosed. One of the primary drugs utilized in correcting anovulation is clomiphene citrate, atriphenyl ethylene derivative mixture of cis and trans-isomers.

Pharmacodynamics of clomiphene citrate
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Pharmacodynamics of clomiphene citrate. The hypothalamic activity of the estrogen agonist/antagonist clomiphene citrate which induces ovulation.
Credits: Serono Laboratories

The predominant site of action of clomiphene citrate is the hypothalamus. Clomiphene possesses both estrogen agonist and antagonist properties and binds to hypothalamic estrogen receptors. The hypothalamus in turns perceives a hypoestrogenic state, which results in the accentuation of discharge of gonadatropin-releasing hormone. GnRH then affects the anterior pituitary gland to produce and secrete follicle-stimulating hormone and luteinizing hormone. Clomiphene may also directly affect the ovary and other estrogen-dependent tissues, as well. Patients who initiate clomiphene therapy will notice hot flushes while taking the drug.

Patients who have adequate endogenous estrogen by demonstrating withdrawal bleeding after a progestin are the primary candidates for the use of clomiphene citrate.

Pharmacodynamics of clomiphene citrate
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Clomiphene citrate/patient selection. Indications and contraindications to the use of clomiphene citrate are listed.
Credits: Serono Laboratories

Poor responders include women with premature ovarian failure demonstrated by an elevated FSH, and women with extremely low estrogen levels who fail to respond to a progestin challenge test. Clomiphene is contraindicated in patients who are pregnant or who have uncontrolled thyroid or adrenal dysfunction, organic intracranial lesions, liver disease or history of liver dysfunction, abnormal uterine bleeding, or ovarian cyst enlargement.

We normally start clomiphene citrate at 50 mg per day on days 5 through 9 of the cycle, and increase this in increments of 50 mg per day as necessary until an ovulatory pattern is demonstrated either by basal body temperature charting, serum progesterone levels, or other appropriate evaluations of ovulation

Tailoring the use of clomiphene citrate
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Tailoring the use of clomiphene citrate. A schematic diagram outlining the routine use of clomiphene citrate.
Credits: Serono Laboratories

If a patient does not respond to 150 mg per day for a five-day course, she may need further evaluation. Patients who do not become pregnant within three or four ovulatory cycles should also receive further evaluation. Consideration must be given to other potentially complicating factors such as endometriosis.

Occasionally, patients develop multiple cysts with the use of clomiphene citrate. If this occurs or if human menopausal gonadotropins (hMG) is used, it is recommended that the patient undergo ultrasound evaluation to document the development of follicles. For routine patients treated with human menopausal gonadotropin, we obtain a day 3 ultrasound, initiate drug therapy, and repeat the scan in five days to document development of mature follicles.

With human menopausal gonadatropin use, we attempt to have one to three follicles measuring approximately 1.7 cm in diameter. Once this level is reached, an injection of human chronic gonadotropin (hCG) is given to induce ovulation. If ultrasound is used in conjunction with clomiphene citrate use, the size of a mature follicle is approximately 2 cm.

Ovarian follicular scanning
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Ovarian follicular scanning. Ovaries are scanned transvaginally to determine the size of the developing follicles.
Credits: Serono Laboratories

Periodically, intrauterine insemination is added to monitoring of cycles or ovulation induction cycles. Intrauterine insemination is used for male infertility, cervical factor problems, endometriosis, unexplained infertility, and female antisperm antibodies.

Indications for IUI.
  • Male infertility
  • Cervical factor
  • Endometriosis
  • Unexplained infertility
  • Female humoral antisperm antibodies
  • Indications for intrauterine insemination.
    Credits: Serono Laboratories