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CLOMIPHENE CITRATE: THE WORKHORSE OF OVULATION INDUCTION

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INTRODUCTION: Clomiphene Citrate (CC) used for inducing ovulation, occupies an important position in the therapeutic repotoire of infertility treatment. This article describes the unique features of this inexpensive drug which is easy to administer as it is orally active.

MECHANISM OF ACTIONCC, a non-steroidal compound has a remarkable structural similarity to Estradiol (E2) which enables it to bind to E2 receptors in various tissues such as the hypothalamus, hypophysis, ovaries and the uterus and cervix. However unlike E2, CC is unable to induce the synthesis of new E2 receptors- a process essential for the continuous binding of E2 to the target cells as well as the expression of estrogenic action. The most commonly accepted simplistic view of CC action in the induction of ovulation is that it binds to the E2 receptors in the hypothalamus to create a state of hypoestrogenicity, thereby causing an enhanced Gonadotropin- releasing harmone (GnRH) release followed by an increased secretion of gonadotropins which induces ovulation. The INTRAFOLLICULAR concentrations of Follicle stimulating hormone (FSH), Luteinizing hormone (LH), E2 and Androgens contribute to follicula growth. CC is known to stimulate E2 synthesis in the ovaries which in turn stimulate formation of FSH and LH receptors in the granulosa cells of other small follicles which would not develop under normal circumstances and thus lead to development of additional follicles during the CC therapy. Thus CC may also act directly on the follicular apparatus to recruit additional follicles. Ovulation is known to occur in about 70% of cases while pregnancy occurs only in about 25-30% of the cases. The low pregnancy rate is due to the anti-estrogenic effects of CC on the cervix, which would make it hostile to sperm penetration and on the Endometrial growth which would therefore be animical to embryo implantation. Other reasons are premature Luteinization, due to the advancement of the LH suge in some instances and the occurrance of un-ruptured follicles in others due to defective ovulatory mechanisms. CC can impair development of the granulosa cells and thus cause Luteal phase defect.

Dose Regiment: CC is administered at daily doses of 50, 100 or 150 mg for 5 days during the follicular phase of the mensutral cycle starting on day 2, 3, or 5 of the cycle depending on the length of the mestrual cycle of that particular individual. The first treatment cycle is usually started with a daily dose of 50 mg and the dose is increased in subsequent cycles to 100 or 150 mg, if the lower dose is ineffective. Overweight patients may benefit from larger than the usual doses. At least 2 or 3 cycles need to be tried with CC before abandoning the drug.

CC Therapy: CC is used to trigger ovulation in women with an ovulatory cycles and in those having secondary amenorrhoea with normal levels of FSH, LH and Prolactin; women with low E2 levels respond poorly to CC. It is imperative that a diligent diagnosis is made to obviate any anatomical or endocrine defects which would preclude pregenancy and to monitor the ovarian response to CC treatment by trans-vaginal ultrasonography so that insemination (e.g. intercourse or intrauterine insemination) can be planned to occur at the appropriate time. Monitoring ovulation by basal body temperature (BBT) or serum levels of reproductive hormones is not satisfactory because the occurance of the un-ruptured follicle or premature Luteinization cannot be detected.

Combined Therapy:  Patients who do not ovulate with CC alone may do so if human chorionic gonadotropin (hCG; 10,000 IU) is given one week after the cessation of CC treatment. Combined therapy with CC (50 mg, 3xdaily) and bromocriptine (2.5 mg, 2xdaily) for 10 days, has been reported to evoke ovulation in 61% of cases. E2 has been used in combination with CC to improve cervical mucus quality and to induce LH surge. E2 benzoate (1 mg) when given 7 days after the last dose of CC will elicit an LH surge 72 hours later. GnRH has been used to induce the LH surge in conjunction with CC. CC in combination with dexamethasone has been found to be beneficial to women having hyperandrogenism of ovarian adrenal or mixed origin. CC is also used in combination with menotropins (Human Menopausal Gonalotropins/hCG).

Side Effects:   Abdominal discomfort, nausea and visual disturbances are reversible side affects of CC therapy. Ovarian hyperstimulation   may occur occasionally but is usually mild. Multiple gestations occur in some instances and such cases can be subjected to fetal reduction.

ConclusionsCC when used judiciously is a safe reliable and in expensive theraputic modality. It should be the drug of first choice for treating infertility before opting for any of the more expensive ovulation-inducing drugs and which carry a higher risk of hyperstimulation and multiple pregnancies.

Author :  Dr. R.  Raikar , Assistant Director (Fertility Studies Lab. )

Albany Memorial Hospital, Albany, NY 12204

E-Mail Dr. Ramdas Raikar

 
 

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This is meant to be an informational exercise and NOT a medical consultation
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