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Clomiphene Citrate (Clomid, Serophene) Therapy

Clomiphene citrate has been approved for treatment of ovulation disorders since 1967. It is marketed in the U.S. under the brand name Clomid and Serophene and is available in 50 mg tablets.
How does Clomiphene works?
Clomiphene increases pituitary production of FSH (Follicle Stimulating Hormone). FSH hormone stimulates the growth of eggs within the ovary until they mature and advance to ovulation.
What are the indications for Clomiphene treatment?

Ovulatory dysfunction is often associated with a low progesterone level, short luteal phase (number of days from ovulation to menses), infrequent or absent ovulations or PCOS (Polycystic Ovary Syndrome)

Clomiphene is most often prescribed for abnormal ovulation. Measuring day 3 FSH and estrogen levels can help your physician determine if you are a candidate for Clomiphene treatment.

  • The treatment is most effective when day 3 FSH and estrogen levels are normal.
  • In women with very low FSH level, Clomiphene can not increase FSH production from the pituitary gland and may not restore normal ovulation. In such cases, FSH injections (gonadotropin therapy) must be taken to stimulate egg development leading to ovulation.
  • When a woman has a high FSH level, the problem is with the ovary (low egg quality). Attempting to increase FSH release from pituitary with Clomiphene is not likely to succeed
  • Thyroid hormone level abnormalities can result in ovulation disorder. In such cases, thyroid medication can often restore normal ovulation.
  • High pituitary prolactin level may also result in abnormal ovulation. Prolactin lowering medications such as Bromocriptine and Dostinex are often prescribed to lower the prolactin level and restore normal ovulation.
How is Clomiphene Citrate Prescribed?
  • It is usually prescribed at 50 mg daily starting between day 3 and day 5 of your menstrual cycle for 5 days.
  • About 50% of the patients will ovulate with the 50mg dose and another 25% will ovulate at a dose of 100 mg daily for 5 days.
  • In women who do not ovulate with 50 or 100mg of Clomiphene, increasing the dose of Clomiphene Citrate to above 150mg daily is not likely to be effective.
  • In some patients a lower dose (25mg) of the fertility medication may be prescribed if too many eggs develop when treated with the standard dose.
How is the fertility medication monitored?
  • Ultrasound (fig. 1) is performed between day 12 and day 14 of the menstrual cycle to monitor the growth of the follicles (fig.2) and to measure the thickness of the lining of the uterus. Ideally the lining of the uterus should be more than 8 mm thick (fig.3). This indicates that the uterus has been optimally prepared for embryo implantation. Once a follicle reaches about 18 mm in diameter, another hormone, HCG, may be given to trigger ovulation.
fig 1

Fig. 1

fig 2

Fig. 2

fig 3

Fig. 3

  • Progesterone level – is measured 7 days after ovulation to confirm that ovulation was adequate. A progesterone level above 15ng/ml is indicative of good ovulation. Intrauterine Insemination (IUI) is often performed at the time of ovulation for male factor or unexplained infertility.
  • If no follicle over 10 mm is noted and the lining of the uterus is thin, Clomiphene Citrate can be increased by 50 mg increments up to 150 mg daily. Although unlikely to be successful, some doctors recommend treatment with even higher doses of Clomiphene (up to 250 mg daily for 5 days).
What are the treatment options if I fail to ovulate with Clomiphene?
  • If you were diagnosed with Polycystic Ovary Syndrome (PCOS) and previously failed to ovulate with Clomiphene, a 5% weight loss may improve the likelihood of ovulatory response; your doctor may otherwise recommend an Insulin-Sensitizing medication such as Metformin alone or in combination with Clomiphene. Metformin alone has been shown to restore ovulation in about 50% of the patients and in 80% of patients when Metformin is combined with Clomiphene.
  • Some women with PCOS who had elevated male hormones (DHEAS) are sometimes treated with Clomiphene and a steroid (Dexamethasone 0.25 mg daily).
  • Ministimulation is often recommended for patients who fail to ovulate with Clomiphene alone. It consists of taking Clomiphene for 5 days plus 2 injections of FSH on day 7 and 9 of cycle. This treatment is often combined with intrauterine insemination (IUI) for patients with male factor or unexplained infertility.
  • Injectable hormones (gonadotropin therapy) may be recommended by your physician if:
    • There is no response to Clomiphene Citrate (Clomiphene resistance)
    • The thickness of uterine lining measured by ultrasound is less than 6mm
    • If you ovulated with Clomiphene but failed to conceive.
  • Laparoscopic ovarian drilling is a minimally invasive outpatient laparoscopic surgery utilized to induce ovulation in Polycystic Ovary Syndrome (PCOS). In this procedure approximately 10 holes are drilled into each ovary utilizing a laser beam or electrical probe resulting in restoration of ovulation in about 85% of patients and pregnancy in 50-60%. The advantage of the therapy is that ovulation occurs spontaneously without the use of ovulation inducing medications and is associated with a very low risk of multiple pregnancies. There is, however, a risk that the surgery may cause scar tissue formation around the ovaries.
  • In women who ovulate with Clomiphene but fail to conceive, other causes of infertility such as endometriosis or pelvic adhesions may be the problem. In such cases your doctor may recommend laparoscopy before pursuing a more complex treatment.
What are the risks and complications of Clomiphene therapy?
  • About 10% of the patients may experience hot flushes while abdominal swelling, breast tenderness, nausea, headaches and visual symptoms are infrequent.
  • Ovarian enlargement as a result of the development of multiple follicles may occur although severe Ovarian Hyperstimulation Syndrome (OHSS) is extremely rare.
  • Multiple pregnancies (mostly twins) occur in 7-8% of patients.

Clomiphene Citrate or injectable gonadotropin therapy should only be administered under close medical supervision. Please consult your doctor to discuss appropriate treatment options.

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