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When clomiphene citrate fails, what's next?

PCOS and clomiphene citratePatients with polycystic ovary syndrome (PCOS) often do not ovulate, and thus getting pregnant with PCOS can be a challenge. The first line of treatment usually is the fertility drug clomiphene citrate (CC).

The starting dose of CC is usually 50 mg orally daily for 5 days. If ovulation does not begin, the dose is increased to 100 mg and then finally to 150 mg.

To detect ovulation, one can do serial blood tests and ultrasounds or measure an appropriately timed progesterone level. What are the treatment options for patients that do not respond to the highest dose of CC?

Please note: One of the assumptions I am making in this situation is that all other infertility tests have come back normal (semen analysis, hysterosalpingogram, TSH, prolactin, day-3 FSH, estradiol and LH level, anti-mullerian hormone level).

The options for this group of patients include:

  1. Weight loss in obese PCOS patients. This remains the BEST treatment for PCOS patients that are obese. Even a weight loss of 20 lb. can make a huge difference in ovarian response. Diet and exercise still remain the best options for weight loss.

  2. Metformin. In PCOS patients with hyperinsulinemia (diagnosed with a 75 gram two hour glucose tolerance test), the addition of metformin can help. Metformin corrects the hormonal imbalance in this patients just enough so that they may start to ovulate on their own or with CC.

  3. Follicle stimulating hormone (FSH) injections. FSH is a hormone the pituitary gland in the brain releases to stimulate the ovary to produce an egg. In PCOS patients, this hormone is NOT released in a cyclic manner and they therefore do not ovulate. One way to induce ovulation is to give PCOS patients FSH injections. These are generally started approximately 3 days after an induced bleed and continued daily for 9 – 11 days.

    PCOS patients generally WILL ovulate with FSH injections. The problem, however, is that instead of releasing a couple of eggs, PCOS patients can release a whole bunch! There thus is an uncontrolled risk of high-order multiple pregnancy! For this reason, especially in young patients, this is NOT a good option. There have been studies where a very low dose of FSH was used to stimulate PCOS patients with good results.

  4. Laparoscopic ovarian drilling. Holes are drilled into the outer layer of the ovaries using a needle cautery or a laser. This corrects some of the hormonal imbalance in PCOS patients and patients can start ovulating on their own. The option, however, involves surgery and is not always successful.

  5. In vitro fertilization (IVF). This involves stimulating the ovaries with FSH (and often another hormone, LH) and harvesting the eggs. The eggs are then fertilized in the embryology laboratory and embryo transfer is performed a few days later. This option is relatively complicated and expensive. However, the pregnancy rate in PCOS patients is excellent! Transferring a single embryo can minimize the risk of multiple pregnancy.

  6. Another affordable option that can be used is a combination of CC and dexamethasone. An elevated serum testosterone level can cause CC resistance. Dexamethasone is a steroid pill that can improve the efficacy of CC by reducing testosterone levels. This was discussed in detail by Dr Robert Barbieri in a recent issue of Ob/Gyn management.

One regimen that has proved to be successful is to treat the CC resistant woman with CC, 100 mg daily, for cycle Days 3 to 7, and simultaneously treat her with dexamethasone, 2 mg daily, for cycle Days 3 to 12 (see Figure).

In one trial, with this regimen, the ovulation rate was 75% in the CC plus dexamethasone group and 15% in the CC-only group. The pregnancy rate was 40% in The CC plus dexamethasone group and 5% in the CC-only group. Dexamethasone is to be taken in the morning (a nighttime dose may energize the patient and cause difficulty falling, and remaining asleep). CC is generally not used for more than 6 to 12 cycles. Approximately 8% of CC-induced pregnancies are twin and < 0.5% are triplet.

To see a fertility specialist who will answer your questions about PCOS and IVF, make an appointment at one of InVia Fertility’s four Chicagoland locations.

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Infertility Infertility treatment InVia Fertility Specialists

Dr. Vishvanath Karande

Dr. Vishvanath Karande

Dr. Karande is Board Certified in the specialty of Obstetrics and Gynecology as well as the subspecialty of Reproductive Endocrinology and Infertility. He is a Fellow of the American College of Obstetricians and Gynecologists and Member of the American Society for Reproductive Medicine.

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