Authors and Affiliations: Vincenzo De Leo, Antonio la Marca, Antonino Ditto, Giuseppe Morgante, and Antonio Cianci; Department of Obstetrics and Gynecology, Universities of Siena and Catania, Italy.

Journal: Fertility and Sterility, Volume 72, Number 2, pp. 282-285

Summarized by Christine M. Schroeder, Ph.D.

Polycystic ovarian syndrome (PCOS) is a common cause of menstrual disruption. PCOS is characterized by elevated androgen, insulin, and luteinizing hormone level. Patients also frequently present male pattern hair growth, with amenorrhea, and above-normal weight.

Patients with PCOS frequently experience infertility; additionally their cases can present a challenge to the fertility specialist. These individuals will often respond very slowly to stimulation and tend not to develop dominant follicles. As a result, these patients will often ultimately develop a large number of mature follicles and are at increased risk for hyperstimulation.

Metformin is a drug normally used to treat individuals with non-insulin dependent diabetes. It has multiple actions, including reduction of glucose production in the liver and increasing glucose uptake throughout the body. Metformin also decreases hyperinsulinism, reduces plasma levels of luteinizing hormone (LH), and reduces ovarian androgen production.

The insulin, androgen, and LH-related actions of metformin form the basis for its use for patients with PCOS. The normalization of these hormone levels addresses many of the underlying mechanisms of PCOS. As a result, patients should respond to ovarian stimulation in a more predictable and orderly fashion.

The current study examines whether metformin affects the response to FSH therapy among PCOS patients resistant to clomiphene citrate (CC). The researchers defined CC resistance as a failure to ovulate or conceive on CC dosages of up to 150 mg for three cycles or more. Study participants were 20 women with PCOS who had normal blood pressure, prolactin levels, thyroid function, and ACTH response. Patients were not screened for insulin resistance. All male partners had normal semen analyses, and none of the patients had taken ovulatory medications within two cycles of starting the study.

Participants were randomly assigned to two groups. In the first group (“F-M”), patients underwent two cycles of FSH treatment, then one cycle of metformin treatment, and another cycle of metformin and FSH treatment. The second group (“M-F”) received metformin treatment for one cycle, followed by a cycle of metformin and FSH treatment. Thus, the structure of the study was as follows:

Group	Cycle One	Cycle Two	Cycle Three	Cycle Four
F-M	FSH only	FSH only	Metformin only	FSH + Metformin
M-F	—–	—–	Metformin only	FSH + Metformin

The treatment protocol began patients on one vial of urinary-derived FSH per day. The dosage was increased by one vial per day until detection of an ovarian response. The patient was then maintained on that dosage until the hCG shot was given. The criteria for administering the hCG shot were: (1) the presence of at least one follicle of 18 mm or greater and (2) no more than three follicles greater than or equal to 17 mm. The Metrodin dosage used was 500 mg three times daily.

A preliminary analysis of the results indicated that the two treatment groups did not differ in terms of age, infertility history, body mass index, or hormonal profiles.
In the first FSH-only cycle that the F-M group underwent, one of the patients conceived. A second patient conceived in the next cycle of FSH-only treatment. Therefore, only eight of the ten patients in the F-M group went on to take Metrodin, and the number of cycles analyzed for each of the protocols was:

• FSH-only: 19 cycles (ten in the first F-M group’s cycle, and nine in the second)
• Metformin-FSH: 18 (ten from the M-F group’s cycle, and eight from the Metformin-FSH cycle of the F-M group)

Because of the risk that PCOS patients have of responding too strongly to medications, the analyses focused not only the pregnancy rate, but also upon the number of follicles developed, the estradiol levels, and the incidence of cancelled cycles. The results indicated that:

• The daily dose needed to cause a detectable ovarian response was similar in the FSH-only and FSH-Metrodin cycles
• The estradiol level for the FSH-only cycles was significantly higher, 720 pg/mL versus 450 pg/mL
• The number of follicles in the FSH-only cycles was significantly higher, 4.5 versus 2.5
• The number of cycles cancelled due to too many follicles was 31.5% in the FSH-only cycles, compared to none in the FSH-Metformin cycle
• The pregnancy rates per cycle were similar for both the FSH-only cycles (10.5%) and FSH-Metformin cycles (16.6%; not statistically significant)
• The hyperstimulation after hCG rate was 26.3% for the FSH-only cycles and 16.6% for the FSH-Metformin cycles (not statistically significant)

The researchers concluded that metformin pretreatment appears to result in more orderly follicular growth in FSH-treated patients with PCOS. Additionally, because the patients were not screened for insulin resistance, the results are not specific to only insulin-resistant PCOS patients. Finally, the researchers also noted that metformin does not seem to have teratogenic effects, it is inexpensive, and has minimal side effects. Nonetheless, they recommend additional research involving a larger sample, so that the ideal metformin dosage and duration of treatment can be determined.
 

Note: These sample sizes were very small. With a larger sample, it is likely that the pregnancy and hyperstimulation rates between the two groups would have been significantly different.