Thursday, February 22, 2007

Ask a Scientist: Metformin and PCOS and Pregnancy

What's PCOS? Polycystic ovary syndrome is characterized by, among other things, a lack of normal menstrual cycles, lack of ovulation, and cysts in the ovaries. It's not clear exactly what causes it.

Some people believe it has to do with gonadotropin-releasing hormone (GnRH), which is itself secreted by the hypothalamus. GnRH acts on the pituitary to control secretion of two of our favorite hormones, luteinizing hormone and follicle-stimulating hormone (LH and FSH). Some studies indicate that GnRH secretion in PCOS patients happens in fast pulses, and doesn't have normal feedback with estrogen/progesterone down the line. The end result is that PCOS patients end up with high LH and low FSH and so don't ovulate.

-Much of the following information is summarized from this review; email me if you want but can't get the pdf.

PCOS and insulin: PCOS is strongly linked to insulin resistance, where cells doesn't react correctly to insulin, and so insulin is produced at high levels as the body attempts to compensate. Although this effect is increased by obesity, even 'lean' women with PCOS have some insulin resistance. Pretty soon testosterone production increases in the ovaries and levels of the main testosterone-binding protein decrease. (This doesn't help any with the ovulation problems.) There are theories that this gets into a feedback loop with the pituitary and then you get even more testosterone-producing-stimulation badness.

Because of this, drugs that counter insulin resistance are frequently prescribed to manage PCOS in women who wish to conceive. Birth control pills are given to women who merely wish to manage symptoms. Metformin, hereafter M, is the best studied (and the one I was asked about). Troglizatone, the next-best-studied drug, has been withdrawn by the FDA due to liver toxicity.

Metformin and ovulation: M alone, in clinical trials, has caused ovulation in 34% of an obese population; when combined with clomiphene, 90% was achieved. This has been confirmed multiple times; the increase is about 4-fold over untreated, or a total of 46% in non-obese patients. Clomiphene is sometimes used alone, but M works better alone or in combination with clomiphene.

There are a few studies where gonadotropins are combined with M; multiple follicles (associated with multiple implantations and, if no reduction is performed, poor pregnancy outcomes) were reduced from an average of 4.5 to 2.5. Cycle cancellations due to too many follicles were also reduced. Another study found that M increased mono-ovulatory cycles and decreased hyperstimulation (These are good things.)

When M is compared to laparoscopic ovarian diathermy (in obesity only), which sounds kind of icky and apparently lacks randomized trials, ovulation is the same but M is better at allowing and maintaining pregnancy (overall: 18 vs. 13% of patients have pregnancies, 15 vs. 29% SAs).

Metformin and pregnancy loss: Spontaneous abortion (SA) is increased dramatically in PCOS. Although anovulation is a major factor in the infertility of PCOS, women with PCOS are also at high risk of first-trimester early pregnancy loss. Compared with an SA rate of 10-15% of clinically recognized pregnancies in controls, the comparable EPL rate of women with PCOS is 30-50%. M treatment seems to knock the risk back down to the basal level, if it is taken throughout pregnancy, and may reduce the risk of gestational diabetes ['GD developed in 4% of pregnancies versus 26% of previous pregnancies without M'].

Metformin and teratogenicity: In a small study of 126 infants, there were no teratogenic effects observed. Other small studies have come to similar conclusions. M is currently a Category B drug (along with Sudafed). Note, however, that in 126 infants one would not expect to see more than 3 congenital defects, and M would have to increase risk at least two-fold to be reliably observed.

Motherisk conveniently summarizes the animal data for us: high doses (600 mg/kg/day) in some animal or other have no effect, and clinical doses have no effect, and cultured embryos are susceptible to M toxicity. There may be a low incidence of malformation in rat embryos.

Type II diabetes is, like PCOS, characterized by insulin resistance and hyperinsulinemia and is associated with not only pregnancy loss and infant mortality, but also a sharply increased incidence of congenital malformations (about 11-fold). This makes it harder to tell if M does cause congenital defects because most of the population taking M has these 'confounding factors'.

  • M is often effective at increasing ovulation in PCOS.
  • It has been combined with other drugs, or with gonadotropins, to successfully induce ovulation in a majority of study subjects.
  • Usage through pregnancy, or at least the first trimester, sharply reduces the risk of SA in PCOS patients.
  • In small studies, there is no teratogenicity in humans and minimal teratogenicity in animals. However, because of complications, it is difficult to tell if there is an effect.