Department Obstetrics and Gynecology, University of Siena, Policlinico Le Scotte, 53100 Siena, Italy E-mail: deleo{at}unisi.it
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Introduction |
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We read with interest the recent study by Yarali and colleagues in which the authors demonstrated in a randomized, placebo-controlled study, that metformin administration is not associated with modification in ovarian response to recombinant (r)FSH treatment (Yarali et al., 2002).
A total of 32 polycystic ovarian syndrome (PCOS) patients were randomized to metformin (n = 16) or placebo (n = 16). After 3 weeks of metformin treatment, five spontaneous ovulations occurred. After 6 weeks of metformin administration, rFSH treatment was undertaken according to a low dose step-up protocol. During metformin treatment no modifications in insulin sensitivity were observed; however, free testosterone was significantly reduced. Combined metformin-rFSH treatment led to a reduced duration of stimulation (17.1 ± 7.8 versus 19.7 ± 10.8 days) and number of vials (21.4 ± 11.8 versus 27.5 ± 18.6), and an increased ovulation rate (90 versus 73.3%) and pregnancy per cycle (30 versus 6.7%). However, none of these differences reached statistical significance.
The authors stated that despite a lack of improvement of insulin sensitivity during metformin treatment, there was a marked and significant increase in spontaneous ovulation which could be due to a direct action of metformin in modulating the sensitivity of ovarian follicles to circulating insulin.
In recent years several studies on PCOS-associated insulin-resistance have demonstrated that ovaries from PCOS were sensitive to hyperinsulinaemia. Defects in insulin signalling may exist in some but not all tissues of a individual, so ovaries from an insulin-resistant subject may be insulin-sensitive. Hence, it seems strange that metformin could increase spontaneous ovulation by modulating insulin sensitivity of follicles without reducing hyperinsulinaemia.
Furthermore, Yarali and colleagues found a significant reduction in free testosterone with no modification in total testosterone plasma levels (Yarali et al., 2002). The authors postulated that the decrease in free testosterone levels is possibly due to increased SHBG levels. Insulin is known to regulate androgen metabolism by regulating circulating levels of SHBG. In-vitro and in-vivo studies indicate that insulin suppresses hepatic SHBG synthesis and secretion (Plymate et al., 1988
; Nestler et al., 1991
). Hence the reduction in hyperinsulinaemia is associated with an increase in SHBG plasma levels (Nestler et al., 1991
). However, Yarali and colleagues did not find modifications in insulin levels following metformin therapy (Yarali et al., 2002
). Readers may argue that metformin treatment is associated with a reduction in the free androgen fraction and improvement in spontaneous ovarian function independently from any reduction in hyperinsulinaemia.
Most studies investigating metformin treatment in PCOS suggest that reduction of hyperinsulinaemia may affect the entire spectrum of endocrine and reproductive abnormalities in PCOS patients. However, not all studies that have assessed the effects of metformin in PCOS women have confirmed that findings (Acbay and Gundogdu, 1996; Ehrmann et al., 1997
). However, where insulin levels were reduced by treatment, PCOS-associated abnormalities were improved as well.
Regarding the combined FSH-metformin treatment in clomiphene-resistant PCOS women, Stadtamauer and colleagues (Stadtmauer et al., 2001) confirmed the results of our previous study (De Leo et al., 1999
). In PCOS patients undergoing IVFembryo transfer, the combined treatment has been shown to be better than gonadotrophin alone, with recruitment of fewer follicles and lower estradiol levels. The authors also showed that metformin treatment was associated with an increased number of mature oocytes and 4-cell embryos on the day of transfer. Fertilization rates and clinical pregnancy rates were higher when metformin was administered.
In conclusion, the paper by Yarali and colleagues (Yarali et al., 2002) adds confusion to the complex pathophysiology of PCOS and possible treatment with insulin-sensitising agents. In recent years it has been widely recognized that most women with PCOS have some degree of insulin resistance. There is currently much interest in the use of insulin-sensitizing drugs in women with PCOS. Insulin-sensitizing agents have been demonstrated to improve insulin sensitivity, decrease androgen levels and improve ovulation, menstrual cycle and metabolic disorders in a large subset of affected women.
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References |
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De Leo, V., la Marca, A., Ditto, A. et al. (1999) Effects of metformin on gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil. Steril., 72, 282285.[ISI][Medline]
Ehrmann, D.A., Cavaghan, M.K., Imperial, J. et al. (1997) Effects of metformin on insulin secretion, insulin action, and ovaian steroidogenesis in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 82, 524530.
Nestler, J.E., Powers, L.P., Matt, D.W. et al. (1991) A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 72, 8389.[Abstract]
Plymate, S.R., Matej, L.A., Jones, R.A. and Friedl, K.A. (1988) Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J. Clin. Endocrinol. Metab., 67, 460464.[Abstract]
Stadtmauer, L.A., Toma, S.K., Riehl, R.M. and Talbert, L.M. (2001) Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors. Fertil. Steril., 75, 505509.[ISI][Medline]
Yarali, H., Yildiz, B.O., Demirol, A. et al. (2002) Co-administration of metformin during rFSH treatment in patients with clomiphene citrate-resistant polycystic ovarian syndrome: a prospective randomized trial. Hum. Reprod., 17, 289294.