Middle East Fertility Society Journal Middle East Fertility Society ISSN: 1110-5690 Vol. 13, Num. 1, 2008, pp. 21-22

Middle East Fertility Society Journal, Vol. 13, No. 1, 2008, pp. 21-22

DEBATE

The current role of metformin in the management of infertility            

Hesham Al-Inany, M.D.

Faculty of Medicine, Cairo University

Code Number: mf08005

Metformin is an anti-diabetic drug from the biguanide class that has been used to help control blood glucose concentrations in people with type 2 diabetes, but does not cause hypoglycemia in non-diabetic patients. It is cheap, safe, with a few infrequent side effects such as gastrointestinal upset, diarrhea, cramps, nausea and vomiting, and the maximum safe dose is thought to be 850 mg three times daily (1).

Metformin is used in induction of ovulation in infertile women with hyperandrogenism, insulin resistance and PCOS as monotherapy or in combination with other ovulation induction drugs (2) and also as pre-treatment before intrauterine insemination or IVF/ICSI in women with PCOS (3-4).

However, looking in depth to the pharmacokinetics of metformin, we may see that it is associated with a reduction in aromataze activity in response to FSH (5). Insulin affects production of both androgen and estrogen; insulin therefore plays a central role in regulating the activity of theca and granulosa cells (5). By acting on the ovary and restoring normal ovarian activity, metformin positively modulates the reproductive axis (namely gonadotrophin-releasing hormone (GnRH)-LH episodic release)(6). Plasma concentrations of estradiol were significantly higher in cycles treated with FSH alone than in those treated with FSH and metformin. Thus it can be assumed that co-administration of metformin before and during gonadotrophin stimulation in the IVF/intracytoplasmic sperm injection (ICSI) cycle would result in a lower estradiol concentration than gonadotrophin alone, although this finding was not consistent in all studies (7). This would help to reduce the risk of OHSS.

But hypothesis alone is not valid without clinical trials and evidence should be based on highest quality clinical trials (the so called randomized controlled trials). Four RCTs studied the effect of metformin during ovarian hyperstimulation in IVF/ICSI in 283 women with PCOS (3, 8-10). Pooling the results of the four trials showed that metformin led to fewer cases of ovarian hyperstimulation syndrome (OHSS) (RR 0.33; 95% CI 0.13–0.80). Accordingly, Metformin is beneficial for prevention of ovarian hyperstimulation syndrome and when we consider its cheap price and safety then one should recommend it for every case undergoing IVF/ICSI program.

REFERENCES

1. Cheang KI, Nestler JE 2004 Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome? Reproductive BioMedicine Online 8, 440–447.
2. Kumari AS, Haq A, Jayasundaram R et al. 2005 Metformin monotherapy in lean women with polycystic ovary syndrome. Reproductive BioMedicine Online 10, 100–104.
3. Kjotrod SB, Von During D V, Carlsen SM. Metformin treatment before IVF/ICSI in women with polycystic ovary syndrome; a prospective, randomized, double blind study. Hum Reprod (2004) 19:1315.
4. Palomba S, Orio F Jr, Falbo A et al. 2005 Metformin administration and laparoscopic ovarian drilling improve ovarian response to clomiphene citrate (CC) in oligo-anovulatory CC-resistant women with polycystic ovary syndrome. Clinical Endocrinology (Oxford) 63, 631–635
5. la Marca A, Morgante G, Palumbo M et al. 2002 Insulin-lowering treatment reduces aromataze activity in response to follicle-stimulating hormone in women with polycystic ovary syndrome. Fertility and Sterility 78, 1234–1239.
6. Genazzani AD, Battaglia C, Malavasi B et al. 2004 Metformin administration modulates and restores luteinizing hormone spontaneous episodic secretion and ovarian function in nonobese patients with polycystic ovary syndrome. Fertility and Sterility 81, 114–119
7. Stadtmauer LA, Toma SK, Riehl RM, Talbert LM 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. Fertility and Sterility 75, 505–509.
8. Fedorcsak P, Dale PO, Storeng R, Abyholm T, Tanbo T. The effect of metformin on ovarian stimulation and in vitro fertilization in insulin-resistant women with polycystic ovary syndrome: an open-label randomized cross-over trial. Gynecol Endocrinol (2003) 17:207–214
9. Onalan G, Pabuccu R, Goktolga U, Ceyhan T, Bagis T, Cincik M. Metformin treatment in patients with polycystic ovary syndrome undergoing in vitro fertilization: a prospective randomized trial. Fertil Steril (2005) 84:798–801.
10. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod (2006) 21, b. 1416–1425

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