Infertility in polycystic ovary syndrome

Polycystic ovary disease (PCOS) is thought to be one of the leading causes of female infertility.^[1][2][3][4] Polycystic ovary syndrome is the cause of more than 75% of cases of anovulatory infertility.^[5]

Pathophysiology

Not all women with PCOS have difficulty becoming pregnant. For those who do, anovulation is a common cause. The mechanism of this anovulation, is uncertain, but there is evidence of arrested antral follicle development, which, in, turn, may be caused by abnormal interaction of insulin and luteinizing hormone (LH) on granulosa cells.^[5]

Endocrine disruption may also directly decrease fertility, such as changed levels of gonadotropin-releasing hormone^[6], gonadotrophins (especially an increase in luteinizing hormone)^[7][6], hyperandrogenemia^[8] and hyperinsulinemia^[8]. Gonadotrophins are released by gonadotroph cells in pituary gland, and these cells appear to harbor insulin receptors, which are affected by too high insulin levels in body.^[6] A reason that insulin sensitizers work in increasing fertility is that they lower total insulin levels in body as metabolic tissues regain sensitivity to the hormone. This will reduce the overstimulation of gonadotroph cells in pituitary.^[6]

Diagnosis

PCOS usually causes infertility associated with anovulation, and therefore, the presence of ovulation indicates absence of infertility, although it does not rule out infertility by other causes.

Ovulation prediction

Ovulation may be predicted by the use of urine tests that detect the preovulatory LH surge, called ovulation predictor kits (OPKs). However, OPKs are not always accurate when testing on women with PCOS.^[9] Charting of cervical mucus may also be used to predict ovulation, or certain fertility monitors (those that track urinary hormones or changes in saliva) may be used. Methods that predict ovulation may be used to time intercourse or insemination appropriately.

While not useful for predicting ovulation,^[10] basal body temperatures may be used to confirm ovulation. Ovulation may also be confirmed by testing for serum progesterone in mid-luteal phase, approximately seven days after ovulation (if ovulation occurred on the average cycle day of fourteen, seven days later would be cycle day 21). A mid-luteal phase progesterone test may also be used to diagnose luteal phase defect. Methods that confirm ovulation may be used to evaluate the effectiveness of treatments to stimulate ovulation.

Management

Management of infertility in polycystic ovary syndrome includes lifestyle modification as well as assisted reproductive technology such as ovulation induction, oocyte release triggering and surgery.

Lifestyle modification

For overweight women with PCOS who are anovulatory, diet adjustments and weight loss are associated with resumption of spontaneous ovulation.

Ovulation induction

For those who after weightloss still are anovulatory or for anovulatory lean women, ovulation induction to reverse the anovulation is the principal treatment used to help infertility in PCOS. Clomiphene citrate is the main medication used for this purpose.

In vitro fertilization

For patients who do not respond to diet, lifestyle modification and clomiphene, in vitro fertilisation can be performed. This usually includes controlled ovarian hyperstimulation with FSH injections, and oocyte release triggering with human chorionic gonadotropin (hCG) or a GnRH agonist.

Surgery

Though surgery is not commonly performed, the polycystic ovaries can be treated with a laparoscopic procedure called "ovarian drilling" (puncture of 4-10 small follicles with electrocautery), which often results in either resumption of spontaneous ovulations or ovulations after adjuvant treatment with clomiphene or FSH.

Inefficacy of metformin

Previously, metformin was recommended treatment for anovulation. But in the largest trial to date, comparing clomiphene with metformin, clomiphene was more effective than metformin alone.^[11] In this trial, 626 women were randomized to three groups: metformin alone, clomiphene alone, or both. The live-birth rates following 6 months of treatment were 7.2% (metformin), 22.5% (clomiphene), and 26.8% (both). The major complication of clomiphene was multiple pregnancy, affecting 0%, 6% and 3.1% of women respectively. The overall success rates for live birth remained disappointing, even in women receiving combined therapy, but it is important to consider that the women in this trial had already been attempting to conceive for an average of 3.5 years, and over half had received previous treatment for infertility. Thus, these were women with significant fertility problems, and the live-birth rates are probably not representative of the typical PCOS woman. Following this study, the ESHRE/ASRM-sponsored Consensus workshop do not recommend metformin for ovulation stimulation.^[12] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.^[13]

References

1. ^ Goldenberg N, Glueck C (2008). "Medical therapy in women with polycystic ovary syndrome before and during pregnancy and lactation". Minerva Ginecol 60 (1): 63–75. PMID 18277353. 
2. ^ Boomsma CM, Fauser BC, Macklon NS (2008). "Pregnancy complications in women with polycystic ovary syndrome". Semin. Reprod. Med. 26 (1): 72–84. doi:10.1055/s-2007-992927. PMID 18181085. 
3. ^ Palacio JR et,al.The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients Clin Exp Immunol. 2006 May;144(2):217-22.PMID 16634794
4. ^ Azziz R. et.al.The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004 Jun;89(6):2745-9. PMID 15181052
5. ^ ^{a b} Gorry A, White DM, Franks S (2006 Aug). "Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment". Endocrine 30 (1): 27–33. doi:10.1385/ENDO:30:1:27. PMID 17185789.  edit
6. ^ ^{a b c d} Brothers, K. J.; Wu, S.; Divall, S. A.; Messmer, M. R.; Kahn, C. R.; Miller, R. S.; Radovick, S.; Wondisford, F. E. et al. (2010). "Rescue of Obesity-Induced Infertility in Female Mice due to a Pituitary-Specific Knockout of the Insulin Receptor (IR)". Cell Metabolism 12 (3): 295–305. doi:10.1016/j.cmet.2010.06.010. PMC 2935812. PMID 20816095. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2935812.  edit
7. ^ Deepak A. Rao; Le, Tao; Bhushan, Vikas (2007). First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1). McGraw-Hill Medical. ISBN 0-07-149868-0. 
8. ^ ^{a b} Qiao, J.; Feng, H. L. (2010). "Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence". Human Reproduction Update 17 (1): 17. doi:10.1093/humupd/dmq032. PMC 3001338. PMID 20639519. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3001338.  edit
9. ^ "Question about opks with pcos". http://www.experts123.com/q/question-about-opks-with-pcos.html. Retrieved 7 May 2010. 
10. ^ Guermandi E, Vegetti W, Bianchi MM, Uglietti A, Ragni G, Crosignani P (2001). "Reliability of ovulation tests in infertile women" (– ^{Scholar search}). Obstet Gynecol 97 (1): 92–6. doi:10.1016/S0029-7844(00)01083-8. PMID 11152915. http://www.greenjournal.org/cgi/pmidlookup?view=long&pmid=11152915. ^{[dead link]}
11. ^ Legro RS, Barnhart HX, Schlaff WD (2007). "Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome". N Engl J Med 356 (6): 551–66. doi:10.1056/NEJMoa063971. PMID 17287476. 
12. ^ Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (March 2008). "Consensus on infertility treatment related to polycystic ovary syndrome". Fertil. Steril. 89 (3): 505–22. doi:10.1016/j.fertnstert.2007.09.041. PMID 18243179. 
13. ^ Johnson NP, Stewart AW, Falkiner J, et al. (April 2010). "PCOSMIC: a multi-centre randomized trial in women with PolyCystic Ovary Syndrome evaluating Metformin for Infertility with Clomiphene". Hum Reprod 25 (7): 1675–83. doi:10.1093/humrep/deq100. PMID 20435692.