Infertility in polycystic ovary syndrome

Infertility in polycystic ovary disease (PCOS) is a hormonal imbalance in women that is thought to be one of the leading causes of female infertility.[1][2][3][4] Polycystic ovary syndrome causes 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] gonadotropins (especially an increase in luteinizing hormone),[6][7] hyperandrogenemia,[8] and hyperinsulinemia.[8] Gonadotropins are released by gonadotroph cells in pituitary gland, and these cells appear to harbor insulin receptors, which are affected by elevated insulin levels.[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 reduces 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, though 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. A test for serum progesterone used to identify a healthy pregnancy from a miscarriage or ectopic pregnancy. Low progesterone levels are linked to miscarriages and ectopic pregnancies, both of which are considered non-viable pregnancies, whereas high progesterone levels are linked to viable pregnancies.[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. Women with PCOS often ovulate at any time during their cycle, to best increase chances of conceiving it is best to have intercourse at least every other day during the 2nd and 3rd week after their period ends.

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.

Basal body temperatures are not reliable for predicting ovulation.[10]

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. Preliminary evidence suggests that exercise may improve menstrual regularity, pregnancy and ovulation rates, but more research is needed.[11]

Ovulation induction

For those who after weight loss still are anovulatory or for anovulatory lean women, ovulation induction to reverse the anovulation is the principal treatment used to help infertility in PCOS. Letrozole and Clomiphene citrate are the first-line treatment in subfertile anovulatory patients with PCOS.[12] A Cochrane review showed that letrozole (an aromatase inhibitor) appears to improve live birth and pregnancy rates as compared to clomiphene citrate.[13] There appeared to be no difference between letrozole and laparoscopic ovarian drilling.[13] Gonadotrophins such as follicle-stimulating hormone (FSH) are, in addition to surgery, second-line treatments.[14]

In vitro fertilization

For patients who do not respond to diet, lifestyle modification and ovulation induction, 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

Surgery can be attempted in case of inefficient result with medications for ovulation induction.[14] 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.

A systematic review and meta-analysis in 2012[15] concluded that there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage, and multiple pregnancy rates in women with PCOS and a BMI less than 32 kg/m2.[15] It emphasized that a lack of superiority of one treatment is not evidence for equivalence.[15]

Another review in 2012[16] concluded that metformin improves pregnancy rates in women with PCOS when compared with placebo, and in addition to clomiphene compared with clomiphene alone, but not when compared directly with clomiphene. Also, however, it concluded that metformin does not improve live birth rates, whether used alone or in combination with clomiphene. It therefore concluded that the benefit of metformin in the improvement of reproductive outcomes in women with PCOS is limited.[16]

The ESHRE/ASRM-sponsored Consensus workshop does not recommend metformin for ovulation stimulation.[17] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene.[18]

When taken prior to or during IVF, there is no evidence that metformin treatment improves live birth rate in women with PCOS. However, metformin was found to increase clinical pregnancy rates and reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women with PCOS and undergoing IVF cycles.[19]

Prognosis

PCOS increases the time to pregnancy but does not necessarily reduce eventual family size.[14] It does not appear to increase miscarriage frequency.[14]

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. S2CID 13930098.
  3. Palacio JR, Iborra A, Ulcova-Gallova Z, Badia R, Martínez P (May 2006). "The presence of antibodies to oxidative modified proteins in serum from polycystic ovary syndrome patients". Clin. Exp. Immunol. 144 (2): 217–22. doi:10.1111/j.1365-2249.2006.03061.x. PMC 1809652. PMID 16634794.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO (June 2004). "The prevalence and features of the polycystic ovary syndrome in an unselected population". J. Clin. Endocrinol. Metab. 89 (6): 2745–9. doi:10.1210/jc.2003-032046. PMID 15181052.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. Gorry, A.; White, D. M.; Franks, S. (August 2006). "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. S2CID 20751100.
  6. Brothers, K. J.; Wu, S.; Divall, S. A.; Messmer, M. R.; Kahn, C. R.; Miller, R. S.; Radovick, S.; Wondisford, F. E.; Wolfe, A. (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.
  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 978-0-07-149868-5.
  8. 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): 17–33. doi:10.1093/humupd/dmq032. PMC 3001338. PMID 20639519.
  9. Cunha, Anita; Póvoa, Ana Margarida (26 January 2021). "Infertility management in women with polycystic ovary syndrome: a review". Porto Biomedical Journal. 6 (1): e116. doi:10.1097/j.pbj.0000000000000116. PMC 7846416. PMID 33532657.
  10. "Basal Body Temperature". Pacific Fertility Center. Retrieved 6 March 2015.
  11. Benham, J. L.; Yamamoto, J. M.; Friedenreich, C. M.; Rabi, D. M.; Sigal, R. J. (August 2018). "Role of exercise training in polycystic ovary syndrome: a systematic review and meta-analysis". Clinical Obesity. 8 (4): 275–284. doi:10.1111/cob.12258. ISSN 1758-8111. PMID 29896935. S2CID 48355953.
  12. Williams, Tracy; Mortada, Rami; Porter, Samuel (2016-07-15). "Diagnosis and Treatment of Polycystic Ovary Syndrome". American Family Physician. 94 (2): 106–13. ISSN 0002-838X. PMID 27419327.
  13. Franik, Sebastian; Le, Quang-Khoi; Kremer, Jan Am; Kiesel, Ludwig; Farquhar, Cindy (2022-09-27). "Aromatase inhibitors (letrozole) for ovulation induction in infertile women with polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 2022 (9): CD010287. doi:10.1002/14651858.CD010287.pub4. ISSN 1469-493X. PMC 9514207. PMID 36165742.
  14. Baird, D. T.; Balen, A.; Escobar-Morreale, H. F.; Evers, J. L. H.; Fauser, B. C. J. M.; Franks, S.; Glasier, A.; Homburg, R.; La Vecchia, C.; Devroey, P.; Diedrich, K.; Fraser, L.; Gianaroli, L.; Liebaers, I.; Sunde, A.; Tapanainen, J. S.; Tarlatzis, B.; Van Steirteghem, A.; Veiga, A.; Crosignani, P. G.; Evers, J. L. H. (2012). "Health and fertility in World Health Organization group 2 anovulatory women". Human Reproduction Update. 18 (5): 586–599. doi:10.1093/humupd/dms019. PMID 22611175.
  15. Misso, M. L.; Costello, M. F.; Garrubba, M.; Wong, J.; Hart, R.; Rombauts, L.; Melder, A. M.; Norman, R. J.; Teede, H. J. (2012). "Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: A systematic review and meta-analysis". Human Reproduction Update. 19 (1): 2–11. doi:10.1093/humupd/dms036. PMID 22956412.
  16. Tang, T.; Balen, A. H. (2012). "Use of metformin for women with polycystic ovary syndrome". Human Reproduction Update. 19 (1): 1. doi:10.1093/humupd/dms040. PMID 23114640.
  17. 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.
  18. 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.
  19. Farquhar, Cindy; Marjoribanks, Jane (17 August 2018). "Assisted reproductive technology: an overview of Cochrane Reviews". The Cochrane Database of Systematic Reviews. 2018 (8): CD010537. doi:10.1002/14651858.CD010537.pub5. ISSN 1469-493X. PMC 6953328. PMID 30117155.
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