Infertility in polycystic ovary syndrome

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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]

Contents

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.[ citation needed ]

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.[ citation needed ] 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.[ citation needed ]

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.[ citation needed ]

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.[ citation needed ]

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] [14] Gonadotrophins such as follicle-stimulating hormone (FSH) are, in addition to surgery, second-line treatments. [15]

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.[ citation needed ]

Surgery

Surgery can be attempted in case of inefficient result with medications for ovulation induction. [15] 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. [14]

Inefficacy of metformin

Previously, metformin was recommended treatment for anovulation.[ citation needed ]

A systematic review and meta-analysis in 2012 [16] 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. [16] It emphasized that a lack of superiority of one treatment is not evidence for equivalence. [16]

Another review in 2012 [17] 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. [17]

The ESHRE/ASRM-sponsored Consensus workshop does not recommend metformin for ovulation stimulation. [18] Subsequent randomized studies have confirmed the lack of evidence for adding metformin to clomiphene. [19]

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. [20]

Prognosis

PCOS increases the time to pregnancy but does not necessarily reduce eventual family size. [15] It does not appear to increase miscarriage frequency. [15]

Related Research Articles

<span class="mw-page-title-main">Polycystic ovary syndrome</span> Set of symptoms caused by abnormal hormones in females

Polycystic ovary syndrome, or polycystic ovarian syndrome (PCOS), is the most common endocrine disorder in women of reproductive age. The syndrome is named after cysts which form on the ovaries of some women with this condition, though this is not a universal symptom, and not the underlying cause of the disorder.

<span class="mw-page-title-main">Ovulation</span> Release of egg cells from the ovaries

Ovulation is the release of egg cells from the ovaries as part of the ovarian cycle for most vertebrates. In women, this event occurs at the end of the follicular phase, when the ovarian follicles rupture and release the secondary oocyte ovarian cells.

<span class="mw-page-title-main">Infertility</span> Inability to reproduce by natural means

Infertility is the inability of a couple to reproduce by natural means. It is usually not the natural state of a healthy adult. Exceptions include children who have not undergone puberty, which is the body's start of reproductive capacity. It is also a normal state in women after menopause.

Amenorrhea or amenorrhoea is the absence of a menstrual period in a female who has reached reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses during childhood and after menopause.

Anovulation is when the ovaries do not release an oocyte during a menstrual cycle. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause. Chronic anovulation is a common cause of infertility.

<span class="mw-page-title-main">Clomifene</span> Infertility treatment for women

Clomifene, also known as clomiphene, is a medication used to treat infertility in women who do not ovulate, including those with polycystic ovary syndrome. It is taken by mouth.

<span class="mw-page-title-main">Hyperandrogenism</span> Excess androgens (male-related hormones) in the body

Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.

An anovulatory cycle is a menstrual cycle characterised by the absence of ovulation and a luteal phase. It may also vary in duration from a regular menstrual cycle.

Fertility medications, also known as fertility drugs, are medications which enhance reproductive fertility. For women, fertility medication is used to stimulate follicle development of the ovary. There are very few fertility medication options available for men.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

<span class="mw-page-title-main">Female infertility</span> Diminished or absent ability of a female to achieve conception

Female infertility refers to infertility in women. It affects an estimated 48 million women, with the highest prevalence of infertility affecting women in South Asia, Sub-Saharan Africa, North Africa/Middle East, and Central/Eastern Europe and Central Asia. Infertility is caused by many sources, including nutrition, diseases, and other malformations of the uterus. Infertility affects women from around the world, and the cultural and social stigma surrounding it varies.

<span class="mw-page-title-main">Follicular atresia</span>

Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.

Ovulation induction is the stimulation of ovulation by medication. It is usually used in the sense of stimulation of the development of ovarian follicles to reverse anovulation or oligoovulation.

Controlled ovarian hyperstimulation is a technique used in assisted reproduction involving the use of fertility medications to induce ovulation by multiple ovarian follicles. These multiple follicles can be taken out by oocyte retrieval for use in in vitro fertilisation (IVF), or be given time to ovulate, resulting in superovulation which is the ovulation of a larger-than-normal number of eggs, generally in the sense of at least two. When ovulated follicles are fertilised in vivo, whether by natural or artificial insemination, there is a very high risk of a multiple pregnancy.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

Ovarian drilling, also known as multiperforation or laparoscopic ovarian diathermy, is a surgical technique of puncturing the membranes surrounding the ovary with a laser beam or a surgical needle using minimally invasive laparoscopic procedures. It differs from ovarian wedge resection, which involves the cutting of tissue. Minimally invasive ovarian drilling procedures have replaced wedge resections. Ovarian drilling is favored over wedge resection because cutting into the ovary might result in adhesions, potentially complicating postoperative outcomes. Ovarian drilling and ovarian wedge resection are treatment options to reduce the amount of androgen producing tissue in women with polycystic ovarian syndrome (PCOS). PCOS is the primary cause of anovulation, which results in female infertility. The induction of mono-ovulatory cycles can restore fertility.

Induction of final maturation of oocytes is a procedure that is usually performed as part of controlled ovarian hyperstimulation to render the oocytes fully developed and thereby resulting in optimal pregnancy chances. It is basically a replacement for the luteinizing hormone (LH) surge whose effects include final maturation in natural menstrual cycles.

Obesity is defined as an abnormal accumulation of body fat, usually 20% or more over an individual's ideal body weight. This is often described as a body mass index (BMI) over 30. However, BMI does not account for whether the excess weight is fat or muscle, and is not a measure of body composition. For most people, however, BMI is an indication used worldwide to estimate nutritional status. Obesity is usually the result of consuming more calories than the body needs and not expending that energy by doing exercise. There are genetic causes and hormonal disorders that cause people to gain significant amounts of weight but this is rare. People in the obese category are much more likely to suffer from fertility problems than people of normal healthy weight.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.

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. 1 2 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. 1 2 3 4 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. 1 2 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. Archived from the original on 5 March 2016. 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. 1 2 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. 1 2 Bordewijk, Esmée M.; Ng, Ka Ying Bonnie; Rakic, Lidija; Mol, Ben Willem J.; Brown, Julie; Crawford, Tineke J.; van Wely, Madelon (2020-02-11). "Laparoscopic ovarian drilling for ovulation induction in women with anovulatory polycystic ovary syndrome". The Cochrane Database of Systematic Reviews. 2 (2): CD001122. doi:10.1002/14651858.CD001122.pub5. ISSN   1469-493X. PMC   7013239 . PMID   32048270.
  15. 1 2 3 4 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.
  16. 1 2 3 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.
  17. 1 2 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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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