PCOS: How Does it Affect Pregnancy Outcomes?

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women of reproductive age, with a prevalence estimated to be between 6-12% globally (Teede et al., 2018). PCOS is characterized by a combination of symptoms and signs that may include hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. The syndrome is also associated with a wide range of metabolic, reproductive, and psychological issues, significantly affecting a woman’s health and quality of life. This article explores what PCOS is, the diagnostic criteria, its pathophysiology, and how it affects a woman’s chances of pregnancy.

Definition and Diagnostic Criteria

PCOS is defined by a spectrum of symptoms and is typically diagnosed based on the Rotterdam criteria, which require the presence of at least two of the following three features:

(1) oligo- or anovulation,

(2) clinical and/or biochemical signs of hyperandrogenism, and

(3) polycystic ovaries on ultrasound, after excluding other etiologies that might present similarly, such as congenital adrenal hyperplasia, androgen-secreting tumors, or Cushing’s syndrome (Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004).

The presence of polycystic ovaries on ultrasound is defined as having 12 or more follicles measuring 2-9 mm in diameter in one or both ovaries, and/or increased ovarian volume (>10 cm³). It is important to note that not all women with polycystic ovaries on ultrasound have PCOS; thus, the diagnosis should be made based on the full clinical picture (Azziz et al., 2009).

Pathophysiology of PCOS

The exact etiology of PCOS is not fully understood, but it is considered to be multifactorial, involving genetic, environmental, and hormonal factors. Insulin resistance and hyperinsulinemia play a central role in the pathogenesis of PCOS and contribute to hyperandrogenism by stimulating ovarian androgen production and reducing sex hormone-binding globulin (SHBG) levels, thereby increasing the bioavailability of androgens (Dunaif, 2016). Hyperandrogenism, in turn, disrupts the normal follicular development, leading to anovulation and the characteristic polycystic ovarian morphology (Goodarzi et al., 2011).

PCOS is also associated with chronic low-grade inflammation, which may contribute to the metabolic and reproductive abnormalities observed in affected women (González et al., 2012). The chronic anovulation observed in PCOS results from dysregulation of the hypothalamic-pituitary-ovarian (HPO) axis, with elevated levels of luteinizing hormone (LH) relative to follicle-stimulating hormone (FSH) being a common finding (Ibáñez et al., 2017).

PCOS and Fertility

PCOS is one of the leading causes of infertility in women due to its association with anovulation and irregular menstrual cycles. The impact of PCOS on a woman’s chances of pregnancy is multifaceted and can be influenced by several factors, including the severity of the syndrome, the presence of metabolic disturbances, and the woman’s age.

Anovulation and Irregular Menstrual Cycles

One of the primary ways in which PCOS affects fertility is through anovulation, where the ovaries do not regularly release an egg. This leads to irregular menstrual cycles, which are often infrequent (oligomenorrhea) or absent (amenorrhea) (Legro et al., 2013). Without regular ovulation, the chances of natural conception are significantly reduced. Women with PCOS may experience long intervals between menstrual periods, during which ovulation does not occur, making it difficult to time intercourse for conception (Balen et al., 2016).

Hormonal Imbalances

The hormonal imbalances characteristic of PCOS, particularly elevated androgen levels and the resulting hyperandrogenism, contribute to impaired folliculogenesis, which is the process of follicle development and maturation within the ovaries (Rosenfield and Ehrmann, 2016). Elevated LH levels relative to FSH can also disrupt the normal menstrual cycle and contribute to the development of anovulatory cycles, further reducing fertility (Teede et al., 2018).

Metabolic Disturbances

PCOS is frequently associated with insulin resistance, which affects approximately 50-70% of women with the syndrome, independent of obesity (Dunaif, 2016). Insulin resistance and compensatory hyperinsulinemia contribute to the pathophysiology of PCOS by exacerbating hyperandrogenism and disrupting normal ovulatory function (Goodarzi et al., 2011). Moreover, women with PCOS are at an increased risk of developing type 2 diabetes and metabolic syndrome, conditions that can further impair fertility and pregnancy outcomes (Legro et al., 2013).

Obesity, which is commonly observed in women with PCOS, particularly central obesity, further aggravates insulin resistance and hyperandrogenism, creating a vicious cycle that perpetuates the reproductive and metabolic abnormalities (Carmina and Lobo, 1999). Weight loss in overweight and obese women with PCOS has been shown to improve ovulatory function and enhance the chances of pregnancy, both naturally and in response to fertility treatments (Moran et al., 2011).

Impact on Assisted Reproductive Technologies (ART)

Women with PCOS often seek assisted reproductive technologies (ART) such as ovulation induction, intrauterine insemination (IUI), and in vitro fertilization (IVF) to achieve pregnancy. However, PCOS can influence the outcomes of these treatments.

Ovulation induction is typically the first-line treatment for anovulatory women with PCOS who are trying to conceive. Medications such as clomiphene citrate (CC) and letrozole, an aromatase inhibitor, are commonly used to induce ovulation (Legro et al., 2014). Letrozole has been shown to be more effective than clomiphene citrate in inducing ovulation and achieving live births in women with PCOS (Legro et al., 2014). However, some women with PCOS may be resistant to clomiphene citrate, necessitating the use of alternative or adjunctive therapies, such as metformin or gonadotropins (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008).

IVF is another treatment option for women with PCOS, particularly those who do not respond to ovulation induction or who have additional infertility factors. However, women with PCOS undergoing IVF are at an increased risk of ovarian hyperstimulation syndrome (OHSS), a potentially life-threatening complication characterized by enlarged ovaries and fluid accumulation in the abdomen and chest (Speroff and Fritz, 2011). Strategies such as the use of a GnRH antagonist protocol, triggering ovulation with a GnRH agonist instead of human chorionic gonadotropin (hCG), and freezing all embryos for later transfer can reduce the risk of OHSS in these women (Humaidan et al., 2012).

Despite these challenges, women with PCOS generally have a good prognosis for IVF, with high numbers of oocytes retrieved and comparable pregnancy and live birth rates to women without PCOS when OHSS is effectively managed (Heijnen et al., 2006). However, the quality of the oocytes and embryos in women with PCOS may be compromised due to the underlying hormonal imbalances and metabolic disturbances, which can affect implantation and early pregnancy outcomes (Palomba et al., 2009).

Pregnancy Complications

Even after achieving pregnancy, women with PCOS are at an increased risk of several obstetric complications, including gestational diabetes mellitus (GDM), preeclampsia, preterm birth, and higher rates of cesarean delivery (Boomsma et al., 2006). The increased risk of GDM is particularly concerning, as it is associated with adverse maternal and neonatal outcomes, including macrosomia, birth injuries, and the development of type 2 diabetes in both the mother and the child later in life (Teede et al., 2018).

The mechanisms underlying these complications are likely related to the metabolic disturbances and chronic inflammation associated with PCOS. Insulin resistance, hyperglycemia, and dyslipidemia contribute to endothelial dysfunction and an increased risk of hypertensive disorders of pregnancy, such as preeclampsia (Boomsma et al., 2006). Additionally, the altered intrauterine environment in women with PCOS may affect fetal development and increase the risk of preterm birth and other adverse outcomes (Palomba et al., 2015).

Management of PCOS for Fertility

The management of PCOS in women seeking to conceive involves addressing both the reproductive and metabolic aspects of the syndrome. Lifestyle interventions, such as weight loss, dietary modifications, and increased physical activity, are recommended as first-line treatments for overweight and obese women with PCOS (Teede et al., 2018). These interventions have been shown to improve insulin sensitivity, reduce androgen levels, and restore ovulatory function, thereby enhancing fertility (Moran et al., 2011).

Pharmacological treatments, such as ovulation induction agents (e.g., letrozole, clomiphene citrate), insulin sensitizers (e.g., metformin), and in some cases, anti-androgens, may be used to manage specific symptoms and improve reproductive outcomes. In women who do not respond to ovulation induction or have additional infertility factors, ART may be necessary, with careful monitoring and individualized treatment protocols to minimize the risk of complications (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008).

Lifestyle Modifications

Lifestyle modifications, particularly those aimed at achieving and maintaining a healthy weight, are foundational in managing PCOS-related infertility. Weight loss, even a modest reduction of 5-10% of body weight, has been shown to significantly improve ovulatory function, menstrual regularity, and insulin sensitivity in overweight and obese women with PCOS (Moran et al., 2011). These improvements are often associated with increased chances of natural conception and better outcomes with fertility treatments.

Dietary interventions focusing on a balanced intake of carbohydrates, proteins, and fats, as well as the reduction of refined sugars and processed foods, are commonly recommended. Regular physical activity is also encouraged, not only for weight management but also for its positive effects on insulin sensitivity and cardiovascular health (Teede et al., 2018).

Pharmacological Interventions

For women with PCOS who do not ovulate regularly or at all, ovulation induction is a primary treatment strategy. As previously mentioned, letrozole has emerged as the preferred first-line agent over clomiphene citrate due to its superior effectiveness in inducing ovulation and achieving live births (Legro et al., 2014). Letrozole works by inhibiting the aromatase enzyme, thereby reducing estrogen levels and allowing for the release of gonadotropins, which stimulates ovulation.

Clomiphene citrate, a selective estrogen receptor modulator, was historically the first-line treatment for ovulation induction. While effective in many cases, clomiphene citrate has limitations, including a lower ovulation and pregnancy rate in women with clomiphene resistance, a condition observed in about 15-40% of women with PCOS (Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008).

Metformin, an insulin sensitizer, is often used in women with PCOS, especially those who exhibit insulin resistance. Metformin improves insulin sensitivity, lowers insulin levels, and may reduce androgen production by the ovaries, potentially restoring ovulatory function (Diamanti-Kandarakis and Dunaif, 2012). While metformin is not as effective as ovulation induction agents in inducing ovulation on its own, it is often used as an adjunct to improve the effectiveness of other treatments or to reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women undergoing IVF (Palomba et al., 2009).

Anti-androgens and oral contraceptives are typically used to manage hyperandrogenic symptoms such as hirsutism and acne rather than directly treating infertility. However, these medications may be used temporarily to regulate menstrual cycles before attempting conception, particularly in women with severe hyperandrogenism (Azziz et al., 2009).

In cases where ovulation induction is unsuccessful or where there are additional factors contributing to infertility (such as male factor infertility), assisted reproductive technologies like intrauterine insemination (IUI) or in vitro fertilization (IVF) may be necessary.

Intrauterine Insemination (IUI): IUI is often considered when ovulation is successfully induced but natural conception has not occurred. This procedure involves placing washed sperm directly into the uterus around the time of ovulation, increasing the chances of sperm meeting the egg. IUI is less invasive and less expensive than IVF, making it an attractive option for some couples (Heijnen et al., 2006).

In Vitro Fertilization (IVF): IVF is a more advanced fertility treatment that may be recommended for women with PCOS, particularly if other methods have failed or if there are significant concerns about other fertility issues. IVF involves stimulating the ovaries to produce multiple eggs, retrieving the eggs, fertilizing them in a laboratory, and then transferring the resulting embryos into the uterus.

While IVF can be highly effective, women with PCOS are at an increased risk of ovarian hyperstimulation syndrome (OHSS), as mentioned earlier. OHSS can be a severe and potentially life-threatening condition, characterized by rapid fluid accumulation, blood clots, and kidney failure. To mitigate this risk, clinicians may employ a “freeze-all” strategy, where all embryos are frozen after retrieval and transferred in a subsequent cycle, or use a GnRH antagonist protocol and trigger ovulation with a GnRH agonist instead of hCG (Humaidan et al., 2012).

Pregnancy and Long-Term Health Considerations

Once pregnancy is achieved, women with PCOS are at higher risk for several complications, including gestational diabetes mellitus (GDM), preeclampsia, and preterm birth (Boomsma et al., 2006). The increased risk of GDM is particularly concerning, as it is associated with a higher likelihood of cesarean delivery, macrosomia, and type 2 diabetes later in life for both mother and child (Teede et al., 2018).

Close monitoring and management of these risks are crucial during pregnancy. For example, screening for gestational diabetes typically occurs earlier in pregnancy for women with PCOS, and lifestyle interventions or pharmacological treatments may be necessary to manage blood glucose levels.

Beyond reproductive health, women with PCOS are at increased risk for a number of long-term health issues, including metabolic syndrome, cardiovascular disease, and type 2 diabetes. These risks are largely driven by the insulin resistance and chronic inflammation associated with PCOS (González et al., 2012). Therefore, ongoing management of PCOS often involves addressing these metabolic concerns through lifestyle interventions, regular screening for cardiovascular risk factors, and, in some cases, pharmacological treatment.

PCOS is a complex and multifaceted condition that significantly impacts a woman’s reproductive health and overall well-being. The syndrome is characterized by a combination of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, all of which contribute to infertility and other reproductive challenges. The impact of PCOS on fertility is largely mediated through anovulation, hormonal imbalances, and metabolic disturbances, including insulin resistance.

While PCOS can pose significant challenges to conception, a range of treatment options is available to improve fertility outcomes. These include lifestyle modifications, ovulation induction agents, insulin sensitizers, and assisted reproductive technologies like IUI and IVF. Despite the challenges, many women with PCOS can achieve pregnancy and have successful outcomes with appropriate management.

Ongoing research into the pathophysiology of PCOS and the development of more effective treatments holds promise for improving the quality of life and reproductive outcomes for women with this common condition.

References

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