30Reproductive and Obstetrical Consequencesof the Polycystic Ovary Syndrome

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333

From: Contemporary Endocrinology: Androgen Excess Disorders in Women:

Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ

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Reproductive and Obstetrical Consequences of the Polycystic Ovary Syndrome

Mary C. Johnson and Richard S. Legro

SUMMARY

Polycystic ovary syndrome (PCOS) is a disorder associated with infertility and subfecundity. There is evidence that both the oocyte and the endometrium have abnormalities that contribute to these disorders. These reproductive abnormalities include anovulation, increased early pregnancy wastage, and probable increased risk for a number of pregnancy complications including gestational diabetes and hypertensive disorders of pregnancy, such as pre-eclampsia. Ovulation induction holds the additional iatrogenic risks of multiple pregnancy and ovarian hyperstimulation syndrome. Gonadotropins and gonadotropin agonist therapies should be used with caution in this group of patients. There is emerging evidence that insulin-sensitizing therapy provides benefit for a wide variety of these reproductive abnormalities. In the long term, women with PCOS have multiple risk factors for the development of endometrial cancer, including centripetal obesity, hyperinsulinemia, diabetes, and chronic anovulation, although the association between PCOS and this cancer is less well established in the epidemiological literature. There is little evidence to date that insulin-sensitizing therapies protect against the development of endometrial hyperplasia and cancer.

Key Words: Hyperandrogenism; insulin resistance; pre-eclampsia; gestational diabetes; pregnancy.

1. INTRODUCTION

Polycystic ovary syndrome (PCOS) is an endocrine disorder of unexplained etiology found in approximately 5–7% of the female population (1). According to a 2003 expert consensus statement, the diagnosis of PCOS requires the patient to have at least two of the following three characteristics:

(1) oligo- or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, and (3) polycystic ovaries. The diagnosis of PCOS also requires the exclusion of other possible etiologies, such as congenital adrenal hyperplasia, androgen-secreting tumors, and Cushing’s syndrome (2). Women with PCOS typically present with menstrual dysfunction, hirsutism, and infertility.

This chapter focuses on the reproductive challenges of women with PCOS. Although there are PCOS-associated reproductive difficulties independent of obesity, obesity acts synergistically with PCOS to further confound attempts to successfully conceive and maintain a pregnancy to full term. It is estimated that approximately 50% of women with PCOS are obese, but more recent studies including multicenter trials and large family studies have shown that the vast majority are obese (up to 80%), and mean body mass index (BMI) approaches or exceeds 35 kg/M². The reproductive challenges associated with PCOS discussed in this chapter are infertility, multiple pregnancy, ovarian hyperstimulation syndrome (OHSS), gestational diabetes, miscarriage and pregnancy loss, pre- eclampsia and eclampsia, and endometrial cancer.

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334 Johnson and Legro

2. BACKGROUND

2.1. Infertility and Anovulation

PCOS is the most common cause of anovulatory infertility and may account for more than 75% of cases of anovulatory infertility (3). However, not all women with PCOS are completely amenorrheic.

The majority of women with PCOS are oligomenorrheic and experience varying intervals of vaginal bleeding.

Abnormal ovulatory function associated with PCOS is distinguished by dysfunctional folliculogenesis and abnormal steroidogenesis. Follicular development within the ovary of a patient with PCOS occurs until an approximate follicular diameter of 5–8 mm, at which point follicular growth arrests. Proper evidence has yet to explain the cessation of development, but androgen excess in the intrafollicular milieu, exogenous follicle-stimulating hormone (FSH) deficiency, and the effects of hyperinsulinemia and insulin resistance in the follicle have all been identified as factors contributing to the follicular arrest and atresia that characterizes PCOS.

The premature discontinuation of follicle maturation occurs at a point when rising FSH levels should influence the developing follicles to produce increasing amounts of estrogen in the granulosa cells; exponential follicular growth should follow. It is postulated that an FSH deficiency prevents this next step and that the FSH deficiency may be secondary to increased inhibin production. Inhibin B, which is normally released in a pulsatile manner, selectively inhibits FSH secretion. In women with PCOS, inhibin B is secreted steadily, without pulsatility, and its abnormal secretory pattern has been postulated to induce the abnormal folliculogenesis (4). The gonadotropic properties of insulin should also be taken into account. In vivo, hyperinsulinemia prematurely stimulates granulosa cells, arresting their growth and aromatase activity. Thus, progesterone production is increased, follicular development ceases, and follicular dominance fails to proceed.

It is interesting to note that of all the clinical and biochemical characteristics of PCOS, hyperinsulinemia is the most strongly associated with anovulation. Abnormal steroidogenesis seems to also be key in the pathogenesis of infertility in women with PCOS. Hyperandrogenemia remains one of the classic biochemical and clinical features of PCOS. Excess androgens have been found to inhibit endometrial epithelial cell growth and secretory activity in vitro (5). By inhibiting growth, hyperandrogenemia may prevent fertility and also increase the probability of early termination of the pregnancy.

Especially with regard to infertility, obesity acts synergistically with PCOS to confound patients and their physicians; patients with PCOS who are overweight are less likely to conceive than those patients with PCOS of healthy weight. In fact, in one large in vitro fertilization series that examined factors associated with failure, obesity was found to significantly predict pregnancy failure and loss (6). Obesity is further associated with an inadequate response to both ovulation-induction agents as well as insulin sensitizers (7).

2.2. Iatrogenic Complications of Ovulation Induction in PCOS

Women with PCOS are at risk for iatrogenic complications of ovulation induction for anovulatory infertility. These include OHSS and multiple pregnancy. An inherent ovarian abnormality may contribute to these complications. One promise of ovulation induction with insulin-sensitizing therapies, as opposed to the more often utilized treatment with traditional ovulation-induction strategies such as clomiphene citrate and gonadotropins, is a lower rate of multiple follicular recruitment and lower risk of these iatrogenic complications (Fig. 1).

2.2.1. Ovarian Hyperstimulation Syndrome

The strongest association between OHSS and PCOS is with young, thin women with polycystic ovaries who undergo superovulation with urinary human menopausal gonadotropin (hMG) prepara- tions and use a gonadotropin-releasing hormone (GnRH) agonist (8). It must also be acknowledged

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that all women with PCOS are not at the same risk for OHSS because of the great confounder of obesity, that with progressive increases tends to ameliorate risk. Nevertheless, it is interesting to note that PCOS has been reported to be associated with OHSS developing in spontaneous cycles as well as with the use of clomiphene citrate, both of which are only rarely associated with OHSS in the larger population.

Severe OHSS results in massive enlargement of the ovaries, formation of multiple ovarian cysts, extravascular fluid accumulation, ascites, and intravascular volume depletion. In severe cases, hyper- coagulability and embolic events can develop, and systemic organ failure can occur (9). To a degree, OHSS is a risk to any woman treated with ovulation induction. However, a consistent relationship has been found between the anatomical finding of polycystic ovaries and OHSS, designating poly- cystic ovaries as an additional risk factor (10). The pathogenesis of OHSS is still unclear.

During ovulation induction with gonadotropins, women with PCOS and OHSS frequently are plagued with an inordinate number of midsize follicles, which are not thought to produce a compe- tent oocyte, but contribute significantly to the circulating estradiol pool and ultimately to the risk for OHSS. Women with polycystic ovaries in the baseline state appear to have an inordinate number of growing primary follicles—up to six times more than women with normal ovaries (11). The increased density of small preantral follicles in polycystic ovaries could result from increased population of the fetal ovary by germ cells or from decreased rate of loss of oocytes during late gestation, childhood, and puberty. More recently, animal data have suggested that oocytes can develop from mesenchymal stem cells in the bone marrow (12), which has challenged one of the central dogmas of ovarian physiology, which states that there are no new developments of oocytes postnatally and there is only atresia, albeit at varying rates, after birth. These data suggest that oocytes can develop from stem cells during the life span of the organism, and it awaits confirmation in human studies.

Patients with polycystic ovaries, which includes but is not limited to patients with PCOS, are a population that should receive special education about the risks of OHSS; primary prevention of OHSS could avoid uncomfortable and potentially life-threatening complications, such as renal failure, hepatic failure, and thromboembolism. Elevated or rapidly rising estradiol levels have been identified as predictive markers for the development of OHSS as well as the absolute number of follicles.

Women with PCOS should be monitored very closely when undergoing ovulation induction with Fig. 1. There are multiple methods to induce ovulation in women with PCOS, which can alter testosterone levels (T), gonadotropins (FSH), and sex hormone-binding globulin (SHBG). GnRH, gonadotropin-releasing hormone.

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gonadotropins. A low-dose step-up ovulation-induction protocol, with the guiding principle of start- ing at a low dose (37.5–75 U/day) and increasing in small increments at 10- to 14-day intervals, appears effective at reducing the risk for OHSS (13). A Cochrane Library meta-analysis has found that FSH-only gonadotropin preparations significantly lower the risk for OHSS compared with human menopausal gonadotropin preparations (odds ratio [OR] 0.20; 95% confidence interval [CI]

0.08–0.46), and the concomitant use of a GnRH agonist with gonadotropin therapy increases the risk for OHSS (OR 3.15; 95% CI 1.46–6.70) (14).

2.2.2. Multiple Pregnancy (seeTable 1)

Multiple pregnancy confers substantially increased fetal and maternal risk compared with a singleton pregnancy. It is assumed that women with PCOS are at increased risk for multiple pregnancy, but it is uncertain whether PCOS confers additional risk above and beyond that of ovulation induction.

There is no evidence that the spontaneous twinning rate is higher in women with PCOS. In a large series of 1803 women who underwent ovarian drilling for anovulatory infertility, there were 1076 pregnancies and a 2.3% twinning rate (15). Although this exceeds the expected spontaneous twinning rate of 0.8%, many of these resulted from subsequent ovulation induction (15). In one large series of pregnancies resulting from ovulation induction with clomiphene citrate (PCOS probably was the largest underlying diagnosis), the twinning rate was 6.9% and the triplet rate 0.5% (16).

In women with PCOS undergoing ovulation induction with gonadotropins, the multiple pregnancy rate was 20%, comparable with women undergoing the same treatment for unexplained infertility (17). However, the same risk factors for OHSS,that is, multiple and excessive follicular develop- ment, probably also place women with PCOS undergoing gonadotropin stimulation at increased risk for multiple pregnancy. The use of insulin-sensitizing agents holds the promise of monofollicular ovulation and singleton pregnancy. A recent randomized trial did demonstrate no multiple pregnan- cies on metformin, but there were also no multiple pregnancies in the clomiphene arm (18).

2.3. Other Pregnancy Complications

Anovulatory infertility is just one mechanism that contributes to subfecundity in women with PCOS. Other causes that lead to a decreased live birth rate and/or perinatal morbidity include higher

Table 1

Maternal and Fetal Complications of Multiple Pregnancy Maternal

• Need for fetal reduction

• Pregnancy complications:

• Anemia, PIH, gestational diabetes, IUGR

• Increased rate of cesarean delivery

• Increased risk of postpartum hemorrhage?

• Increased risk of postpartum stress/depression?

• Increased risk of miscarriage?

Fetal

• Prematurity

• Low birthweight

• Malformations

• Cerebral palsy from traumatic deliver

• Learning disabilities?

• Delayed development?

• Diabetes mellitus in the long term?

PIH, pregnancy-induced hypertension; IUGR, intrauterine growth restriction.

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rates of first-trimester pregnancy loss and an increased risk for later pregnancy complications, including pre-eclampsia and gestational diabetes.

2.3.1. Early Pregnancy Loss and Miscarriage

Women with PCOS appear to have increased rates of pregnancy loss, and this has been associated with increased luteinizing hormone (LH) secretion (19), excess androgen production (20), and most recently insulin resistance (21). It is difficult to untangle the contributions of these reproductive and metabolic abnormalities in PCOS and their effect on early pregnancy loss. Because these women are subfecund and undergo infertility treatment and the accompanying increased surveillance, early non- viable pregnancies are more likely to be detected in this population. Depending on when the pregnancy is detected, pregnancy loss rates in humans have been estimated to range from 20 to 50% per conception (22). Thus, we are not a particularly fecund species compared with some of our mamma- lian counterparts. There is likely a considerable detection bias in examining the early pregnancy outcomes in women with PCOS, and it is difficult to determine if pregnancy loss rates exceed those of other subfecund populations receiving similar surveillance. However, there remain concerns about the competency of oocytes that develop in the PCOS milieu, and clearly endometrial abnormalities appear common, such that implantation failure may further contribute to pregnancy loss.

Obesity, which affects up to 80–90% of women with PCOS in the United States, is also a major factor in pregnancy loss. The high risk of spontaneous abortion associated with PCOS is partially related to the increased prevalence of obesity in women with PCOS; the incidence of spontaneous abortion increases with increasing BMI (6,23). Small randomized trials of pregnancy and pregnancy outcomes have shown lower pregnancy loss rates in pregnancies conceived with metformin (18,24) compared with conventional treatments, providing support for the idea of insulin resistance contributing to pregnancy loss in these women. Many researchers have begun empirically to use metformin throughout the first trimester (and longer) to prevent pregnancy loss and have reported a marked improvement in pregnancy rates (21,25). These remain essentially large case series and await confir- mation in prospective, appropriately powered, multicenter trials. A healthy skepticism is in order because the track record of interventions to prevent pregnancy loss has been marred with treatments causing fetal and maternal harm (e.g., diethylstilbestrol [DES], administration of intravenous J-globulin, paternal leukocyte immunization).

2.3.2. Gestational Diabetes

Gestational diabetes affects about 4–5% of pregnancies in the United States and entails the risk of both maternal and fetal complications. Fetal risks include macrosomia, an increased perinatal morbidity rate, an increased likelihood of birth trauma, including shoulder dystocia and related brachial plexus injuries, and neonatal hypoglycemia and hypocalcemia. Maternal complications include birth trauma related to macrosomia, an increased risk for gestational hypertension, including pre-eclampsia, and complications of diabetes.

Gestational diabetes is usually detected at around 28 weeks gestation by routine glucose challenge testing. The etiology of gestational diabetes is thought to be primarily a result of an acquired insulin resistance that is induced by the hormonal changes of pregnancy. Women with PCOS are thought to be at a higher risk for developing gestational diabetes because they often exhibit insulin resistance even before pregnancy; up to 80% of obese and 30% of lean women with PCOS demonstrate insulin resistance prior to pregnancy (26). There are a number of placental hormones, including human pla- cental lactogen, and maternal hormones, such as glucocorticoids, whose ultimate physiological goal is to blunt maternal glucose uptake and shunt glucose to the fetus, because glucose remains the primary and preferred growth substrate of the developing fetus. In women who also have preexisting insulin resistance and some degree of E-cell dysfunction (thought to characterize the majority of women with PCOS), pregnancy and its accompanying acquired insulin resistance may exceed the compensatory ability of the pancreas. Gestational diabetes occurs when a woman’s body cannot com- pensate for increased metabolic demands of pregnancy.

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Although obesity is one of the primary predicting factors for gestational diabetes, the effects of PCOS have also been found to be significant, even after adjusting for the effect of increasing BMI (27). PCOS carried a nearly twofold increased risk for developing gestational diabetes, with a rate of 20% compared to 9% in the control population (27). In another report, 9 of 22 women with PCOS developed gestational diabetes (28).

One critique of these and other studies involves the relatively small sample size. Some authors have recommended the use of metformin throughout pregnancy to reduce the risk of gestational diabetes, and in one small randomized trial there appeared to be a benefit, but this remains an extreme and unproven strategy for the prevention of gestational diabetes. The effects of developing gestational diabetes carry on well after the pregnancy, because women with a history of gestational diabe- tes mellitus have a 50% chance of developing type 2 diabetes later in life (29). This necessitates periodically rescreening women with gestational diabetes for the development of type 2 diabetes.

2.3.3. Pre-Eclampsia and Eclampsia

Pre-eclampsia is characterized by maternal hypertension and proteinuria. Onset is typically after the 20th week of pregnancy, and pre-eclampsia complicates 3-4% of pregnancies. Eclampsia occurs when the pre-eclampsia condition results in seizures; eclampsia is the second leading cause of maternal death in the United States. Currently, the only mainstay therapy for severe pre-eclampsia is delivery of the baby.

A significant association has been found between first-trimester insulin resistance and risk of pre- eclampsia (30). This is particularly notable for women with PCOS, who, as noted before, are typi- cally insulin resistant before pregnancy. In addition, women with PCOS have been found to be at an increased risk of pre-eclampsia independent of BMI and ovulation induction (31). Because elevated BMI, preexisiting insulin resistance and metabolic syndrome, the iatrogen contribution of multiple pregnancies, from fertility treatment are also associated with pre-eclampsia, of women with PCOS are at great risk for pre-eclampsia and should be monitored accordingly.

2.4. Endometrial Cancer

Endometrial cancer is the most common malignancy of the lower female genital tract but fortu- nately in its most common form, adenocarcinoma, has the best prognosis, with overall 5-year sur- vival for stage 1 cancers well above 90%. Endometrial cancer is considered a late reproductive sequele of PCOS and is thought to be increased as a result of the history of chronic anovulation and unop- posed estrogen (32). However, it can equally be considered a late metabolic sequela of PCOS, as the classic risk factors for endometrial cancer are age, obesity (especially centripetal obesity), and diabe- tes (33). In case series, women with PCOS have been overrepresented in developing endometrial cancer and often at an early age (34).

However, when the hard evidence is closely observed, there is a paucity of studies, especially well-designed prospective studies, or even retrospective case-control studies documenting increased risk of endometrial cancer in women with PCOS (34). This may be because endometrial cancer remains primarily a disease of postmenopausal women, with 90% of the cases occurring in the population past 50 years of age, and it is difficult to diagnose PCOS in this age range after natural ovarian failure and cessation of menses. A Scandinavian study that looked at a group of both pre- menopausal and postmenopausal women with endometrial carcinoma found hirsutism and obesity in both affected groups more often compared to controls (35). In the younger group they additionally noted a recent history of anovulation and infertility, two of the most common presenting complaints of women with PCOS (in addition to hirsutism and obesity).

Adenocarcinoma of the endometrium is thought to be a progressive disease that originates from adenomatous hyperplasia, specifically atypical hyperplasia. Endometrial hyperplasia has also often been noted in association with anovulation and infertility (32). In a large case–control study, increased endometrial cancer risk was noted in women with lower levels of sex hormone-binding globulin (36)

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and elevated insulin levels (37), both biochemical stigmata noted in women with PCOS. There are no systematic prospective studies of the prevalence of endometrial hyperplasia/neoplasia in a population with PCOS or conversion rates over time, although one single-center study noted a high preva- lence of endometrial hyperplasia in women with PCOS (36%) seeking fertility (38). No routine screening recommendations can be made at this time, and there have been no prospective preventive trials in at-risk women, although in epidemiological studies, use or any-time use of the oral contraceptive pill provides a strong preventive benefit against endometrial cancer (Fig. 2) as well as against the development of ovarian cancer (39). See Chapter 27 for further discussion of the mechanisms underlying a potential increased rise of endometrial carcinoma in PCOS.

3. CONCLUSIONS

PCOS is a disorder associated with infertility and subfecundity. These reproductive abnormalities include anovulation, increased early pregnancy wastage, and increased probability for a number of pregnancy complications including gestational diabetes and hypertensive disorders of pregnancy, such as pre-eclampsia. There is evidence that both the oocyte and the endometrium have abnormalities that contribute to these disorders. In the long term, women with PCOS have multiple risk factors for the development of endometrial cancer, although the association between PCOS and this cancer is less well established in the epidemiological literature.

4. FUTURE AVENUES OF INVESTIGATION

A number of issues remain to be addressed in our understanding of the reproductive and obstetrical consequences of PCOS, including the need for the following:

1. Prospective trials examining pregnancy complications of weight-matched women with and without PCOS from conception to delivery

2. Randomized trials of metformin to prevent pregnancy loss in women with PCOS and a history of pregnancy loss

3. Improved understanding of the long-term cardiovascular sequelae of women with PCOS who develop gestational complications such as diabetes or pre-eclampsia

4. Prevention trials of endometrial hyperplasia and or cancer in obese women with PCOS.

Fig. 2. Protective effect of oral contraceptives in preventing endometrial cancer in population-based epidemiological trials examining the association between ever use of the oral contraceptive pill and the development of endometrial cancer. (Adapted from ref. 39.)

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KEY POINTS

• The strongest association between OHSS and PCOS is with young, thin women with polycystic ovaries who undergo superovulation with human menopausal gonadotropin preparations and concomitant use of a GnRH agonist.

• It is assumed that women with PCOS are at increased risk for multiple pregnancy, but it is uncertain whether PCOS confers additional risk above and beyond that of ovulation induction.

• Women with PCOS appear to have increased rates of pregnancy loss, and this has been associated with increased LH secretion, excess androgen production, and most recently with insulin resistance.

• Women iwth PCOS appear to be at increased risk for gestational diabetes and pre-eclampsia.

• Women with PCOS share a risk factor profile that overlaps with that for the development of endometrial cancer, although there is a paucity of well-designed studies indicating increased event rates in women with PCOS.

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