**7.1. PCOS and abortion**

[89]. Some researchers suggest that oral contraceptive use in some anovulatory women with PCOS may protect against ovarian cancer through gonadotropin suppression rather than the prevention of ''incessant ovulation'', with its putative dangers of inclusion cyst formation,

Obesity, hyperandrogenism and infertility occur frequently in PCOS, and are feature known to be associated with the development of breast carcinoma [89]. In this respect, meta analysis about the association between PCOS and breast cancer showed that the risk of breast cancer was not significantly increased overall [90]. However, some studies showed that women with PCOS independently of age, age at menarche or menopause, parity, using oral contraceptive pill, BMI and family history of breast cancer, have 1.8 times as likely to report benign breast

Normal pregnancy is characterized by induction of insulin resistance associated with com‐ pensatory hyperinsulinemia in second and third trimesters [49]. This insulin resistance of normal pregnancy is a physiologically advantageous adaptation designed to restrict maternal glucose uptake and to ensure shunting of nutrients to the growing fetus. It is probably mediated by increases in hormonal levels of estradiol, progesterone, prolactin, cortisol, human chorionic gonadotropin, placental growth hormone (PGH), and human placental lactogen (HPL) [33]. HPL and PGH are the hormones mainly responsible for insulin resistance in pregnancy. HPL is responsible for adaptive increase in insulin secretion necessary for preg‐ nancy and for diversion of maternal carbohydrate metabolism to fat metabolism in the third trimester. PGH seems to be a paracrine growth factor probably regulating the metabolic and growth needs of the fetus partially [92]. There is approximately 200 to 250% increase in insulin secretion in lean women with normal glucose tolerance with advancing gestation [93]. However, there is comparatively less robust increase in insulin levels of obese women with

As we state before, hyperandrogenism and insulin resistance are the metabolic hallmark of PCOS women. In these patients, the baseline insulin resistance seems to be exacerbated with entry into pregnancy. There is an increased risk of pregnancy complications in PCOS women [94]. Nowadays a growing body of evidence points to a high prevalence of pregnancy complications in PCOS women. PCOS was strongly associated increased risk of early preg‐ nancy loss, gestational diabetes (GDM), pregnancy-induced hypertension, preeclampsia, preterm birth, small for gestational age, large for gestational age, caesarean section, operative vaginal delivery, neonatal meconium aspiration and having a low Apgar score (<7) at five

epithelial proliferation, genetic damage and ovarian carcinogenesis [89].

disease [91]. In this regard there is a need for more research.

**7. Polycystic ovary syndrome and pregnancy**

**6.3. Breast cancer and PCOS**

88 Contemporary Gynecologic Practice

normal glucose tolerance.

minutes and admission to an NICU [95-98].

Abortion is the spontaneous loss of a fetus before the 20th week of pregnancy. Women with PCOS most probably have an increased risk of spontaneous Abortion [95]. It occurs in 30 to 50% of PCOS women compared with 10 to 15% of normal women [99]. Several mechanisms underlying the increased risk of abortion in women with PCOS have been proposed. Treatment with ovulation-inducing agents is associated with a higher incidence of abortion in PCOS women [95]. Obesity has been conclusively associated with an increased prevalence of miscarriage and obesity is obviously more common in PCOS patients than in the normal population. Also, elevated LH levels in women with PCOS and hyperandrogenemia play important role in increased risk of abortion. High androgen levels antagonize estrogen, which may adversely affect endometrial development and implantation [100]. Researchers showed that sex steroids regulate uterine receptivity for embryo implantation by controlling the expression of HOXA10 gene, which is spatially and temporally regulated during embryonic development. Elevated testosterone in PCOS down-regulates the expression of HOXA10 gene, thereby decreasing the uterine receptivity and implantation [100]. In addition high plasmino‐ gen activator inhibitor-1(PAI-1) activity which has been found to be associated with unex‐ plained recurrent abortion, is significantly higher in women with PCOS, possibly due to impaired fibrinolysis, which results in placental insufficiency through increased thrombosis of the placental bed [101]. It is suggested that *metformin* therapies before and throughout pregnancy, could decrease the risk of early abortion, but more studies are needed [102].

#### **7.2. PCOS and gestational diabetes mellitus**

Gestational diabetes mellitus (GDM), defined as carbohydrate intolerance at onset of preg‐ nancy (or first recognition), affects 4–7% of pregnancies overall [103]. There are 2.4-fold increased risks of GDM among PCOS women, independent of age, race/ethnicity, and multiple gestations. It means that GDM complicates 40 to 50% of PCOS pregnancies. The increased odds of GDM among women with PCOS symptoms are consistent with the overlap of metabolic perturbation and reproductive abnormalities and the possibility that some women actually had PCOS. It intervenes in pregnancy when pancreatic β cells cannot overcome the superim‐ posed insulin resistance of pregnancy on intrinsic insulin resistance of PCOS women. It is too suggested that metformin may decrease of GDM among GDM, but recent meta-analysis, strictly, showed that metformin did not significantly effect on GDM with PCOS, though more multi-centers RCTs still need to be investigated [104].

#### **7.3. PCOS and hypertensive disorders in pregnancy**

Hypertensive disorders of pregnancy include: i. new onset of hypertension during pregnancy (or gestational hypertension which is defined as new-onset hypertension in pregnancy after 20 weeks of gestation), ii. Preeclampsia (defined as defined as gestational hypertension with proteinuria due to endothelial dysfunction and damage), iii. Pre-existing hypertension, and iv. exacerbation of pre-existing hypertension. The etiology of hypertensive pregnancy is uncertain and includes immune, genetic, and placental abnormalities. Three main hypotheses have been proposed regarding the metabolic alterations involved in the etiology of hyperten‐ sive disorders in pregnancy, namely endothelial dysfunction and activation, oxidative stress and insulin resistance [105]. Hypertensive disorders occurs in 8% of PCOS pregnancies [106]. Increased levels of androgens in PCOS have been associated with the development of pree‐ clampsia [107]. Various studies have documented hyperinsulinemia and/ or hyperglycemia in early or mid pregnancy, before the development of preeclampsia, gestational hypertension, or both [108]. Hyperinsulinemia may directly predispose to hypertension by increased renal sodium re-absorption and stimulation of the sympathetic nervous system. Insulin resistance and/or associated hyperglycemia may impair endothelial function.

Two other factors, obesity and physical inactivity, are closely associated with insulin resist‐ ance, and are predictive of hypertensive pregnancy. A higher body mass index before pregnancy or early in pregnancy is associated with increased risk for both gestational hyper‐ tension and preeclampsia. Furthermore, it has been suggested that gestational diabetes, which itself is associated with underlying insulin resistance, is a risk factor for the development of hypertensive pregnancy. This association persists even after adjusting for obesity and maternal age. Also, a higher prevalence of preeclampsia and gestational diabetes may account for increased fetal stress leading to preterm birth, low Apgar scores at five minutes, and meconium aspiration.
