**8.1. Weight reduction**

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

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

There was evidence of a significant positive association between PCOS and preterm births (<37weeks) [109]. It complicates 6 to 15% of pregnancies of PCOS women [110]. Although preterm birth may be higher in this group of women, PCOS by itself may not be an independent risk factor. Patients who have received ovulation induction agents are more likely to be at higher risk of preterm births, because these medications, together with the increased chance of multiple pregnancies related to them, will increase the risk of preterm birth or delivery [111]. Preeclampsia itself is a risk factor for preterm deliveries. Also, Obstetric intervention may be

**7.5. PCOS and Small for Gestational Age (SGA) and Large for Gestational Age (LGA)**

There is still some controversy as to whether women diagnosed as having PCOS were more likely to have been born small for SGA and LGA, and whether theses baby is more prone to develop the symptoms of PCOS later in life. Whereas the probable association of higher maternal body weight, increased weight gain during pregnancy, and increased prevalence of gestational diabetes in women with PCOS would be expected to produce birth weights higher than the mean. Also, the prevalence of SGA offspring seems to be increased in women with PCOS. Insulin resistance resulting in impaired insulin-mediated growth and the fetal pro‐ gramming hypothesis are the possible explanations for this higher prevalence of SGA infants

and/or associated hyperglycemia may impair endothelial function.

aspiration.

**7.4. PCOS and preterm birth**

90 Contemporary Gynecologic Practice

in mothers with PCOS [33].

responsible for iatrogenic prematurity [110].

As mentioned above the central obesity related to PCOS hyperandrogenism and anovulation. Also, obesity reduces the treatment effect in women with PCOS [112]. Weight lose can modified the hormonal profile, and androgen level therefore has good effect on ovulation and treatment of infertility. It is showed that 5 % weight reduction can modify menstruation cycle and ovulation. However, weight reduction is effective for women, who are overweight, a BMI 25-27 kg/m2. It includes change in life style with diet, exercise and surgery. Low carbohydrate and fat diets is recommended for obese PCOS women. Bariatric surgery may be recommended for morbidly obese women [112].

### **8.2. Induction ovulation**

In PCOS, patient complaints of menstrual disturbance, that often related to chronic anovula‐ tion. It can increase risk of endometrial hyerplegisa and carcinoma. Therefore, this complica‐ tion needs treatment. Low FSH concentration, high LH, androgen and insulin have roles in anovulation. Medications and another option apply for correct these underlying disturbance [112]. Treatments options are explained further in the following sections.

#### **8.3. Clomiphene citrate**

The first line medication for treatment of anovulation is clomiphene citrate (CC). CC is a nonsteroidal triphenylethylene with both estrogenic agonist and antagonist properties. CC bind to estrogen receptors by structural similarity with it. Improvement in ovulation happens with the CC effect at hypothalamic level. Reduction of hypothalamic estrogen receptor leads to mis interpretation of blood level estrogen. Therefore, estrogen feedback reduces and pulsatile GnRH secretion modify. As a result, FSH and LH secretion from pituitary normalized, in turn, improve follicular activity in ovarian. CC is administered for 5 days with doses of 50–150 mg, starting on days third or fifth days of mensural cycle or a progestin-induced menss. Most pregnancies occurred within the first six cycles with ovulation following the application of 50 mg CC. Higher doses may be required in patients with greater BMI. The rates of multiple pregnancies are under 10%, and ovaraian hyper stimulation syndrome is rare [112].

#### **8.4. Metformin**

Metformin is a biguanide, insulin-lowering effects, which are used for treatment of type 2 diabetes mellitus. Metformin has several benefits to manage PCOS complication. It improves ovulation, menstrual irregularity and reduces concentration of androgen. Also metformin help to weight reduction. Metformin has more effect in obese PCOS women [115]. Serious side effects of metformin are rare. Hypoglycemia is a rare side effect. For reducing common complication with metformin, it is start at 500 mg daily after food. The week after increase to achieved 1000 mg daily. After one week, the dose is increase to 1500 mg daily. The target is 1500–2550 mg/day. Usually, treatment effect appears at 1000 mg/day [113].

#### **8.5. Aromatase inhibitors**

The third generation aromatase inhibitors available include anastrozole and letrozole. They block production of estrogen from ovarian, conversion of androgen in referral fat cells, and suppress locally estrogen produced in brain. Therefore, this condition acts as positive feedback for hypothalamous to secrete GnRH, in turn, increase gonadotropin secretion. Also, reduction in estrogen concentration leads to increase activin that is a positive stimulation for FSH secretion. This positive feedback helps to growth of ovarian follicles. Usually Letrozole is used as anaromatase inhibitor for ovulation induction in women with PCOS. The administration dose is between 2.5–7.5 mg daily for 5 days starting on third day of the menstrual cycle. The main advantage of letrozole is antiestrogenic effect on endometrium, despite of stimulating follicle growth [113].

#### **8.6. Gonadotropins**

After resistance to CC, gonadotropins are another option for induction ovulation. Gonado‐ tropins induce ovulation, and help to achieve a capable follicle for fertilization. The serious side effect of gonadotropins is ovarian hyperstimulation syndrome (OHSS) that result from simultaneous growth of multiple follicles. Several treatment protocols have been developed, one of the low-dose gonadotropin protocols regimen starts with a 37.5–50 IU/day, which increases, if confirm the lack of follicle response. Control is made by ultrasound. HCG is act as LH surge; leading to maturation of the oocyte, rupture of the follicle, and formation of the corpus luteum [112].

#### **8.7. Laparoscopic ovarian diathermy**

In clomiphene resistant condition, and when gonadotropin is not useful, laparoscopic ovarian diathermy is an acceptable treatment. The mechanism of action of ovarian diathermy is correction of hypersecretion of LH via modification in ovarian pituitary feedback. To assess the efficacy of unilateral laparoscopic ovarian diathermy in the induction of ovulation, researchers find unilateral ovarian diathermy resulted in ovulation from both ovaries [112, 113].

## **8.8. Treatment of menstrual dysfunction**

**8.4. Metformin**

92 Contemporary Gynecologic Practice

**8.5. Aromatase inhibitors**

follicle growth [113].

**8.6. Gonadotropins**

corpus luteum [112].

ovaries [112, 113].

**8.7. Laparoscopic ovarian diathermy**

Metformin is a biguanide, insulin-lowering effects, which are used for treatment of type 2 diabetes mellitus. Metformin has several benefits to manage PCOS complication. It improves ovulation, menstrual irregularity and reduces concentration of androgen. Also metformin help to weight reduction. Metformin has more effect in obese PCOS women [115]. Serious side effects of metformin are rare. Hypoglycemia is a rare side effect. For reducing common complication with metformin, it is start at 500 mg daily after food. The week after increase to achieved 1000 mg daily. After one week, the dose is increase to 1500 mg daily. The target is

The third generation aromatase inhibitors available include anastrozole and letrozole. They block production of estrogen from ovarian, conversion of androgen in referral fat cells, and suppress locally estrogen produced in brain. Therefore, this condition acts as positive feedback for hypothalamous to secrete GnRH, in turn, increase gonadotropin secretion. Also, reduction in estrogen concentration leads to increase activin that is a positive stimulation for FSH secretion. This positive feedback helps to growth of ovarian follicles. Usually Letrozole is used as anaromatase inhibitor for ovulation induction in women with PCOS. The administration dose is between 2.5–7.5 mg daily for 5 days starting on third day of the menstrual cycle. The main advantage of letrozole is antiestrogenic effect on endometrium, despite of stimulating

After resistance to CC, gonadotropins are another option for induction ovulation. Gonado‐ tropins induce ovulation, and help to achieve a capable follicle for fertilization. The serious side effect of gonadotropins is ovarian hyperstimulation syndrome (OHSS) that result from simultaneous growth of multiple follicles. Several treatment protocols have been developed, one of the low-dose gonadotropin protocols regimen starts with a 37.5–50 IU/day, which increases, if confirm the lack of follicle response. Control is made by ultrasound. HCG is act as LH surge; leading to maturation of the oocyte, rupture of the follicle, and formation of the

In clomiphene resistant condition, and when gonadotropin is not useful, laparoscopic ovarian diathermy is an acceptable treatment. The mechanism of action of ovarian diathermy is correction of hypersecretion of LH via modification in ovarian pituitary feedback. To assess the efficacy of unilateral laparoscopic ovarian diathermy in the induction of ovulation, researchers find unilateral ovarian diathermy resulted in ovulation from both

1500–2550 mg/day. Usually, treatment effect appears at 1000 mg/day [113].

In patient complaints of menstrual irregularity, often there is chronic anovulation that associated with risk of endometrial hyperplasia and carcinoma. Thus, treatment of menstrual dysfunction is important. Endometrial biopsy is recommended for PCOS women, who have not menstrual bleeding for a long time (m0re than 6 months). In women, who does not intent to be pregnant, oral contraceptive pills (OCPs) or cyclic progestin are recommended. OCPs increase production of SHBG at liver, thus reduce androgen concentration, and improved LH secretion. It is important to consider the androgenic effect of progestin component of OCPs. New OCPs have less androgenic effects [112].

#### **8.9. Treatment of androgen-related symptoms**

Hirsutism, acne, alopecia are the androgen-related symptoms that appeared in patients with PCOS. Antiandrogens such as spironolactone, cyproterone acetate (CPA), or flutamide act by competitive inhibition of androgen-binding receptors or by decreasing androgen production.

Spironolactone is a specific antagonist of aldosterone, acting through blocks androgen receptors. Its treatment effect is dosage-dependent: low dosages are less effective than other antiandrogens, whereas high dosages (200 mg/day) are very effective but have several adverse effects such as dysfunctional uterine bleeding but the concurrent use of OCPs may prevent from it. Spironolactone have feminizing effect on male fetus, therefore concomitant use of OCPs with spironolactone is useful for sexually active women [112]. Cyproterone acetate (CPA) is a progestin agent. This drug inhibits gonadotropin secretion and suppresses androgen action. CPA is recommended in 50-100mg (high dose) for ten days of cycle with 20-50 µg Ethinyl Estradiol. CPA is effective for management of hirsutism and acne. It may leads to nausea, headaches, and breast tenderness, reduce libido, and weight gain. CPA rarely appears hepatotoxicity effects. This drug has feminizing effect such as Spironolactone. Finasteride restrain 5α-reductase and inhibit androgen production, therefore, it is useful for management of hirsitism. In a study that patients treated with finasteride, reduction in hirsutism occurred after 6 months. Concomitant use of OCPs with 5 mg Finasteride was shown to be more effective than OCPs alone. It has feminizing effect, thus risks and benefits of treatment must be carefully considered and discussed with the patient. In conclusion, at least 6 months is required to see benefit from medication and prolong treatment is often necessary for maintain benefit. Pregnancy must be avoided during treatment with all antiandrogens [112, 113].
