Principles and Practice of Controlled Ovarian Stimulation in ART 1st ed.

30. Polycystic Ovarian Syndrome and Response to Stimulation

Nandita P. Palshetkar Hrishikesh D. Pai Manisha Bhagat  and Rohan Palshetkar4

(1)

In Vitro Fertilization Unit, Bloom IVF Center, Lilavati Hospital and Research Centre, B-123, Heera Panna, B. Desai Rd, Haji Ali, Mumbai, Maharashtra, 400026, India

(2)

In Vitro Fertilization Unit, Bloom IVF Centre, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, 400050, India

(3)

National Board of Reproductive Medicine, In Vitro Fertilization Unit, Lilavati Hospital and Research Center, 2nd Floor, A-791 Bandra Reclamation 2 Bandra West, Mumbai, Maharashtra, 400040, India

(4)

Department of Obstetrics and Gynaecology, Dr. D.Y. Patil Hospital and Research Centre, D.Y. Patil Hostel Priyadarshini Bldg 5th Floor, 502, Neruy (E), Navi Mumbai, Maharashtra, India

Nandita P. Palshetkar (Corresponding author)

Email: nanditapalshetkar@hotmail.com

Hrishikesh D. Pai

Email: hdpai@hotmail.com

Manisha Bhagat

Email: manish.bhgat@gmail.com

Abstract

Polycystic ovary syndrome (PCOS) is a polygenic, multifactorial heterogeneous disorder of uncertain etiology. It is one of the most common endocrine disorders affecting females. The prevalence of PCOS is around 6–8 % in reproductive age group females. PCOS remains an enigmatic disorder, the etiology of which is still unclear. The evidence that PCOS is dependent on genetic factors is very strong. The features of PCOS can be seen in early childhood as premature adrenarche, adolescent PCOS, hirsutism, and acne. In a reproductive age group female, PCOS can present as menstrual irregularities like amenorrhea, oligomenorrhea, and infertility. Obesity is common in patients with PCOS. The optimal treatment for infertility with PCOS is yet to be contemplated. Various regimens have been developed for the treatment ranging from lifestyle modification to clomiphene to IVF with no consensus.

Lifestyle modification is the first line in the management of PCOS. Weight loss as little as 5 % will lead into normalization of menses and ovulation. Clomiphene citrate is the first choice for induction of ovulation in most anovulatory women with PCOS with a conception rate of 22 % and ovulation rate of 75 %. If clomiphene citrate fails to result in pregnancy, then the second-line treatment is either gonadotrophins or laparoscopic ovarian drilling. In vitro fertilization can be offered to those couples that do not conceive after 3–6 cycles of IUI. Also there is advantage of doing a single embryo transfer in a young good prognosis patient. Use of GnRH trigger in patients with PCOS has lead to dramatic decrease of OHSS.

Keywords

PCOSOvulation inductionAnovulationClomiphene citrate

30.1 Introduction

Polycystic ovary syndrome (PCOS) is a polygenic, multifactorial heterogeneous disorder of uncertain etiology. It is one of the most common endocrine disorders affecting females. The prevalence of PCOS is around 6–8 % in reproductive age group females [1]. It has many different clinical manifestations like infertility, menstrual irregularities, and hirsutism. Stein and Leventhal in 1935 described a symptom complex associated with anovulation. They reported a subset of patients having amenorrhea, hirsutism, and enlarged ovaries who resumed menstruation after bilateral wedge resection of ovaries [2].

PCOS remains an enigmatic disorder whose etiology is still unclear. The evidence that PCOS is dependent on genetic factors is very strong. Familial clustering of cases is the most important evidence, as features of PCOS are seen in identical twins than in nonidentical twin. The mode of inheritance of PCOS is unclear; given the clinical and biochemical heterogenecity of the syndrome, it is unlikely to be a single-gene disorder.

The origin of PCOS can be traced to in utero exposure of excess testosterone. Frank et al. (2012) [3] stated that genetic factors have an important part to play and that the disorder has its origins in early, possibly prenatal, life. They stated that polycystic ovary syndrome is a genetically determined, primary ovarian disorder resulting in excess androgen production. The capacity to hypersecrete androgens begins in fetal life and that the typical clinical and biochemical features of PCOS are “downstream” effects of exposure to androgen excess at or before puberty [3].

30.2 Etiopathogenesis of PCOS

To understand the pathogenesis of PCOS, the physiology of normal menstrual cycle should be understood. Normal menstrual cycle is a complex process of events involving the hypothalamus, pituitary, ovary, and uterus. During the follicular phase, there is a rise in the level of FSH hormone, which causes an increase in E2 levels and LH. Increase in LH causes androgen production in theca cell that with the help of aromatase enzyme gets converted to E2. As the follicle grows and E2 levels rise, it causes negative feedback on FSH so that the growth of smaller follicle stops and the follicle having maximum E2 levels and highest number of FSH and LH receptors emerges as the dominant follicle. E2 level rises, causing a surge, which is followed by an LH surge that leads to ovulation. Corpus luteum is formed and this causes rise in progesterone and E2. The LH and FSH levels reach nadir during late secretory phase, which is followed by menstruation if the corpus luteum is not rescued by pregnancy.

In patients of PCOS, there is a steady state of hormone levels with no fluctuation as compared to normal fluctuations observed in normal menstruation cycle. The level of FSH is usually low or normal due to increased inhibition by estrogen and inhibin B levels. Also, the level of LH is raised. It is the frequency, not amplitude, that is increased, but there is no cyclic variation as seen in normal menstrual cycle. The bioavailability of LH is also increased due to glycosylation, which causes more basic forms leading to increased bioactivity. Also there is abnormality in GnRH pulse generator and sensitivity of GnRH to progesterone is decreased There is decreased dopamine neuronal activity because of lack of progesterone [4].Since level of LH is increased, there is increased production of androgen which does not get converted to estrogen, and there is increased intraovarian androgen. So, new follicles are recruited each cycle, but due to lack of estrogen dominance, no dominant follicle is selected. Anovulation and multiple small follicles of 2–10 mm are present in the ovary giving the PCO morphology on ultrasound (USG).

Around 40–50 % of PCOS females suffer from insulin resistance and hyperandrogenemia. Insulin resistance is a condition where endogenous and exogenous insulin has less than normal effect on the muscle, fat, and liver. Hyperinsulinemia causes increased androgen by two mechanisms. It acts through its receptor in ovarian theca cell and IGF-1 receptor in ovarian theca cell. Also it acts on the liver and causes decreased production of SHBG leading to increased level of free androgen. Insulin potentiates level of LH on theca cells. So a self-propitiatory cycle is formed where increased insulin leads to increased androgen, which causes hyperinsulinemia.

30.3 Definition of PCOS

Many systems of classification have been proposed for defining PCOS (Fig. 30.1):

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Fig. 30.1

Criterion for diagnosis of PCOS

1.

2.

3.

30.4 Clinical Presentation of PCOS

The features of PCOS can be seen in early childhood as premature adrenarche, adolescent PCOS, hirsutism, and acne. In a reproductive age group female, PCOS can present as menstrual irregularities like amenorrhea, oligomenorrhea, infertility, hirsutism, and metabolic syndrome and in postmenopausal women, endometrial hyperplasia (Fig. 30.2).

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Fig. 30.2

Clinical picture of PCOS

30.4.1 Laboratory Investigations and Differential Diagnosis

There are many conditions that can present as PCOS like androgen-producing tumor, Cushing syndrome, and nonclassical congenital adrenal hyperplasia. So it is important to distinguish these conditions from each other. There are many tests available. Table 30.1 mentions the relevant tests needed for distinguishing the above conditions.

Table 30.1

Differential diagnosis of PCOS and laboratory tests

Condition

Test

Range

PCOS

Total testosterone

DHEA

LH/FSH

<200 ng/ml

Increased

>2:1

Hypothyroidism

Free T3

Free T4

TSH

Decreased

Decreased

Increased

Hyperprolactinemia

Serum prolactin

Increased

Late-onset CAH

17-hydroxyprogesterone

>200 ng/ml (>800 diagnostic)

Androgen-secreting ovarian tumor

Testosterone

>200 ng/ml

Androgen-secreting adrenal tumor

DHEAS

>700 μg/dl

Cushing syndrome

Cortisol

Increased

Severe insulin resistance

OGTT

S. insulin (2 h)

B. sugar (fasting)

Postprandial (2 h)

>80 μU/ml

>126 mg/dl

>200 mg/dl

Idiopathic hirsutism

Menstrual history

Serum progesterone

Serum testosterone

Oligo-/amenorrhea

Decreased

Normal to increased

30.4.2 Antimüllerian Hormone (AMH) and PCOS

In PCOS women AMH levels are often raised due to increased number of follicles and granulosa cells. Women with hyperandrogenemia tend to have higher AMH levels. It is found that high AMH levels inhibit folliculogenesis. Thus, there is a subgroup of women with PCOS who have a high AMH and will not respond to ovarian stimulation. There are some women who respond to treatment with lowering of AMH levels.

30.5 Management

The main focus of management will be in the context of infertility, ovulation induction, and response to ovulation (Fig. 30.3).

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Fig. 30.3

Management of PCOS

The optimal treatment for infertility with PCOS is yet to be contemplated. Various regimens have been developed for the treatment ranging from lifestyle modification to clomiphene to IVF with no consensus. Due to varied etiology and symptomatology different therapies go side by side like lifestyle modification and ovulation induction. Also, different forms of therapies are complementary to each other like weight loss leading to a better response in ovulation induction.

30.5.1 Preconceptional Counseling

The treatment of a PCOS woman planning pregnancy is started preconceptionally. The patient is started with tablet folate 5 mg daily starting 3 months before planning pregnancy as it decreases the incidence of congenital malformations in the offspring. The patient is recommended to stop smoking and illicit drug usage.

The main part of counseling is weight loss as it is well known that obesity is associated with multiple pregnancy complications like miscarriage, gestational diabetes mellitus (GDM), and preeclampsia. Losing as much as 5 % weight is associated with resumption of menstruation, ovulation, and pregnancy [8].

30.5.2 Lifestyle Modification and Weight Loss

Obesity is common in patients with PCOS. The obesity per se decreases the chance in getting pregnant and decreases the response to ovulation induction with drugs and ART. The obesity is centripetal in distribution with increase in visceral fat; even in the case of lean PCOS, there is a tendency of weight gain in abdominal area.

Therefore, the first line of management in the case of PCOS is weight loss and more important is the maintenance of the weight loss. Even a loss of 5 % weight can lead to decrease in irregularities of period and in some cases resumption of menstruation [9]. Weight loss decreases the complication like miscarriage rate, preeclampsia, and gestational diabetes mellitus (GDM) in patient of PCOS planning pregnancy. The treatment of obesity is multidisciplinary and involves behavioral counseling, diet, exercise, and pharmacological therapy. The intervention should be started in preconceptional period (see Fig. 30.3). Weight loss leads to decrease in free testosterone levels by increasing SHBG levels [8].

It can be achieved by the following means:

1.

2.

3.

4.

5.

30.5.2.1 Diet

This is one of the most important aspects as calorie restriction is the key to weight loss. Many researchers have suggested different types of diets like the Atkins diet, high protein diet, and no carbohydrate diet, but without much results. There is increased evidence in favor of diets utilizing food having reduced glycemic load and high glycemic index. In the absence of good level of evidence, calorie restriction of 500 kcal/day is presently recommended for PCOS female [8]. An overall decrease in calorie intake is more important than any specific composition. Lifestyle treatment leads to weight loss, decrease in free androgen, abdominal obesity, and surrogate marker of insulin resistance and an improved quality of life in PCOS.

30.5.2.2 Exercise

Daily exercise is one of the key factors for weight loss. Exercise reduces the risk of having DM type 2 and cardiovascular disease in a PCOS. Moderate activity that is sustained is better than vigorous activity that is not regular. The aim is to develop a healthy lifestyle that is continuously followed. Moran et al. [10] described that climbing 8000 steps a day along with change in diet pattern decreases the testosterone level by 57 %. Insufficient physical activity is one of the reasons obese PCOS women put on weight. Patients who are morbidly obese should be advised rigorous weight loss under supervision because of possible orthopedic and cardiovascular risk involved in unsupervised exercise. Hoeger et al. [11] advised weekly exercise for 150 min/week along with dietary restriction with the goal of 5–7 % weight loss leading to decrease in SHBG and insulin resistance.

30.5.2.3 Pharmacological Management

Drugs are used either to suppress appetite or those which have an antiobesity effect. Antiobesity drugs include orlistat which acts by decreasing intestinal absorption of fat [12]. Appetite suppressant like sibutramine acts by decreasing the appetite and has dose-dependent action [13]. Statins act by inhibiting HMG-CoA reductase enzyme, which is the rate-limiting step in cholesterol pathway. There is decrease in levels of testosterone along with dyslipidemia and therefore PCOS patients are at risk for developing diabetes and cardiovascular disorder. They are teratogenic in pregnancy. According to Cochrane (2011), statins are effective in reducing serum androgen levels and LDL, but statins are not effective in reducing fasting insulin or insulin resistance. There is no good evidence available on the long-term use of statins alone or in combination for management of PCOS [14].

30.5.3 Behavioral Therapy

PCOS women have increased chances of having depression due to obesity and infertility. Counseling is very helpful for these PCOS women.

30.5.3.1 Bariatric Surgery

Bariatric surgery can be offered to morbidly obese women with BMI of >35 kg/m2 [15]. With surgery the weight loss is maintained. The pregnancy per se becomes high risk, as there is increased chance of IUGR and decreased weight gain in these females.

30.5.4 Insulin Sensitizers

30.5.4.1 Metformin

Metformin is a biguanide, oral insulin-sensitizing agent used in the treatment for diabetes mellitus type 2. It acts by increasing the peripheral uptake of glucose in the muscle and intestine [16], decreases hepatic glucose uptake, and inhibits lipolysis, thereby decreasing the circulating levels of free fatty acids and increasing the insulin sensitivity. It thus helps in decreasing weight and LDL cholesterol. The tablet is available in both regular and sustained release form starting with a minimum dose of 500 mg per day along with meals to a maximum level of 1500–2000 mg per day [3].

Metformin should be given to women having impaired glucose tolerance, diabetes mellitus type 2, and severe insulin resistance. It is also given where there is metabolic syndrome like dyslipidemia and central obesity. In adolescent PCOS girls, it has been shown that metformin treatment can result in decrease in hyperandrogenemia and hyperinsulinemia. Cochrane analysis (2013) has found that metformin decreases the incidence of OHSS in females undergoing ovulation induction, but it does not increase the chance of having a live birth [17]. The drug is prescribed only in patients having glucose intolerance [8]. Also in cases of ovulation induction, there is no benefit of prescribing metformin alone or with clomiphene citrate except in cases where patient has BMI [18] of >35 kg/m2.

Precautions

Metformin can cause lactic acidosis in 1:33,000 cases. It is a serious condition with a mortality of 50 %, mainly occurring in women with renal impairment. Symptoms are often nonspecific like fatigue, myalgia, abdominal distension, vomiting, and respiratory depression. Immediate cessation of the drug is indicated on observing any of the symptoms. Serum electrolytes, blood glucose, ketones, pH, serum lactate level, and serum metformin levels, if possible, should be checked. To take precautions against this condition, metformin should be discontinued 48 h before any planned surgery or any radiographic study utilizing intravenous contrast dye. Ethanol potentiates the effect of metformin and patients should be warned against high alcohol intake. Hemodialysis may be needed to resolve the situation.

Minor side effects like nausea, vomiting, diarrhea, bloating, flatulence, and metallic taste occur in 20 % of patients. It resolves if drug is taken with food. Since this effect is dose dependent, the dose of metformin should be increased in an incremental fashion. If discomfort is significant, the drug should be discontinued. There may be weight loss associated with the nausea and vomiting accompanying the drug. Megaloblastic anemia may occur in some patients because of subnormal B12 levels. Before starting metformin, renal and liver functions should be tested.

Hypoglycemia does not occur with metformin in euglycemic patients. It may be seen in special cases where there is deficient caloric intake and concomitant use with sulfonylureas and strenuous exercise is not compensated with adequate intake or excessive alcohol consumption. It is contraindicated in renal disease and myocardial infarction. Drug interaction occurs with diuretics, oral contraceptives, and phenytoin.

Metformin induces regular cycles in some women treated for 4–6 months. It improved ovulation, hirsutism, hyperandrogenemia, and insulin resistance. Lowering of fasting insulin levels is seen in 2–3 months. A repeat test is required only after this period. If amenorrhea persists, clomiphene or rosiglitazone is added. Ovulation rates are higher when combined with clomiphene. Patients with elevated pretreatment levels of testosterone show the best results in resumption of ovulation with significant reduction in testosterone. Those with raised fasting insulin responded less and those with normal testosterone showed no effect.

30.5.4.2 Thiazolidinediones

Thiazolidinediones include rosiglitazone and pioglitazone. They are less effective than metformin in decreasing insulin resistance and lead to weight gain and are category C drug in pregnancy [4]. They are synthetic agonists for peroxisome proliferator-activated receptor gamma (PPAR), which serves as a regulator gene for metabolism of carbohydrate, fats, and lipids [3].

30.5.4.3 Myoinositol and D-Chiro-Inositol

Myoinositol positively modulates insulin sensitivity in nonobese PCOS patients without compensatory hyperinsulinemia, improving hormonal parameters. Thus, myoinositol improves reproductive axis functioning in PCOS patients. Menstrual cyclicity was restored in all ammenorrheic and oligomenorrheic patients.

30.5.5 Ovulation Induction

Lifestyle modification forms an important part of PCOS, but around 40–50 % of these females have anovulation and suffer from infertility. The first-line drug for ovulation induction is clomiphene citrate (Fig. 30.4).

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Fig. 30.4

Ovulation induction in PCOS

Problems in Ovulation Induction in PCOS

1.

2.

3.

30.5.5.1 Clomiphene

Clomiphene citrate is a nonsteroidal triphenylethylene derivative [3]. It is a selective estrogen receptor modulator which normally acts as estrogen receptor antagonist, but when the level of estrogen in the body is very low, it acts as an agonist [4]. It is available as two racemic isomers En (62 %) and Zu (38 %). Clomiphene is excreted in stools and around 85 % is excreted in 6 days. En clomiphene is more potent and responsible for the action of clomiphene for ovulatory induction. Zu clomiphene is less potent and stays in circulation for a longer time. It accumulates over series of time and is probably responsible for adverse effect of clomiphene on endometrium and cervix [19].

Indications for Usage of Clomiphene Citrate [20]

It is useful in anovulatory females who have PCOS, obesity, thyroid disorder, luteal phase defect or in some cases of hypothalamic dysfunction related to eating disorders, extreme weight loss, hyperprolactinemia, and pituitary tumors. Before starting clomiphene, thyroid dysfunction and hyperprolactinemia if present, should first be corrected for underlying cause. According to Cochrane meta-analysis, clomiphene is effective in inducing ovulation in PCOS patients [21].

The efficacy of clomiphene citrate in unexplained infertility is by inducing superovulation of more than a single ovum. But studies have found out that only clomiphene citrate with timed intercourse is no better than no intervention as there is no improvement in only clomiphene citrate group. IUI along with clomiphene citrate is more useful in patients with unexplained infertility as it leads to increase in pregnancy rate [22]. At least three cycles of clomiphene citrate should be offered.

Treatment Regimen

Standard therapy: clomiphene citrate is started from day 2 to day 5 after onset of spontaneous menstruation or progesterone-induced menstruation, for 5 days.

The dosing of clomiphene citrate should be based upon BMI, age, AMH, antral follicle count, response to previous stimulation, and day 2 FSH [8]. The dose of the tablet is 50 mg per day, but in the case of lean PCOS, the dose is as less as 25 mg/day. The maximum response is obtained with 150 mg/day. The maximum dose that can be safely used is 250 mg/day, but that is rarely required. Higher dose may be useful in patients with higher BMI. In obese, anovulatory women with at least 2 years of infertility, success rates generally are lower, with 16 % achieving live birth in women with BMI >35 kg/m2compared with 28 % for women with BMI 14 < 30 kg/m2.

If clomiphene citrate is used for ovulation induction, then it must be given for a maximum of 3–6 cycles. The likelihood of pregnancy is very low after this period. The cumulative pregnancy rate after six cycle of CC is 50–60 %[9]. If no pregnancy occurs after six cycles, then the second line of therapy with gonadotrophins or laparoscopic ovarian drilling should be offered.

Efficacy

Approximately 75 % of patients of PCOS will ovulate with clomiphene citrate, but the pregnancy rate is only 22 %. This could be because of the negative effect of clomiphene citrate on endometrium and cervix [2324].

Monitoring

Monitoring is done with ultrasound (USG). The baseline scan is done on the second day of the cycle to see for any ovarian cyst and endometrial thickness. The patient is started on tab clomiphene citrate and advised USG from day 9 onward. Patient is advised to have intercourse on alternate days starting from day 10 of the cycle. Whether to give HCG or not is optional [25]. If there is unruptured follicle in the previous cycle, the patient is advised HCG in the next cycle. Many investigators do a baseline scan and then start using LH kit to predict ovulation rather than doing repeated USG.

Adverse Effect

Adverse effects of clomiphene are hot flushes, vaginal dryness, visual disturbances, headache, mood swings [26], blurring of vision, double vision, and scotoma [27] (<2 %). The drug is stopped in case of visual side effect.

Complications

Complications include multiple pregnancy which occur in 7 % of the patient’s most common being twin [28]. There is no evidence of any risk of anomalies in baby born after treatment with clomiphene citrate or of a higher miscarriage rate. There is a slight increase in ovarian hyperstimulation syndrome (OHSS). Risk of ovarian cancer is not increased.

30.5.5.2 Combined Therapy

Metformin

Metformin was prescribed along with clomiphene citrate in cases of PCOS. Evidence has shown that it is useful only in patients having BMI >35 kg/m2 and in patients with clomiphene citrate resistance [18]. However, Moll et al. [29] showed no added benefit of metformin along with clomiphene citrate in ovulation induction.

Glucocorticoids

Some of the women with PCOS show involvement of an adrenal component with raised DHEAS. In these women glucocorticoids may be given. The desired effect should be to normalize without suppressing the adrenal component, with dexamethasone (0.25–0.5 mg/day). Dose of 0.25 mg/day is seen to suppress 50 % of patients. Dexamethasone may be started with clomiphene and stopped when ovulation is documented. Dexamethasone gives best results when administered at night, as adrenals are most active early morning. DHEAS and testosterone levels are monitored after 1 month. They are found to produce good results in clomiphene resistance with raised DHEA.

30.5.5.3 Alternative Therapy

Tamoxiphen

Tamoxiphen is a selective estrogen receptor modulator that is useful in breast cancer and appears to be as effective as clomiphene citrate. It has an agonist action on the uterus, bone, and pituitary and an antagonist on the breasts and blood vessels. It can be offered to females who are intolerant to clomiphene citrate. It is started with a dose of 40 mg per day from day 2 to day 6 of cycle and can be increased to 80 mg per day. According to a Cochrane review, it is as effective as clomiphene in inducing ovulation induction [21].

Aromatase Inhibitor

Letrozole is an aromatase inhibitor. It acts by inhibiting the action of the aromatase enzyme, which converts androgens to estrogens. The drug is started with 2.5 mg from day 2 of menses for 5 days. The use of this drug is prohibited in India.

30.5.6 Second Line of Treatment

30.5.6.1 Laparoscopic Ovarian Drilling (LOD)

There are two categories of treatment that can be offered to a patient with PCOS not responding to clomiphene citrate: laparoscopic ovarian drilling and gonadotrophin with GnRH analogues [8]. Laparoscopic ovarian drilling achieves unifollicular ovulation without the risk of OHSS and multiple pregnancy [30]. Four to ten punctures are made in the ovarian stroma either by monopolar electrocautery or laser. Forty percent of the patients start ovulating, but the rest will require other form of ovulation induction after LOD [3132].

The indications are:

1.

2.

3.

4.

5.

Predictor of Success

Normal BMI, LH >10 IU/ML, and shorter duration of therapy are predictors of success [33].

Side Effects

There could be adhesion formation due to trauma to ovarian surface. Sometimes it may lead to a decreased ovarian reserve if too much drilling is done. According to Cochrane [34], LOD is an effective method for inducing ovulation alone with additional advantage of a decreased rate of multiple birth.

30.5.6.2 Gonadotrophin and GnRH Analogues

Gonadotrophins are used in induction of ovulation as the second line to clomiphene citrate in a patient of PCOS. The goal of treatment in PCOS is unifollicular development as PCOS patients are at increased risk of OHSS. The gonadotrophins increase the duration and threshold of FSH window so that there is growth of multiple follicles in the same menstrual cycle [35]. Patients with PCOS have normal to low FSH levels with high LH levels. Gonadotrophin stimulation is indicated in patients who are resistant to clomiphene. Ideally as the levels of LH are raised in PCOS, FSH only preparations are used, but recent Cochrane database has shown that HMG is as effective as FSH for ovulation induction [36]. Gonadotrophins are useful in clomiphene citrate-resistant cases. With the help of GnRH analogues, LH surge can be prevented. It causes an increase in cost of therapy and an increased risk of OHSS and multiple pregnancy.

The challenges in the case of PCOS are:

1.

2.

3.

4.

It is important to evaluate the women completely before starting gonadotrophins. Uterine cavity evaluation for myomas and adhesions, HSG (hysterosalpingography) for tubal obstruction, semen analysis, and complete endocrinal workup including prolactin and thyroid function should be done. Ovarian reserve assessment by AMH and antral follicle count should be evaluated.

30.5.7 Regimes for Ovulation Induction

There are two types of stimulation protocols used: chronic step-up and chronic step-down (Table 30.2) [37] (Figs. 30.5 and 30.6).

Table 30.2

Regimes for ovulation induction

 

Step-up

(From Balasch [37])

Step-down

(From Balasch [37])

Dose

Starting dose: 37.5 IU. After one week, increment of 37.5 is made until follicular growth starts

Start with higher dose of 150–225 IU. On ultrasound if follicle grows up to 10–12 mm, decrease by increments of 37.5 IU to 112.5 IU. If follicle continues to grow, reduce dose to 75 IU

Advantages

Encourages monofollicular growth and hence risk of OHSS and multiple pregnancy much less

Length of cycle is shorter and it is more like a natural cycle

Disadvantages

Length of cycle increased

Frequent and intensive monitoring, as high doses can lead to hyperstimulation

Increased chances of multiple pregnancy

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Fig. 30.5

Chronic step-up regime

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Fig. 30.6

Chronic step-down regime

30.5.7.1 Monitoring

Patient should be counseled before starting the gonadotrophins of the risk of hyperstimulation and chances of cancellation and multiple pregnancy. Monitoring can be done by ultrasound and blood estradiol levels. Ultrasound is one of the best measures to monitor the cycle. According to ASRM guidelines [38], cancellation is advised when there are two follicles of 16 mm or one follicle of 16 mm and two follicles of 14 mm in women less than 38 years, with blood E2 levels >2500 ng/ml. Some studies have kept the values to 1000 ng/ml. Ovulation can be triggered with HCG either urinary 5000 IU or recombinant 250 μgm. According to a Cochrane review, both have been found to be equally efficacious [39].

30.5.7.2 GnRH Analogues

There is an increase in LH in PCOS. It is postulated that increase in LH can cause premature luteinization as well as deleterious effect on oocyte quality. So the GnRH analogues came into vogue as they can prevent premature LH rise. However, there is no significant benefit and the use of analogues leads to higher hyperstimulation, increased rate of multiple pregnancy, and increased cost of therapy. Currently, the use of analogues is not recommended during ovulation induction in a patient of PCOS [40].

Gonadotrophins give a 70 % ovulation rate, with a 20 % pregnancy rate and 5–6 % multiple pregnancy rate. Intensive monitoring is required for gonadotrophin cycle. The patient is started with a minimum dose of 37.5–75 IU/day and monitored strictly. The goal of the therapy is unifollicular development. Patient should be counseled beforehand for chances of cancellation.

30.5.7.3 ART (IUI, IVF, and IVM)

ART will be required in around 20 % of the patients. In vitro fertilization is a reasonable option for prevention of higher-order births especially in PCOS patients who are prone for multiple pregnancy. Patients can start with simple treatment like IUI with gonadotrophins and then proceed to IVF.

Intrauterine Insemination

Ovulation induction with clomiphene or gonadotrophins is followed with ultrasound monitoring. Pregnancy rate of 11–20 % is observed. It has been recommended in some studies that IUI with gonadotrophins is better than the use of gonadotrophins alone [41]. Patient can be offered double IUI with one at 12 h and the other at 36 h of HCG injection. However, studies have not shown increased results with double IUI [42].

In Vitro Fertilization

In vitro fertilization is the third line of therapy in the case of PCOS patients. It is indicated in the following subset of patients:

1.

2.

3.

4.

5.

6.

Patient can be offered multiple regimens ranging from classical long protocol to antagonist protocol to mild stimulation protocol. Classical long protocol is still the most commonly practiced (Table 30.3).

Table 30.3

Difference in GnRH agonist and antagonist protocols in PCOS

Feature

Agonist

Antagonist

Acceptance

Less

Patient friendly

OHSS

More

Less

Multiple pregnancy

Same

Same

GnRH agonist trigger

Cannot be used

Can be used

Oocyte yield

More

Slightly less

Pregnancy rate

Slightly high

5 % less [47]

It has been suggested that increased luteinizing hormone (LH) secretion in PCOS may interfere with fertility. The mechanisms include premature oocyte maturation and deleterious LH effect on granulosa cell steroidogenesis. In addition, elevated LH levels may be associated with an increased pregnancy loss, as early secretion of progesterone makes endometrium unreceptive for implantation. Keeping this view in mind, long agonist protocol which first causes downregulation of pituitary followed by stimulation with gonadotrophin came into vogue. However, due to triggering with HCG, there was increased incidence of OHSS. So options were sought and antagonist protocol came into use.

This is a shorter protocol than agonist where stimulation begins on day 2 or day 3 of natural menstrual cycle. There is no downregulation of the pituitary, and premature LH surge is prevented by adding GnRH antagonist when follicle is 14 mm (flexible protocol) or on day 5 (fixed protocol) of stimulation when there is high probability of LH surge. According to Cochrane (2011) [43], the antagonist protocol in comparison to the long GnRH agonist was associated with a large reduction in OHSS without a difference in live birth rates.

In Vitro Maturation (IVM)

As PCOS women are prone to hyperstimulation, there is an option in high-risk women to retrieve immature oocytes without stimulating the ovary and mature them in vitro following which they are fertilized. Since the ovaries are not stimulated, there is no chance of OHSS. The pregnancy rate is lower in IVM.

30.5.7.4 Triggering Ovulation in PCOS

Once there are three follicles of more than 18 mm, a trigger with HCG can be given. With antagonist protocol, there is a possibility of triggering follicle with agonist trigger, which can lead to decrease in incidence of OHSS. GnRH agonist acts at the level of the pituitary, displaces GnRH antagonist, and activates GnRH receptor, which causes a surge of gonadotrophin LH, and FSH which leads to ovulation. It is as close to natural cycle as possible. There is first FSH surge as in a natural cycle followed by LH surge, which leads to resumption of meiosis. Unlike natural cycle LH surge, GnRH agonist surge is a short surge lasting from 24 to 36 h with only two phases unlike three phases of LH surge [44]. So less amount of gonadotrophins are released which leads to early demise of corpus luteum. This is one of the major drawbacks of GnRH triggering. There is deficient corpus luteum leading to deficient luteal phase and significantly lower pregnancy rates.

Many strategies have been adopted to correct this luteal phase defect. Dual trigger GnRH agonist along with HCG, which combines the benefit of endogenous release of FSH and LH by agonist trigger and small bolus of HCG to cover early luteal phase insufficiency caused by agonist trigger, has been used. Peter Humaidan [45] in their study gave 1500 IU of HCG along with GnRH agonist to correct this luteal defect at the time of egg retrieval and got good pregnancy rates. Engmann et al. [46] supplemented the luteal phase with intramuscular progesterone and estradiol valerate as modified luteal phase supports post GnRH agonist trigger. According to Cochrane database, a comparison of GnRH agonist with HCG trigger concluded that agonist should not be routinely used for triggering ovulation in normal responder as it leads to significantly lower live birth rates (Table 30.4) [47].

Table 30.4

Comparison of GnRH agonist with HCG trigger

Comparison

GnRH agonist trigger

HCG trigger

OHSS

Very rare

High

Cost

Cost of GnRH trigger is minimal

Expensive

Total duration of action

Short (24–36 h)

Long (half-life is 48–73 h)

Luteal phase

Deficient

Adequate

FSH surge

Present

Absent

Pregnancy rate

Lower

Higher

Indication for use of agonist trigger is PCOS patients having high risk for OHSS or previous history of OHSS. GnRH agonist trigger could be Decapeptyl in the dose of 0.2 mg subcutaneously or leuprolide acetate 1 mg subcutaneously.

30.5.8 PCOS and OHSS

PCOS patients have very high chances of going into OHSS. Since they have high AMH levels and even with very small dosage of gonadotrophins, they may land up in growth of excessive follicles leading to OHSS.

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication. Regarding moderate cases, it has an incidence of 5 %. The incidence of cases requiring hospitalization is up to 2 %. With the increasing use of antagonist protocol, the incidence of OHSS has come down drastically. The cases of OHSS severe enough to get admitted are relatively few and occur most commonly with HCG trigger. To overcome this drawback of HCG trigger, GnRH agonist triggering is recommended in high responders and women having history of OHSS.

30.5.8.1 OHSS-Free Clinic

With the advent of GnRH agonist triggering, the concept of OHSS-free clinic has come. It is based on a three-segment approach to prevent OHSS.

·               Segment A: It consists of optimization of the ovarian stimulation including GnRH agonist triggering in a GnRH antagonist cycle.

·               Segment B: It consists of optimum cryopreservation methods for oocyte or embryo vitrification.

·               Segment C: It includes embryo replacement in a receptive, non-stimulated endometrium in a natural cycle or with artificial endometrial preparation (Fig. 30.7) [48].

A319836_1_En_30_Fig7_HTML.gif

Fig. 30.7

OHSS-free clinic three-segment approach to prevent OHSS

30.6 Summary

Lifestyle modification is the first line in the management of PCOS. Weight loss as little as 5 % will lead into normalization of menses and ovulation. Clomiphene citrate is the first choice for induction of ovulation in most anovulatory women with PCOS with a conception rate of 22 % and ovulation rate of 75 %. Use of metformin in PCOS should be restricted to those patients with glucose intolerance. There seems to be no advantage to adding metformin to clomiphene citrate in women with PCOS. If clomiphene citrate fails to result in pregnancy, then the second-line treatment is either gonadotrophins or laparoscopic ovarian drilling. Low-dose FSH protocols are effective in achieving ovulation with starting dose of 37.5 IU/day. Intensive monitoring is required in patients taking gonadotrophin. There is higher risk of OHSS and multiple pregnancy with gonadotrophin therapy. Laparoscopic ovarian surgery is an alternative to gonadotrophin therapy for clomiphene citrate-resistant anovulatory PCOS. Surgery can achieve unifollicular ovulation with no risk of OHSS or high-order multiples. Induction of ovulation in combination with IUI is indicated in women with PCOS and associated male factor infertility. In vitro fertilization can be offered to those couples that do not conceive after 3–6 cycles of IUI. Also there is advantage of doing a single embryo transfer in a young good prognosis patient. Use of GnRH trigger in patients with PCOS has lead to dramatic decrease of OHSS.

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