|REVIEW ARTICLE: ISSUE IN FOCUS
|Year : 2016 | Volume
| Issue : 4 | Page : 87-93
Polycystic ovarian syndrome: Treatment options for infertility
Sumi Thomas, S Sudharshini
Department of Reproductive Medicine, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Web Publication||22-Nov-2016|
Department of Reproductive Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Polycystic ovarian syndrome (PCOS) is a common cause of infertility and is characterized by clinical features of irregular menstrual cycles, hirsutism, and anovulatory infertility. The diagnosis is made based on the presence of two of three features (oligo/anovulation, hyperandrogenism, and polycystic ovaries on transvaginal ultrasound) according to the Rotterdam diagnostic criteria. Lifestyle modifications to reduce weight and the use of ovulation induction medications form the cornerstone of treatment of anovulatory infertility secondary to PCOS. Clomiphene citrate is the most effective as an agent for ovulation induction. The other therapeutic options include laparoscopic ovarian drilling, ovulation induction with gonadotropins, and in vitro fertilization.
Keywords: Clomiphene citrate, gonadotropin, infertility, polycystic ovarian disease
|How to cite this article:|
Thomas S, Sudharshini S. Polycystic ovarian syndrome: Treatment options for infertility. Curr Med Issues 2016;14:87-93
| Introduction|| |
Polycystic ovarian syndrome (PCOS) is a metabolic syndrome with impact on the reproductive, metabolic, and cardiovascular health of women. It affects approximately 5%-10% of women in the reproductive age groups ,,,, and is the most common cause of anovulatory infertility. PCOS is a complex biochemical disorder that is associated with conditions such as obesity, insulin resistance, hyperinsulinemia, cardiovascular risk factors, and sleep apnea. It presents with clinical features of irregular menstrual cycles, hirsutism, and anovulatory infertility.
This syndrome was first described by Stein and Leventhal in 1935.  They observed that "bilateral polycystic ovaries are most probably a result of some hormonal stimulation and very likely relate to the anterior lobe of the pituitary gland." Since then several theories have been postulated for the pathogenesis of this syndrome including inflammation/dystrophy of the ovaries, hyperandrogenism secondary to adrenal or ovarian hypersecretion of androgens, and environmental factors associated with obesity. Currently, PCOS is thought to be a complex genetic trait involving several genes coding for hormones such as luteinizing hormone (LH), follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) (especially on chromosome 2 and 9). Environmental factors such as obesity and insulin resistance contribute to the genetic factors to result in this syndrome. Heredity plays a role, with studies showing an increased the prevalence of PCOS in first-degree female relatives of affected women and in twins.
| Diagnosis of Polycystic Ovarian Syndrome|| |
There have been several criteria developed over the years for the diagnosis of PCOS which has led to much confusion. The Rotterdam Criteria developed in 2003 , has brought uniformity and is currently the most accepted universally for the diagnosis of PCOS [Table 1]. In clinical practice, a history of irregular cycles (suggestive of oligoovulation or anovulation) along with polycystic ovaries on ultrasound is often sufficient to diagnose PCOS in the absence of other obvious clinical features of hyperandrogenism [Box 1].
|Table 1: Rotterdam diagnostic criteria for the diagnosis of polycystic ovary syndrome |
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| Treatment Options for Infertility in Polycystic Ovarian Syndrome|| |
PCOS is a complex disease, and treatment should include interventions to address the problems of infertility, hyperandrogenism, obesity, insulin resistance, and other features. The treatment options available to manage the problem of infertility in PCOS will be discussed in this review. Often a single intervention may not address this issue, and a combination of two may have a beneficial effect. The treatment options for infertility include:
- Lifestyle modification (diet and exercise)
- Ovulation induction (clomiphene citrate [CC] and other medications)
- Surgical - Laparoscopic ovarian drilling (LOD)
- Ovulation induction with homologous intrauterine insemination (IUI)
- In vitro fertilization (IVF).
Obesity is associated with irregular menstrual cycles. Abdominal obesity, in particular, has been shown to cause failure to respond or delayed response to ovulation induction medications and surgical interventions, in women with PCOS. Weight loss through lifestyle modifications in diet and exercise is therefore recommended as first-line therapy in obese women. It also reduces outcomes of procedures such as IVF.  On the other hand, weight loss has been shown to improve spontaneous ovulation rates as well as reproductive outcome. 
The European Society of Human Reproduction and Embryology (ESHRE) recommends a low-calorie diet (1000-1200 kcal/day) with a decreased glycemic load or any calorie restricted diet to achieve 5% weight loss. Atkins' diet which comprises a very low-calorie diet has shown to cause significant weight loss in PCOS (12% in 24 weeks) and improves reproductive outcome. 
Exercise also plays an important role in patients with PCOS. Several nonrandomized studies have shown that a combination of diet and exercise improved menstrual function.  Current American Society for Reproductive Medicine (ASRM) recommendations  for lifestyle modification in obesity include:
- Weight loss of 7% of body weight
- Increased physical activity to at least 150 min weekly of moderate activity such as walking.
CC is the drug of choice for ovulation induction. It is a nonsteroidal triphenylethylene derivative and estrogenic antagonist. It was introduced in 1961 and is still the first-line drug for ovulation induction in PCOS. It is metabolized in the liver and is excreted through feces.
About 80% of patients with PCOS ovulate with CC treatment, however, only about 30%-40% conceptions occur. This is often because of the thinning effect of clomiphene on cervical mucus and endometrium coupled with other infertility factors. Multiple gestation rate varies between 2% and 8% and they are mostly twins. Miscarriage rates are similar to those with spontaneous ovulation [Table 2] and [Figure 1].
|Figure 1: Mechanism of action of clomiphene citrate. LH: Luteinizing Hormone, FSH: Follicle stimulating hormone, GnRH: Gonadotropin releasing hormone|
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Dose and monitoring
CC is started at a dose of 100 mg daily for 5 days, starting on any day between the 2 nd and 5 th day of a menstrual cycle (spontaneous or progestin-induced). Ultrasound monitoring for follicular response is done on the 13 th day of the menstrual cycle (or 7 days after the last dose) and a follicle >17 mm is appropriate. Following this, the couple is advised to have timed intercourse.
In case, there is no dominant follicle on ultrasound, then the dose of clomiphene is stepped up to 150 mg and then 200 mg in the subsequent cycles, and similar monitoring is continued. If the follicular response is documented after any one of these doses, then the same dose of clomiphene is continued for the three to six cycles.
A maximum of six cycles is recommended as more than that does not seem to improve the ovulation or pregnancy rates. Maximum dose is 200 mg/day. There is a slight increase in efficacy with an increase in dose; however, there is no additional benefit beyond 200 mg [Table 3]. 
Some facts regarding treatment with clomiphene
There is no role for hCG trigger in patients undergoing ovulation induction with CC.  It adds to the cost and rarely can cause ovarian hyperstimulation syndrome (OHSS).
Other methods of detecting ovulation
- There is no role for progesterone support during luteal phase 
- The largest and most reliable studies show a conception rate of 22% per cycle and cumulative live birth rates 50%-60% for up to six cycles (Hammond et al., 1983; Kousta et al., 1997; Eijkemans et al., 2003)
- Ultrasound is useful in detecting follicular growth but is not mandatory for documentation of follicular response. It has not been shown to improve reproductive outcome. 
In centers were facilities are not available, ovulation can be detected using urine detection kits (urinary LH kit). Another simple method of determining ovulation is a history of regularization of cycle following intake of clomiphene [Figure 2].
|Figure 2: Options for clomiphene resistance (a) and clomiphene failure (b)|
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Women who fail to ovulate with maximum (200mgs) dose of clomiphene (15-20% of PCOS), are said to have clomiphene resistance.
Failure to conceive after 3 - 6 ovulatory cycles is termed clomiphene failure [Figure 3] and [Figure 4].
Management options for clomiphene citrate resistance and clomiphene citrate failure
About 15%-20% of patients on clomiphene are resistant to treatment. The options available for management of these patients are insulin sensitizers such as metformin and pioglitazone, gonadotropins and LOD. Gonadotropins and aromatase inhibitors may be used as treatment options in CC failure. These options are described briefly below.
This drug has been in use for PCOS since 1984. Metformin is an insulin-sensitizing agent. PCOS is associated with hyperinsulinemia and insulin resistance. Metformin appears to reduce insulin resistance in PCOS patients. Metformin alone has not shown to improve ovulation rates or live birth rates compared to clomiphene. 
Recommendations for the use of metformin
Metformin is not recommended as the first line in patients with PCOS but can be used in PCOS with glucose intolerance, CC resistance and those with a body mass index (BMI) >35 kg/m  (ESHRE/ASRM 2008).  It should be given for a minimum of 6 months for benefits to be seen. In Clomiphene resistance, metformin may be given for 3 months followed by clomiphene + metformin for three cycles.
Dose of Metformin
Dose finding studies for PCOS are lacking; however, the recommended dose is a maximum of 1000 mg twice daily. It can be started as 500 mg once daily and slowly increased to the maximum dose, so as to reduce the side effects. 
It is an aromatase inhibitor with an anti-estrogenic effect. It has similar ovulation and pregnancy rates as clomiphene but without any anti-estrogenic effect on endometrium and cervical mucus. Anastrozole has shown to lead to lesser number of follicles compared to clomiphene and hence can be tried in patients at high risk of OHSS and where multiple pregnancy is not desired.  The dose of anastrozole 1 mg/day for 5 days.
Letrozole is another aromatase inhibitor with similar action; however, it is banned in India as a fertility drug.
An anti-cancer drug, Tamoxifen is an alternative ovulation induction agent. It is an anti-estrogenic compound with a beneficial effect on cervical mucus and endometrium similar to aromatase inhibitors. It results in ovulation in 70%-80% patients and has a pregnancy rate of 35%-40%. 
It is, however, not as effective as clomiphene and is not used as a first-line therapy. A recent prospective randomized trial has shown that clomiphene is more successful than tamoxifen for ovulation induction.  The dose of tamoxifen is 20 mg twice daily for 5 days.
The use of gonadotropins dates back to 1961. They are derivatives of urinary products but recently gonadotropins have been manufactured using recombinant technology. Both types have similar ovulation and pregnancy rates. Gonadotropins developed from recombinant techniques are more patient friendly as they can be given subcutaneously; however, they are expensive when compared to those derived from urinary products which are given intramuscularly. Gonadotropins can be used for clomiphene resistance and clomiphene failure.
The prerequisites for gonadotropin therapy are exclusion of uterine cavity abnormalities (myomas/adhesions), tubal obstruction and advanced endometriosis, pelvic adhesion, and poor semen quality.
Chronic low-dose step-up protocol
The chronic low-dose step-up protocol is the convenient protocol for ovulation induction in women with PCOS as it minimizes hyperstimulation which results in multifollicular growth.
The protocol followed in our institution is as follows [Figure 5]. Gonadotropins (human menopausal gonadotropin [HMG]) is started at a dose of 75 IU daily (mixture of FSH and LH) which is administered intramuscularly, from 5 th day of the menstrual cycle for 5 days. Ultrasound monitoring for number and growth of follicles is started from the 10 th day of the cycle and repeated every 1-2 days depending on the growth of the follicle. Gonadotropins are continued till the follicle grows to a size of 18 mm. Once the dominant follicle reaches 18 mm in size, hCG (5000 IU) is administered as a trigger, and the couple is advised sexual intercourse.
If there is no dominant follicle after 10-12 days of stimulation with 75 IU of HMG initially, the dose can be stepped up to 150 IU/day (usually by the 17 th day) and follicular monitoring is continued as described.
Results following gonadotropin ovulation induction have shown 70% ovulation rates and 20% pregnancy rates. Multiple pregnancy rate is approximately 5.7% and OHSS rate <1%. 
Treatment with gonadotropins is expensive and can be associated with significant risks such as multiple pregnancy and ovarian hyperstimulation. Clinician experience and training are, therefore, critical for its use. Intensive monitoring with multiple ultrasound examinations over several days is required to monitor follicular growth.
Ideally, ovulation induction with gonadotropins must be offered in a secondary level center with facility for referral to tertiary center in case of any complications such as OHSS or higher order pregnancy.
Prevention of complications with gonadotropin
The following precautions will help preventing complications with gonadotropin:
Close monitoring with ultrasound is important, especially if there is multifollicular growth
Laparoscopic ovarian drilling
- Strict cancellation criteria must be followed. Our recommendation is cancellation if there are >3 follicles of 16 mm and sexual abstinence till the onset of next menstrual cycle
- Withhold hCG if there is multifollicular growth. GnRH agonist may be used as an alternative as a trigger
- Aspiration of excess follicles (can be done at a tertiary center) before advising sexual intercourse
- Conversion to IVF, in case of hyperstimulation (which can be done at a tertiary care center).
This is a surgical option for ovulation induction, first described by Gjonaess in 1984. LOD is an attractive option in CC resistance, for those who hypersecrete LH and for where intensive monitoring is not feasible [Figure 6].  LOD is done using a monopolar cautery at 30 W. Four to five punctures at a depth of 8 mm are made in each ovary using the cautery which is held for 5 s each time. Different techniques have been described in literature. However, it is not advisable to drill more than 5 punctures due to the risk of ovarian failure. 
Mechanism of action
The destruction of ovarian androgen producing tissue reduces peripheral conversion of androgens to estrogen. This results in a fall in the levels of androgen and LH and rise in FSH level which leads to follicular genesis.
Various randomized studies have shown that there was no difference in pregnancy rate, live birth rate, or miscarriage rate when LOD was compared to other modes of ovulation induction; however, a reduction in multiple pregnancy rate and cost of treatment was observed in a Cochrane review.  The review also showed that the predictors of success with LOD were LH >10 mIU/ml, normal BMI, and a short duration of infertility (<3 years).
IUI can be added to ovulation induction methods if there is associated male factor infertility or if there is no conception despite successful ovulation with gonadotropins alone for the two to three cycles. Ovulation induction with gonadotropins combined with IUI in anovulation results in pregnancy rate of 11%-20%. However, this can be offered in a secondary level center with facilities for referral to tertiary center as mentioned earlier.
In vitro fertilization
Anovulation is not a direct indication for IVF. In cases where the woman has not conceived in spite of other method of ovulation induction and IUI then IVF would be the next step. At our institution, we recommend two to three cycles of ovulation induction with gonadotropins followed by two to three cycles of ovulation induction with gonadotropins combined with IUI and if the patient still does not achieve a pregnancy; then, we suggest IVF as the next option. In women with other associated pathologies such as bilateral tubal damage, severe endometriosis, and severe male factor infertility IVF would be the first step.
The major complication of multiple pregnancy can be minimized by exploring single embryo transfer and aiming at a OHSS free clinic.
| Conclusion|| |
Lifestyle modification, weight loss, and exercise form the first line of treatment in infertile women with PCOS. The recommended first-line drug for ovulation induction remains CC and recommended second-line treatment involves gonadotropins or LOD. Metformin has been recommended in patients with clomiphene resistance, glucose intolerance, or those with a BMI > 35 kg/m  . There is insufficient evidence to recommend routine use of aromatase inhibitors or tamoxifen for ovulation induction.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]