What is the best first-line treatment for infertility due to anovulation in women with polycystic ovarian syndrome?

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1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects What is the best first-line treatment for infertility due to anovulation in women with polycystic ovarian syndrome? Erin Casey Roper The University of Toledo Follow this and additional works at: This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 What is the Best First-Line Treatment for Infertility Due To Anovulation in Women with Polycystic Ovarian Syndrome? Erin Casey Roper The University of Toledo 2009

3 ii Dedication I would like to thank my wonderful husband, Patrick, for being a single dad while I was in PA school. Thank you, Sweetie! I would like to thank my parents and in-laws for their support with watching the kids. I would also like to thank my friends Jena and Laura for the many hours we spent studying whether in a frigid Starbucks or in Jena s apartment complex pool. I would never have survived PA school without you!

4 iii Acknowlegments I would like to thank Dr. Moynihan for all of her help with my project. She was a fabulous major advisor, always supportive and never in a hurry!

5 iv Table of Contents Introduction... 1 Purpose... 3 Pathophysiology of polycystic ovary syndrome... 5 Normal Menstrual Cycle... 5 The PCOS Profile... 7 Clomiphene Citratrate... 9 Metformin Clomiphene citrate versus metformin versus both drugs together for the treatment of anovulation or oligo-ovulation Metformin plus clomiphene in clomiphene-resistant women PCOS s affects on pregnancy Metformin use in pregnancy Conclusion... 27

6 v List of Figures 1. Table 1. Proposed Diagnostic Criteria in Polycystic Ovary Syndrome 2. Figure 1: Changes During the Menstrual Cycle 3. Table 2. Results of Legro et al study

7 1 Introduction The value of family is shown in all major religions and the desire to bear children weighs heavily on many couples who are struggling to get pregnant. There are a number of verses in the bible that emphasize the importance of family. These include, Behold, children are a heritage from the LORD, the fruit of the womb a reward. Like arrows in the hand of a warrior are the children of one s youth. Blessed is the man who fills his quiver with them! He shall not be put to shame when he speaks with his enemies in the gate. (Psalms 127:3-5 English Standard Version) And when Esau lifted up his eyes and saw the women and children, he said, Who are these with you? Jacob said, The children whom God has graciously given your servant. (Genesis 33:5) He gives the barren woman a home, making her the joyous mother of children. Praise the LORD! (Psalms 113:9) Culturally, conception and childbirth is not seen as a privilege but rather a right and those who are not able to bear children can feel isolated and bereft. This has caused the demand for fertility-related services to grow. The 2002 National Survey of Family Growth analyzed a sample of 12,571 noninstitutionalized men and women aged The survey included analysis of factors affecting infertility and actions taken to get pregnant. In that survey, 73.7% sought advice, 58.7% went through infertility testing and 45.7% took drugs

8 2 to improve ovulation (Vahratian, Anjel, 2008). This means 9,265 people sought advice, 7,379 went through testing, and 5,745 women took drugs to improve fertility. Because there are many different causes of infertility, many different treatment options are available. Some examples follow. There are a number of drugs used to regulate oocyte development and induce ovulation. Intrauterine insemination delivers sperm directly into the uterus of a woman who has ovulated naturally or whose ovulation has been induced. In-vitro fertilization involves the laboratory-controlled union of a sperm and egg outside of the body. The resulting zygote is placed into the uterus to allow for implantation. In the process of intra cytoplasmic sperm injection (ICSI), one sperm is placed directly into a retrieved egg and the resulting zygote is placed into the uterus for implantation. Polycystic ovary syndrome (PCOS) causes infertility in 5-10% of all American women (Knochenhauer, et al, 1998; Carmina 1999). Of those women who have PCOS, 75% are infertile. PCOS causes insulin resistance in peripheral tissues and causes the ovary to produce excess androgens, resulting in chronic anovulation or oligoovulation. This manifests as amenorrhea or oligomenorrhea. Purpose The primary purpose of this clinical review is to determine the optimal firstline treatment for those women desiring conception who are not ovulating or not

9 3 ovulating regularly due to PCOS. The secondary purpose is to analyze the data on metformin use during pregnancy to determine if using this medication may lead to a healthier pregnancy and greater live-birth rate. These parameters were chosen because they will offer useful information to the generalist, either in family practice or in obstetrics and gynecology. The optimal drug will be defined as the one that produces the most live births. Live birth was chosen as an end point because women who come for treatment want a baby. While ovulation and conception rates may be valuable indicators of success of a medical regimen in research terms, patients presenting for care are unlikely to perceive these rates as relevant. They want a baby and, for them, the only acceptable outcome is live birth. One cannot look at live-birth rates without looking at pregnancy complications associated with a syndrome such as PCOS. The pathophysiology of PCOS and how it relates to infertility and maintenance of pregnancy will be discussed first. Then, the literature will be analyzed to determine the current consensus regarding optimal first-line therapy for ovulation induction. The main treatments under analysis are clomiphene citrate (CC), metformin, and a combination of both CC and metformin. Finally, emerging literature will be analyzed to assess the benefits of metformin treatment during early pregnancy, both as therapy for insulin resistance and as a means to reduce the incidence of miscarriage in early pregnancy. A woman will often present to the generalist with a complaint of not having regular periods or of trying and not being able to get pregnant. Both of these complaints can be a result of anovulation or oligoovulation. There are many

10 4 reasons why a woman may not be ovulating. These include dysfunction of the hypothalamus, gonadotropin deficiency, hypothalamic-pituitary damage including tumors, inappropriate feedback mechanisms, and other endocrine and metabolic disorders (Goldman 2008).

11 5 Pathophysiology of polycystic ovary syndrome Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women, affecting between 5 and 20% of all women (Knochenhauer, et al, 1998; Carmina 1999). However, the etiology is unclear and even the diagnostic criteria are debated. The syndrome was first recognized by Stein and Leventhal in 1935 and described as being associated with excess androgen release by the ovaries, oligo- or amenorrhea, and multiple ovarian cysts seen on ultrasound (Stein 1935). Because PCOS is a heterogenous disorder, diagnosis can be complicated. There is not one gold standard test to diagnose the syndrome. Diagnostic criteria have changed and evolved over the past several decades. Richard Legro included a proposed list of potential diagnostic criteria in his article Diagnostic Criteria in PCOS. See Table 1. Normal menstrual cycle Many complex interactions between the central nervous system, hypothalamus, pituitary, and ovary must occur for a normal ovulatory cycle to result (see Figure 1). Any interruption in these interactions may result in anovulation. During the early follicular stage, serum estradiol and progesterone concentrations are low. Low levels of these hormones trigger a negative feedback loop, inducing an increase in pulsatile release of GnRH and an increase in FSH concentrations. FSH plays a role in selecting a group of follicles. One dominant follicle will result from this group. This select group of

12 6 follicles releases inhibin B which suppresses FSH and increases pulsation of GnRH. An early predominance of FSH results in follicular growth and induction of LH receptors and causes the conversion of androgens into estradiol by aromatase. During the mid-follicular phase, the increase in estradiol production and inhibin A stimulates a negative feedback loop in the hypothalamus and pituitary and suppresses FSH and LH concentrations and LH pulse amplitude. GnRH pulses increase. This is postulated to occur from negative feedback effects of progesterone from the previous cycle. Slower pulses seem to cause the release of FSH while faster pulses seem to favor LH release (Haisenleder, 1994). During the late follicular phase, estradiol and inhibin A concentrations increase due to release from the growing dominant follicle. This causes FSH and LH concentrations to fall. Once the dominant follicle is selected, FSH induces LH receptors on the ovary and increases secretion of intrauterine growth factors such as insulin-like growth factor. The dominant follicle continues to grow to 20-26mm and the other follicles stop growing. Mid-cycle, GnRH pulsations increase causing an LH surge that results in ovulation. The LH surge also occurs due to a rise in estradiol (E 2 ), which causes a positive feedback loop and enhanced LH production. Progesterone rises just after ovulation and FSH falls. The rise in E 2 and progesterone causes GnRH to pulse erratically. The involution of the corpus luteum causes progesterone levels to drop and FSH again becomes the dominant hormone, allowing for development of a new follicle and the cycle repeats (Marshall, 1999).

13 7 The PCOS profile The PCOS profile varies greatly among women with the syndrome. However, the majority of women with PCOS experience anovulatory infertility (Knochenhauer, 1998). There is no consensus to explain this phenomenon. One theory postulates a complex genetic trait, similar to type II diabetes or heart disease. Environmental factors such as diet and obesity also seem to play a role and are thought to interact with the genetic component. This theory makes sense because PCOS seems to have a familial pattern and there is much variation in the phenotype of the disorder. Another theory suggests that it a combination of altered hormone levels and poor follicle development. Both theories, in combination, probably contribute to an explanation of the constellation of symptoms. FSH levels in women with PCOS tend to be normal or slightly suppressed while LH levels are markedly higher throughout the cycle with no surge midcycle. Androgen levels are also increased (Franks, 1995). Insulin resistance and hyperinsulinemia are seen in anovulatory women with PCOS although not in those PCOS patients who have ovulatory cycles. This suggests a relationship between excess serum insulin and anovulation (Barber, 2007). Hyperinsulinemia may also disrupt antral follicle development. Women with PCOS develop many small follicles but fail to develop a dominant follicle which is necessary for ovulation. It is believed that larger, nondominant follicles simply fail to develop (Franks 2000). This may be due to the

14 8 fact that FSH levels rarely rise above the threshold level required for follicles to develop properly (Hillier, 1994). There is evidence to show that abnormalities in oocytes in women with PCOS affect ovulation as well. Granulosa cells, which surround oocytes and produce steroids and growth factors, are hypersensitive to FSH resulting in excess estradiol production. This is only seen in women with PCOS who are also anovulatory and not in women with PCOS who have ovulatory cycles. A study done by Franks et al (2000) showed that granulosa cells from a dominant follicle (13 mm) will respond to LH. This finding held true in both normal women and women with ovulatory PCOS. Women with anovulatory PCOS, however, showed granulosa response to LH in follicles as small as 2-4 mm. There was also an inappropriate response to FSH and LH in medium sized follicles of women with anovulatory PCOS while there was no response in the granulosa cells of medium sized follicles in the other two groups. In a normal ovary, only the dominant follicle acquires LH receptors but this study showed that many small antral follicles in a polycystic ovary acquired LH receptors which eventually led to granulosa differentiation and caused the follicles to stop growing. It has been proposed that hyperinsulinemia and/or increased secretion of LH may be the reason for the inappropriate response of the granulosa cells to LH (Franks et al, 2000). It is also shown that women with anovulatory PCOS have impairment of glucose uptake and metabolism even though production of progesterone (which is stimulated by insulin) is intact. Increased insulin decreases sex hormone binding globulin which allows for more free estradiol and

15 9 an increase in LH levels (Nestler, 1991). All of this may have an effect on cessation of antral follicle development. Clomiphene citrate The two most common drugs currently used to induce ovulation are clomiphene citrate and metformin. They have very different mechanisms of action and can be used separately or in conjunction. Clomiphene citrate (CC) came on the market more than 40 years ago. Prior to the 1960 s, the only treatment for anovulation was wedge resection of the ovaries. This offered some success but led to pelvic adhesions. There were also the risks associated with general anesthesia and surgery itself. Clomiphene, the first drug of its kind, was originally used to treat hypothalamicpituitary dysfunction in women who fell into WHO group 2. Women with PCOS make up about 80% of WHO group 2. More recently, clomiphene has been used, with some success, in women with unexplained infertility. While the mechanism of clomiphene is not entirely known, it has properties of both estrogens and anti-estrogens (Adashi 1984). It is thought to block estrogen receptor sites in both the hypothalamus and pituitary, thus blocking the negative feedback loop caused by estrogens in the blood. The hypothalamus reads this as an estrogen deficiency which induces a change in the pulsatile pattern of GnRH. This causes the pituitary to make and release more follicle stimulating hormone (FSH). Often, this is enough to reset the ovulation cycle.

16 10 Clomiphene is a relatively inexpensive oral drug given at a dose of mg per day for several days each cycle. Usually, the lowest dose is given first and signs of ovulation are monitored. Ovulation is implied if a patient has a spontaneous menstruation at the end of the cycle. More definitive monitoring includes checking the levels of progesterone mid-luteal phase via blood work or using an ultrasound to determine exact follicle size and number. If ovulation is not achieved, a higher dose (increasing in increments of 50 mg) of clomiphene is administered in the subsequent month. There is some debate about the timing of administration. Some clinicians give it days 3-7 and some give it days 5-9 (with day 1 being the first day of the menstrual period). Not every woman will ovulate on clomiphene and it is impossible to determine who will respond to it. A study by Imani (1997), showed that 77.5% responded to CC at doses of 50, 100, or 150 mg while 22.5% did not. Women who do not respond to clomiphene at 150 mg for three consecutive cycles are considered clomiphene-resistant. Women who were obese, insulin resistant, and hyperandrogenic were more likely to be resistant than those who did not display these traits. Clomiphene not only increases FSH, it also produces an undesirable rise in luteinizing hormone (LH). In women with PCOS, who already have high basal levels of LH, this can interfere with conception (Shoham et al, 1990). There are very few side effects related to CC. These can include hot flushes, headaches, and nausea. Risk of multiple pregnancy increases slightly from a base rate of 3% in the general population to 8-13% due to increase in

17 11 FSH causing multiple follicles to grow (Kousta 1997). In some studies, clomiphene is shown to adversely affect cervical mucus and reduce endometrial thickening. This is due to its primary action as an anti-estrogen in the uterus and cervix. CC also has a relatively long half-life of 5 days. If it is given later in the cycle, it may produce anti-estrogen effects during the sensitive implantation period. A study by Dehbashi, Vafaei, Parsanezhad, and Alborzi (2006) found that giving clomiphene days 1-5 (n=37) of the cycle led to higher pregnancy rates than administering it days 5-9 (n=41) of the cycle. Pregnancy rates were 40.5% (15/37) and 19.5% (8/41) respectively (P=0.04). The small sample size (n=78) may introduce confounders into the results. Clomiphene citrate can also cause hyperstimultion of the ovaries. A small amount of hyperstimulation actually increases pregnancy rates three-fold (Tulandi, 1984). This is considered mild hyperstimulation and is expected. Moderate to severe ovarian hyperstimulation syndrome (OSHH) occurs in 3.1-6% and % respectively (Lunenfeld, 1984). Symptoms of moderate hyperstimulation include nausea, vomiting, and diarrhea. A sudden weight gain of greater than 5 pounds may signify moderate hyperstimulation. Rapidly rising estradiol levels and very large follicles (>12 cm) are also seen. Ultrasonographic evidence of ascites is also present (Whelan, 2000). Severe hyperstimulation can include symptoms of mild and moderate hyperstimulation plus difficulty breathing, change in blood volume, increased blood viscosity due to hemoconcentration, coagulation abnormalities and diminished renal perfusion and function (Whelan,

18 ). Severe hyperstimulation can be fatal (Cluroe, 1995). PCOS is a risk factor for OSHH (Buyalos, 1996). Ovarian hyperstimulation syndrome can sometimes be prevented through monitoring. Ultrasound images of the ovaries will show number and size of recruited follicles. Blood tests detect estradiol levels. If evidence of OHSS is seen, medications can be discontinued or dosage lowered to prevent hyperstimulation from getting worse (Whelan, 2000). Some debate also continues about how long to treat with clomiphene. Kousta (1997) showed that 71% of pregnancies occurred within the first three cycles of CC treatment. He did not mention dosage in relationship to pregnancy rates. He also showed that cumulative pregnancy rates continued to rise after 6 months of treatment but reached a plateau at 12 months of treatment. There was a study done in 1994 by Rossing et al that showed that there may be an association between more than 12 cycles of CC and increased risk of a borderline or invasive ovarian tumor. A more recent study done by Mosqaard et al (1998) showed that there was no statistical probability that ovulation-inducing drugs lead to ovarian cancer. Because there are no recent controlled studies, more research needs to be done. Metformin

19 13 Metformin, which belongs to a class of drugs called biguanides, is used to lower blood sugar and reduce hyperinsulinemia. It works by decreasing liver gluconeogenesis thus decreasing insulin secretion. It also sensitizes peripheral cells to insulin by helping the glucose transporters in liver and muscle cells to uptake glucose more efficiently. This lowers serum gluose and reduces peripheral resistance. Finally, it decreases glucose uptake in the small intestine (Bailey 1996 and Patane 2000). One of the benefits of metformin over other antidiabetic drugs is that it does not directly lower blood sugar and will not cause hypoglycemia. Meformin can cause some side effects, mainly gastrointestinal in nature. These are related to build up of lactic acid in the bowel wall (Wilcock 1994) and include nausea, vomiting, flatulence, diarrhea, indigestion, and abdominal discomfort. Side effects can be reduced by taking the drug with food. Very few patients (5%) experience side effects great enough to discontinue use (Garber 1997). Likelihood of side effects correlates with dose of metformin. Metformin is available as a generic and is given in doses of 500 mg to 2550 mg. Due to side effects, metformin is usually started at the lowest dose and titrated up to achieve optimal serum glucose levels. The drug is taken with meals, often starting 500 mg at the evening meal and then adding 500 mg at lunch and then a third dose at breakfast. If 1500 mg is not producing optimal glucose levels, additional amounts can be added. The drug comes in 500, 850, and 1000 mg tablets. The best dose at which to induce ovulation is still under debate. Two regimens include 500 mg three times daily and 850 mg twice daily.

20 14 Many clinicians will start with 500 mg three times daily and monitor side effects. If well tolerated, 850 mg can be given twice daily to increase compliance (Barbieri 2008). Metformin may take up to six months to regulate (or start) ovulatory cycles. Metformin is not metabolized and is excreted by the kidneys. Therefore, it should not be given to patients with renal insufficiency or congestive heart failure. A rare complication is lactic acidosis (Misbin 1998). Any condition lowering the excretion rate can increase risk for this. Metformin can also cause a B 12 deficiency in up to 30% of patients (DeFronzo 1995). The mechanism is not completely clear but one theory suggests that metformin alters calcium-dependent membrane potential in the cells of the small intestine (Schafer, 1976). Baumen, Shaw, Jayatilleke, Spungen, and Herbert (2000) suggest that metformen may actually act as a calcium channel blocker. Because B 12 intrinsic factor uptake in the ileum is also calcium-dependent (Carmel, Rosenberg, Lau, Streiff, & Herbert, 1969), metformin can interfere with B 12 absorption. This can lead to a deficiency. A small study (n= 21) done in 2000 (Baumen, et al.) showed that calcium supplementation (1.2 g/day) reversed the B 12 deficiency found in men taking metformin. All patients taking metformin should be urged to get enough calcium in their diets and to take a high-quality prenatal vitamin. If they are still not getting enough calcium, a calcium supplement should be added. B 12 levels should also be monitored annually.

21 15 Clomiphene citrate versus metformin versus both drugs together for the treatment of anovulation or oligo-ovulation Clinicians have been prescribing clomiphene citrate for decades and for many years it was the only treatment available. It induces ovulation in as high as 80-85% of patients and has conception rates as high as 40% (Clark, 1981 and Hammond 1983). Metformin has a safe profile and a recent meta-analysis (Creanga et al, 2008) showed that, as compared to placebo, it is effective in inducing ovulation in PCOS patients. The meta-analysis reviewed 17 studies and found that ovulation rates varied among different sub-populations of patients. Metformin also has positive secondary effects on the PCOS patient such as weight reduction and a decrease in insulin resistance. The question becomes, Which drug is best for treatment of anovulation or oligo-ovulation in the PCOS patient? The heterogeneity of the syndrome makes it difficult to answer this question. Many studies have attempted an answer but only four have used live birth rate as the primary outcome (Palomba, 2005; Moll, 2006; Legro, 2007; and Zain, 2008). Palomba et al. (2005) studied a group of100 nonobese Italian women between the ages of 20 and 34. Exclusion criteria included (but were not limited to) women with a BMI greater than 30, women who had taken oral contraceptives or ovulation induction drugs in the previous 6 months, any medical disorders, and women who failed to have withdrawal bleeding following the progesterone challenge test. One hundred women were randomly assigned to two groups.

22 16 Group A was given metformin plus placebo. Group B was given clomiphene plus placebo. There was no statistical difference between the characteristics of the two groups. Results came from 92 patients (8 had to be excluded for various reasons), 45 in group A and 47 in group B. Ovulation, pregnancy, spontaneous abortion, and live-birth rates were studied. The ovulation rates did not vary significantly between the two groups over 6 cycles. However, after 6 cycles, 6.7% of metformin users and 34.0% of clomid users remained anovulatory or oligo-ovulatory (P=0.02) Pregnancy rates per ovulatory cycle, however, favored the metformin group (15.1% vs. 7.2%, P=0.009). Spontaneous abortion rates also significantly favored the metformin group (9.7% vs. 37.5%, P=0.045) while live birth rates showed a positive trend with metformin but results were not significant. No multiple pregnancies were seen in either group. Cumulative pregnancy rates after 6 months of treatment were also significant (68.9% in group A and 34.0% in group B, P<0.001). This study had some flaws. It only included nonobese women. No definitive, controlled studies have been done to determine the true incidence of obesity among women with PCOS. Most observational studies show that at least 50% are obese (Barbieri, 2008). Because so many women with PCOS are obese (BMI >30), the results of this study on non-obese women may not be valid for the majority of women with PCOS. A second study published in 2006 by Moll et al showed very different results. Two hundred twenty eight Danish women under the age of 40 were invited to participate. All had chronic anovulation as defined by menstrual cycle

23 17 35 days, WHO type II, normogonadotropic, normo-estrogenic, oligoanovulation, or anovulation. They also had polycystic ovaries identified by ultrasound. Exclusion criteria included age >40, other causes of anovulation, liver, kidney, or heart disease (or failure) and women whose partner had low sperm count (<10 *10 6 ). Women were randomized into two groups: the metformin group (n=111) and the placebo group (n=114). Either metformin or placebo was given for one month to allow metformin s insulin-sensitizing effects to occur. If no spontaneous menstruation occurred at the end of the month and a pregnancy test was negative, menstruation was induced with dydrogesterone, a synthetic progesterone. Then, women were given clomiphene from the third or fifth day to the seventh or ninth day after that menstruation. Doses of clomiphene were started at 50 mg per day. If a woman did not ovulate (as defined by a rise in the biphasic temperature curve, luteal phase progesterone level 14 nmol/l, or a follicle with a diameter of 16 mm on transvaginal ultrasound), the dose of clomiphene was raised 50 mg each cycle until she did ovulate. Women who ovulated but did not achieve pregnancy stayed at the same dose of clomiphene for the following month. The maximum dose given was 150 mg. If a women ovulated one month on a certain dose and then failed to ovulate the next month on that dose, she was considered temporarily ovulatory and given the next higher dose of clomiphene the following month. Women who failed to ovulate at 150 mg were considered resistant to clomiphene.

24 18 Twenty-eight women in the metformin group stopped taking the medication before the study was over (18 because of side effects and 10 for unspecified reasons). Twenty-one in the placebo group stopped the medication early (6 due to side effects, 10 for unspecified reasons and 5 due to a concomitant disease). There was a significant percentage of women who stopped taking metformin due to side effects (16% vs. 5% who stopped placebo). This study provided no significant evidence to indicate that adding metformin to clomiphene is better for ovulation or live-birth rates than clomiphene alone. Ovulation rates were 71% in the metformin group and 82% in the placebo group. Ongoing pregnancy rates were 44% in the metformin group and 52% in the placebo group. Neither of these rates showed a significant difference between the groups. There were no significant differences in ovulation rates between the groups of women receiving different doses of clomiphene. Spontaneous abortions occurred in 13% of the metformin group and 12% of the placebo group. This was also a non-significant difference. While metformin appears to be safe in pregnancy (no significant number of birth defects between the groups), this study shows no reason to add it to clomiphene to induce ovulation and achieve a pregnancy. This was a large study that included both obese and non-obese women and represents a realistic group of PCOS patients. The largest study done comparing metformin to clomiphene therapy was done by Legro et al and published in This study included 626 women with PCOS (as defined by oligomenorrhea [no more than 8 spontaneous menses in a year] and

25 19 hyperandrognemia [defined by elevated testosterone level]. Exclusion criteria included any disorder that may have accounted for the oligomenorrhea, suspected Cushing s disease, or androgen-secreting neoplasm. The mechanism of this study was similar to the previous studies but there were three arms: clomiphene plus placebo (n=209), metformin (extended release formula) plus placebo (n=208) and metformin plus clomiphene (n=209). The subjects were blinded to avoid participant bias. Subjects were told to have intercourse every 2-3 days and had various hormone level testing done at various times during the study. If pregnancy was achieved, they discontinued the drugs they were taking. There were no significant differences between the study groups in terms of age, BMI, fertility history, etc. Fifty-five women in the clomiphene group (26.3%), 72 women in the metformin group (34.6%), and 49 (23.4%) women in the combination group dropped out of the study. There was significantly greater drop-out of women in the metformin group as compared to the combination group (P=0.01). Clomiphene therapy (47/209, 22.5%) and combination therapy (56/209, 26.8%) gave much higher live-birth rates as compared to the metformin group (15/208, 7.2%) (P<0.0001). However, there was no significant advantage to combination therapy over clomiphene therapy regarding live-birth rate. Of the women who ovulated on the various medications, 62/157 (39.5%) of women in the clomiphene group as compared to only 25/115 (21.7%) in the metformin group, and 80/174 (46%) in the combination group conceived. There

26 20 was no significant difference in the rate of pregnancy loss among the groups. See table 2. Interestingly, women in the metformin group and women in the combination group both showed a significant drop in BMI and waist circumference compared to the clomiphene group, reinforcing the positive effect of metformin on weight. Clomiphene, on the other hand, raised BMI, insulin levels, and levels of sex-binding hormone significantly. Compared to clomiphene, the combination group showed significant decrease in BMI, testosterone levels, proinsulin, insulin, and insulin resistance. The pregnancy rates in this trial were lower than in other trials (Palomba, 2005; Moll, 2006). This may be attributable to the average morbid obesity of the participants (BMI s 36.0± 8.9 in the clomiphene group, 35.6±8.5 in the metformin group, and 34.2±8.4 in the combination group). Another interesting finding was shown in the post-hoc testing done comparing BMI of mother to live-birth rate. Independently of treatment, women with a BMI of <30 had a significantly higher live-birth rate compared to those women with a BMI >30 (P<0.001 by univariate analysis). The most recent study regarding best first-line drug treatment was done by Zain et al in This study included 115 Asian women, had the same exclusion criteria and produced similar results to the Legro et al (2006) study. The drug protocol was the same, as well, however, clomiphene was given days 2-6 rather than days 3-7 or 5-9 as in the Legro et al trial. This study showed no

27 21 significant differences among the groups with regard to age, BMI or waist-to-hip ratio. Results showed no significant difference in ovulation rates between the combination arm and clomiphene arm of the study. However, clomiphene and combination therapy were significantly better (23/39, 59%; and 26/38, 68.4% respectively) at inducing ovulation than metformin alone (9/38, 23.7%). There were no significant differences in pregnancy or live birth rates in this trial. In contrast to Legro et al (2006), this study showed no significant effect on BMI or waist-to-hip ratio among the women taking metformin (either alone or in combination). With the exception of Palomba et al (2005), which studied only lean women, study results to date indicate that clomiphene surpasses metformin in inducing ovulation and producing live birth. While combination therapy tended to show higher ovulation, pregnancy, and live-birth rates, they were never significantly higher than those rates for clomiphene alone. It is interesting that the Palomba et al study (2005) showed more success with metformin. As shown in the Legro et al (2007) study, metformin lowers BMI, waist-to-hip ratio, testosterone levels, and insulin resistance. One would think that these benefits would have more impact on the fertility of obese women but the studies that have included obese women have not proven these fertility benefits.

28 22 Metformin plus clomiphene in clomiphene-resistant women Metformin has shown some promise in sensitizing women to clomiphene. A small study (n=56) done by Kocak et al in 2002, showed that metformin added to CC greatly improved ovulation rates and slightly improved pregnancy rates in women known to be clomiphene resistant. Seventy-seven percent ovulated in the metformin group versus 14.2% in the placebo group (P<0.001). There were 3 total pregnancies (11%) in the metformin group versus zero in the placebo group (P=0.04). Another small study (n=25) supported these results (Vandermolen, 2001), further suggesting that metformin added to clomiphene works significantly better than clomiphene alone in women who are known to be clomiphene-resistant. Seventy-five percent (9/12) women in the metformin group ovulated compared to 27% (4/15) in the placebo group (P=0.02). Fifty-five percent (6/11) women in the metformin group achieved pregnancy while only 7% (1/14) in the placebo group became pregnant (P=0.02) Even though metformin alone has not been proven to be the superior drug at inducing ovulation and producing live birth, it still has many benefits for the woman with PCOS. PCOS s effects on pregnancy Polycystic ovary syndrome not only affects the ability to get pregnant but can also have adverse effects on pregnancy itself. Women with PCOS are at higher risk for early pregnancy loss (Jakubowicz 2002), gestational diabetes

29 23 (Holte 1998), and pregnancy-induced hypertension (Hamasaki 1996). All of these appear to be linked to hyperinsulinemia. Early spontaneous abortion or early pregnancy loss (EPL) is clinically recognized in women with PCOS who are able to conceive (either naturally or with ovulation induction medication). The EPL in normally fertile women is estimated to be 10-15%. There is a three-fold risk of spontaneous abortion in women with PCOS (Jakubowicz, 2002). Originally, elevated LH levels were thought to be the culprit. Recently a number of new theories have been presented. Hyperandrogenemia may play a role. Okon et al (1998) studied the androgen levels in women with recurrent miscarriage and found that the levels were higher in women with PCOS compared with levels in normal fertile controls. It is known that excess androgens antagonize estrogen. Estrogen is the hormone that helps the embryo to implant and helps to maintain the endometrium. Another theory suggests that the activity of plasminogen activator inhibitor (PAI-fx) is elevated in women with PCOS who have recurrent miscarriages (Glueck, 1999). PAI-fx can causes a hypofibrinolytic (or hypercoaguable) state resulting in placental insufficiency. Hyperinsulinemia can also cause decreased uterine vascularity (Jakubowicz, 2004). Decreased uterine vascularity can lead to decreased placental perfusion and to hypoperfusion to the fetus. Obesity, as defined by a BMI >30, appears to be the most prominent risk for miscarriage in women with PCOS (Fedorcsak, 2000). Fedorcsak and

30 24 coworkers did a study in 2000 that studied 383 obese and nonobese women who conceived via IVF or ICSI. Obesity raised the risk of miscarriage to 22% from 12% in lean women (P=0.03). Hyperinsulinemic insulin resistance in obese women is classified as an independent risk factor (Fedorcsak, 2000). Women with PCOS display many risk factors for gestation diabetes mellitus (GDM). As many as 80% of obese women and 30% of nonobese women with PCOS have insulin resistance prior to conception (Dunaif, 1989). Because it tends to be more difficult for women with PCOS to conceive, women are often older when they become pregnant. Increased maternal age is also a risk factor for GDM. Holte studied a group of women with GDM over 3-5 years. Using ultrasonographic evidence of polycystic ovaries as defining PCOS, he found that 41% of the women with GDM had PCOS as compared to 3% of the non-gdm group (P<0.0001) (Holte, 1998). No prospective studies exist of women with PCOS to identify the incidence of GDM in this population. PCOS and obesity are associated with pregnancy-induced hypertension and preeclampsia (examples of pregnancy induced hypertensive disorders [PIHD]).. Pregnancy-induced hypertension is defined as hypertension during pregnancy with no systemic symptoms. Preeclampsia is defined as elevated blood pressure with proteinuria. Proteinuria indicates involvement of the kidneys. Preeclampsia can also cause or result from placental abnormality. Other manifestations of preeclampsia include disseminated intravascular coagulation, hemolysis, and elevated liver function tests. An untreated woman can quickly progress to eclampsia which is manifest by seizures.

31 25 A 2002 study by Bjercke and coworkers showed that the risk for gestational hypertension significantly increased in women with PCOS (11.5% vs. 0.3%; P<0.05) and preeclampsia was also found to be more common in insulin resistant women with PCOS (22% vs. 7%, P<0.05). Bryson and colleagues (2003) found that gestational diabetes increased the risk of pregnancy-induced hypertension 1.5 times that of women without GDM. The risk was greatest in black women. Both GDM and PIHD pose risk to the developing fetus and can cause miscarriage. A 1995 study by Ibrahim and colleagues showed an associated risk of poorly controlled GDM with stillbirth, macrosomia, hypoglycemia, bacterial infection, birth trauma, pre-term delivery, respiratory distress, anemia, and polycythemia. Chronic hypertension during pregnancy also poses many risks for the fetus. These risks include intrauterine growth restriction and perinatal mortality. Risks for the mother include Cesarean-section and post-partum hemorrhage (Vanek, 2004). Metformin use in pregnancy Recently, clinicians have speculated about the benefits of giving metformin before and during pregnancy. The drug is a class B pregnancy drug which the FDA defines as presumed safety based on animal studies, with no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester and there is no evidence of a risk in later trimesters.

32 26 A number of studies have been done by Glueck and collegues that show that an insulin-sensitizing drug such as metformin, when continued into pregnancy, may decrease the risk of miscarriage. Their 2002 study compared women taking metformin into pregnancy to women not taking metformin. They also studied a smaller population of women who had spontaneous abortions while not on metformin. They administered metformin and compared their SA rates while on metformin with the same women s previous SA rates while not on metformin. This study showed a miscarriage rate of 26% on metformin compared to 62% not on metformin (P<0.0001). Pregnancy outcomes were not significantly different in those women continuing metformin through the rest of their pregnancy compared to those who stopped after the first trimester. In this study, one infant was diagnosed with achondroplasia (Glueck 2002). No other birth defects were noted. A recent meta-analysis (Gilbert et al, 2006) compared eight PCOS studies for malformations found after metformin was used in pregnancy. It showed that there was no increased risk for fetal malformations with the use of metformin. In a sub-group of diabetic women, malformations in the untreated group were 7.2%, which is in the usual range for diabetic women. Only 1.7% of babies born to women treated during the first trimester with metformin showed malformations. This suggests there may be some protective effect of the drug. Metformin has also shown some promise in reducing early pregnancy loss (spontaneous abortion). A relatively small study done by Nawaz et al (2008) studied 137 women with PCOS who had either conceived while on metformin or

33 27 spontaneously (controls). This was a case-control study done in 2005 and There were three groups: group A (n=40) discontinued metformin use between 4-16 weeks of pregnancy, group B (n= 20) took metformin up until 32 weeks of pregnancy and group C (n=45) continued throughout the entire pregnancy. The control group consisted of 32 women who did not take metformin. There were no significant differences among the groups in terms of age, BMI, duration of infertility, or pre-existing conditions. Compared to the other groups and the controls, women in group C showed a significant reduction in miscarriages (P=0.006) and preterm deliveries (P=0.035) and a higher live-birth rate (P=0.016). The spontaneous abortion rate decreased significantly in group B as compared to group A (10% vs. 20% respectively, P<0.014). This would suggest that continuing metformin past 24 weeks, the age of viability, may have a protective effect in maintaining the pregnancy. Similarly, the rate of preterm delivery was significantly lower in group C than in group B (4.8% vs. 27% respectively, P<0.025). This would also suggest that metformin may protect against preterm delivery. This study shows a 50% decrease in early spontaneous abortions with metformin use. One of the suggested theories for the mechanism is that metformin increases glycodelin in the endometrium. Glycodelin is an adhesive glycoprotein that helps with implantation (Nawaz, 2008). Nawaz et al (2008) also found that metformin use throughout pregnancy significantly lowers the rate of gestational diabetes mellitus (GDM). The rate of

34 28 GDM in group C was 2.3% compared to 18.7% and 33.3% in groups A and B respectively (P<0.001). Both Legro et al (2007) and Glueck et al (2002) have shown similar results. There is some question about whether PCOS alone causes pregnancyinduced hypertension (PIH) or whether there are other factors involved. This study showed an improvement in pregnancy-induced hypertension rates of group C (13.9%) compared to group A (43%) (P<0.02). Another study (Thatcher, 2006) showed that 14% of their patients on metformin had PIH. This falls into the normal range of 12-22% for all pregnancies (ACOG 2005) and suggests that there are factors other than PCOS alone that cause PIH. The current evidence shows metformin to be safe in pregnancy and does not appear to increase adverse events in pregnancy. Metformin appears to be associated with fewer complications of pregnancy in those women with PCOS who take metformin compared to PCOS patients who do not take it. Due to conflicting evidence of efficacy in preventing adverse events in pregnancy, more controlled studies need to be done. These studies need to include duration of treatment into pregnancy versus outcome. Conclusion PCOS is a heterogenous syndrome with many different manifestations. No two women are going to present with exactly the same symptoms and hormone levels. This poses a problem to the clinician who is looking for an optimal treatment. There is not one optimal treatment that fits for every women

35 29 presenting with PCOS who wants to get pregnant. The clinician must look carefully at each woman individually and come up with an individualized treatment plan. From the research presented, the following suggestions can help in individualizing a plan: o Clomiphene appears to be the best drug at inducing ovulation in the largest population of women (Moll, 2006; Legro, 2007; Zain, 2008). o Metformin used in combination with clomiphene leads to higher ovulation, pregnancy, and live birth rates than clomiphene alone. Although these rates are not significantly higher than rates when using clomiphene alone (Moll, 2006; Legro, 2007; Zain, 2008), they suggest sensitization of women who are resistant to clomiphene, resulting in an improved ovulatory response to clomiphene. o Metformin alone has shown some positive effects in inducing ovulation in lean women who have PCOS (Palomba, 2005). o Metformin use throughout pregnancy has been associated with the reduction of the risk of adverse events such as early pregnancy loss and preterm birth (Glueck, 2002; Nawaz, 2008) o Obesity is an independent risk factor for miscarriage and other adverse outcomes such as GDM and PIH (Fedorcsak, 2000).

36 30 Even a small weight loss of pounds has been shown to improve ovulation (Clark, 1995) rates. The following cases illustrate how different treatment plans may be. Case 1: A 25-year old woman presents to your office because she has not had regular periods in years. She and her spouse are interested in conceiving. She is 5 6 and weighs 230 pounds (BMI 37.1). She has hirsutism and polycystic ovaries on ultrasound. You diagnose her with polycystic ovarian syndrome. What is the best treatment plan for this woman? Because she is relatively young and only beginning to try to achieve pregnancy, weight loss may be a good place to start. The National Institutes of Health recommends a small weight loss (10% of total body weight) as a goal. Clark (1995) has shown this to be effective in regulating periods and inducing ovulation even in obese women. Lifestyle modifications and diet are a good way to start losing weight. Metformin can be added to reduce hirsutism and reduce insulin resistance. If lifestyle modifications, weight loss, and metformin do not induce ovulation, clomiphene can be added, gradually increasing the dose until ovulation is achieved. Case 2: A 28-year old woman presents to your office complaining that she and her husband have been trying to get pregnant for 7 months. She is 5 4 and weighs 165 (BMI 28.3). She has polycystic ovaries on ultrasound and very mild

37 31 hirsutism. She says that she has been charting her temperatures for three months and only ovulated one of the months. The chances are very good that this woman will ovulate on clomiphene alone and this can be tried first. Weight loss should be encouraged but because she has been trying to get pregnant for 7 months, clomiphene at its lowest dose can be started concurrent with the weight loss. If clomiphene resistance is seen, metformin can be added. Case 3: A 33 year-old woman presents to the office after trying to get pregnant for almost a year. She is 5 8 and weighs 145 pounds (BMI 22). She has moderate hirsutism, elevated testosterone levels, and has had irregular periods since adolescence. This woman, who is within the normal weight range can be started on metformin and clomiphene. Over the course of 6 cycles, 93.3% of lean women ovulated on metformin alone (Palomba, 2005). However, a larger study (Legro, 2007) showed that more women ovulated on combination therapy than metformin alone. It is not known if metformin holds an advantage over clomiphene in lean women. Palomba s (2005) study showed an advantage. However, larger studies that included obese women contradict these results. More controlled studies are necessary. Part of the problem with coming up with an effective treatment plan is that PCOS itself varies from woman to woman. There is no strict definition, only

38 32 guidelines to follow. This makes a uniform treatment plan unrealistic. Many factors must be evaluated before a woman can be diagnosed with PCOS. However, treatment with metformin may be beneficial even if a woman does not fit all of the PCOS criteria, particularly if she is insulin-resistant. More studies need to be done to evaluate metformin in pregnancy. PCOS can cause infertility but does not end once a woman is pregnant. It has an effect on both the pregnant woman and the fetus. This would suggest that treatment should include something during pregnancy, as well. Most clinicians agree that it is best to give patients as few medications as possible. Because it is shown that clomiphene is statistically best for inducing ovulation and achieving pregnancy (Moll, 2006; Legro, 2007; Zain, 2008), one would expect clomiphene alone to be best for women with PCOS. While clomiphene alone is statistically best, clinically this may not be the case. As discussed in the beginning of this paper, women who present to the clinician will want a healthy infant. Clomiphene alone does nothing to ensure a healthy infant in women with PCOS. Clomiphene and metformin together give better results, for both ovulation and pregnancy. There are simply more babies born when a combination of clomiphene and metformin are used to induce ovulation and achieve pregnancy. Metformin can be continued into pregnancy to lower insulin and to prevent some of the complications associated with PCOS. While metformin appears to be safe in pregnancy, more studies need to be done.

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48 42 Table 1. Proposed Diagnostic Criteria in Polycystic Ovary Syndrome 1. Inappropriate gonadotropin secretion a. Elevated LH-to-FSH ratio b. Abnormal response to GnRH agonist testing 2. Hyperandrogenemia a. Hirsutism, androgenic alopecia, acne b. Hyperandrogenemia i. Total testosterone ii. Free testosterone (free androgen index, etc.) 3. Ovarian appearance a. Polycystic-appearing ovaries b. Increased stromal size 4. Insulin resistance a. Acanthus nigricans b. Fasting measures of insulin/glucose c. Oral glucose tolerance test d. Dynamic tests of insulin sensitivity i. Euglycemic clamp ii. Frequently sampled intravenous glucose tolerance test 5. Chronic anovulation a. Self-reported history b. Tests of ovulatory function i. Basal body temperature charting ii. Urinary LH testing iii. Serum progesterone measurement iv. Endometrial biopsy Legro et al, Reprinted with permission.

49 43 Table 2. Results of Legro et al study (adapted from Legro, 2006) Variable Clomiphene Group (n=209) Metformin Group (n=208) Combination Group (n=209) Difference between clomiphene and metformin (P Value) Difference between combination and metformin (P Value) Ovulation 462/ / /964 <0.001 <0.001 (percentage)* (49) (29) (60.4) Conception 62/209 25/208 80/209 <0.001 <0.001 (percentage) (29.7) (12.0) (38.3) Pregnancy 50/209 18/208 65/209 <0.001 <0.001 (percentage) (23.9) (8.7) (31.1) Live Birth 47/209 15/208 56/209 <0.001 <0.001 (percentage) (22.5) (7.2) (26.8) Pregnancy 16/62 10/25 24/ Loss (percentage) (25.8) (40.0) (30.0) Among subjects who ovulated* Conception 62/157 25/115 80/ <0.001 (percentage) (39.5) (21.7) (46) Singleton live-birth 47/462 (29.9) 15/296 (13.0) 56/174 (32.2) <0.001 *Over a total of 6 cycles Ovulation defined as serum progesterone level >5 ng/ml Conception defined as any positive serum level of human chorionic growth hormone Pregnancy defined as intrauterine pregnancy with fetal heart motion, determined by transvaginal ultrasound Live birth defined as delivery of viable infant

50 44 Figure 1 Changes During the Menstrual Cycle From The Merck Manual of Medical Information Second Home Edition, edited by Robert S. Porter. Copyright 2007 by Merck & Co., Inc., Whitehouse Station, NJ. Available at: Accessed January 14, Reprinted with permission.