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Introduction
Our knowledge of polycystic ovary syndrome (PCOS) dates back to the clinical work and publications by two gynecologists: Irving Stein and Michael Leventhal from Chicago. Their publications in 1935 were about this syndrome and its treatment. The syndrome was named after them and it was common to write about “Stein–Leventhal syndrome,” where the ovaries are morphologically enlarged with multiple cysts. These women presented with irregular cycles in the form of oligomenorrhea, hirsutism, infertility, and obesity [1]. At that time, there were no hormonal studies, but the clinical picture was evident. Stein and Leventhal also treated their patients with wedge resection of the ovaries [2]. Their published report of several pregnancies that occurred following this procedure introduced this procedure as basic treatment for PCOS, which was carried out for several decades until the endocrinology of this syndrome was evaluated when the hormonal assays became available about 40 years ago.
The endocrinology studies that were done certainly explain many of the abnormalities that affect the hypothalamic–pituitary–ovarian axis. These include high luteinizing hormone (LH) levels, low follicle-stimulating (FSH) levels, and an increase in androgen production by the ovaries and/or the adrenal glands. These increased androgens will result in increased pulsatility of gonadotropin-releasing hormone (GnRH), leading to more LH secretion. The increase in estrogens as a result of conversion of androgens leads to suppression of FSH. As a result of this disproportionate LH and FSH pattern, these women become anovulatory, leading to the main symptoms of this syndrome of oligomenorrhea and amenorrhea [3,4]. Hormonal studies facilitated the recognition of the mechanisms by which wedge resection of the ovary helps those patients to achieve ovulation and pregnancy. Essentially, removal of a segment of the ovary in the form of a wedge, taking out a good part of the stroma, results in changes in the androgen levels and consequently, reversal of the effect on the hypothalamic–pituitary axis, leading to good levels of FSH to stimulate folliculogenesis and then ovulation accordingly. This is evident from the work done by Howard Judd and Sam Yen, in which they evaluated hormonal levels before wedge resection and immediately after wedge resection for a period of time. They also discovered that the effect of wedge resection is not a permanent one, because several months after surgery, the levels of androgens will start to rise again and these patients will become anovulatory [5].
PCOS might mimic other clinical conditions that lead to anovulation. It therefore became important to define diagnostic criteria for this syndrome. This was evident from the 1990 NIH-NICHD conference on PCOS at which diagnostic criteria were agreed which included (1) chronic anovulation after exclusion of other factors, including thyroid disease, adrenal disease, and hyperprolactinemia; and (2) hyperandrogenism that could be biochemical or clinical [6].
In 2003, an international conference was held in Rotterdam and the committee agreed on the inclusion of chronic anovulation, hyperandrogenemia, and polycystic appearance on ultrasound evaluation [7,8]. It was stated that two out of these three criteria will make the diagnosis. The inclusion of polycystic appearance criteria by ultrasound suggests that some of these patients may be ovulatory. Therefore, the criteria of polycystic appearance need to be seen either as part of the diagnosis or as a separate phenotype of PCOS, which is somewhat confusing. In 2006, the Androgen Excess Society met and confirmed the NIH criteria, and added ultrasound polycystic appearance as a separate phenotype [9].
Furthermore, the wedge resection that was initially started by Stein and Leventhal has been deleted from our management of patients with PCOS, since we in the field of human reproduction have many other medical advances with good treatment of these patients, helping them to achieve ovulation and pregnancy without surgical intervention.
Management of PCOS depends on the patient’s needs. If pregnancy is not the goal, management should be directed towards suppression of androgens and cycling of the endometrium to prevent hyperplasia and cancer, which is common if these patients are not treated properly. Therefore, in this category, cyclic progestins or steroidal oral contraceptives, if there are no contraindications, will be the line of treatment. On the other hand, for those patients who desire pregnancy, induction of ovulation should be the principal mode of management.
The incidence of PCOS has been about 6–12% of reproductive age women. However, with the use of the modern criteria, this incidence could be much higher [10,11]. This constitutes a large part of the female population who will need evaluation and management for their infertility at some point. The management course includes the use of many of the available fertility medications. In this chapter we will discuss the merits, indications, and contraindications for the use of every medication.
Pharmacologic agents for induction of ovulation in PCOS patients
Clomiphene citrate
Clomiphene citrate is the first estrogen receptor modulator to be used for fertility purposes. The pharmacology indicates that it has two isomers: the Z isomer and the E isomer. The Z is zuclomiphene and the E is enclomiphene. The Z clomiphene has a longer half-life than the E clomiphene. Studies have shown that the Z clomiphene remains in the body for some time after ovulation.
It is metabolized in the gastrointestinal tract and excreted through the intestines, and traces of clomiphene have been detected for 6 weeks following the administration of this medication [12]. The starting dose for induction of ovulation is 50 mg from days 3–7 of the cycle for a total of 5 days. If there is no response, then the dose is increased in increments of 50 mg up to 150–200 mg daily for 5 days of each cycle. If ovulation is not achieved by this dose, then the medication is not effective and the treating physician should move to a different type of fertility medication. The success rate of induction of ovulation with clomiphene citrate reaches up to 85%. However, only half of these patients will achieve pregnancy [13,14]. If other factors are normal, i.e., patency of the fallopian tubes and normal semen analysis, then the failure to achieve pregnancy, despite ovulation, might be due to the antiestrogenic effect of clomiphene citrate. This antiestrogenic effect is mainly on the endometrium and also on the cervical mucus [15]. The antiestrogenic effect on the endometrium will interfere with the production of the various adhesive molecules, pinopodes, resulting in poor decidualization, which will not be conducive to implantation. If pregnancy happens, the miscarriage rate will be high.
Clomiphene citrate acts by attaching itself to the estrogen receptors in the hypothalamus, thus interfering with the estrogen mechanism at the hypothalamic level. The end result will be an increase in the secretion of the GnRH pulses, both in frequency and amplitude. This will lead to secretion of both FSH and LH. FSH will be secreted at a higher level than LH, thus stimulating the process of folliculogenesis and eventually ovulation [16].
Treatment with clomiphene citrate increases the incidence of multiple births, mainly twins by 7–9% and triplets by 0.3%. Other side effects include antiestrogen effects, leading to vasomotor symptoms and visual symptoms in the form of blurring of vision in 1–2% of the patients, which might be due to the effect of clomiphene citrate on the visual cortex. It should be noted that these symptoms will disappear after the course of treatment is completed. The incidence of congenital malformations in pregnancies following clomiphene citrate is the same as in the general population [17].
Some patients with PCOS may have an elevation of dehydroepiandrosterone sulfate (DHEA-S) from the adrenal gland. This might affect the response of these patients to clomiphene citrate. In these patients, dexamethasone is given in combination with clomiphene citrate during induction of ovulation and for several days after that. This has been shown to increase the response to clomiphene citrate, and consequently the pregnancy rate [18].
Similarly, some patients with PCOS have elevated prolactin levels without any evidence of a space-occupying lesion in the pituitary gland. These patients may benefit from receiving a dopamine agonist in addition to clomiphene citrate to potentiate its effect [19].
Letrozole for induction of ovulation
Letrozole is an aromatase inhibitor that was approved by the FDA in 1997 for chemotherapeutic treatment of postmenopausal patients with a history of breast cancer [20]. The trials for the use of letrozole for induction of ovulation started in 2000, with the first report presented at the American Society of Reproductive Medicine Meeting in 2001 [21]. The mode of action in induction of ovulation is to inhibit aromatase and therefore, the conversion of testosterone to estrogen is decreased. The negative feedback mechanism of estrogen on the hypothalamic–pituitary axis will be diminished and this will result in an increase in secretion of gonadotropins, which will stimulate the process of folliculogenesis and ovulation. Several doses were used, starting with 2.5 mg and increments of 2.5 mg up to 12.5 mg dosage starting on day 3 of the cycle till day 7.
Several comparative studies were done comparing letrozole to clomiphene citrate, and it was found that the ovulation rate was nearly identical. However, the pregnancy rate is higher with letrozole than with clomiphene citrate. It should also be noted that many of the side effects of clomiphene citrate do not occur with the use of letrozole. Specifically, endometrial thickness is much better with the use of letrozole than with clomiphene citrate. The investigators also found that the incidence of congenital malformations in resulting pregnancies was less in patients who received letrozole, as compared hose administered clomiphene citrate for induction of ovulation.
It appears that the use of letrozole is effective in induction of ovulation in PCOS, as well as in other patients who have failed clomiphene citrate treatment. It might also be used as the first line of treatment for induction of ovulation, rather than using clomiphene citrate, in PCOS patients. Other studies also demonstrated the effectiveness of letrozole when used in combination protocols with gonadotropins to treat the poor responders in cycles for assisted reproduction. This is really a great advance and a new addition to our medications that are used for induction of ovulation in anovulatory infertility patients [22,23].
Ovarian drilling in the management of PCOS
In 1935, Stein and Leventhal introduced this syndrome of anovulation, hirsutism, and enlarged ovaries. The management they started and continued for several decades was wedge resection of the ovaries. Some of these patients achieved pregnancy, and therefore, surgical management became a standard type of management at that time and for some time after that. It was then realized that with the surgical management of these ovaries, the patients are subjected to development of adhesions, peri-ovarian and peritubal, which complicates the matter and interferes with the management of infertility. With the advances in reproductive medicine and the introduction of fertility medications, the medical management of PCOS gained the upper hand and a good percentage of these patients respond to the induction of ovulation using medications like clomiphene citrate and human menopausal gonadotropins.
Today, we have more medications on trial such as the use of aromatase inhibitors. In addition, human menopausal gonadotropins have been purified and widely used. Furthermore, recombinant gonadotropins have been introduced for induction of ovulation and are widely used now. Certainly, there is a very good response by PCOS patients to these medications, with very good rates of ovulation and pregnancy. However, some of these patients fail to respond to the fertility medications and this might be due to the fact that their androgen levels are too high or there is an associated hyperprolactinemia or thyroid disease. Therefore, it is imperative to do a thorough endocrine evaluation of these patients and to treat endocrinopathies to facilitate the response of the patients’ ovaries to fertility medications.
In the past three decades, the surgical management of PCOS to facilitate induction of ovulation has been reintroduced. This is in the form of a laparoscopic type of surgical treatment in which the ovaries are subjected to several unipolar electrode punctures. Some studies evaluated the response of these ovaries after surgery to ovulation-inducing medications and found them to be reasonably successful. They attributed this success to decrease in the size of the ovaries and decrease in the level of testosterone and LH [24]. This was associated with improvement in FSH levels, and ovulation and pregnancy after that. It is evident from some studies that the pregnancy rate after ovarian drilling is equal to the pregnancy rate with the use of fertility medications to induce ovulation in these patients [25].
The main drawback of ovarian drilling is the development of adhesions, and sometimes excessive thermal effect, which can lead to the development of amenorrhea in such patients [26].
Another study compared the effect of ovarian drilling on pregnancy rate and occurrence of diabetes during pregnancy in women with and without metabolic syndrome. The study found no difference in pregnancy rate or the occurrence of diabetes in pregnancy in patients with/without metabolic syndrome [27].
The use of insulin-sensitizing agents for induction of ovulation in PCOS patients
Patients with PCOS have also been described as highly susceptible to the development of metabolic syndrome [28]. In this syndrome, the tissues are insulin resistant resulting in an increase in the level of blood sugar and frequently hemoglobin A1c, suggesting a prediabetic or diabetic status. High insulin levels in these patients also act on the insulin-like growth receptors in the ovary; and together with high LH levels, these will lead to high levels of testosterone. These elevated levels of testosterone will result in anovulatory cycles by their effect on the hypothalamic–pituitary axis. Many of these patients are overweight or obese. Some may not be in this category, but they still might have the metabolic syndrome. In some cases, these patients might have hyperlipidemia and may develop raised blood pressure and increased incidence of heart disease [29].
Metformin is essentially a dimethyl biguanide, and is used in non-insulin-dependent diabetes mellitus. It inhibits glucose production by the liver, its half-life is 4–8 hours, and it is excreted through the kidneys. Historically, metformin was discovered in 1920 to be useful in reduction of blood sugar, and was introduced in the United States in 1995 [30,31].
Metformin is widely used for induction of ovulation in PCOS. It can result in ovulatory cycles when it is given alone or in addition to clomiphene citrate. There have been various trials, all which suggest that the combination of clomiphene citrate and metformin might lead to a slight increase in the pregnancy rate as compared with clomiphene citrate alone. However, in some of these studies, the difference may not be statistically significant. Nevertheless, the use of metformin for induction of ovulation in these patients will reduce the number resistant to medical treatment for this purpose [32,33].
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