3. Pharmacologic agents and ovulation induction

#### 3.1. Use of pharmacologic agents in induction of ovulation

Several pharmacologic agents have been used to induce ovulation in these patients. They have achieved varied success with attendant setbacks from these drugs especially in achieving pregnancy and with adverse pregnancy outcomes. These drugs include clomiphene citrate, metformin, letrozole, gonadotropins, inositol, and tamoxifen.

## 3.1.1. Clomiphene citrate

ovulatory dysfunction in patients with PCOS. The prevalence is between 8.5 and 20%

Anovulation is a cause of infertility in up to a quarter of all cases of infertility. Normogonadotropic anovulation classified as World Health Organization (WHO) group II is the most common category of anovulatory infertility. PCOS is the most common in this group and notably the commonest endocrine disorder and cause of anovulation [1–3]. Insulin resistance is implicated in the ovulatory dysfunction in PCOS by disrupting the hypothalamo-pituitaryovarian axis. Insulin resistance also leads to other comorbidities such as metabolic syndrome, hypertension, dyslipidemia, glucose intolerance, and diabetes mellitus as well as mental disorders such as depression, anxiety, bipolar disorders and binge eating [1, 4]. Women with PCOS present to the fertility clinic with chronic oligo/anovulation and hyperandrogenism, with attendant negative effects on their fertility. The desire to reproduce is very intense in many communities where there is high premium placed on reproduction as a means of survival. So, these women having learnt the diagnosis of their conditions are very expectant that their conditions will soon be reversed following treatment such that they could ovulate, become pregnant, and successfully have children. Many a times, the drug to bring about the reversal of anovulation refuses to work due to innate characteristics within the woman, the drug, or even the environment. This challenge has led to the development and use of several different pharmacologic agents used singularly and in combination to deal with the challenge of anovulation. Other physical methods and herbal preparations have also been deployed to

depending on the criteria used for the identification of the condition [1, 2].

varying degree of success to combat anovulation in women with PCOS.

2. Weight reduction and ovulation induction

pregnancy or ovulation [6].

80 Debatable Topics in PCOS Patients

outcomes [4, 16–19].

Central to the management of women with infertility from PCOS is the induction of ovulation. The treatment options for infertility in women with PCOS include clomiphene citrate, gonadotropins, laparoscopic ovarian drilling (LOD), and assisted reproductive technology [1, 5]. Common to all methods is the induction of ovulation. Letrozole and metformin also play important roles in ovulation induction as has been now well demonstrated. The use of these pharmacologic agents has been shown to be superior to placebo or no treatment in terms of

Scientific studies have not confirmed that women could regain spontaneous ovulation with voluntary weight loss and other life style modifications as systematic reviews did not identify studies that confirm that ovulation and other clinical reproductive outcomes improved with weight loss in women with PCOS but the studies identified increased total testosterone, androgen index, hirsute, fasting blood glucose, fasting insulin, and worsened lipid profile in the obese women compared with normal weight women with PCOS [7–9]. Obesity is linked to anolution and pregnancy loss as well as poor response with ovulation induction methods such as clomiphene citrate, gonadotropins, letrozole, and ovarian drilling [10–15]. This is important as previous authors have surmised that since obesity is found in some women with PCOS and worsens insulin resistance, that weight loss would improve ovulation and other reproductive

Clomiphene citrate is traditionally the first-line drug used to induce ovulation in women with anovulation due to PCOS [2]. This drug has both estrogenic agonist and antagonist effects. It produces its effect principally by blocking the estrogen receptors in the hypothalamus to increase the endogenous follicle-stimulating hormone (FSH) to bring about folliculogenesis and ovulation. Clomiphene citrate when compared to other pharmacologic agents used for induction have been found to be inferior to drugs like letrozole, or a combination of clomiphene citrate and metformin with respect to ovulation, pregnancy, or live birth [6]. Clomiphene citrate in combination with metformin showed a higher pregnancy rate than clomiphene citrate alone or metformin alone. The odds ratio for pregnancy when clomiphene citrate in combination with metformin is compared to clomiphene citrate alone is 1.8 (1.35–2.42) indicating that clomiphene citrate in combination with metformin is a better treatment and offers 1.8 times the chance of pregnancy compared to the clomiphene citrate alone.

metformin is the absence of anti-estrogenic effects at the level of the endometrium, which perhaps is responsible for its higher pregnancy and live birth rates [1]. Despite the promising results with letrozole, neither letrozole nor metformin is approved for the treatment of anovulation in many countries and it is outrightly prohibited in several other countries.

Ovulation Induction in Women with Polycystic Ovary Syndrome: What is the Optimal Option?

http://dx.doi.org/10.5772/intechopen.70812

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Metformin is an oral hypoglycemic agent; a biguanide used for treatment of type 2 diabetes mellitus. It works as insulin sensitizer and reduces insulin resistance, which is a feature in PCOS. It improves ovulation and other reproductive functions. It assists in weight reduction and its effect is better in obese women with PCOS. Alone, metformin is a weak induction agent. However, it is very effective when used along with clomiphene citrate for the induction of ovulation in the patients with PCOS. When metformin is given in combination with clomiphene citrate, there were significantly higher pregnancy rates than metformin or clomiphene citrate alone. The chances of pregnancy increased over 1.7 times in those with the combination of clomiphene and metformin when compared to metformin alone. Letrozole and metformin are also superior to metformin or letrozole alone in inducing ovulation. However, metformin is also useful after ovarian drilling. It reduces insulin resistance and androgens levels, and increases ovulation and pregnancy rates in clomiphene citrate-resistant PCOS after laparo-

The gonadotropins have been used to bring about ovulation in several anovulatory conditions including PCOS. It acts directly on the primordial follicles replacing endogenous gonadotropins to bring about folliculogenesis and ovulation. All forms of gonadotropins ranging from the human menopausal gonadotropins (HMG) to the highly purified follicle stimulating hormone have been recognized to cause ovulation in women. The active agent is the follicle stimulating hormone. The major set back has been that it cannot be administered orally. When compared to other pharmacologic agents, the efficacy of the follicle-stimulating hormone in bringing about ovulation is the highest. It also has the highest live birth rates after letrozole in the network meta-analysis comparing the efficacy in the use of these agents [6]. In the patient with clomiphene resistance, FSH was superior to clomiphene-metformin combination in ovulation rates, pregnancy, and live birth rates as well [1]. The follicle-stimulating hormone led to a higher multiple pregnancy rates when compared to the other pharmacologic agents with a higher risk of ovarian hyperstimulation syndrome. These are the two most serious side effects of gonadotropins resulting from simultaneous growth of many follicles [6, 18, 25]. Gonadotro-

pins could be the second-line drug for clomiphene-resistant PCOS patients [26, 27].

Laparoscopic ovarian drilling has been demonstrated to induce ovulation in women with PCOS. This method of ovulation induction is used for clomiphene-resistant and FSH-resistant PCOS.

3.1.3. Metformin

scopic ovarian drilling (LOD).

4. Surgery and ovulation induction

4.1. Use of ovarian drilling to induce ovulation

3.1.4. Gonadotropins

A small group patients do not ovulate at a maximum dose of 150 mg of clomiphene citrate for 5 days; they are taken to be clomiphene-resistant and anyone unable to achieve pregnancy for a period of 6 months on clomiphene citrate is termed to have clomiphene failure. Those resistant to clomiphene citrate will require other forms of ovulation induction, which may include a combination of the clomiphene citrate and metformin, other pharmacologic therapy or ovarian drilling to produce ovulation in this subset of women. Other disadvantages of clomiphene citrate are its antagonist effect on the estrogen receptors within the endometrium, which is thought to reduce the pregnancy rates in women treated with clomiphene citrate. The rates of multiple pregnancies with clomiphene citrate are below 10% and the risk of ovarian hyperstimulation is rare when compared to follicle stimulating hormone with higher chances of both multiple pregnancy and ovarian hyperstimulation syndrome [23]. The prolonged use of clomiphene may increase the risk development of uterine fibroid or endometrial cancer.

#### 3.1.2. Letrozole

Letrozole is a third-generation aromatase inhibitor. In inducing ovulation, the drug acts primarily in the ovary where it antagonizes the effect of the enzyme 5α-reductase in the production of estrogen in the ovary. Its effect is to inhibit the conversion of testosterone and androstienedione to estradiol and estrone. It also blocks the conversion of androgen to estrogens in the peripheral fat cells and suppresses local estrogen production in the brain. The reduced levels of estrogen release the hypothalamus from the negative feedback effects of estrogen and cause increased production of FSH for folliculogenesis and ovulation.

Letrozole has been found to be superior to clomiphene citrate alone or even clomiphene citrate in combination with metformin. The systemic review and meta-analysis of the Rui Wang group showed that Letrozole produced a higher pregnancy and ovulation rates when compared with clomiphene citrate alone. The odds ratio for pregnancy or ovulation with letrozole compared with clomiphene citrate is 1.58 and 1.99, respectively. Similar outcome was also noted when compared to tamoxifen (another estrogen antagonist similar to clomiphene citrate).

Letrozole also led to higher live-birth rates when compared to clomiphene citrate alone. The chances of birth with letrozole are about 1.6 times higher than clomiphene. It also resulted in lower multiple pregnancy rates compared to the clomiphene citrate. In these regards, Letrozole is better than the clomiphene citrate used traditionally to induce ovulation in women with PCOS. However, the systematic review acceptably did not review the negative effects of these drugs. It also found that the risks of abortions are lower with letrozole group [6]. In patients with clomiphene citrate resistance, Letrozole in combination with metformin showed better efficacy than clomiphene-metformin combination in terms of ovulation rates, pregnancy rates, and live births rates. It also has less abortion rates in the meta-analysis of treatments of patients with clomiphene citrate-resistant PCOS [24].

Letrozole can be used as a first-line drug in the treatment of anovulation because of its higher ovulation, pregnancy and live birth rates, and lower multiple pregnancy rates. The main advantage of letrozole over clomiphene citrate or clomiphene citrate combination with metformin is the absence of anti-estrogenic effects at the level of the endometrium, which perhaps is responsible for its higher pregnancy and live birth rates [1]. Despite the promising results with letrozole, neither letrozole nor metformin is approved for the treatment of anovulation in many countries and it is outrightly prohibited in several other countries.
