3.1.3. Metformin

citrate in combination with metformin is a better treatment and offers 1.8 times the chance of

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.

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

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

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

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

estrogen and cause increased production of FSH for folliculogenesis and ovulation.

compared to tamoxifen (another estrogen antagonist similar to clomiphene citrate).

with clomiphene citrate-resistant PCOS [24].

pregnancy compared to the clomiphene citrate alone.

3.1.2. Letrozole

82 Debatable Topics in PCOS Patients

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 laparoscopic ovarian drilling (LOD).

#### 3.1.4. Gonadotropins

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