Infertility in PCOS - Clomiphene, Letrozole and Metformin

Not all women with Polycystic Ovarian Syndrome (PCOS) have difficulty becoming pregnant. For those that do, anovulation or infrequent ovulation is a common cause. Therefore, treatment for infertility is directed at getting the woman to ovulate.

Medications called clomifene, letrozole and metformin are usually the first-line treatments:

Clomiphene (Clomid, Serophene)
Clomiphene is a selective estrogen receptor modulator (SERM), it blocks estrogen receptors in the hypothalamus, which tricks the pituitary into producing FSH and LH by preventing negative feedback in hypothalamus. An increased level of FSH improves the chances of growing an ovarian follicle that can then trigger ovulation.
However, anti-estrogenic peripheral activity at the level of the cervix and uterus causes decreased mucous production and poor development of the uterine lining respectively. Mucus produced by the cervix helps to transport the sperm into the uterus during conception. This explains why clomiphene may be associated with lower pregnancy rate, offsetting the ovulation rate benefit.
Around 20– 25% of anovulatory women with PCOS do not respond at all to clomiphene.
Women treated with clomiphene are also more likely to have twins or triplets than women who get pregnant naturally.

Letrozole (Femara)
Letrozole, a selective aromatase inhibitor, prevents the conversion of androgens to estrogen, thus releasing the hypothalamo-pituitary axis from the negative feed back of estrogen, resulting in an increase of FSH secretion from the anterior pituitary.
As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with PCOS.
Unlike clomiphene, letrozole is devoid of any anti-estrogenic peripheral action; it does not adversely affect either the endometrium or the cervical mucus. This explains the discrepancy in ovulation rates and pregnancy rates.
There is also some evidence supporting a reduced rate of twins with letrozole (approximately 5%) compared to clomid (approximately 10%).

Metformin
Insulin resistance has been identified as a significant contributor to the pathogenesis of PCOS.
Metformin improves parameters of insulin resistance, hyperandrogenemia, anovulation, and acne in PCOS.
Metformin is an option when conception is not urgent and reduced multiparity is desired (Clomiphene is preferred when time to conceive is essential)
Metformin may also be used as an adjunct to increase or regulate ovulation in women with PCOS; Adding metformin to clomiphene in clomiphene-resistant PCOS patients increases ovulatory response. In clomiphene-resistant PCOS patients, the combination of letrozole and metformin leads to higher full-term pregnancies.

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