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Letrozole vs Clomiphene

by egpat         03 May 2024

Polycystic ovary syndrome, or PCOS, is one of the important disorders in women that is associated with decreased ovulation. In such conditions,we can give medications that can increase ovulation. We have two types of drugs, letrozole and clomiphene, both of which can be used in PCOS to increase ovulation. Letrozole is well known by its brand name Femara, whereas clomiphene is well known by its brand name Clomid. Even though both of these drugs are going to increase ovulation, they are still acting in a different way.

1. Mode of action

How are these two drugs going to act to increase ovulation? Letrozole is one of the drugs that are classified as aromatase inhibitors. It is a nonsteroidal aromatase inhibitor, so this drug is going to inhibit one of the enzymes, aromatase.

On the other hand, clomiphene is one of the SERM, selective estrogen receptor modulators, which means this medication is a modulator that can modulate the activity of estrogen receptors, so it can act as either an agonist or antagonist. Therefore, clomiphene shows estrogenic as well as anti-estrogenic effects.

Both of these drugs are going to increase ovulation. Within the body, estrogens like estrone and estradiol are biosynthesized, and they can act on the hypothalamus and pituitary axis. On the hypothalamus and anterior pituitary, estrogen receptors are expressed. Now estrogens like estrone and estradiol can bind to these estrogen receptors in the hypothalamus and anterior pituitary, and they produce a negative feedback mechanism. Because of the negative feedback mechanism, they inhibit the release of gonadotrophs, which reduces ovulation.

Now these estrogens can be synthesized from the two precursors, one of which is androstenedione. This androstenedione is going to be converted into estrone by one of the enzymes, aromatase. Similarly, another hormone is testosterone, which is going to be converted into estradiol by the same enzyme aromatase.

Letrozole is an aromatase inhibitor; it can block this conversion so that it can inhibit the synthesis of these estrogens. When these estrogens are not synthesized, their negative feedback mechanism is inhibited, which results in the increased release of gonadotrophs. When the gonadotrophs are increased,it can increase ovulation. In this way, letrozole can increase ovulation by inhibiting the production of estrogens.

Clomiphene acts in a different way. Clomiphene is a SERM; it is a selective estrogen receptor modulator, and at the hypothalamus as well as at the anterior pituitary,it can block the estrogen receptors. When these receptors are blocked, the estrogens cannot activate these receptors, so the negative feedback mechanism is again inhibited. So this results in the increased release of gonadotrophs, which are follicle-stimulating hormones and luteinizing hormones. These two hormones can act on the ovary to induce ovulation; in this way, clomiphene can also increase ovulation.

So both letrozole and clomiphene can increase ovulation, but they act in different ways. Letrozole can reduce estrogen production, thereby inhibiting the negative feedback mechanism in the hypothalamus and anterior pituitary. Whereas clomiphene blocks the estrogen receptors, it can increase the production of gonadotrophs, resulting in the stimulation of ovulation.

2. Effect on estrogen levels

Letrozole is one of the aromatase inhibitors, so it can reduce estrogen synthesis. With the use of letrozole, we can observe decreased levels of estrone and estradiol within the body. On the other hand, clomiphene is an estrogen receptor modulator, so this drug is not affecting estrogen levels; instead, it is going to affect the actions of estrogen.

So clomiphene can produce anti-estrogenic effects, which result in the increased release of gonadotrophs like follicle-stimulating hormone and luteinizing hormone, which further increase ovulation. This is one of the beneficial effects that can be observed with clomiphene. But this medication can also produce estrogenic effects, which result in increased uterine weight, so here both letrozole and clomiphene are different; letrozole is mainly reducing estrogen levels, whereas clomiphene can produce estrogenic as well as anti-estrogenic effects.

3. Clinical indications

Letrozole can be used in various conditions, particularly as an adjuvant in the treatment of breast cancer in postmenopausal women. It can also be used as a first-line agent as well as a second-line agent in the advanced stage of breast cancer in postmenopausal women. And the third clinical indication is used for off-label purposes; it can be used for the treatment of infertility in women with PCOS.

On the other hand, clomiphene is particularly indicated to induce ovulation; it is a SERM estrogen receptor modulator, and it can be used to induce ovulation in anovulatory women. So here, letrozole can be used for different conditions, whereas clomiphene is only indicated for ovulation.

4. Ovarian hyperstimulation

Clomiphene is one of the medications on cyclic use; it can stimulate the ovaries, and when it is combined with gonadotrophs, it further produces ovarian stimulation, resulting in ovarian hyperstimulation syndrome (OHSS). Even though it is a rare condition, when this clomiphene is repeatedly used, or when it is used in combination with gonadotrophs, it can produce ovarian hyperstimulation, resulting in increased weight gain, increased ovary size, abdominal distension, and abdominal pain.

All these can be observed with ovarian hyperstimulation. On the other hand,letrozole does not show ovarian hyperstimulation; instead, it can reduce this action because of decreased estrogen levels. So here, letrozole has some advantages over clomiphene.

5. Multiple pregnancy

This is another disadvantage of clomiphene. Clomiphene has a long half life, so because of its long half life, on cyclic use, this drug can be accumulated within the body, which can act on the ovaries to produce multifollicular ovulation. It can release the eggs from both of the ovaries, resulting in multifollicular ovulation, which may result in the birth of twins, so multiple births are observed with clomiphene.

On the other hand, letrozole is not showing multiple births because this drug only produces monofollicular ovulation. So here, letrozole has an advantage compared with clomiphene because it does not produce multiple pregnancies.

6. Visual dysfunction

With the use of clomiphene, visual disturbances can be observed, and people may observe blurring, spots, and flashes; these visual disturbances are not observed with letrozole.

7. Bone mineral density

Here, letrozole shows its effect. Because of decreased estrogen levels, letrozole can increase bone resorption, thereby reducing bone mass and increasing bone loss. So bone mineral density is reduced by letrozole, whereas clomiphene, because of its estrogenic effects on the bones, can reduce bone loss and osteoporosis, so bone mineral density is increased with clomiphene whereas decreased with letrozole.

So letrozole has the disadvantage of reducing bone mineral density, and in women with significant bone loss, letrozole should be carefully used.

8. Birth rate

Both of these drugs are going to increase ovulation, but the live birth rate is higher with letrozole compared with clomiphene. And clomiphene can increase abortion and multiple pregnancies, so birth rates are somewhat lower with clomiphene.

9. Dosage

For the treatment of infertility, letrozole can be used at a dose of 2.5 to 7.5 mg given for 5 days as one cycle; on the other hand, clomiphene can be used at a dose of 50 mg once daily for 5 days as one cycle. So letrozole can be used at a low dose compared with clomiphene.


So these are the various comparisons and differences between the two drugs, letrozole and clomiphene, that are used to induce ovulation in women with polycystic ovary syndrome. Letrozole has some advantages: it can be used at a low dose, it cannot produce multiple pregnancies, it is not producing any ovarian hyper stimulation, and live birth rates are higher with letrozole.

But one of its disadvantages is that it can reduce bone mineral density, which increases the risk of bone loss. And clomiphene is the old-generation drug that can be used to induce ovulation in polycystic ovary syndrome, but it has a few disadvantages, like multiple pregnancies, ovarian hyperstimulation, and visual disturbances.