Letrozole vs Clomiphene Citrate in Maintenance of Endometrial Thickness

Letrozole is superior to clomiphene citrate in maintenance of endometrial thickness, finds a new study.

Millions of women of reproductive age are affected by infertility worldwide. For infertility, PCOS (Polycystic ovarian syndrome) is the most common female endocrine disease and a frequent cause. Characteristics of PCOS are anovulation, clinical or biochemical hyperandrogenism, and presence of polycystic ovaries. Ovulation induction is the cornerstone for treatment of women with PCOS suffering from infertility, because about 80% of women with PCOS have anovulation or oligo-ovulation.

Clomiphene citrate (CC) belongs to a selective estrogen receptor modulator drug classification, has traditionally been used as the drug of first-choice for ovulation induction or superovulation in women with PCOS. CC has an antiestrogenic effect, which results in estrogen receptor (ER) depletion, and has a long half-life; therefore, it accumulates in the body causing long-lasting ER depletion. CC lasts for a long time in the body and may due to it have an adverse effect on cervical mucus and uterine lining, such as endometrial proliferation leading to thinning of endometrium. The endometrial thickness is one of the most important factors affecting pregnancy. The pregnancy rate can be very low if endometrial thickness is less than 6-8 mm. Clomiphene citrate is one of the treatment modalities which reduce endometrial thickness.

Letrozole is an aromatase inhibitor, has also been recommended as a first-line drug therapy for improvement of the fertility outcomes in women with PCOS. Aromatase is an enzyme which is responsible for the production of estrogen in the body. Letrozole works by inhibiting aromatase by completely binding to it, which results in a reduction of estrogen biosynthesis in all the tissues. It has a short half-life, thereby it is rapidly eliminated from the body within 42 hours, with less risk of ovarian hyperstimulation. On the other hand, clomiphene citrate blocks estrogen receptors. As a result, the pituitary gland produces more hormones which are needed to stimulate the ovaries. FSH and LH, these hormones can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in ovaries of women who already ovulate. Letrozole offers significantly better endometrial response compared to clomiphene citrate.

Letrozole, clomiphene citrate like fertility drugs can be used to induce an ovum to develop and to be released in women who are not ovulating on their own. This is known as ovulation induction. For increasing the chances of pregnancy in women who are already ovulating, these drugs can be used; which is known as superovulation.

In order to study the effectiveness and safety of different ovulation induction protocols with less side effects and higher pregnancy rates in women with PCOS treated with clomiphene citrate and letrozole to assess the impact of mono- versus multi-follicular growth, Pandya and Patel compared the live pregnancy rates among women with who had ovulation induction with CC and letrozole in a Scientific Research Institute, Surendranagar, Gujarat, India.

The study included 100 women presented with anovulatory infertility. The infertile women were divided into 2 groups of 50:

• Group A received 100 mg Clomiphene Citrate from day 3 to day 5 and continued up to 5 consecutive days of menstrual cycle, Estradiol Valerate 4 mg on the 12th day of menstruation until 16th day of menstruation.
• Group B treated by 5 mg Letrozole from day 3 to day 5 of the menstruation and continued up to 5 consecutive days as Group A, Estradiol Valerate 4 mg on the 12th day of menstruation until 16th day of menstruation given to Group B, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies.

Participants were of 20 to 39 years age, had normal uterine cavity and had a male partner with a sperm concentration of at least 14 million per millilitre; and during the study, the women and their partners agreed to have regular intercourse with the intent of conception. The live birth during the treatment period was the primary outcome.

Women who received letrozole had more cumulative live births than those women who had received clomiphene citrate (72% vs. 56%), without significant differences in overall congenital anomalies, there were no congenital anomalies. With letrozole as compared to clomiphene the cumulative ovulation rate was higher. Higher incidence of hot flushes was associated with clomiphene, and letrozole was associated with fatigue and dizziness. Rates of other adverse effects were almost similar among these 2 groups. A significant difference in the follicular and endometrial development was evident among these 2 groups.

This study showed that endometrial thickness was higher in letrozole group than clomiphene group. As per study authors found that letrozole was more effective drug as a fertility treatment than clomiphene citrate in women with infertility and polycystic ovary syndrome. Although multiple pregnancy (twins, triplets) rate was higher with clomiphene citrate.

In this study authors used letrozole and clomiphene citrate for ovulation induction has been designated by FDA as pregnancy category X (although clomiphene is approved for ovulation induction). The live-birth rate was higher with letrozole than with clomiphene citrate among women with infertility and polycystic ovary syndrome in our study.

An aromatase inhibitor, letrozole, as compared to clomiphene, was associated with higher live-birth and ovulation rates among infertile women. The results of the study demonstrated letrozole to be superior to clomiphene citrate in the maintenance of endometrial thickness. Clomiphene citrate has some drawbacks; including its overall poor efficacy (56% rate of live birth), a relatively high multiple pregnancy rate, and an undesirable side effect profile which includes mood changes and hot flushes. The important public health goal is to develop the effective, simple, and safe treatments for infertility. Aromatase inhibitors, letrozole, which blocks estrogen synthesis, directly affect hypothalamic-pituitary-ovarian-uterine function and theoretically might increase pregnancy rates. Potential advantages of letrozole over clomiphene citrate include a more physiological hormonal stimulation of endometrium, a lower multiple pregnancy rate through single-follicle recruitment, a better side effect profile with lesser vasomotor and mood symptoms, and greater rapid clearance, thus reducing chances of periconceptional exposure.

Source: Pandya and Patel / Indian Journal of Obstetrics and Gynecology Research 2021;8(4):553–558