Letrozole effectively terminates ectopic pregnancy without serious side effects: Study
Ectopic pregnancy is the implantation and growth of the embryo outside the uterine cavity, which accounts for maternal morbidity and mortality. Ectopic pregnancy affects around 1–2% of all pregnancies. Although ectopic pregnancy–related mortality was recently reduced, ruptured ectopic pregnancies represent approximately 6% of all maternal deaths.
Although some ectopic pregnancies resolve spontaneously and need only conservative treatment, others continue to grow and lead to tubal rupture that results in severe or persistent abdominal pain and life-threatening intraabdominal hemorrhage that required further interference. Medical and surgical treatment are two methods for the management of growing ectopic pregnancy.
Recently, medical treatment has been used as the first choice to treat the early discovered ectopic pregnancy. While using methotrexate as a medical treatment for ectopic pregnancy was associated with terrible adverse effects on different body systems, as well as high proportions of failure in ectopic pregnancy termination. Therefore, it was necessary to find more cost-effective and safe alternatives.
Letrozole, a nonsteroidal competitive aromatase inhibitor, is approved for the management of estrogen-sensitive breast cancer. Letrozole inhibits estrogen production from androgen aromatization via inhibition of the electron transfer chain of cytochrome P450 (CYP19A1). Letrozole is also used in the treatment of many gynecological disorders, mainly due to its high tolerability, low cost, and low side effects, including the reduction of the size of uterine myomas, induction of ovulation in cases of polycystic ovarian syndrome, and the reduction of endometriosis recurrence. In humans, letrozole inhibits estrogen production during pregnancy and negatively affects placental, estrogen, progesterone, and VEGF expression, with subsequent disruption of progesterone physiological function, which was required to support early pregnancy, and the interruption of VEGF vascular support signals, which is the angiogenic factor involved in implantation and placentation of ectopic pregnancy, which drew attention to how letrozole hinders pregnancy progression.
The objective of the study by Mohamed Ali Alabiad and team was to evaluate different doses of letrozole for the treatment of ectopic pregnancy to reach the optimal and most safe dose with the highest success rate of ectopic pregnancy termination, and also, to investigate the possible underlying mechanisms through determining ER and PR expression, apoptosis signaling molecules, and their consequence on placental angiogenesis. The study showed that the resolution rate for ectopic pregnancy using a high dose of letrozole (10 mg day−1) was 85%, while the resolution rate for a low dose of letrozole of 5 mg day−1 was 65%.
Sixty patients with undisturbed ectopic pregnancy were classified into three equal groups.
Group I: the control group that contained women who underwent laparoscopic salpingectomy,
Group II: patients who received letrozole (5 mg day−1) for 10 days, and
Group III: patients who received letrozole (10 mg day−1) for 10 days.
Subsequently, the β-hCG levels were determined on the frst day and after 11 days of treatment. Group IV consisted of patients of GII and GIII; their β-hCG did not drop below 100 mIU/ml within 11 days, and underwent salpingectomy. Placental tissues from patients undergoing salpingectomy either from the control group or GIV were processed for the evaluation of estrogen (ER) and progesterone (PR) receptors, vascular endothelial growth factor (VEGF), and cleaved caspase 3 (CC-3) expression.
Cases exposed to high dose letrozole 10 mg day−1 resulted in a higher ectopic pregnancy resolution rate of 85% (17/20), while the resolution rate of the low dose letrozole-treated group (5 mg day−1) was 65% (13/20), and also showed a signifcant reduction in β-hCG levels on the 11th day, 25.63±4.29 compared to the low dose letrozole group 37.91±7.18 (P<0.001).
The study showed that the resolution rate for ectopic pregnancy using a high dose of letrozole (10 mg day−1) was 85%, while the resolution rate for a low dose of letrozole of 5 mg day−1 was 65%.
There was a difference in the resolution rate between the high-dose administered letrozole group GIII 85% and the low-dose administered letrozole group 65%, but statistically, these differences did not appear (P=0.144) due to the small number of participants in this study, but the resolution rate of the high-dose group 85% was very close to the ideal results of the control group 100% (P=0.230)
The resolution rat of the low-dose group 65% could not get close enough to the optimal results of the control group 100% to dissolve the significant statistical difference between them, where the results between them were statistically significant difference (P=0.008)
The higher dose letrozole group was able to reduce the β-hCG in a way that is close to the total removal of the ectopic pregnancy by surgery (control group).
In this study, the Letrozole-treated group IV showed a significant reduction in ER and PR expression, which play a major role in maintaining pregnancy. Low estrogen levels caused by the aromatase inhibitor letrozole can cause inhibition of progesterone receptors that disrupt the physiological functions of progesterone, which are necessary to maintain early pregnancy.
Vascularization occurs in the human placenta by the formation of new blood vessels from pluripotent precursor cells in the mesenchymal core of the villi, rather than starting from fetal blood cells; the placental villi begin to vascularize on day 21 after conception. Study results showed that the trophoblastic tissues of the letrozole-treated group IV showed a marked reduction in vascular endothelial growth factor (VEGF) compared to the expression of VEGF in the trophoblastic tissue of the control group. VEGF is a powerful mitogenic agent that promotes the formation of blood vessels in the fetoplacental unit that keeps the fetus alive. Estrogen is a primary stimulatory factor for VEGF, promoting the development of the vascular network and uterine permeability; therefore, antiestrogenic drugs, such as aromatase inhibitors, are angiogenesis inhibitors and can result in complete failure of fetal expansion by interfering with placenta formation and embryonic vascular development.
Additionally, in ectopic pregnancy, maternal cells at the implantation site usually show very limited decidual diferentiation, if any, which markedly attenuates the secretion of placental growth factor PIGF, in addition to the unfavorable environment represented by hypoxia, added further inhibition of PIGF expression; at the same time, as a compensatory mechanism, ectopic trophoblastic tissue increases VEGF expression more than normal intrauterine conception responding to hypoxia, and other stimulators including estrogen, which enables it to continue to grow, while tubal implantation that cannot overcome these unfavorable conditions of implantation undergoes spontaneous resolution.
In this study, the placental apoptotic index was measured using the cleaved caspase-3 expression which was found to be higher in trophoblast cells of the letrozole-treated group GIV in comparison to the trophoblastic tissue of the control group that showed lower expression. Caspase-3 is one of the proteases involved in the initiation and execution of apoptosis. Therefore, limiting caspase activity is essential for effective cell survival management.
Letrozole deprives the placenta of estrogen signals, which have a vascular supporting effect, destroying the placental vascular system with marked apoptosis. This study showed that using 10 mg day−1 of letrozole resulted in a considerably safe and high success rate of ectopic pregnancy termination without imposing any serious side effects, but even with the higher dose of letrozole, preparation for potential salpingectomy is needed.
Source: Mohamed Ali Alabiad, Warda M. M. Said, Abdalla Hassan Gad et al; Reproductive Sciences
https://doi.org/10.1007/s43032-022-00993-0
