There have been no reports of primary ovarian insufficiency (POI) caused by lenvatinib. We experienced a case in which a young female patient with liver cancer showed amenorrhea and high FSH levels during the administration of lenvatinib as preoperative chemotherapy for 3 months and then recovered to normal menstruation.
Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases and suppresses stem cell factor (SCF)-producing tumors via vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), SCF, inhibition of tyrosine-protein kinase (KIT), and VEGF signaling. The kinases that lenvatinib inhibits are vascular endothelial growth factor receptor (VEGFR)1–3, fibroblast growth factor receptor (FGFR)1–4, platelet-derived growth factor receptor (PDGFR), rearranged during transfection (RET), and KIT [15, 16] (Fig. 2). An in vitro study also reported that it suppresses FGFR and PDGFR signaling [17]
Lenvatinib was found to inhibit kinase-insert domain-containing receptor and KIT kinases more strongly than did imatinib [14]. The antiangiogenic activity of lenvatinib in an in vivo experiment was similar to that of lenvatinib 10 mg/kg and sorafenib 100 mg/kg in an experiment using human pancreatic cancer VEGF121 [18].
The effect of lenvatinib on malignant tumors has been reported in HCC [13], thyroid carcinoma [19], and advanced endometrial carcinoma [20]. Currently, treatment of advanced HCC with lenvatinib significantly prolongs overall survival compared to sorafenib, and lenvatinib has become one of the first-line treatment drugs [21].
The toxicities of lenvatinib are hypertension and proteinuria, which are likely to occur with drugs that target the VEGF pathway [22]. Bevacizumab, sorafenib, and sunitinib, which act on the VEGF pathway, have similar mechanisms of hypertension risk [23–25].
VEGF has several isoforms: VEGF145 is expressed in carcinoma cells, whereas VEGF121 and 165 are expressed in the ovary [26]. Follicle development requires angiogenesis, for which the action of VEGF is important [27, 28]. When VEGF Trap was administered in the early luteal phase of macaques in in vivo experiments on the corpus luteum, attenuation of E2 and elevation of LH and FSH occurred. These findings suggested that VEGF plays an important role in ovarian function and fertility [29]. The anti-angiogenic drug bevacizumab is thought to affect the process of ovulation by this mechanism [30].
In the present patient, it is most likely that the inhibitory effect of lenvatinib on VEGF impaired follicle angiogenesis, inhibited follicle development, and caused temporary ovarian insufficiency (Fig. 2).
The definition of POI is ovarian insufficiency in women under 40 years of age that causes infertility [31], the criterion of which is a FSH ≥ 40 mIU/ml with amenorrhea [32]. According to a prospective cohort study by Coulam et al., premature ovarian failure was reported to occur in 0.1% of women by age 30 years and in 1% by age 40 years, and it increased with age [33]. The present patient met the criterion of FSH ≥ 40 associated with amenorrhea during lenvatinib administration, and ovarian insufficiency could be diagnosed. There have been no reports of ovarian insufficiency due to administration of the Xa inhibitor rivaroxaban, which was taken during the same period [34].
There are few reports of ovarian insufficiency caused by molecular-targeted drugs. An 18-year-old female patient with breast angiosarcoma was reported to have POI due to the effects of pazopanib [35], which is also an inhibitor of multiple receptor tyrosine kinase. Pazopanib also inhibits VEGFR, PDGFR, and c-Kit [36]. c-Kit and PDGFR are thought to be involved in primary follicle formation [37], but three regimens were administered in this case. Doxorubicin, ifosfamide, and gemcitabine, among others, were administered, and there was a delay before the administration of pazopanib. Ifosfamide-containing regimens have been reported to cause ovarian insufficiency [38] that may result in some damage to the ovaries. Multitargeted tyrosine kinase inhibitors that impair VEGFR include sorafenib and sunitinib, and these drugs may also have side effects that impair ovarian function [24, 25]. The administration of pazopanib, sorafenib, and sunitinib doses in in vivo rat experiments did not cause a meaningful change in the number of ovarian follicles [39].
In conclusion, a young women with HCC experienced transient ovarian hypofunction as a possible side effect of lenvatinib use. Although this side effect has not been reported so far, to our knowledge, when treating such patients, it may be necessary to consider the risk of POI caused by molecular-targeted drugs that impair the VEGF pathway.