In this study, adverse effects of TAM on the ovarian function during hormone therapy for breast cancers were observed in Japanese women of reproductive age. Although the precise incidence rate is unclear, considering the low frequency of post-operative follow-up, 2 or 3 visits a year, the association of a high concentration of serum estradiol with TAM therapy may be a relatively common phenomenon in Japanese patients.
The formation of a couple of ovarian follicular cysts was observed not only in three cases with regular menstruation, but also in the other three cases that had been clinically diagnosed as chemotherapy-induced menopause. This suggests that TAM can induce multiple follicular development, which is usually observed in ovulation induction using an anti-estrogenic agent, clomiphene (Nasseri and Ledger 2001). Anti-estrogenic drugs are considered to inhibit the hypothalamic-pituitary-axis by negative feedback to stimulate the secretion of pituitary gonadotropins such as FSH and luteinizing hormone (LH) (Fig. 1). Since the pulsatile secretion of pituitary gonadotropins is important in the selection and/or promotion of follicular development (Skorupskaite et al. 2014), more examinations including the rhythmic changes in pulsatile secretion by TAM are necessary to clarify the precise mechanisms.
Theoretically, the anti-estrogenic effects on the hypothalamic-pituitary-axis also interfere with positive feedback, leading to inhibition of the LH surge (Fig. 2). Once the LH surge occurs, granulosa cells in the mature follicles will undergo luteinization, in which the steroid hormone production shifts from estradiol to progesterone (Devoto et al. 2002). Therefore, the formation of the single functional follicular cyst that produced estradiol at more than 500 pg/mL in the serum, strongly suggests the absence of the LH surge.
Although the direct effects of TAM on steroid hormone production of granulosa cells in the follicles were proposed to explain the high concentration of serum estradiol in the TAM-treated patients (Groom and Griffiths 1976), our findings could not confirm the presence of this mechanism since the inhibitory effects of TAM on estrogen-induced negative and positive feedbacks to the hypothalamic-pituitary-axis could successfully explain the ovarian hyper-stimulated phenomenon observed in this study.
It should also be noted that four cases, with a mean of 36.5 ± 8.35 years old, had been diagnosed with chemotherapy-induced menopause. However, a high value of serum estradiol was observed during the amenorrheic period that had continued from chemotherapy. Furthermore, in three of the four cases, these episodes were detected more than 1 year after the initiation of TAM treatment. From these findings, we suggest an important consideration that anovulatory hyperestrogenic conditions may be induced by TAM treatment even during the amenorrheic period in patients diagnosed with chemotherapy-induced menopause.
In addition, there was no significant difference in the duration from the start of single administration of TAM to the initial detection of a high concentration of estradiol between both chemotherapy-treated and non-treated groups. Importantly, although previous reports suggested that the development of an ovarian cyst is extremely rare after 2 years of TAM treatment (Madeddu et al. 2014), the average duration in both groups in this study was around 700 days, indicating that ovarian hyperstimulation can occur after 2-year treatment with TAM in Japanese women. Therefore, the risk of TAM-induced ovarian hyperstimulation should be considered throughout TAM treatment in Japan.
In conclusion, our findings indicate that anti-estrogenic hormonal treatment by TAM could stimulate the ovarian function even after single treatment for more than 2 years. Since single and multiple follicular developments were equally observed and follicular sizes were relatively large, we propose dual mechanisms of adverse effects of TAM on the ovarian function, that is, mediated through the inhibition of both negative and positive feedbacks to the hypothalamic-pituitary-axis.