In this study, we demonstrated that detection of very low serum AMH levels in patients with POI can be used as a marker for predicting follicle growth of the current cycle. In patients with POI, it has been reported that the possibility of spontaneous ovulation is about 4% during a cycle (3); however, it is difficult to predict the exact cycle which will present with follicle growth. Gonadotropin therapy with exogenous estrogen is one of the most common strategies for the induction of follicle growth in patients with POI (17)(6)(4). It has been reported that ovulation only occurred in patients with lower serum FSH (< 15 IU/mL) after estrogen therapy (6), resulting in an ovulation rate of 32% with this therapy, higher than the spontaneous ovulation rate of patients with POI. However, 70% of the patients who underwent ovarian stimulation did not achieve ovulation.
In the current study, serum FSH levels in cycles with follicle growth were significantly lower than those in cycles without follicle growth. However, the PPV and NPV of serum FSH < 10 mIU/mL as a prediction marker for follicle growth were 0.25 and 0.837, respectively, resulting in 75% of the cycles with lower FSH levels not presenting with follicle growth. In contrast, the PPV and NPV of AMH-positive serum were 0.643 and 0.935, respectively, significantly higher than those of low levels of serum FSH (< 10 mIU/mL). Moreover, the median serum AMH level of cycles with follicle growth was 2.77 pg/mL (25th, 75th percentile: 0.0, 9.64), an undetectable level using the Gen II AMH ELISA (LoD: 80 pg/mL) or automated assay systems such as the Elecsys AMH (LoD: 10 pg/mL, Roche Diagnostics) and the Access AMH (LoD: 20 pg/mL, Beckman Coulter Inc.) (18)(15).
There were five cycles presenting with follicle growth which had AMH-negative serum. Of these five cycles, two were AMH-positive in the previous cycle. Additionally, patients who had positive AMH levels one or more times presented with follicle growth during the observational periods. These results indicate that the measurement of very low serum AMH levels was useful for predicting follicle growth in patients with POI.
We acknowledge that there were several limitations to this study. Firstly, the numbers of patients and cycles included in this study were small. However, the frequency of ovulation of the patients and the frequency of cycles were 3.7% and 1.5%, respectively, and these rates were similar to those reported in a previous study (3). Secondly, an automated assay system for picoAMH is not presently available, and consequently, it is difficult to get same-day results of picoAMH testing. Since serum AMH levels are not affected by hormonal status (19)(20), clinicians may measure AMH serum levels during hormonal therapy, or several days before the withdrawal periods, in order to predict follicle growth. Thirdly, the results of this study are limited to the prediction of follicle growth, and all seven patients who exhibited follicle growth in this study have failed to achieve pregnancy. Previous reports indicated that the median serum AMH level of patients with successful IVF was 837 (range: 141.6-2750) pg/mL (21), and live birth rate was significantly lower in women with AMH ≤ 0.1 ng/mL (22). Consequently, it cannot be declared that detection of AMH by the picoAMH kit in POI patients raises the probability of successful IVF or pregnancy. Fourthly, donor oocytes are available for patients with POI in some countries. However, there are still difficulties regarding accessing oocyte donations in some countries. Moreover, in vitro fertilization (IVF) with donor oocytes has some issues, such as the high expense and concerns regarding genetics. In addition, some reports have suggested that patients with spontaneous POI have an increased risk of perinatal complications, such as pregnancy-induced hypertension and postpartum hemorrhage, when they become pregnant using IVF with oocyte donation (23)(24). Therefore, the availability and feasibility of IVF with autologous oocyte could be significant for patients with POI.
In 2018, the U.S. Food and Drug Administration permitted marketing of the picoAMH ELISA diagnostic test as an aid in the determination of a patient’s menopausal status (25). In addition to predicting menopausal status, the picoAMH ELISA kits may have significance for patients with POI who desire to have children.