Our findings were consistent with previous reports [1,2,3, 7], where a high overall prevalence of PCOM in FHA patients was found (about 45%). As hypothesized, the stress-associated FHA group revealed a significantly higher prevalence of PCOM compared to the excessive exercise group (Table 2). Stress versus excessive exercise was the most important parameter associated with PCOM (Table 3). Women with stress-induced had higher mean AMH levels, as previously reported in women with FHA and PCOM compared to those without PCOM [1,2,3]. Though these differences were not statistically significant, there were only ten more patients with PCOM in the stress group, which may mean that the lack of a difference was attributable to sample size. Keeping in mind that women with PCOS reveal a generalized increase in sympathetic nerve activity, which suggests that they suffer from increased stress and/or less adequate response to stressors [4], and that stress and stress sensitivity are well-recognized causes for FHA [5], our data support a link between stress and the presence of PCOM.

Notably, literature about the influence of stress on AMH levels is scarce. In non-PCOS women seeking infertility treatment, high stress levels did not correlate with AMH levels [8]. Cortisol is a well-known stress-biomarker [9]. While DHEA has been reported to be associated with cortisol levels, very low DHEA also negatively affected total testosterone [10]. It is well-established that abnormally low testosterone inhibits growth of small growing follicles, which then leads to reductions in granulosa cell mass and AMH levels [11]. However, this might not be true for women with PCOS, where high AMH is a marker of disease severity and likely the main disruptor of normal ovarian function [12] and usually higher cortisol levels are found than in controls [13]. In fact, we will not be sure about the changes which happen in women who develop FHA until we will be able to acquire longitudinal data.

In addition to the rate of PCOM, there were higher prolactin as well as a trend towards higher DHEAS levels in stress-induced FHA (p = 0.058). Chronic stress induces an intense cortisol production via an increased ACTH production and release from the POMC-neurons. At the same time, these neurons also secrete GABA, which acts as a stimulator of prolactin and can therefore lead to increased prolactin secretion [14]. Notably, prolactin has been mentioned as a possible serum biomarker of chronic stress and was found to be elevated in patients with burn out [15]. In addition, there was a trend towards higher DHEAS levels in stress-associated FHA. Due to stress-induced adrenal activity, this may be why adrenal androgens may be increased to a greater extent than ovarian androgens. Notably, DHEAS has also been claimed to be linked to chronic stress [15].

However, an alternative explanation could include underlying PCOS predisposing patients to stress, as PCOS is associated with higher rates of mood disorders, including depression.

The study limitations, which need to be addressed, include the fact that matching of age and of duration of amenorrhea was not possible and the retrospective study design, which might have introduced some kind of selection bias despite the strict in- and exclusion criteria (Table 1). Moreover, we cannot provide the exposure time to either excessive exercise or stress. This should also be seen as a limitation, since, hypothetically, exposure time might be associated with the development of PCOM, despite the fact that the duration of amenorrhea was not of relevance (Table 3). One could also argue that the sample size was comparably small. However, only patients with FHA diagnosed by strict criteria were included. In addition, FHA patients with either stress or excessive exercise only - which excludes patients with a combination of both, weight loss, and/or eating disorders - are rare to find.