Interpretation
Our data supports the strength of known FHA risk factors including,
high-level cardiovascular exercise, psychological
stress19 and weight loss preceding
amenorrhoea.20-22 Fat loss and dieting decrease
circulating leptin; hypoleptinemia reduces stimulation of hypothalamic
neuronal networks, thus suppressing GnRH secretion.
23,24 Despite increased exercise states, however,
21/50 and 8/50 of women with FHA who a received DEXA scan, were
osteopenic and osteoporotic, respectively. We observed lower rates of
reduced BMD, than those in the literature; with reported rates of
osteopenia and osteoporosis as high as 83% and 33% respectively in
women with FHA
25,26;this may have been attributed to the low rates
of DEXA scanning in our study group. 50% of women with FHA reported a
positive ED history, which was comparable to previously reported rates
of 55%. 27
A large retrospective study investigating the potential for misdiagnosis
of FHA found that 86% of lean women with FHA would have met the
Rotterdam criteria for PCOS diagnosis, had FHA not been detected.
17 Although we have highlighted the pertinent clinical
features of FHA, it is important to recognise that the underlying
aetiology of FHA often involves a varying degree of interacting factors
and there remains a lack of consensus on what constitutes excessive
exercise, significant nutrition restriction or psychological stress.
This is deemed problematic in the absence of reliable investigative or
biochemical diagnostic tests and the growing concerns around
misdiagnosing women with FHA with PCOS.
An important finding of our study was the significantly lower BMI in
women with FHA compared to those with PCOS, this is supported by
previous reports.28 Whilst BMI was found to best
distinguish between FHA from PCOS extremely effectively, the large range
reported emphasises the importance of not ruling out PCOS or FHA based
on BMI alone. The heterogenous and often insidious presentation of FHA
calls for a comprehensive clinical approach, which includes combining
clinical parameters with the patient’s history (occupational, exercise
and nutrition) to first suspect and second, diagnose FHA. A recent study
by Rodino et al demonstrated 65% of fertility specialists did not
screen for eating disorders during preconception assessments, despite
83.7% of fertility specialists in their study agreeing it was important
to do so, this was perhaps explained by the fact that only 37.5% felt
confident in their ability to recognise symptoms of an eating disorder.29 This is of particular significance given that
76.4% to 100% of patients do not disclose their eating
disorder.30,31In their retrospective study, Bradbury
et al argue that lack of a detailed diet and exercise history in
patients with a low BMI may result in them being misdiagnosed with PCOS.
17
Similarly, to our biochemical findings, one study comparing women with
FHA with PCOS, found lower baseline LH and estradiol in women with FHA,
with no difference in FSH levels.32 Low estradiol
levels are typical of FHA, secondary to suppression or insufficient
stimulation of the HPO axis, in which no anatomic or organic pathology
can be identified. 33 Elevated LH and mild FSH
suppression characterises PCOS 10 whereas, whilst both
gonadotropins are reduced in FHA, LH is suppressed more significantly.34,35 This likely explains why estradiol and LH were
highly effective at distinguishing FHA from PCOS and why FSH was a poor
distinguisher. The highly significant difference in LH between FHA and
PCOS combined with the similar FSH levels meant that the LH:FSH ratio
was also good at distinguishing the two conditions. Knowledge of the
patient’s baseline LH and FSH levels is important in the context of
diagnosis but also when considering fertility treatment options. For
example, the use of clomiphene citrate is unlikely to be recommended,
owing to the underlying hypoestrogenic state in FHA
patients.36 Nonetheless the use of exogenous
gonadotrophin therapy will likely require both LH and FSH
stimulation37; this would require patients to be
educated on the risks of ovarian hyperstimulation syndrome (OHSS),
especially in the presence of low BMI which increases sensitivity to
gonadotrophin stimulation.38