Counting ovarian follicles: updated threshold for diagnosis of hyperandrogenic anovulation

The first description of the association between enlarged ovaries and subfertility was reported almost 300 years ago, when Vallisneri described a ‘young peasant woman’ who was ‘moderately plump, infertile, with ovaries larger than normal that, like doves' eggs, were lumpy, shiny and whitish’1. The more common term used to describe such ovaries – ‘polycystic ovaries’ – was not introduced until 19352 and since the mid-1950s the associated health conditions, including subfertility, menstrual disorders and hyperandrogenism3, have been referred to as ‘polycystic ovary syndrome’ (PCOS)4, 5. PCOS is reported to occur in 5–10% of women of reproductive age, and the prevalence is even higher in obese women6. Referring to the ovaries as being polycystic is misleading; the term has negative connotations and its use distracts from the real problems of subfertility, menstrual disorders and hyperandrogenism7, 8. Many women, and some healthcare practitioners, are confused by the term; often women start requesting repeat ultrasound scans to see if the ‘cysts’ are still present and, if they are, whether they can be removed surgically. Furthermore, an Australian study showed that almost half of women with this health condition incorrectly identified the ovarian cysts as the key finding9. In fact, these ovaries contain multiple functional follicles (from which oocytes can be retrieved for in-vitro maturation), which grow when stimulated, leading to an increased risk of ovarian hyperstimulation syndrome (OHSS)10. We therefore believe that the term ‘polycystic’ should be avoided in order to prevent unnecessary preoccupation, and therefore anxiety, in the many women who are diagnosed with this condition every day. Although some recent publications have suggested alternatives11, 12, they are rather complex and, in some cases, even more difficult to understand. In our opinion, the sonographic ovarian appearance would be better described simply as being one of an increased number of follicles, or ‘multifollicular’. Additionally, we feel that the condition would be easier to explain and understand if, rather than ‘PCOS’, it was named ‘hyperandrogenic anovulation’ (HA). This term encapsulates the essence of the condition: an endocrine disorder with reproductive features, or, specifically, an association between hyperandrogenism and anovulation. HA can be either idiopathic or have a known cause (e.g. insulin resistance, congenital adrenal hyperplasia). The main problem in trying to group all causes into a single ‘syndrome’ is that it becomes too complex or heterogeneous to be understood13. Furthermore, classifying all women with HA as having a single disease is misleading: insulin resistance, which is associated with obesity, metabolic syndrome and increased risk of cardiovascular disease, is one of the causes of HA and therefore more common among women with HA14-16; however, this does not mean that all women with HA have insulin resistance and a subsequent increased risk of metabolic syndrome and cardiovascular disease17. Just pointing out that obesity and subsequent insulin resistance can cause HA (rather than the reverse) should help to clarify why losing weight can improve menstrual pattern13 and dispel the common misconception that getting rid of ‘ovarian cysts’ (e.g. by using hormonal oral contraceptives, which increases the risk of venous thrombosis18) will also improve obesity, metabolic syndrome and cardiovascular risk. It has been shown that different PCOS phenotypes have different clinical consequences19. However, we believe that the division into different phenotypes emerged only because of the low follicle number per ovary (FNPO ≥ 12) that was suggested as a diagnostic criterion for HA more than a decade ago20, and that this can be overcome by using a more precise threshold (Table 1). People with HA may or may not have a large number of ovarian follicles; there is no need to classify them accordingly. However, the follicle count might be important in identifying the most probable cause of HA. The number of follicles used as a diagnostic criterion for HA needs to be updated. Since the early 1980s, several studies have reported on the sonographic appearance of the ovary in women with HA21; despite this, in 1990, the National Institutes of Health (NIH) recommended that only hyperandrogenism and ovulatory dysfunction should be used as diagnostic criteria and that ultrasound findings should not be taken into consideration. However, the 2003 ASRM (American Society for Reproductive Medicine)/ESHRE (European Society of Human Reproduction and Embryology) criteria, which have been adopted by most practitioners, recognize the importance of ultrasound as a diagnostic tool20, suggesting that the diagnosis should be suspected when two of the following three criteria are present: oligo-/amenorrhea; clinical and/or biochemical signs of hyperandrogenism; and polycystic ovaries on ultrasound. The ASRM/ESHRE threshold to define polycystic ovaries on ultrasound was the presence of 12 or more follicles measuring 2–9 mm in diameter or an increased ovarian volume (>10 mL) in at least one ovary. This threshold of 12 follicles was based on a study published by Jonard et al.22 in 2003, which reported that a FNPO of 12 or more offered the best compromise between specificity (99%) and sensitivity (75%) in the detection of HA. However, recent studies, using new ultrasound machines with improved resolution, have shown a high prevalence of ovaries with more than 12 follicles in healthy young women23-25. A task force from the Androgen Excess and Polycystic Ovary Syndrome Society (AE-PCOS) reviewed results from recently published studies23, 24, 26-29 and reported an urgent need to update the diagnostic criteria30, recommending that the threshold be increased to ≥ 25 follicles when using new ultrasound machines. We agree; this new threshold should be used immediately. We also agree with the AE-PCOS task force's suggestion of using only ovarian volume ≥ 10 mL in the detection of HA (in the absence of a dominant follicle or a corpus luteum) when a new ultrasound machine is not available30. The time is right to improve both the ultrasound criteria and the name of this health condition31, 32. Women approaching menopause have a reduced number of ovarian follicles33, 34. Therefore, regardless of how many or few, the number should always be reported in women undergoing ultrasonography because of menstrual disorders (Table 1). A recent study showed that women with a total number of follicles ≤ 4 (the sum of the number observed in both ovaries) have an increased risk of menopause within 7 years33. However, it should be borne in mind that use of hormonal contraception might reduce the total follicle count35. Many women without a menstrual disorder are likely to undergo an ultrasound examination of their ovaries at some stage during their reproductive life; some of them will have a large follicle count while others will have a small count. We feel that ovaries without any indication of disease (i.e. tumors) should be reported as normal, regardless of the number of follicles they contain, and that the follicle count should always be reported when the examiner is an experienced sonographer using a high-resolution ultrasound machine. Of course, one should be aware that the follicle count might not be reliable in every situation, as some exams will suffer from technical limitations36. A reduced follicle count in asymptomatic women might indicate either the use of hormonal contraception35 or a reduced functional ovarian reserve37, which may be either natural or iatrogenic (e.g. following ovarian surgery or chemotherapy). Women with a reduced follicle count should be asked about their desire to conceive and advised not to delay attempting to become pregnant since the chances of a successful natural pregnancy decrease with increasing age and women with a reduced follicle count have a reduced chance of success when undergoing assisted reproduction8. A large number of follicles might indicate a high risk of HA; but what should be done when a large number of follicles is observed in a woman who shows no signs of either anovulation or hyperandrogenism? It is important to make very clear that we do not know the clinical consequence of this ultrasound finding in asymptomatic women38 and, as such, we should be mindful not to label someone based only on ultrasound findings; even more importantly, we should not report these ovaries as being ‘polycystic’, which will only cause unnecessary anxiety. A stratification of ovarian morphology based on FNPO might be used (Table 1). However, it is important to stress that neither an ‘oligofollicular’ nor a ‘multifollicular’ ovary should be considered a disease. Sonographers should be aware that the threshold used for diagnosing HA should differ from that used to identify women at risk of an excessive response to controlled ovarian stimulation during assisted reproduction; a much lower threshold should be adopted to identify the latter. Women with a total antral follicle count (AFC) (considering both ovaries) of >20 have been shown to have a higher risk of developing OHSS10, 39, while those with a reduced total AFC are known to be at risk of poor ovarian response8 and have a reduced chance of pregnancy following assisted reproduction40, 41. Thus, total AFC is frequently used for the individualization of controlled ovarian stimulation39, 42, 43. We suggest a second stratification system based on the total AFC44 for use in fertility centers (Table 1). The term ‘polycystic’ should not be used when describing ovarian morphology as it is misleading and can lead to unnecessary anxiety. PCOS is equally problematic and should be replaced by HA. The current ultrasound criterion for the diagnosis of HA is no longer adequate: we endorse use of the newly suggested threshold of ≥ 25 follicles per ovary for this diagnosis.