Mariagrazia Stracquadanio1 and Lilliana Ciotta1
(1)
Obstetrics and Gynecological Pathology, P.O. “S. Bambino”, University of Catania, Catania, Italy
Keywords
PCOS diagnosisHormonal evaluationOGTTMetabolismMicropolycystic ovaries
Currently the ESHRE/ASRM or Rotterdam criteria are the agreed international diagnostic criteria for PCOS [1].
PCOS diagnosis can be raised only after the exclusion of other known causes of hyperandrogenism and amenorrhea and when there are at least two of the three following parameters:
1.
2.
3.
5.1 Differential Diagnosis
First of all, to establish a differential diagnosis is a primary goal when a patient complains of menstrual disorders, infertility, hyperandrogenism, and overweight/obesity, in order to identify all possible clinical scenarios that are characterized by symptoms and signs similar to PCOS features.
These are the following:
· Hyperprolactinemia: history of galactorrhea, spontaneous or induced.
· Thyroid dysfunctions: frequent symptoms are hot or cold intolerance, tremors, diffuse scalp hair loss, weight change, and textural skin changes.
· Ovarian/adrenal androgen-secreting tumors: symptoms of deep virilization such as increased libido, deepened voice, and clitoromegaly.
· Non-classic congenital adrenal 21-hydroxylase deficiency: this disorder is caused by a partial adrenal enzyme defect that leads to impaired cortisol production, compensatory elevation in adrenocorticotropic hormone, and subsequent excess androgen production. Premature pubarche could be a clue symptom.
· Cushing’s syndrome: late-onset hirsutism, mood or sleep disturbance, hyperpigmented striae, easy bruising, thin/fragile skin, facial plethora, supraclavicular fullness, excessive thirst, and increased susceptibility to infections.
· Virilizing drugs: anabolic steroids, glucocorticoids, valproic acid, etc.
· Simple obesity.
· Premature ovarian failure or stress amenorrhea.
It is important to assess the onset and evolution of hyperandrogenism signs because a rapid onset (2–6 months) is suspicious of androgen-secreting neoplasms, while a slow onset and evolution (especially during the adolescence) is more peculiar of PCOS. Moreover, it is relevant to investigate the possible intake of virilizing drugs.
5.2 Risk Factors
Anamnesis is important to assess the presence of various risk factors, such as:
· Family medical history positive for:
· Type II diabetes
· Hyperandrogenism
· Impaired glucose tolerance
· Hyperinsulinemia
· Obesity
· Metabolic syndrome
· Preeclampsia
· Gestational diabetes
· Personal medical history positive for:
· Early pubarche
· Overweight/obesity
· Macrosomia
· Sedentary lifestyle
· Poor dietary habits
5.3 Clinical–Endocrine Features
5.3.1 Oligomenorrhea and Anovulation
Oligomenorrhea is defined as menstrual periods occurring at intervals of greater than 35 days, with only four to nine periods in a year.
During the early post-menarche years, the menstrual cycles can last between 21 and 45 days [2]. The characteristic menstrual regularity of the adult female is usually reached several years following menarche; according to some studies, the persistent presence of cycles longer than 45 days, 3–5 years following the menarche, suggests the presence of ovulatory dysfunction in adolescent girls [3].
Progesterone levels <5 ng/mL in days 20–24 (luteal phase) of the menstrual cycle is a good cutoff to diagnose an anovulatory cycle. In contrast, a patient can be diagnosed as anovulatory after ascertaining anovulation in at least two subsequent cycles, in the presence of hypoprogesteronemia.
5.3.2 Hirsutism
Hirsutism can be assessed through the Ferriman–Gallwey score [4] that evaluates the presence of the terminal hair in the upper lip, chin, chest, upper and lower back, upper and lower abdomen, thighs, and arms.
A score of 0–4 is assigned to each area examined, based on the visual density of terminal hairs, such that a score of 0 represents the absence of terminal hairs, a score of 1 minimally evident terminal hair growth, and a score of 4 extensive terminal hair growth. Terminal hairs can be distinguished clinically from vellus hairs primarily by their length (i.e., >0.5 cm), coarseness, and pigmentation. On the contrary, vellus hairs generally measure <0.5 cm in length and are soft and nonpigmented.
Integrated scores from all body areas beyond 15 points are related to a hirsutism diagnosis, although current recommendations suggest the use of 95th percentile of the score in specific populations, adapting to ethnic groups, hair pattern, and age-related features, in order to properly diagnose hirsutism [4].
This score system has limitations because of the subjective nature of the assessments and the difficulty of evaluating women who have cosmetically removed their hairs [5].
Moreover, the F–G score was developed in Caucasian adult women and may not be applicable to younger women from different ethnic backgrounds (e.g., for Indian women) [6].
5.3.3 Acne
The two commonly used measures to assess the severity of acne are grading and lesion counting, but no grading system has been universally accepted [7].
In 1956, Pillsbury, Shelley, and Kligman published the earliest known grading system [8], which includes the following:
· Grade 1: comedones and occasional small cysts confined to the face
· Grade 2: comedones with occasional pustules and small cysts confined to the face
· Grade 3: many comedones and small and large inflammatory papules and pustules, more extensive but confined to the face
· Grade 4: many comedones and deep lesions tending to coalescence and canalize and involving the face and the upper aspects of the trunk
A more recent and complete system is the one created, in 1997, by Doshi, Zaheer, and Stiller [9], called “Global Acne Grading System (GAGS)”. This system divides the face, chest, and back into six areas (forehead, each cheek, nose, chin, chest, and back) and assigns a factor to each area on the basis of size.
Each type of lesion is given a value depending on severity:
· No lesions = 0
· Comedones = 1
· Papules = 2
· Pustules = 3
· Nodules = 4
The score for each area (local score) is calculated using the formula:
The global score is the sum of local scores, and acne severity was graded using the global score. A score of 1–18 is considered mild; 19–30, moderate; 31–38, severe; and >39, very severe.
5.4 Endocrine Blood Tests
Blood tests should be done within 10 days from the beginning of a menstrual cycle, during the early follicular phase. Many studies suggest that hyperandrogenemia may be the most useful diagnostic feature in adolescents because menstrual irregularities, ovarian morphology, and clinical hyperandrogenism do not correlate strongly with PCOS in this population [10, 11], even if there is a physiological increase in androgen levels during puberty [12, 13].
The following are the blood substrates and their values characteristic of PCOS.
As explained previously, in the meanwhile, it is crucial to assess other blood values (TSH, fT3, fT4, anti-TPO, anti-Tg, prolactin, DHEAS, 24 h urinary cortisol and creatinine) in order to exclude other pathologies:
· LH ≥10 mUI/mL
· LH/FSH ratio ≥2.5
· Estradiol ≥30 pg/mL
· 17-OHP ≤2 ng/mL
If the value is >2 ng/mL (6 nmol/l), it is suspicious of non-classic congenital adrenal 21-hydroxylase deficiency (NCAH), and ACTH test is required: it is an acute adrenal stimulation test that measures 17-OHP before and 60 min after the intravenous administration of an adrenocorticotropic hormone analog. If the stimulated 17-OHP exceeds 30 nmol/l, and preferably 45 nmol/l, the diagnosis of NCAH is confirmed [14].
· Androstenedione ≥2.5 ng/mL
· SHBG ≤15 nmol/l
· Testosterone ≥1 ng/mL
A serum testosterone level >200 ng/dL is highly suggestive of an adrenal or ovarian tumor. If serum testosterone is elevated despite a normal DHEAS level, an ovarian source is more likely. If a DHEAS level >700 mcg/dL is present despite a normal serum testosterone level, an adrenal source should be suspected as the cause of hirsutism [4].
Mildly elevated serum testosterone and DHEAS are often present in functional ovarian hyperandrogenism (FOH) and late-onset congenital adrenal hyperplasia (CAH).
A very recent study has revealed that PCOS patients with co-elevation of androstenedione and testosterone have impaired indices of insulin sensitivity compared with those with normal androgens or milder hyperandrogenemia [15].
· FAI: free androgen index or FAI is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone-binding globulin (SHBG) level and then multiplying by a constant, usually 100. The concentrations of testosterone and SHBG are normally measured in nanomoles per liter, while FAI has no units [16, 17].
The majority of testosterone in the blood does not exist as free molecule, while half is tightly bound to sex hormone-binding globulin, and the other half is weakly bound to albumin. Only a small percentage is unbound (<3 % in females and <0.7 % in males). Since only free testosterone is able to bind to tissue receptors to exercise its effects, it is believed that free testosterone is the best marker of a person’s androgen status. However, free testosterone is difficult and expensive to measure, and many laboratories do not offer this service.
The free androgen index is intended to give a guide to the free testosterone level, but it is not very accurate. Consequently, there are no universally agreed “normal ranges,” and levels slightly above or below quoted laboratory reference ranges may not be clinically significant.
Typical values for the FAI in women are 7–10 [18].
· A serum AMH ≥35 pmol/l (or ≥5 ng/mL) appears to be more sensitive and specific than a USS follicle count >19 [19].
There is not yet an international consortium that validates the threshold for AMH.
In another recent study, Lin et al. have divided all patients into three groups: high AMH (>11 ng/mL), moderate AMH (4–11 ng/mL), and low AMH (<4 ng/mL). As the AMH level increased, the prevalence of PCOS increased significantly from 21 % in the low-AMH group to 37 % in the moderate-AMH group and 80 % in the high-AMH group [20].
5.5 Ultrasound Features
Polycystic ovarian morphology (PCOM) is an important element for the diagnosis of polycystic ovarian syndrome in adult women. The Rotterdam consensus defined PCOM as the presence of 12 or more follicles of 2–9 mm in diameter and/or an ovarian volume greater than 10 mL in at least 1 ovary (Fig. 5.1).
Fig. 5.1
Polycystic ovarian morphology
Some studies have shown that a combination of these characteristics is better than one, to give greater sensitivity and specificity [21–23].
The subjective aspect of the ovaries, their follicular distribution, or the appearance of the stroma is not considered as important:
· Ovarian volume: there are many formulas available for the calculation of ovarian volume, but investigators stated that it should be calculated on the basis of the simplified formula for an ellipsoid: 0.5 × length × width × thickness of the ovary [21, 23–25].
· Number of follicles: the adoption of the above-cited criterion for defining a polycystic ovary is different from the methodology used in prior works, which attempted to define PCOM on the basis of the presence of at least ten follicles arranged peripherally around an echodense stroma [26] in a single US imaging plane. The key technical requirement for the assessment of the number of follicles is that the number of antral follicles present throughout the entire volume of the ovary must be counted [27].
· Stromal echogenicity and volume: one of the features of polycystic ovary is the increased stromal echogenicity [26]. However, the intrinsic echogenicity of the ovarian stroma is no different in PCOS than in the normal ovary; the subjective impression of increased stromal echogenicity is due to the increased stromal volume, which positively correlates with serum androgen levels [28]. At the moment, no standardized method is available for this determination. Because overall ovarian volume correlates well with stromal volume in polycystic ovaries [28] and is more easily to evaluate, the determination of overall ovarian volume is a reliable surrogate for ovarian stromal assessment [27].
Moreover, the Rotterdam consensus states that, wherever possible, ultrasounds should be carried out endo-vaginally particularly in obese patients [1] because of its better resolution in comparison to the transabdominal route.
In fact, data suggest that, compared with transvaginal US, the appearance of polycystic ovaries may not be detected at transabdominal US in up to 30 % of women with PCOS [29].
All ultrasounds have to be carried out in the early follicular phase (3rd–6th day) in women with regular menstrual cycles or in patients with oligomenorrhea (often after MAP test); in case of amenorrhea, the study can be carried out on any given day.
A history of oral contraceptive use should be obtained, since oral contraceptive use causes a decrease in ovarian size, decreasing the sensitivity of US evaluation.
The above-reported criteria are of limited value in the adolescent population [30]. In primis, transvaginal USS is inappropriate in virginal patients, diminishing the quality of imaging obtained [31]. Moreover, ovarian morphology changes during the lifespan, with a maximum size and antral follicle count around menarche [32, 33]: in fact, the mean ovarian volume is larger in young women. The consensus group also cites the difficulty in distinguishing a polycystic ovary from what has traditionally been referred to as a multifollicular ovary, defined as an ovary in which there are six or more follicles (usually 4–10 mm in diameter) with normal stromal echogenicity and described as the common appearance of ovaries in adolescents [26]. Given these physiological features, many adolescents might meet the adult criteria for PCOM [34]. For the explained reasons, there is a lack of high quality evidence on which to base a recommendation on appropriate criteria for ultrasound diagnosis of PCOM in adolescents [30]: thus, USS results should be interpreted with caution [34].
Moreover, it is known that ovarian volume and follicle number decrease linearly with age in women with PCOS and controls, but some studies showed that the follicle number was higher at all ages in PCOS compared with control women [35, 36]: thus, regarding the follicle number count, it is necessary to create an age-based criteria to define PCOM [33].
On the other hand, some studies showed that these ultrasonographic findings are frequent in young women and decrease with age [33, 37, 38]. In adults, these USS findings may be present in 10–20 % of healthy women with regular menstrual cycles and without clinical hyperandrogenism [39, 40].
Other data suggest that 23 % of women of reproductive age will have findings of PCOM [39] and only 5–10 % of these patients will have classic symptoms of PCOS [41].
The use of polycystic ovaries as an inclusion/exclusion criterion for a diagnostic test study is controversial; much of the debates, in fact, have arisen from reports of unusually high rates of polycystic ovaries in healthy women of reproductive age using the ultrasound-based criteria supported by the Rotterdam consensus [38].
According to a very recent study, an average value of 26 or more follicles per ovary is a reliable threshold for detecting PCOM in women with frank symptoms of PCOS; a lower follicle threshold may be required to detect milder variants of the syndrome [42].
Thus, given the significant number of women of reproductive age who have PCOM as defined on the basis of US criteria, actually it would be ideal and prudent to write this observation in the report: “Findings meet the Rotterdam Consensus definition for polycystic ovaries. In the absence of ovulatory dysfunction or either clinically or biochemically diagnosed hyperandrogenism, findings are not specific and do not indicate the presence of polycystic ovarian syndrome” [27].
Summarizing, Lee and Rausch in a recent study propose the “pertinent USS reporting parameters in PCOS” [27]:
· Separate reporting for each ovary
· Number and size range of follicles
· Size of the largest follicle should be measured in three axes and the average diameter calculated
· Documentation of any follicle >10 mm or corpus luteum (presence of either suggest the necessity of repeating USS during the next menstrual cycle)
· Ovarian volume, calculated with the simplified formula for an ellipsoid: (0.5 × length × width × thickness)
5.6 Clinical–Metabolic Features
As largely explained in the previous chapters, a metabolic evaluation is necessary for every PCOS patient. From a clinical–metabolic point of view, physician should:
1.
2.
5.7 Metabolic Blood Tests
As reported previously, ~50–70 % of women with PCOS are characterized by hyperinsulinemic insulin resistance, which plays a causative role in the development of the metabolic syndrome.
The American College of Obstetricians and Gynecologists currently recommends screening women with PCOS for glucose intolerance and lipid abnormalities.
Metabolic Blood Tests Recommended in PCOS Women
· OGTT (biannual rescreening) or HOMA-IR
· Total cholesterol + LDL-C + HDL-C
· Triglycerides
· Transaminases
5.7.1 Glucose Metabolism Assessment and Calculation of Insulin Resistance
First of all, a correct evaluation of carbohydrate metabolism is necessary, and so it is important to remember which are the normal glycemic and insulinemic values.
· Fasting glycemia:
· Normal, 70–100 mg/dL
· “Grey zone,” 100–126 mg/dL
· Diabetes, >126 mg/dL
· Fasting insulinemia: <10 mUI/mL
The World Health Organization (WHO) criteria for impaired fasting glucose (IFG) differ from the American Diabetes Association (ADA) criteria because the normal range of glucose is differently defined.
The WHO has defined the upper limit of normal at less than 110 mg/dL.
However, fasting glucose levels of 100 mg/dL and higher have been shown to significantly increase complication rates, and so the ADA has accordingly lowered the upper normal limit to a fasting glucose under 100 mg/dL.
· WHO IFG criteria: fasting plasma glucose level from 6.1 mmol/l (110 mg/dL) to 7 mmol/l (126 mg/dL).
· ADA IFG criteria: fasting plasma glucose level from 5.6 mmol/l (100 mg/dL) to 7 mmol/l (126 mg/dL) [57].
· OGTT (oral glucose tolerance test): the most accurate method to diagnose insulin resistance is the OGTT after 75 g glucose challenge, even in adolescent women [58]. Normal values are the following:
· Glycemia:
· Fasting, 70–100 mg/dL
· 60 min after glucose administration, <180 mg/dL
· 120 min after glucose administration, <140 mg/dL
Impaired glucose tolerance (IGT) is defined when glucose level is >140 mg/dL 2 h after glucose load, but <200 mg/dL.
Diabetes is defined when glycemia is >200 mg/dL 2 h after glucose load.
· Insulinemia:
· Fasting, <10 mUI/mL
· 60 min after glucose administration, <60 mUI/mL
· 120 min after glucose administration, ≈10 mUI/mL
Of course, the majority of PCOS patients are not diabetic yet, but only insulin resistant; insulin resistance is defined when insulin value 1 h after OGTT is >60 mUI/mL and/or its level is not very close to the fasting insulin value after 2 h post-glucose administration.
It has been suggested that an OGTT should be performed every 2 years for those with normal glucose tolerance and annually if IFG or IGT is present [59].
Glucose screening recommendations for PCOS women are summarized in Table 5.2
Table 5.2
Glucose assessment in PCOS patients—screening recommendations
|
AACE (American Association of Clinical Endocrinologists) ACE (American College of Endocrinology) |
OGTT for all PCOS patients aged >30 year. Periodically reassess |
|
RCOG (Royal College of Obstetricians and Gynaecologists) |
Screen all by fasting glucose regularly. If fasting glucose >100 mg/dL or BMI >30 kg/m2 or positive family history, screen by OGTT |
|
ACOG (American College of Obstetricians and Gynecologists) |
OGTT for all women with PCOS. Repeat every 2 years |
|
AE-PCOS (Androgen Excess and Polycystic Ovary Syndrome Society) |
OGTT for PCOS women with BMI >30 kg/m2 or in lean women with advanced age (>40 years), personal history of gestational diabetes, or family history of diabetes mellitus type II |
· HOMA index: OGTT is not a very confortable method, and it is also expensive and time-consuming; for this reason, the need for a simple way of measuring insulin resistance has led to the creation of a large number of insulin sensitivity indices [60, 61]. The most used model is the HOMA index.
The homeostatic model for assessment of insulin resistance (HOMA-IR) is a simple and noninvasive method of estimating insulin sensitivity from the steady glucose and insulin concentrations measured under fasting conditions.
It was calculated using the following formula [62]:
HOMA index values for percentiles 50–75 ranged from 2.07 to 2.83 [63].
· Glucose/insulin ratio: this simple measure of insulin resistance in PCOS women has been correlated well with more complicated dynamic tests of insulin action [64].
It has been reported that a fasting G:I ratio of 4.5 or less is a measure of IR in obese PCOS women, and this cutoff value has a sensitivity of 95 %, specificity of 84 %, positive predictive value of 87 %, and negative predictive value of 94 % [65].
· Diabetes screening
Recently, a study group from Holland proposed a stepwise screening for glucose metabolism abnormalities by fasting glucose for all women with PCOS and subsequent OGTT screening for diabetes in the small proportion of PCOS women with fasting glucose concentration between 110 and 126 mg/dL only, without compromising early diagnosis of diabetes [66].
However, validation of this new screening algorithm is waited.
Previously, it has been shown that fasting glucose rather than OGTT underestimates the prevalence of diabetes mellitus type II in PCOS women by >50 % [67].
Hemoglobin A1c is a commonly used marker of chronic glycemia, and it reflects the average blood glucose levels over a 2–3-month period [68].
ADA suggests HbA1c levels as a screening tool for diabetes and prediabetes in the general population with cutoff levels of 6.5 and 5.6 %, respectively [69], even if other studies stated that it is insensitive for prediabetes [68].
5.7.2 Lipid and Hepatic Profile
Dyslipidemia is common in PCOS and is present in up to 70 % of subjects [59, 70].
The AE-PCOS Society consensus statement [59] recommends a complete lipid and hepatic profile in all patients with PCOS. Pathological values are:
· Total cholesterol >200 mg/dL
· LDL cholesterol >130 mg/dL
· HDL cholesterol <50 mg/dL
· Triglycerides >150 mg/dL
· AST >30 U/l
· ALT >35 U/l
· γ-GT >38 U/l
The fatty liver index (FLI) is an algorithm based on BMI, waist circumference, triglycerides, and γ-GT and might serve as a simple and accurate predictor of hepatic steatosis in general population. FLI <30 rules out fatty liver disease, while FLI >60 indicates fatty liver disease [71]. FLI is calculated by the following formula:
A recent study revealed that high FLI levels are a common finding in obese PCOS women and are closely linked to metabolic syndrome. Thus, FLI might be a useful index to identify PCOS women at high metabolic and hepatic risk in whom a very careful surveillance is needed and who might benefit from lifestyle counseling [72].
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