Hanifullah Khan
Women’s Health and Endometriosis Care Centre, Lumut, Malaysia
Introduction
Polycystic Ovary Syndrome (PCOS) has become the most common endocrine abnormality of women with a reported prevalence of 6% to 7%1. It is frequently associated with ovulatory dysfunction that begins in the perimenarchal period. The classic symptoms are a result of a primarily ovarian overproduction of androgens, hyperinsulinaemia and chronic anovulation causing symptoms such as menstrual abnormalities, hirsutism and acne. Obesity can also be an associated feature. Additionally, the ovaries display a typical morphologic pattern that appears to be unique to the disorder.
From a reproductive point of view, puberty can be considered as the process by which hormonal changes take place in order to permit the expulsion of mature oocytes from the ovary, thus allowing fertilization to occur2. For ovulation to happen however, a series of sequential hormonal events must take place in a highly synchronized manner. A healthy ovary will subsequently exhibit regular monthly ovulations, characterized by a 25 to 36 day cycle, although anovulatory cycles and irregular periods may occur during the first 2-5 years after menarche3. Irregular menstrual cycles that persist beyond these years may be a sign of an underlying hormonal disorder4. As previously stated, many women with PCOS recall the onset of their symptoms around the time of puberty or during the early adolescent period.
The metabolic syndrome is characterised by central adiposity, hypertension, increased triglycerides, low levels of high density lipoproteins, impaired glucose tolerance and diabetes mellitus. It is also associated with long term health risks such as cancer and cardiovascular disease. This syndrome has been shown to be very prevalent in women with PCOS5. Compared to a normal adolescent girl, adolescents with PCOS are at increased risk for the development of type 2 diabetes mellitus and the metabolic syndrome6. In fact, PCOS is now considered a major risk factor for the development of Type 2 diabetes mellitus. Because of the established link between PCOS and the metabolic syndrome, many have now begun to view PCOS as a premetabolic syndrome condition7. Establishing PCOS status in adolescence provides a unique opportunity for early intervention, the failure of which may result in delayed treatment and a lower quality of life8.
Although many issues surrounding the understanding and diagnosis of PCOS remain clouded, its management in adult women is now fairly well determined. Quite the reverse, the diagnosis and management of PCOS in adolescents leaves many questions requiring solutions. As most of the accepted clinical features of PCOS (menstrual irregularities, acne and hirsutism) are associated with a “normal” adolescence, definitive diagnostic criteria have become blurred. Typical biochemical features of PCOS such as increased androgen and insulin secretion can often be a feature of normal growing up.
It is apparent that a greater appreciation of initial symptomatology is essential to allow for early therapeutic intervention to minimize the acute and chronic consequences of PCOS. Generally speaking, the diagnosis of this disorder can be indicated by the clinical presentation, although laboratory testing and imaging is necessary to exclude other possible conditions that may mimic it. The following review is an attempt to aid in the reliable clinical diagnosis of PCOS in adolescent and young adult women based on the historical and physical signs and a cost-effective use of investigational procedures.
Diagnostic quandry
Difficulties in the diagnosis of PCOS and controversies in definition arise from the heterogeneous nature of the disorder. Girls and women may present with a variety of concerns and symptoms, including irregular periods, excess hair growth, acne, and obesity. Numerous attempts have been made to define and quantify PCOS from its earliest description in 19359. So far, 3 sets of criteria have been proposed for the diagnosis of PCOS in adult women; the NIH, Rotterdam and Androgen Excess Society criteria. No set criteria exist for such a diagnosis in adolescents and teenagers.
In the United States, diagnosis has been based on the findings of irregular cycles (oligo/anovulation) and clinical or biochemical evidence of androgen excess with the absence of any tumour or adrenal enzymatic defect. These criteria came from a conference held at the US National Institute of Health (NIH) in 199110. Although the original descriptor of this condition, these criteria did not include the presence of a particular ovarian morphology for diagnosis. It also did not allow for the inclusion of women who ovulate and have PCOS, a fact that had been previously documented.
On the other hand, the European definition of PCOS is highly reliant on the demonstration of polycystic morphology on ultrasound scanning. To reconcile these differences, a meeting in Rotterdam crafted compromise criteria which now carry the name of that city, and requires any two features from irregular cycles, hyperandrogenism and ultrasound demonstration of polycystic ovaries to diagnose PCOS11. This definition results in four subsets of PCOS: (1) irregular menstrual pattern plus polycystic ovary morphology plus (clinical or laboratory) hyperandrogenism, (2) irregular menses plus hyperandrogenism, (3) hyperandrogenism plus polycystic ovary morphology, and (4) irregular menses plus polycystic ovary morphology12. Importantly, the Rotterdam criteria allows for the previously excluded ovulatory women with features of PCOS, as well as for women who have irregular cycles and polycystic ovaries but no evidence of androgen excess. This latter phenotype of patients remains the centre of debate, as there is strong sentiment that androgen excess is key to the pathophysiology of PCOS.
Not surprisingly, the Androgen Excess Society (AES) Task Force on the Phenotype of PCOS in 2006 narrowed the Rotterdam consensus to exclude women who did not have androgen excess13. This criteria defines PCOS as a condition with hyperandrogenism (clinical or biochemical) and ovarian dysfunction (either oligo-anovulation and/or polycystic ovarian morphology on ultrasound) with the obvious exclusion of other disorders. This seems to be the most adequate for the diagnosis of PCOS in adolescence.
Some factors underlie the basis of this diagnostic quandary. Many of the features of PCOS may be a normal occurrence in the young woman. For example, menstrual cycles are frequently anovulatory; acne and mild hirsutism are common and obesity prevalent. Ultrasound scanning can be contradictory as polycystic-type ovaries can occur in healthy asymptomatic adolescents14, whereas only about half of adolescents with PCOS demonstrate polycystic ovaries15. Inaccuracies in current assay systems, coupled with limited laboratory data on androgen levels in pubertal and adolescent girls do not allow for a clear cut diagnosis of androgen excess. Furthermore, documented hyperandrogenemia amongst these patients has been associated with later normal ovulatory cycles16.
It is thus painfully apparent that quantifying PCOS in an adolescent girl is a challenging exercise. Understanding the clinical features with optimal use of investigative procedures would go a long way towards identifying the adolescent patient who might have PCOS.
Menstrual irregularity
Normal puberty is a gradual process which takes several years to be completed. During this time, certain developmental events such as acceleration of growth in height, breast budding and enlargement, appearance of sexual hair and menstrual bleeding occur. The onset of ovarian steroidogenesis is linked to hypothalamic Gonadotrophin Releasing Hormone (GnRH) and pituitary gonadotrophin secretion which in turn stimulate ovarian follicular maturation and subsequent menarche. Normal menstruation, however, does not commence immediately as there is a period of transition of between 1 to 3 years before regular ovulatory and menstrual cyclicity is achieved, although this itself can be very variable17. During this time, the bleeding pattern can be irregular and unpredictable as a result of anovulation. In addition, even if normal cycles do occur, they may not signify ovulation. This period of time may be referred to as one of physiologic anovulation.
As menstrual dysfunction occurs in about two thirds of adolescents with PCOS, and since the inception of irregular menses is frequently traced to menarche, it may be difficult initially to distinguish between PCOS and physiologic anovulation. The spectrum of anovulatory symptoms includes primary or secondary amenorrhea, oligomenorrhea (defined as irregular infrequent menses), dysfunctional uterine bleeding (due to endometrial hyperplasia) and anovulatory regular menses. What is important to know is that this disruption of menstrual bleeding is not uniform in all women with PCOS. It is now also recognized that some affected individuals can have normal ovulatory function, which implies that the presence of regular menses does not preclude the possibility of PCOS.
Because of the similarity of irregular, infrequent, or absent menstrual bleeding between those with normal puberty and those with PCOS, it may not be wise to base the diagnosis of PCOS solely on menstrual irregularity. Nevertheless, certain features of menstruation may suggest the presence of anovulation, if not PCOS. Irregular menstruation not typically preceded by premenstrual symptomatology is highly suggestive of anovulation. An irregular bleeding pattern that persists for more than 2 years after menarche also makes it likely that it is due to hyperandrogenemia. Apart from the aforementioned cycle irregularity, complete history taking for provisional identification of PCOS should also include age of menarche and presence of menstrual cramps and other symptoms of premenstrual stress.
Hyperandrogenism
Hyperandrogenism is one of the most common endocrine abnormalities in women of reproductive age and is most often caused by PCOS. It is characterized by excessive androgen production by the ovary and/or the adrenal glands. The increased circulating androgen levels affect mainly the pilosebaceous unit and the reproductive system, leading to diverse clinical conditions, ranging from acne, hirsutism, male pattern baldness, diffuse alopecia, seborrhoea to frank virilisation18. Hirsutism can be the most distinctive and visible sign of PCOS, especially in combination with acne. Although prolonged exposure to elevated circulating androgen levels may lead to mild virilising signs such as temporal balding and a change in body habitus, extreme expressions of androgen excess such as virilisation and clitoromegaly are not typical findings in this syndrome. Needless to say, these common manifestations of hyperandrogenism are a cause of acute embarrassment to young girls and prime reasons for seeking help.
Hirsutism
Hirsutism is defined as the presence of sexual hair in a male pattern (increase in the number of terminal hairs on the face, back, chest, abdomen and inner thighs) and often graded with the Ferriman and Gallwey scoring system19. Excessive facial hair may be common soon after puberty, gradually increasing and involving the side of the face, chin and neck. Abdominal hair growth can be similar to the male pattern with hair extending from the mons pubis to the umbilicus. Initially thin and lightly pigmented, this excess hair will eventually become abundant, dark and thick. Unabated PCOS may lead to further hair growth over the back, chest and upper arms.
It is important to emphasize that the hair growth is gradual and slowly progressive and any hirsutism of rapid onset and growth (over a few months) should raise the concern of an androgen secreting tumour or intersex state. A concise history should thus include the timing, location, and rate of progression and recent changes in the amount of hair.
The diagnosis of clinical hyperandrogenism by the assessment of excess hair is not without its challenges. The Ferrimen Gallwey system was established by the study of only white women, the majority of which where over 24 years of age. Ethnic variations, time since puberty and varying androgen levels make its use impossible as a sensitive gauge in adolescents. Furthermore, adolescents who experience transient hyperandrogenemia run the risk of being prematurely labelled as PCOS. Biochemical assays can be of only limited assistance due to significant interlaboratory variability.
Nevertheless, persistent and progressively increasing hair growth should be investigated, given the rather common occurrence of PCOS, and any evidence of increased hair growth warrants consideration of the diagnosis in early adolescence. It may also be helpful to enquire on methods employed for hair removal to fully appreciate the degree of hirsutism.
Acne
Chronic inflammatory lesions of the pilosebaceous unit are called acne vulgaris. It is a multifactorial disorder most common in adolescents and young adults with prevalence rates of up to 90% among teenagers20. The lesions of acne include open and closed comedones, papules, pustules, and nodules usually distributed over the face, chest, arms and upper back. A characteristic feature is the varying stages of formation and resolution of the lesions which makes diagnosing this condition quite straightforward.
The reasons for the occurrence of acne remain unclear although a strong link to androgens is plainly demonstrated. The inciting event is believed to be stimulation of the pilosebaceous units by circulating androgens evidenced by the appearance of acne during puberty and its attendant sex hormone surge. The increased androgen levels at this time cause excess sebum production and the shedding of hyperkeratinized epithelium to occlude the hair follicle. Hyperandrogenic states such as the menstrual and premenstrual period and corticosteroid and androgen drug therapy are also associated with acne flare-ups. Even the use of contraceptives such as depo-provera and progestin containing intrauterine devices have been known to exacerbate it21,22.
Having established this link between hyperandrogenism and acne, it has to be pointed out that the majority of women with acne have normal circulating androgen levels without any evidence of an endocrine problem. This means to say that acne as an isolated symptom should not be considered a sign of PCOS; other signs and symptoms of androgen excess or insulin resistance should be present prior to pursuing a workup for an endocrinopathy. However, an underlying hyperandrogenic state has to be excluded in cases of early or late onset of acne, persistent acne and severe acne requiring treatment. Recalcitrant acne despite hormonal manipulation is another reason for further investigation23.
Insulin resistance
Insulin resistance is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. It appears to be the key etiologic feature in the development of PCOS and is noted in the majority of women24. 50% of all women with PCOS have been estimated to have insulin resistance25.
The clinical recognition of insulin resistance in PCOS is based on associated physical features that accompany the disorder. Obesity and acanthosis nigricans are both markers for insulin resistance, such that in the presence of these findings, insulin resistance may be strongly suspected unless proven otherwise. By comparison, identification of insulin resistance by laboratory testing has been inaccurate and difficult as most patients exhibit normal circulating insulin and fasting blood glucose levels. As a result, the clinical determination of insulin resistance relies mainly on its physical manifestations.
Obesity
It is a well-documented fact that more than half of women with PCOS are obese26. This relationship between obesity and androgen secretion also holds true among adolescent PCOS patients. The notion that obesity facilitates androgen excess is borne out by the exhibition of significantly more hyperandrogenemia in overweight peripubertal girls as compared to those with normal weight. Although present in both lean and obese patients, obesity has an additive role on the severity of insulin resistance that is seen in PCOS27. The importance of obesity lies in its association with insulin resistance and hyperinsulinaemia and their contribution to potential long-term health consequences for young individuals with PCOS, with the demonstration of increased likelihoods of dyslipidemia, cardiovascular disease and diabetes mellitus28.
The characteristic pattern of fat distribution in young PCOS women has been termed android obesity. There is increased upper body adiposity with a preponderance of visceral fat that gives rise to a raised waist to hip ratio. In contrast, obese girls without PCOS usually display enhanced accumulation of fat in the hips, buttocks, and thighs, frequently termed truncal obesity, and resulting in a waist to hip ratio of less than one
Although the relationship between android obesity and adolescent girls with PCOS is consistently demonstrated, it is worth highlighting that such a pattern of fat distribution does not in itself confer a diagnosis.
Acanthosis nigricans
Acanthosis nigricans arises from epidermal hyperkeratosis and dermal fibroblast proliferation. It is a velvety rash which can be found on the nape of the neck, the axilla, the area beneath the breasts and other intertrigenous areas, as well as on exposed surfaces such as the elbows and knuckles. It is supposedly more common among obese women with PCOS.
Differential diagnoses and confirmatory tests
The diagnosis of PCOS has become one of exclusion due to the unavailability of reliable hormone assays, especially those for androgens. The goals of laboratory assessment are threefold. First and foremost, androgen excess has to be documented since elevated levels are part of the criteria for making a diagnosis of this disorder. Secondly, other causes of androgen excess and irregular menses such as late onset variant of congenital adrenal hyperplasia (CAH), Cushing’s syndrome, prolactinoma, hyper- and hypothyroidism and premature ovarian failure have to be ruled out. Finally, metabolic abnormalities commonly seen with PCOS such as dyslipidemia and glucose intolerance have to be looked for. Only the most helpful tests for the assessment of PCOS should be ordered and a cost effective evaluation strategy developed.
From among the differential diagnoses of PCOS previously alluded to, it may be pertinent to further elaborate on two of these. CAH and Cushing’s syndrome need particular attention due their similarities in clinical presentation to PCOS. Furthermore, confirmation of these conditions requires detailed laboratory and radiological testing which is usually unnecessary if practicality is to be employed in diagnosing PCOS.
Whilst the cause of disordered adrenal steroidogenesis may be due to several different enzyme defects, the 21-hydroxylase deficiency is of particular interest due to its frequency of occurrence and its ability to simulate the features of PCOS. This non-classical CAH form presents in adolescence and early adulthood with a clinical presentation, complete with polycystic ovarian morphology, that may be indistinguishable from PCOS. Several clinical features of CAH that may suggest the diagnosis include severe hirsutism, clitoromegaly, regular menses, familial tendency, short stature and hyperandrogenemia of adrenal origin.
Excessive cortisol or adrenocorticotropin (ACTH) production results in the features of Cushing’s syndrome, of which obesity, hirsutism, acne, and menstrual irregularity may be mistaken for PCOS. However, the additional presence of moonlike facies, a buffalo hump, abdominal striae and hypertension should indicate a problem of cortisol excess. This should elicit a search for an adrenal or pituitary neoplasm although rare ectopic sources of ACTH such as adenocarcinoma of the lung may also be causal. An important and early differential might be the absence of the typical polycystic features of the ovaries. More elaborate biochemical testing will be able to confirm this rare syndrome.
Blood tests can be obtained at the time of the first clinic visit. Testosterone, free testosterone, and dehydroepiandrosterone sulphate (DHEAS) all determine circulating androgen levels, with DHEAS being of importance in localising hyperandrogenemia of adrenal origin. It has been demonstrated that between 60-90% of PCOS patients have elevated androgen levels12. Although measurement of androgens is important in the evaluation of PCOS, it should be kept in mind that interpretation of results is not all that easy29.
Hyperprolactinaemia can be excluded by drawing blood for serum prolactin and similarly a thyroid stimulating hormone (TSH) level can indicate over or under performance of the thyroid gland. If suspicion of non-classical CAH is entertained due to the presence of virilisation (especially if marked), then a serum 17 hydroxyprogesterone (17-OHP) test in the follicular phase between 7 and 8 AM (to assess 21-Hydroxylase function in the adrenal gland) can be obtained. Elevated serum levels of follicular stimulating hormone (FSH) and luteinising hormone (LH) help determine ovarian failure and may add to clinical suspicion of PCOS if an LH:FSH ratio of more than 2 is found.
On the metabolic side, a lipid panel including cholesterol and high density lipoprotein (HDL-C) can be carried out to assess for dyslipidemia. Fasting glucose and 2 hour glucose level after 75 g oral glucose, in essence, the oral glucose tolerance test (OGTT), is the most reliable screening method for impaired glucose tolerance and diabetes mellitus. About one third of adolescents with PCOS may be thus impaired30. Relying on a fasting glucose level alone is inadequate as it is a poor predictor of impaired glucose tolerance or diabetes31. Based on this evidence, some groups have recommended routine OGTT in adolescents diagnosed with PCOS32.
Imaging
The role of imaging must be elaborated at this point. Both the Rotterdam and AES criteria include the assessment of ovarian morphology for identification of polycystic ovaries. This can be achieved by the use of transvaginal ultrasound (TVS), computed tomography (CT) scan or magnetic resonance imaging (MRI). TVS is a cost effective, sensitive and specific tool and most gynaecologists are trained in its use. It is most useful in the clinic setting but is not widely employed in the adolescent population because of religious and cultural sensitivities. As an alternative, transabdominal ultrasound is limited by its inability to visualize the ovaries in a majority of women.
The ultrasound image of the ovary in PCOS has been described rather specifically as ovarian enlargement with increased central stroma and 10 or more antral follicles ranging from 2 to 10 mm in diameter arranged in a peripheral distribution33,34. A distinction must be made from the multifollicular ovary which is normal sized and contains 6 or more follicles without any specific arrangement or increase in central stroma, and which can arise as a consequence of hormonal manipulation for fertility treatment35. The value of pelvic ultrasound scanning lies not so much in its ability to make a diagnosis of PCOS, but in the rapid and relatively easy exclusion of an ovarian neoplasm.
In the presence of rapidly progressive hirsutism or virilisation with high testosterone levels, the added cost and time of employing a CT scan or MRI may be warranted to rule out an adrenal or pituitary tumour. Utilisation of similar imaging techniques are also relevant in the evaluation of elevated prolactin levels.
Summary recommendation
The early detection and management of PCOS provides the advantage of allowing for the institution of interventional therapies against such consequences of this condition as the metabolic syndrome, fertility and quality of life issues. Although there exist 3 sets of criteria for diagnosis of adult PCOS, all unite in the necessity to exclude other disorders. Bearing this in mind, the Androgen Excess Society criteria of 2006 seem the most suited for the diagnosis of PCOS in adolescence, underscoring the presence of primary hyperandrogenaemia and ovarian dysfunction.
Irregular, infrequent, or absent menstrual bleeding may suggest the presence of anovulation, especially if the irregular menstruation is not typically preceded by premenstrual symptoms. Irregular bleeding that persists for more than 2 years after menarche increases the likelihood of hyperandrogenemia. Hirsutism with a preponderance of terminal hairs over the face, back, chest, abdomen and inner thighs may be the most visible sign of PCOS. Essentially, this occurrence is gradual after puberty and slowly progressive, without signs of overt virilisation and clitoromegaly. In concert with this pattern of hair growth, persistent or severe acne requiring treatment should prompt an evaluation for hyperandrogenism. More than half of women with PCOS present with increased upper body and visceral fat for which the waist to hip ratio is an objective assessment. Presence of acanthosis nigricans may provide the strongest suspicion of insulin resistance and PCOS.
Laboratory screening test should include measurement of serum Testosterone, free testosterone, and DHEAS both to document hyperandrogenemia and exclude an adrenal cause for it. Similarly, serum prolactin and TSH can screen for prolactinoma and thyroid causes respectively. If CAH is suspected, an early morning specimen of blood may be obtained during the follicular phase of the menstrual cycle to check for 17-OHP. At this same sitting, blood for serum LH and FSH levels may be helpful in determining ovarian failure as well as confirming PCOS. Determination of metabolic status via a lipid panel and an OGTT may also be carried out, or deferred to a later time.
A pelvic ultrasound scan, preferably a transvaginal one, may conveniently aid in the determination of typical polycystic ovarian morphology as well as ruling out pelvic tumours. If warranted, CT scanning or MRI can be ordered to exclude neoplasms in the pelvis, abdomen, brain and elsewhere.
Although adolescents with PCOS may appear normal without any signs of hyperandrogenism or hyperinsulinism, this diagnosis should be considered in any adolescent girl who presents with irregular menstrual bleeding, hirsutism, persistent acne or obesity, especially if these features occur in concert.
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