Acne - a potential skin marker of internal disease

    Is Acne a Systemic Disease: The Polycystic Ovary Syndrome Joseph L. Pace MD, FRCPEdin, FRCPLond PII: DOI: Reference:

S0738-081X(15)00125-X doi: 10.1016/j.clindermatol.2015.05.010 CID 6959

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Clinics in Dermatology

Please cite this article as: Pace Joseph L., Is Acne a Systemic Disease: The Polycystic Ovary Syndrome, Clinics in Dermatology (2015), doi: 10.1016/j.clindermatol.2015.05.010

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Is Acne a Systemic Disease: The Polycystic Ovary Syndrome

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Authors and affiliations: Joseph L. Pace, MD, FRCPEdin, FRCPLond,

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Address correspondence to:

Naxxar 2069, Malta

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Email address [email protected]; Fax +356 25401123

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16 Marquis Scicluna St

Private Practice at Clinica San Giuseppe, Naxxar. Malta Running Title: PCOS

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Key Words: PCOS, hyperandrogenism, acanthosis nigricans, androgenic alopecia

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Conflict of interests: none

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Funding sources: none

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Acknowledgements: none

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2 Abstract:

In recent years major changes have occurred with regards to PCOS:

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The polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in adult females. Hyperandrogenism is the crux of the pathogenesis of both acne and hirsutism, the most frequent clinical presentations of the syndrome. The chronic anovulation that may occur, often but not always associated with enlarged cystic ovaries, has long been recognized as an important feature of PCOS.

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(1) Sophisticated radiologic technology together with increased awareness and clinical suspicion have led to a massive increase in patients diagnosed with PCOS, and Guidelines for diagnosis have been agreed upon with any two of clinical or biochemical evidence of hyperandrogenism, chronic anovulation, and cystic changes in the ovaries essential for a diagnosis; (2) Insulin resistance has been found to be a major component of PCOS; interaction can occur whereby hyperinsulinemia can promote hyperandrogenism and possibly also vice-versa. Insulin resistance is also thought to have a major role in the pathogenesis of the metabolic syndrome, an ever increasing worldwide cause of morbidity and mortality from ischemic heart disease and type 2 diabetes mellitus. (3) Patients with PCOS appear to have a fourfold increased risk of developing the metabolic syndrome although this is not equal in all PCOS patients.;

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While management of the common cutaneous manifestations mainly acne, hirsutism, alopecia, and acanthosis nigricans remain strictly within the realm of daily dermatologic practice, the pendulum is shifting towards greater

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awareness of the longer term systemic implications of PCOS, with emphasis on the unique opportunity and privileged position of the dermatologist to diagnose this potentially serious problem at an early stage, when effective

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long term treatment can be instituted. Patients need to be advised that PCOS cannot be cured but can be controlled. Management should involve a multi-disciplinary team with emphasis on life-style change, insulin sensitizing agents,

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androgen blockers, and attention to specific cutaneous manifestations.

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Introduction In 1935, two American gynecologists, Irving F. Stein, Sr.(1887-1976) and Michael L. Leventhal (19011971) At at Michael Reese Hospital in Chicago (1) defined a syndrome consisting of obesity, amenorrhoea, hirsutism and infertility associated with enlarged polycystic ovaries. The polycystic ovary syndrome (PCOS)

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has evolved from a gynecological curiosity to a multisystem endocrinopathy of apparently quasi epidemic

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proportions, with WHO estimating 116 million cases in 2010. Dermatologists manage the cutaneous manifestations of PCOS and, therefore, play a key role in its diagnosis and management.

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Long before 1935, Hippocrates (460 – c. 370 BCE) had noted ‘‘But those women whose menstruation is less than three days or is meagre, are robust, with a healthy complexion and a masculine appearance; yet they are not concerned about bearing children nor do they become pregnant’’

(2 ) and even earlier , Soranus of Ephesus (first century CE) remarked that

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‘‘sometimes it is also natural not to menstruate at all . . . It is natural too in persons whose bodies are of a masculine type . . . we observe that the majority of those not menstruating are rather robust, like mannish and sterile women’’

(3). Antonio

Vallisneri (1661-1730) in 1721 described: “Young Italian peasant women moderately obese and infertile with two larger than normal shiny ovaries with surface like pigeons eggs”,

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related changes to the ovaries (4).

and in 1844 Achille Chereau (1817-1885) noted Cyst-

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The prevalence of PCOS had been remarkably uniform in all ethnic races studied (5) raising the possibility that gene variants that are eventually found to be associated with PCOS will be similar across ethnic groups.

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The striking evolutionary paradox of this genetically-based condition, which impairs fertility, is that not only should it have diminished in prevalence, but it should have done so rapidly - unless there has been some

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form of balancing selection such as greater sturdiness and improved energy utilization, a rearing advantage for their children and kin, and a reduction in the risk of perinatal mortality. The emerging discipline of evolutionary medicine can provide important insights into the causes and patterns of occurrence of common diseases such as PCOS. (6)

PCOS is a common endocrine disorder among women of reproductive age (5-18%) with chronic anovulation and factors related to androgen excess. The hallmark features of hyperandrogenism and hyperinsulinemia have systemic long-term implications. The clinical definition of PCOS has changed in recent years and includes as one of its core criteria the dermatologic manifestations of hyperandrogenism, chiefly hirsutism, acne vulgaris, and androgenetic alopecia. Acanthosis nigricans, a cutaneous sign of hyperinsulinemia, may also be present. These dermatologic features may provide early clinical clues to recognition of PCOS (7). In 1990, “hyperadrenalism” was reported to occur in 10% of patients with late-onset acne (8) , but it is likely that the vast majority of women with severe acne have PCOS. This is partly due to a real increase in PCOS and partly due to a broadening of the criteria for its diagnosis. In particular, modern imaging techniques

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have revealed the presence of polycystic ovaries in normal women and mildly polycystic ovaries in hirsute women with normal menses. Many women, labelled as having idiopathic hirsutism, have polycystic ovary syndrome (9,10,11).The increase in PCOS has been linked to childhood obesity, (American Association of Clinical Endocrinologists Position Statement on Childhood Obesity Linked to Early Development and

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PCOS in Young Girls - September 13, 2005) eating disorders, and increasingly stressful life styles.

The dermatologic manifestations of hyperandrogenism include hirsutism, persistent acne, male pattern

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alopecia, and occasionally acanthosis nigricans. Clinical findings vary within a patient population as a result of the complex relationships between genetics, end-organ susceptibility, and hormonal variations. Acne may frequently be the presenting problem and has occurred in over 90% of PCOS patients diagnosed

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at an endocrinology clinic (fig.1). In this series, obesity occurred in less than 50% of patients, while hirsutism and alopecia were found in 70% and 10%, respectively. In a recent report, (12) acne was the most commonly observed dermatologic manifestation (95.0%), followed by hirsutism (60.0%), seborrhea (47.5%), acanthosis nigricans (20.0%) ,and androgenetic alopecia (12.5%). Earlier studies had reported a

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prevalence range, 9.8–50 %,( 14. 15)

PCOS is prevalent in women with late-onset acne, persistent acne, and acne resistant to conventional therapies (16), but only a minority of women, presenting with acne, are known to have prior PCOS: approximately 80% of women with severe acne, 50% with moderate acne, and 30% with mild acne have some elevation of plasma androgen (17).

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In a recent study, the prevalence of acne, hirsutism, seborrhea, androgenetic alopecia, and acanthosis nigricans was 53%, 73.9%, 34.8%, 34.8%, and 5.2%, respectively. Acne was not associated with the hormonal, metabolic, and anthropometric variables. Hirsutism had positive associations with total

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to be related with free testosterone, fasting glucose, and insulin (18).

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testosterone, fasting glucose, and total cholesterol and a negative association with age. Seborrhea was found

Numerous factors contribute to the development of acne, foremost being the requirement for androgens and androgenic stimulation of the sebaceous glands. A number of women with acne may have at least one

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abnormal hormone level. Both circulating serum androgens and locally produced androgens play a role . Some studies have reported a positive correlation between acne severity and circulating serum androgen

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levels. Women with acne have been reported occasionally to have elevated serum levels of total testosterone, free testosterone, dehydroepiandrosterone (DHEAS), 3α-androstanediol glucuronide, and androstenedione, as well as low levels of sex hormone binding globulin (SHBG). Acanthosis nigricans (AN) is a cutaneous marker of insulin resistance presenting with velvety, thickened, hyperpigmented patches occurring on the nape, axilla, groin, and antecubital fossa. The proliferation of

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keratinocytes is caused by hyperinsulinemia and increased binding of excessive serum insulin to IGF-1 receptors in the peripheral tissues. AN is present in 50% of obese women with PCOS and 5% to 10% of

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non-obese women with PCOS and was observed in 8 (20%) of the 40 PCOS subjects, and was more frequent than androgenetic alopecia. Obesity is also independently associated with AN; therefore,

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dermatologists need to carefully evaluate this skin manifestation, especially in obese PCOS patients (19).

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Less severe degrees of AN may be found in many more patients when carefully looked for.

Androgenic alopecia

In a recent study, the proportion of PCOS patients with androgenetic alopecia, 12.5%, was slightly higher than that reported from Western populations. Consistent with previous findings, androgenetic alopecia is a poor indicator of biochemical hyperandrogenemia (19, 20).

ETIOLOGY OF PCOS Hyperandrogenemia and Hyperinsulinism The most common causes of clinical hyperandrogenism are polycystic ovary syndrome (PCOS) and “idiopathic” hyperandrogenism –around 72% and 23% respectively; non-classic adrenal hyperplasia - 4.3% and androgen secreting tumours - 0.2% are found in a very small minority of cases.

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The enzyme 5α-reductase converts testosterone to the more potent androgen dihydrotestosterone within the sebaceous glands. It is likely that genetic factors may determine abnormal follicular keratinization or sebaceous gland androgen response in individuals with persistent acne. Individuals who have acne tend to have a higher rate of sebum excretion than those who do not have acne. n Besides androgens, increased

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insulin-like growth factor 1 (IGF-1) levels may influence acne in adult men and women. . While IGF-1

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appears to have a stronger effect on acne in women, androgens may play a greater role in acne for men; however, in both men and women these hormones are interrelated, possibly owing to reciprocal effects on

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hormone production. Associated Insulin resistance

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Hyperinsulinemia plays a central role in the pathogenesis of PCOS, and many women with PCOS are metabolically insulin resistant, in part due to genetic predisposition and in part secondary to obesity. It has been proposed that hyperandrogenemia may contribute to insulin resistance in PCOS and that hyperinsulinemia can promote hyperandrogenism. PCOS is the most common disorder in which the

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association between insulin resistance and ovarian function appears to be important. The metabolic syndrome, a group of interrelated risk factors for cardiovascular disease and type 2 diabetes

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mellitus, has become a serious public health concern. Insulin resistance plays a crucial role as the lynchpin of the various components of this syndrome and may be the thread that links it to the PCOS (21). An

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approximate 4-fold increase in the prevalence of the metabolic syndrome is found in women with PCOS, compared with the general population, consistent with the proposed major role of insulin and obesity in the

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syndrome, implying a greater risk of cardio metabolic disease in women with PCOS. This estimate will vary according to PCOS definition, ethnicity (in Malta for example, 10% of the population have late onset diabetes mellitus compared to 2-3% in the rest of Europe) (22) , and different etiological pathways to PCOS (23).

Links between hyperinsulinemia and increased androgen production include direct stimulation of ovarian androgen secretion by insulin, direct stimulation of LH secretion by insulin or sensitization of LH-secreting pituitary cells to GnRH stimulation, decreased levels of SHBG, with concomitant elevation of free androgens, and the synergistic growth- and cyst-promoting action of insulin and LH. MANAGEMENT Diagnosis Family doctors and dermatologists are the first line clinician, provided they consider a possible PCOS diagnosis. Early diagnosis and treatment may prevent the long term metabolic sequelae and reduce the emotional distress that can significantly affect patients' quality of life.(24)

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Evaluation of women with possible PCOS (i.e. presenting with any of possible cutaneous signs especially acne) requires a complete history, physical examination for evidence of androgen excess, and appropriate laboratory investigations to exclude other causes of hyperandrogenism. Although the Endocrine Society Guidelines recommend that patients with mild hirsutism need not be investigated further, nearly 50% of

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such patients may have PCOS with all its short and long term implications.

Thyroid disorders, especially Hashimoto's thyroiditis (HT) and PCOS, are closely associated, but the mechanisms of this association are not as clear, and a common genetic background has not yet been

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established. HT and PCOS are associated not only with respect to their prevalence, but also with regard to aetiology and clinical consequences (25).One study foundi ncreased positive anti-TG antibodies, with 25.2%

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of the acne group and 8.3% of the control group having elevated (>40U/mL) anti-TG levels, respectively(26). It is likely that thyroid autoimmunity is more frequent in adult acne patients and this should be included in evaluation of these patients..

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There is consensus that for a diagnosis of PCOS any 2 of the following 3 criteria should be present: Where is number 3

Clinical or biochemical evidence of hyperandrogenism Measurement of total testosterone, even using

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1.

modern immunoassays, has a low sensitivity for diagnosing some conditions such as the PCOS. This is because high concentrations of sex hormone binding globulin (SHBG) eg with the use of oral contraceptive pills, or low concentrations

2.

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of SHBG eg in insulin resistance or obesity, can affect total testosterone values

Chronic anovulation, A clinical diagnosis of oligomenorrhoea / amenorrhoea - menstrual cycles longer than 35

3.

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days or fewer than 10 periods a year

Imaging of polycystic ovaries, using specific ultrasonographic criteria,excludes other diagnoses. It has been suggested that images throughout the entire ovary should be collected for the ultrasonographic evaluation of PCOS, because follicle number appears to be more informative than ovarian volume.

NB Valproate therapy for epilepsy is associated with weight gain in approximately 50% of women patients. Hyperinsulinemia and low serum levels of insulin-like growth factor-binding protein 1, may lead to hyperandrogenism and polycystic ovaries (27). Hormonal intra-uterine contraceptives which contain levonorgestrel may also trigger /aggravate acne.

Investigations (1) Free testosterone level (In PCOS: high normal or slightly elevated serum free and total testosterone levels may be present ) (2) 17-α hydroxyprogesterone (re congenital adrenal hyperplasia) (3) Dehydroepiandrosterone sulfate (adrenal androgens ) (4) Prolactin / LH / FSH levels

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(5) Fasting blood glucose , OGTT , HbA1C level(46), and serum lipid profile (?including HDL-C*) (6) Insulin levels (valuable but not a routine test) (7) Ultrasound of the pelvis

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(8) Thyroid function and antibodies

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*PCOS patients with marked hirsutism may have higher testosterone and DHEA levels with lower serum cholesterol and HDL levels ; The relatively lower level of HDL-C might individually act as a marker of dyslipidaemia in the severe form of PCOS (28)

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TREATMENT

Although not curable, this condition is treatable with medication, diet, exercise with early detection, and

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careful management reducing many serious long term PCOS-related complications. While treating individual signs, such as hirsutism, acne, or fertility, remains important,“core management” has shifted towards correcting insulin resistance, which in turn improves many other symptoms of the condition. The management of PCOS should be tailored to each woman's specific goals, reproductive interests, and specific related problems, and is ideally undertaken by a multi-disciplinary team.

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The different factors that must be addressed are often inter-related and include:

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A. Life style and psychological issues: Anger / cosmetics / diet / exercise Obesity is probably not a cause of PCOS, as the high prevalence of PCOS among relatively thin populations

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demonstrates, but this may be an aggravating factor. It may increase cardiovascular risk factors, such as glucose intolerance and dyslipidemia. (29)Weight loss in obese PCOS patients leads to decreased insulin

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resistance and a fall in testosterone levels. Other possible benefits include reduced hirsutism and regularisation of menstrual cycles. Psychologic co- morbidity in hyperandrogenic states is often a very disturbing feature. Stress (and anger)can be major factors both in provoking acne as well as making successful outcomes more difficult. Lifestyle modification counselling is recommended. (9). IVOTE(30)is a recognised psychotherapy method of dealing with these factors and can be utilised at an early stage. B. Hyper-androgenism Hirsutism has a relatively high prevalence among women. Depending upon societal and ethnic norms, it can cause significant psychosocial distress. Treatment of hirsutism often requires a multidisciplinary approach, and a variety of physical or pharmacologic modalities can be employed. Efficacy of these therapies is varied and depends, among other things, upon patient factors including the underlying aetiology, hormonal drive, and local tissue sensitivity to androgens. (31) The primary goal of pharmacologic therapy for cutaneous disorders of hyperandrogenism is reduction of androgen production and action. Hormonal treatments can be effective for women with acne whether or not

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their serum androgen levels are abnormal(14). Anti-androgens, or androgen receptor blockers, are defined as agents that inhibit directly the binding of dihydrotestosterone (DHT) to its receptor in a competitive way. They include cyproterone acetate, drospirenone, spironolactone, and flutamide . Low-dose glucocorticoids, or gonadotrophin-releasing hormone (GnRH) agonists have also been used to inhibit pituitary release of LH

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and thus reduce the secretion of ovarian hormones. Oral contraceptives

Oral contraceptive pills (OCPs) remain first-line treatments. Antiandrogenic and low-dose neutral OCPs

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may be slightly more efficacious in improving hirsutism compared with other types of OCPs. While insulin sensitizers improve important metabolic and endocrine aberrations in polycystic ovary syndrome, they are

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not recommended when hirsutism is the sole indication for use. Combined oral contraceptives with cyproterone acetate or drospirenone exert their action either by suppressing the secretion of pituitary gonadotrophins, thereby inhibiting ovarian androgen production, or by increasing liver synthesis of sex hormone-binding globulin (SHBG).

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Cardiovascular risk is not the same in all PCOS women, and individual cardiovascular risk should be assessed before staring any estroprogestin treatment. The available data show that products containing both 2nd-generation and 3rd-generation progestins (including drospirenone and cyproterone acetate)

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represent a safe treatment in PCOS patients with regular cardiovascular risk while in PCOS patients with increased cardiovascular risk, a careful choice of OCP (if necessary) is needed and cardiovascular risk

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should be monitored during treatment. (32)

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Spironolactone, a powerful antiandrogen, can reduce acne and also body hair growth over time. It is less effective for alopecia. It cannot be used by women who are trying to conceive, as it can cause birth defects. This drug has both anti-androgenic and anti-mineralocorticoid properties. Many women with sporadic outbreaks of inflammatory lesions or isolated cysts respond well to 25 mg twice daily or even less. The drug is best avoided in women who have a family history of breast cancer . Evidence supports the use of electrolysis for permanent hair removal in localized areas and lasers (particularly alexandrite and diode lasers) for permanent hair reduction. Topical eflornithine can be used as monotherapy for mild hirsutism and as an adjunct therapy with lasers or pharmacotherapy in more severe cases.

C. Insulin resistance Metformin (and gliatazone antidiabetic medications) decrease insulin resistance and the amount of insulin in the blood (33), and together with diet and exercise changes may prevent diabetes in people who are at high risk for becoming diabetic. It is also used in women with polycystic ovary syndrome.

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Metformin reduces serum glucose level by several different mechanisms, notably through non-pancreatic mechanisms without increasing insulin secretion. It increases the effects of insulin; hence, it is termed “insulin sensitizer”(34). Metformin also suppresses the endogenous glucose production by the liver. Insulin-sensitizing drugs have been shown to decrease free serum testosterone levels by reducing ovarian

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androgen synthesis and increasing sex hormone–binding globulin levels (35, 36,37). Recent studies, especially in women with PCOS, support the efficacy and safety of metformin for the treatment of acne. Within the pathophysiologic cascade of PCOS, Flu-Met (Flutamide-Metformin

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combination) seems to counter upstream anomalies like hyperinsulinemia or hyperandrogenism, thereby preventing or reversing downstream effects. In contrast, an OC essentially masks downstream signs like

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hirsutism, acne, or irregular menses, whereas the upstream aberrations remain unaltered or may even be worsened.

Women with PCOS, treated with combination therapy involving oral contraceptive pills, antiandrogen, and insulin-sensitizing agents, also have improvements in multiple metabolic abnormalities in addition to improvements in hirsutism and circulating serum androgen levels.PCOS patients treated with metformin

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alone showed improvement in acne, hirsutism-score, re started normal menstrual cycles, fulfilled their wish to conceive when previously unsuccessful, and attained a decrease of insulin, glucose, and androgen levels.

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These improvements occurred in both obese and lean individuals (38).Recent evidence suggests that in PCOS, metformin has effects on other targets besides its insulin sensitizing action (39), and that certain

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parameters such as acne, menstrual pattern, and ultrasound ovarian features may be improved irrespective of pre-treatment insulin resistance or obesity (40,41). This may partially explain the apparent beneficial effect

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of metformin in women with acne p without overt PCOS. The beneficial effect of metformin in decreasing hyperinsulinemia and its associated conditions, such as acanthosis nigricans, is probably at least partly mediated by its effect in reversing GLUT4 endocytosis and increase GLUT4 mRNA expression in adipose tissue, which also leads to significant decrease in serum total testosterone levels. Another explanation is that metformin may have different efficacy in different populations (40,41). Acanthosis nigricans may diminish with long term treatment with metformin combined with topical retinoids.

Side effects of metformin (42)–Recent reports indicate that adverse effects are negligible when the drug’s benefits are brought into account. Nausea and other upper gastrointestinal tract symptoms are common, but severe hypoglycaemia is almost unknown. Lactic acidosis occurs rarely but is the most serious potential adverse effect. Although statins improve lipid profiles and reduce testosterone levels in women with PCOS, there is no evidence that statins improve resumption of menstrual regularity or spontaneous ovulation, nor is there any improvement of hirsutism or acne.(43).

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D. Cardio vascular risk A crucial step is for patients to lose weight if overweight, to exercise, and to stop smoking (an additional risk factor for thrombosis if the oral contraceptive is required , and also a risk factor for long term

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cardiovascular complications) if a smoker.

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Compared with age- and body mass index-matched women without the syndrome, women with PCOS appear to have a higher risk of insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, and an increased prothrombotic state, possibly resulting in a higher rate of type 2 diabetes mellitus, fatty liver

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disease, subclinical atherosclerosis, vascular dysfunction, and finally cardiovascular disease and mortality(44). A retrospective cohort study (total follow-up >12 000 person-years) indicated a high

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incidence and age-group-specific prevalence of Type 2 diabetes and ischaemic heart disease in women with PCOS, with over a quarter having had MI or angina in those >65 years (45). Current data support a strong recommendation that women with PCOS should undergo comprehensive evaluation for diabetes and recognized cardiovascular risk factors and receive appropriate treatment as needed. Regular screening for risk factors and timely early interventions are critical to reduce the overall

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risk burden. An HbA1C ≥5.7% identified the subgroup of PCOS patients with higher insulin resistance, inadequate compensatory insulin response, impaired glucose disposition, and increased cardiovascular risk

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factors. A1C represents an inexpensive and informative biomarker to identify PCOS patients at risk for

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metabolic abnormalities (46). HDL-C tests have also been proposed as markers of increased risk (28).

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With regards to PCOS in teenagers (the adults of tomorrow), the hormonal abnormalities inherent in PCOS often begin in adolescence and include hyperinsulinemia and rapid luteinizing hormone (LH) pulse frequency, both of which mediate ovarian and adrenal overproduction of androgens. Early metformin therapy (age 8–12 years) in girls with a combined history of low birth weight and precocious pubarche was shown to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea and PCOS more effectively than late metformin . Recognizing and reducing androgen levels in adolescence is critical given their association with the metabolic syndrome, diabetes, and infertility in adulthood (47).

In addition, Isotretinoin is used for severe acne, or where there has been no response to first line treatment. It cannot be used by women who are pregnant or trying to conceive, as it can cause birth defects. Isotretinoin is the only medication that targets all pathophysiologic factors in acne and is frequently the only effective treatment in adult acne and PCOS. Its side effects are well known and preventive measures strictly adhered to.

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Relapses (48, 49)are not infrequent after isotretinoin and women with PCOS may experience only partial remission with isotretinoin therapy. It must be remembered that both ovarian and adrenal androgens may be raised persistently or intermittently at least until the menopause. This has clear implications for both initial and follow up management. PCOS may result in recurrence of acne even after initial successful clearance

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with isotretinoin and long term maintenance therapy with metformin or OCP and topical retinoids is

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recommended. Generally only a small dose of isotretinoin is needed to control flare ups e.g. 20 mg twice weekly or 0.5 -1 mg/kg/day for one week out of every four weeks for a minimum of six monthly cycles. A

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small number of patients with particularly troublesome acne and PCOS may require long term treatment with low dose isotretinoin.

Hair removal measures such as shaving, electrolysis, and chemical and waxing creams can be used to treat

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hirsutism.

Conclusions

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PCOS is treatable but not curable, with medication, diet, and exercise. Early detection and careful management can prevent serious PCOS-related co-morbidity from occurring later in life and long term

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treatment may be indicated even in adolescent patients. Dermatologists routinely treat the cutaneous manifestations of PCOS effectively. Even most importantly,

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they should remember their occupying a unique position to act in recognizing the syndrome early on, enabling appropriate treatment that may prevent serious life threatening non- dermatologic complications

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that may occur later in a number of these patients.

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42 Nisbet Janelle C, Sturtevant Joanna M and Prins Johannes B Metformin and serious adverse effects Med J Australia 2004; 180 53-54

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Figure Legends: Fig. 1: Presenting symptoms of PCOS patients in an endocrinology clinic (from Petranyi G,

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Zaoura-Petranyi M ;Endocrine Abstracts 26:p.93, 2011)

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Fig. 2: Acanthosis nigricans- obvious and not so obvious

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Figure 2