PCOS – An underrated condition with myriad problems

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder of reproductive women (15-45 years). Early mention of PCOS as a disorder can be traced back to ancient history by Hippocrates (460 BC-377 BC). In his groundbreaking work “Diseases of Women’’, he 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”.[1] In 1935, Stein and Leventhal first published their observations regarding symptoms and ovarian appearance of this condition.[2] It is manifested by oligo or anovulation, hyperandrogenism, and polycystic ovarian morphology. It has got impact across the lifespan of the woman from adolescence to post menopause. The prevalence of PCOS is between 10 to 13% globally.[3] Prevalence of PCOS in India as per recent ICMR study varies from 7.2% (NIH 1990 criteria) to 19.6% (Rotterdam 2003 criteria). As per the study by Ganie MA et al., 43.2% of the PCOS subjects had obesity, 91.9% had dyslipidaemia, 32.9% had non-alcoholic fatty liver disease, 24.9% had metabolic syndrome, 3.4% had diabetes, and 8.3% had hypertension.[4] The aetiology of PCOS is complex and clinical phenotype is heterogeneous with reproductive, metabolic, and psychological features. DIAGNOSIS The basic pathophysiology is insulin resistance and dysregulation of gonadotrophin secretion. There is excess androgen production predominantly from ovary namely testosterone which causes hirsutism and acne and alopecia. Menstrual irregularity can be oligomenorrhoea, polymenorrhea, amenorrhoea. Polycystic ovary with follicular count more than ten or volume more than 10 cc is diagnostic feature of PCOM. Though PCO morphology can be seen in many other conditions like hypothyroidism, NCCAH, cushing’s syndrome, acromegaly, hyperprolactinemia. In primary hypothyroidism, polycystic morphology is not seen. Ovaries are multicystic with larger follicles under the effect of high level of FSH and pathophysiology is different from PCOS [Tables 1 and 2].Table 1: Diagnostic criteria of PCOS[ 5 ]Table 2: PCOS phenotype classification[ 6 ]Exclusion of other androgen excess disorders is mandatory before a diagnosis of PCOS. These are hypothyroidism, hyperprolactinemia, NCCAH, Cushing’s, androgen secreting adrenal and adnexal tumors, drugs. As cycles are generally irregular in the first year after menarche, diagnosis of PCOS during initial years after menarche is challenging. Irregular cycles are defined as oligomenorrhoea (> 35 days or < 8 cycles per year), polymenorrhoea (<21 days) in adults and more than 90 days for any one cycle in 1 year post menarche girls. Clinical hyperandrogenism in the form of hirsutism is defined as modified FG score ≥ 4-8 based on the ethnicity. Polycystic ovaries are defined as follicle number per ovary (FNPO) ≥ 20 in at least 1 ovary or follicle number per section (FNPS) ≥ 10 with diameter of 2-8 mm in at least 1 ovary in adults. Ovarian volume (OV) ≥ 10 mL is considered threshold for PCOM. Transvaginal ultrasound with transducer frequency of ≥ 8MHz is recommended where possible.[7] Biochemical hyperandrogenism is assessed by measuring serum total and free testosterone, androstenedione, and DHEAS. Free testosterone can be estimated by the calculated free androgen index (PCOS: >2.9%). Measurement of testosterone in female by immunoassay is less accurate and lacks precision; ideally it should be measured by LC/MS.[7]. The upper limit of serum testosterone in women is in the 45 to 60 ng/dL range (1.6 to 2.1 nmol/L); a serum testosterone >150 ng/dL require evaluation for ovarian and adrenal androgen-secreting tumors.[8] PATHOPHYSIOLOGY The hypothalamic-pituitary-ovarian axis plays a crucial role in regulating the reproductive cycle by ensuring the pulsatile secretion of gonadotropins necessary for ovarian function.[9] FSH facilitates follicle development and maturation, hence augments oestradiol synthesis. As the follicles reach a critical size, LH is triggered by positive feedback mechanism by a certain concentration of oestradiol resulting in LH surge and ovulation.[10] In PCOS, increased sensitivity of the pituitary gland to GnRH, results in excessive LH secretion. Elevated LH stimulates the ovarian stroma and theca cells producing excess androgens thus disrupting dominant follicle formation. Insulin resistance plays vital role in causation of PCOS in diverse ways. Hyperinsulinemia resulting from insulin resistance increases LH binding sites and increases ovarian sensitivity to LH, thereby promoting intraovarian testosterone synthesis. Elevated insulin levels not only activate IGF-1 receptors in ovarian stromal cells but also directly bind to insulin receptors on theca cells. Additionally, insulin exerts an inhibitory effect on the expression and activity of aromatase resulting in elevated testosterone level. Hyperinsulinemia also reduces SHBG and therefore increases free testosterone. PHENOTYPE PCOS has been subclassified into 4 types. Phenotype A (HA/OD/PCOM), Phenotype B (HA/OD), Phenotype C (HA/PCOM) and D (OD/PCOM). Phenotype D however does not fall under PCOS according to AEPCOS criteria. This approach is convenient for clinical practice and epidemiological research purpose. It is important to know that all features may not be present in a particular case of PCOS and PCOS with normal cycles is possible.[11] COMPLICATIONS Apart from infertility, untreated PCOS subjects have many long-term health complications. They are prone to type 2 diabetes, hypertension, cardiovascular disease, fatty liver spectrum, obstructive sleep apnoea, depression, anxiety, and endometrial cancer. TREATMENT Lifestyle measures including dietary modification and aerobic exercise remain the first line therapy in PCOS. Combined oral contraceptive pills (COCP) is the first line pharmacotherapy for management of hirsutism and/or irregular menstrual cycles in PCOS who do not want conception at that time. Metformin can be used alone or in combination with COCP. Metformin is more beneficial when BMI ≥ 25 kg/m2. However, Metformin plays an important role also in the maintenance of ovarian cycles of lean PCOS as well.[12] Antiandrogens like spironolactone can be used if there is suboptimal response to COCP. Letrozole is the first line pharmacological therapy for ovarian stimulation in infertility. Clomiphene in combination with metformin and gonadotrophins are used as second line therapy for infertility.[13,14] FUTURE PERSPECTIVES In recent years, with the fast development in molecular genetics, high-throughput sequencing, transcriptomics, and proteomics, researchers have made great progress in genetics, epigenetics, metabolomics in PCOS pathogenesis. PCOS is a complex trait with more than 20 identified common susceptibility variants from genome-wide association studies and rare variants in DENND1A, AMH, and AMHR2 discovered by next-generation sequencing.[15] Studies showed that methylation in DNA is altered in women with PCOS; which indicates that women with PCOS have epigenetic regulation, which might be triggered by an adverse intrauterine environment or by postnatal environmental factors like dietary factors.[16] CONCLUSION PCOS is an extremely heterogenous and complex disorder. Prevalence of PCOS is increasing over the years along with its complications. This put increasing burden on the healthcare. We need to aware women regarding this condition and screen them and treat them early. These people need to be monitored lifelong for development of metabolic and other complications as well as cancer. Ongoing genetic analyses promise to unravel the distinct etiologies of PCOS, enabling the development of precision therapies to reverse and prevent the development of this syndrome. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.