The universally recognized definition of PCOS was set during a consensus meeting of the American Society of Reproductive Medicine (ASRM) and European Society of Human Reproduction and Embryology (ESHRE) in May 2003 in Rotterdam. Which was of late endorsed by international evidence-based guidelines for the assessment and management of polycystic ovary syndrome (2018), published by the Centre for Research Excellence in Polycystic Ovary Syndrome(CREPCOS) in collaboration with the ASRM and ESHRE and, in alliance with professional societies and consumer advocacy groups internationally.
To diagnose the PCOS two out of three of the below criteria should be met:
Clinical and/or biochemical evidence of androgen excess after the exclusion of other related disorders, Oligo-ovulation or anovulation, Ultrasound appearance of the ovaries. The 2003 criteria made imperative for the presence of >12 follicles in each ovary measuring 2-9 mm and/or elevated ovarian volume (>10 ml); in 2018 the cut-off for follicle number was increased to 20 or more in either ovary, to contemplate the improvement in ultrasound technology (transvaginal scanning with a frequency band- width including 8MHz).
PCOS clinical observations
(A)Anovulation is suspected from the history of oligomenorrhoea and/or amenorrhea. PCOS is the major cause of secondary amenorrrhoea and as well as usual cause of primary amenorrhoea.
(B). The patient’s body mass index (BMI) and general appearance may give indications regarding systemic and endocrine problems including PCOS. About 40- 50% of women with PCOS are overweight. Increase in abdominal obesity and waist-to- hip circumference are frequently noticed.
(C)Signs of hyperandrogenism (e.g. male- pattern balding, acne, hirsutism) are also evocative of PCOS.
(D) Acanthosis nigricans sign of extreme insulin resistance and is usually related with PCOS and obesity.
Pathophysiology
The pathophysiology of PCOS is due to excess ovarian androgen production with insulin resistance. Hyperinsulinemia augments LH-stimulated androgen production. The Anti-Mullerian Hormone (AMH) which is elevated in PCOS plays a restrictive role in follicular development, follicular arrest and anovulation.
Laboratory findings
(A)Increased serum total testosterone concentration observed in one third of PCOSwomen. If the value is more than 5 nmol/L, it is then mandatory to exclude other causes. Free androgen index and free testosterone are believed to be more sensitive methods of testing hyper- androgenaemia. In Overweight women presented with clinical hyperandrogenism we may see a total testosterone normal levels but increased free testosterone levels as only little is bound to sex hormone binding globulin (SHBG) and which is suppressed by hyperinsulinaemia.
(B)A rise in LH pulse frequency or elevated LH are frequent observation in PCOS.FSH is not elevated, and high serum LH levels linked with menstrual cycle disturbance, anovulation and reduced chance of conception.
(C)Rise in AMH is observed in PCOS. Serum AMH measurement suggests the follicle poolsize, together with pre-antral and small antral follicles(<2mm), which are difficult to observe by ultrasound. However, serum AMH is not a independent diagnostic tool currently recommended.
(D)Other biochemical investigations include: Thyroid disorders, especially hyperthyroidism, gently elevated serum prolactin is seen in 10-15% of PCOSwomen. Women with the mostusual form of CAH (21-hydroxylase deficiency) seen withincreased serum 17-hydroxyprogesterone concentration.The usual causes of secondary amenorrhoea and concerned anovulation are listed in Box 1.
Ultrasound findings
(A)The polycystic ovary is distinguish by at least one of the following: follicles measuring 2-9 mm in diameter 20 or more or rise in ovarian volume (>10 ml). Often, there is elevated central stroma with peripherally arranged follicles.
(B)Ultrasound scanning (USS) is also an essential diagnostic tool to see for other pathologies in the pelvis.
(C)Diagnosis can be done without USS in women with features ofovulatory dysfunctionand hyperandrogenism especially in adolescents.
Management
Management of PCOS-related infertility is outlined in Figure 1.
Weight loss
(A)Not less than 50% of women diagnosed with PCOS are obese (BMI >30 kg/m2). These are at greater risk of developing type II diabetes or impaired glucose metabolism and should be motivated to lose weight. Studies show that even 5% weight loss results in enhance in reproductive outcome in PCOS.
(B)Lifestyle modification is first-line therapy in weight management, accompaniedby pharmacological intervention and weight loss surgery. Lifestyle recommendations include decline in daily caloric consumption and regular physical exercise.
(C)If the above measures do not resolve morbid obesity, bariatric surgery needs to be considered.
Pharmacological treatments for ovulation induction
(A)Clomifene Citrate(CC)
Anti-oestrogen therapy withCCis first-line therapy in management of anovulatory PCOS. CC is believed to be bind and block the oestrogen receptors in the hypo- thalamus for longer periods, thus decreases the normal ovarian-hypothalamic feedback. This blockade elevates the GnRh pulsatility, which begin to elevate the pituitary secretion of gonadotrophins in turn promote ovarian follicular development.
The main goal of ovulation induction is to mirror a physiological menstrual cycle with monofollicular ovulation. The starting dose of CC is 50 mg/day orally for five days beginning on day 2 of the menstrual cycle. if there is no response dose must be raised to 100 mg. Discontinuation of CC should be observed if the patient is anovulatory after the dose has been increased or used for 3-4 cycles.
In amidst anovulatory infertile woman who respond to CC treatment, pregnancy rate per cycle is around 15%. A 67% of cumulative pregnancy rates can be expected over 6 months in woman who have no other subfertility factors.
(B)Aromatase Inhibitors
Aromatase inhibitors are not licensed in the UK for use in ovulation induction.
The mechanism of action is to inhibit the aromatization of androgen to oestrogen and thus release the hypothalamic pituitary axis from negative feedback. Dosage is 2.5 up to 7.5mgs daily for five days and ultrasound monitoring is advised.
(C)Metformin
It is an insulin sensitiser which could be used for ovulation induction, commonly in a dose of 1500 mg daily, either alone or in combination with Letrozole or CC. Metformin with CCcombination therapy shows better ovulation and clinical pregnancy rates compared with either agent alone. Metformin could behelpful for patients with pre-diabetes and also who are at likelihood of gestational diabetes despite the fact that it is linked with gastro-intestinal side-effects.
(D)Gonadotrophins
Gonadotrophin are second line therapy in ovulation induction, given in those women who failed to ovulate and resistant to oral agents. It is essential to start with low doses of gonadotrophins (37.5-75iu daily by subcutaneous injection) and observe the response attentively by USS. Different regimens have been reported (step up, low-dose step-up, step down) to decrease the risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS).PCOS patients are at risk of OHSS.
Multiple pregnancy has been observed in up to a third of patients, but this risk is reducedby low-dose regimens. Treatment should be suspended if 3 or more follicles >14 mm develop as the risk of multiple pregnancy obviously increases.
(E)Laparoscopic ovarian drilling (LOD)
LOD indicated for clomifene-resistant PCOS patients. Furthermore,no risks of OHSS and multiple pregnancy. This surgical procedure has the risk of postoperative adhesions and damaging ovarian reserve.
Pregnancy and PCOS
(A)PCOS has been linked to an increase in risk of miscarriage. The exact mechanism remains unclear, but has been attributed to insulin resistance, hyperinsulinaemia and hyperandrogenaemia.
(B)PCOS patients are at more risk of developing gestational diabetesmellitus (GDM). This risk is significant in women with high BMI. These women must be screened for gestational diabetes.
(C)PCOS women also havegreater risk of developing pregnancy-induced hypertension and pre-eclampsia with associated complications of prematurity.
(D)Obesity aloneraise the risk of miscarriage, congenital anomalies, and obstetric complications.
In vitro fertilization (IVF)
IVF is not the first- line treatment for PCOS. However, the patients are referred to IVF treatment because they fail to conceive in spite of ovulation induction or due toanother possible causes for infertility (eg: male factor).
Patients with PCOS have a significantly increased risk of OHSS (5 -10%). Strategies to lower the risk of OHSS in women with PCOSin IVF include the usage of GnRH antagonist protocol, giving low doses of gonadotrophins, vigilant monitoring while stimulation to adjust the doses of gonadotrophin, and providing an agonist trigger. OHSS is intensified by pregnancy, so in women at high risk, embryo transfer should be deferred and embryos cryopreserved.
Figure 1: Management of PCOS-related infertility.1
Reference:
1.Kriedt KJ et al., PCOS: diagnosis and management of related infertility, Obstetrics, Gynaecology and Reproductive Medicine, https://doi.org/10.1016/j.ogrm.2018.12.001.
Experience: Assistant Prof PSG College in1995.
Consultant Alwa Medical Centre, Moodbidri, Karnataka.
Worked in Warangal 1996,1997 & Vijayawada from 1998.
Awards: Won the First Prize in lap Quiz at warangal in 1990.
Dr. G N Mathur Prize in Physiology.
Dr. Rama Memorial Gold Medal in OBG.
Progress 2001, Won the 2nd Prize held at the Conference.
India