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PCOS is one of the primary causes of infertility in women. Women with PCOS have a 11-fold increased risk of developing metabolic syndrome and glucose intolerance when compared with age-matched controls.
PCOS is one of the primary causes of infertility in women. Women with PCOS have a 11-fold increased risk of developing metabolic syndrome and glucose intolerance when compared with age-matched controls. In India, the prevalence estimates for PCOS are between 8.2% and 22.5% depending on the diagnostic criteria used. The etiology of this condition remains uncertain but its diagnosis is based on abnormalities of the reproductive system, hyperandrogenism, and persistent anovulation after exclusion of primary diseases of the ovaries and adrenal and pituitary glands.1
The diagnosis of PCOS is made when two out of three of the following criteria are met:
PCOS clinical presentation
(A) Anovulation in the context of PCOS is suspected from the history of oligomenorrhoea and/or amenorrhea. Anovulatory PCOS is the leading cause of secondary amenorrrhoea in patients attending fertility clinics and it is also a common cause of primary amenorrhoea.
(B) The patient’s general appearance and body mass index (BMI) may give clues about systemic and endocrine problems including PCOS. About 40- 50% of women with PCOS are overweight. Increased abdominal obesity and waist-to- hip circumference is correlated with reduced menstrual frequency and subfertility in association with insulin resistance.
(C) Signs of hyperandrogenism (e.g. acne, hirsutism, malepattern balding) are also suggestive of PCOS. Acanthosis nigricans is a sign of profound insulin resistance and is usually associated with PCOS and obesity.
The pathophysiology of PCOS usually includes excess ovarian androgen production with an abnormal degree of insulin resistance being a non-essential but common aggravating factor. Hyperinsulinemia augments LH-stimulated androgen production. The precise mechanism of follicular arrest and anovulation is uncertain but it is known that Anti-Mullerian Hormone (AMH) which is elevated in PCOS plays a restrictive role in follicular development.
Other conditions with features similar to PCOS include thyroid dysfunction and non-classic congenital adrenal hyperplasia (CAH). Other causes of amenorrhea and anovulation: hyperprolactinemia, estrogen deficiency [WHO Type I]. Androgen-secreting ovarian and adrenal tumours, ovarian hyperthecosis, CAH or Cushing’s syndrome specially in women with severe hyperandrogenism.
(A) One third of women with PCOS have elevated serum total testosterone concentration. If the value is greater than 5 nmol/L, it is then necessary to exclude other causes. Free testosterone and free androgen index are sensitive methods of assessing hyper- androgenaemia. Overweight women with clinical hyperandrogenism may have a normal total testosterone but an elevated free testosterone as less is bound to sex hormone binding globulin (SHBG), which is suppressed by hyperinsulinaemia.
(B) An elevated LH is frequent observation in PCOS. High serum LH levels are associated with menstrual cycle disturbance, reduced chance of conception, and an increased risk of miscarriage.
(C) AMH is elevated in PCOS. Serum AMH measurement indicates the size of the follicle pool, including pre-antral and small antral follicles(<2mm), which are harder to detect by ultrasound. However, serum AMH is not currently recommended as a stand-alone diagnostic tool.
(D) Other biochemical investigations should be arranged based on the clinical presentation. The common causes of secondary amenorrhoea and related anovulation are: Thyroid disorders, particularly hyperthyroidism. Mildly elevated serum prolactin is found in 10-15% of women with PCOS. Women with the most common form of CAH (21-hydroxylase deficiency) will have an elevated serum 17-hydroxyprogesterone concentration.
(E) A progesterone concentration of greater than 30 nmol/L in the middle of the luteal phase is indicative of ovulation. However, it can be difficult to know when to take a blood sample if the patient has an erratic menstrual cycle, and a lower level of progesterone does not confirm anovulation. In general, a cycle length <42 days suggests ovulation
(A) Lifestyle modification is the first-line therapy for PCOS. At least 50% of patients diagnosed with PCOS are obese (BMI >30 kg/m2). These women are at higher risk of developing type II diabetes or impaired glucose metabolism and should be screened for diabetes mellitus. Studies show that even modest weight loss will results in improvement in reproductive outcome for all forms of fertility treatment. Decrease in daily caloric intake and regular physical exercise are recommended.
(B) Lifestyle modification is the first-line therapy for weight control, followed by pharmacological treatment and weight loss surgery. In morbid obesity, bariatric surgery needs to be considered.
Anti-oestrogen therapy with clomifene citrate (CC) is used as first-line therapy for anovulatory PCOS.
The starting dose of CC is 50 mg/day orally for five days beginning on day 2 – 5 of the menstrual cycle. The dose should be increased to 100 to 150 mg if there is no response or decreased to 25 mg/day if there is exuberant response.
CC will induce ovulation successfully in 70- 80% of selected patients. The pregnancy rate per cycle is approximately 15%. Cumulative pregnancy rates of 67% can be expected over 6 months in woman who have no other subfertility factors.
CC is associated with 6- 11% risk of multiple pregnancy, so careful monitoring with ultrasound is recommended. Discontinuation of CC should be considered if the patient is anovulatory after the dose has been increased or used for 3-5 cycles.
The mechanism of action of aromatase inhibitors 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. Aromatase inhibitors are not licensed in the UK for use in ovulation induction.
Metformin is an insulin sensitiser which can be used for ovulation induction, usually at a dose of 1500 mg daily, either alone or in combination with Letrozole or CC. Combination therapy of metformin with CC shows improved ovulation and clinical pregnancy rates compared with either agent alone. Metformin may be useful for patients with pre-diabetes who are at risk of gestational diabetes and can be continued in pregnancy.
Gonadotrophin ovulation induction is a second line therapy, indicated in those patients who were resistant to oral ovulation agents. It is important to start with low doses of gonadotrophins (37.5-75iu daily by subcutaneous injection) and monitor the response carefully by USS. Different regimens have been reported (step up, low-dose step-up, step down) to minimize the risk of multiple pregnancy and OHSS.
Multiple pregnancy has been reported in up to a third of patients, but this risk is minimized by low-dose regimens. Treatment should be suspended if 3 or more follicles >14 mm develop as the risk of multiple pregnancy obviously increases.
PCOS patients are at risk of ovarian hyperstimulation syndrome (OHSS)
LOD has been shown to have similar efficacy to gonadotrophins in the treatment of clomifene-resistant PCOS. The favoured method is to use monopolar diathermy at 4 points per ovary for 4 seconds at 40 W.
Patients with high LH are more likely to benefit and respond to LOD while those with marked hyperandrogenism, obesity, or long duration of infertility are more likely to be resistant. LOD is particularly appropriate in women who need laparoscopic assessment of their pelvis or who are unable to attend the frequent monitoring required for gonadotrophin therapy. The surgical procedure, has the risk of postoperative adhesions and the risk of damaging ovarian reserve.
IVF is not the first- line treatment for PCOS. However, patients may be referred for IVF either because they fail to conceive despite ovulation induction or hyperstimulation or because there is an additional reason for infertility.
Patients with PCOS have a significantly increased risk of OHSS (5 -10%). The use of a GnRH antagonist protocol, using low doses of gonadotrophins, careful monitoring during stimulation to adjust the gonadotrophin dose, and giving an agonist trigger will minimize the risk. OHSS is worsened by pregnancy, so in women at high risk, embryo transfer should be deferred and embryos cryopreserved.
In vitro maturation (IVM) has been suggested as an alternative to conventional IVF in young women with PCOS or history of prior OHSS. The maturation of retrieved immature oocytes in the laboratory minimizes gonadotrophin stimulation. However, pregnancy rates are low and this technique is not widely used.
Figure 1: Management of PCOS-related infertility.
Dr Padmaja Veeramachaneni
MBBS, MD, FCGP, FAMS, FICOG
FOGSI, IMA, FCGP, IMS, PCOS society India, ISAR, AP chapter of Isar, ISOPARB, ICOG Director, Padmaja Clinic, Vijayawada.