Polycystic Ovary Syndrome (PCOS)

Introduction: Polycystic ovary syndrome (PCOS) is the most common endocrinological condition seen in women of reproductive age affecting 8-13% of women in this cohort. In Ireland it is reported to affect 128 in 100’000 women, but a higher incidence is seen in women of eastern European and Asian descent. It is a complex condition with endocrine, reproductive and metabolic health implications.

Pathogenesis

The cause of PCOS is not fully understood, but is thought to be a multifactorial relationship between genetic predispositions, lifestyle and environmental factors. A complex interplay between insulin resistance and androgen excess appears to be a key driver in the pathogenesis of PCOS. Abnormalities in gonadotrophin releasing hormone (GnRH) pulsation and gonadotrophin secretion with raised luteinising hormone (LH) compared to follicle stimulating hormone (FSH) leads to impaired folliculogenesis, ovulatory dysfunction and increased ovarian androgen synthesis. This results in a vicious cycle as androgen excess further exacerbates abnormal GnRH pulsation. Insulin resistance enhances ovarian androgen production from theca cells and inhibits hepatic sex hormone binding globulins (SHBG) production thereby increasing circulating free androgens.

Clinical manifestations

PCOS can have a varied clinical presentation. It most often presents in the teenage years/early to mid-20s but many women will not seek medical advice for many years so it is not unusual to diagnose in women in their 30’s. The most common symptoms are menstrual irregularity with oligomenorrhea/amenorrhoea but some women have polymenorrhoea. Features of androgen excess including acne, hirsutism and androgenic alopecia are also common presenting complaints. For some women fertility issues may be the initial presentation. Women with PCOS may also have secondary metabolic effects of PCOS including obesity, diabetes, hyperlipidaemia or obstructive sleep apnoea. There are also significant psychological impacts from PCOS, particularly around fertility, obesity and overall body image.

Diagnosis

There are a number of diagnostic criteria for PCOS, but the most widely accepted is the Rotterdam criteria. This criterion requires at least two of the three following features for diagnosis: 1. Biochemical or clinical features of hyperandrogenism 2. Ovulatory dysfunction 3. Polycystic ovaries on ultrasound with exclusion of other potential causes. The most important conditions to exclude are late-onset (non-classic) congenital adrenal hyperplasia (CAH), androgen secreting tumours, Cushing’s syndrome, hyperprolactinaemia and thyroid disorders. A thorough history, clinical examination and initial laboratory investigations outlined in Table 1 will guide further investigations if needed.

Table 1: Recommended investigations for diagnosis of PCOS and for exclusion of alternate causes

Initial Laboratory investigations

• LH, FSH and oestradiol
• Androgens: Testosterone, Androstenedione, DHEAS
• Prolactin
• Thyroid function tests
• 17 hydroxyprogesterone (to outrule CAH)

Further tests if indicated

• Dexamethasone suppression test (to outrule Cushing’s)
• Transvaginal ultrasound/CT adrenals (to exclude androgen secreting tumour)

The recent 2023 international consensus guidelines suggest the stepwise approach outlined in figure 2 for diagnosis. Ovulatory dysfunction is characterised by irregular menstruation with cycles <21 or >35 days apart or <8 menses a year in women who are at least 3 years post menarche. For adolescents between 1-3 years post menarche, cycles <21 or >45 days are considered irregular. It is important to note that pelvic ultrasound is not required for the majority of patients in order to make a diagnosis of PCOS.

Polycystic ovarian morphology is defined as ≥20 follicles per ovary in either ovary and/or ≥10 cm3 ovarian volume based on transvaginal ultrasonography. However, 20-40% of normal healthy women may have polycystic ovarian morphology (PCOM) on ultrasound but do not have PCOS.

Management

Treatment is aimed at tackling the varying symptoms of PCOS and these may change throughout a patient’s lifetime. However, a particular continual focus should be to promote a heathy lifestyle
to prevent weight gain and metabolic complications, improve fertility potential and reduce pregnancy complications.

Metabolic Health

Lifestyle factors should firstly be addressed with the promotion of healthy diet and exercise. Research has shown that a modest weight loss of up to 5% of body weight improves insulin sensitivity and reduces hirsutism. It can also lead to recovery of a normal menstrual cycle and restoration of fertility. Weight loss is therefore a key initial management of PCOS. This is best approached by linking with dieticians and exercise programs. Consideration can also be given to the addition of medications such as glucagon-like peptide-1 (GLP1) agonist to aid weight loss. Unfortunately, these medications must be self-funded in Ireland when used for obesity and ongoing supply issues pose a challenge. For women seeking fertility, GLP1 agonist must be stopped at least 8 weeks prior to conception as the safety of these agents in pregnancy is unknown. In more difficult cases, surgical options for weight loss can also be explored.

All women with PCOS should be considered as at increased risk for cardiovascular disease and should have assessment of cardiovascular risk factors including blood pressure, lipids and screening for diabetes regardless of age and BMI. Obstructive sleep apnoea is also more common in women with PCOS and again can occur in women with normal BMI.

Irregular menses

In women with PCOS who are not seeking fertility, it is important to manage amenorrhoea/ very infrequent menses due to the risk of endometrial hyperplasia. Women with PCOS are five times more likely to develop endometrial carcinoma because of endometrial hyperplasia which can occur due to chronic exposure to oestrogen which is unopposed by progesterone in women with infrequent menses. To reduce this risk, it is recommended to ensure women with PCOS have a menstrual bleed at least once every three months. Strategies to achieve this include weight loss, hormonal contraceptives, regular progesterone therapy or hormonal intrauterine device (IUD).

Hormonal contraceptives are generally considered first line for regulation of the menstrual cycle. Combined oral contraceptive pills (COCP) also help to manage symptoms of androgen excess in a number of ways. Firstly, the progesterone component inhibits LH and in turn reduces ovarian androgen production. The oestrogen component increases SHBG levels and therefore reduces free androgen concentrations. However, many women may not be suitable for COCP due to risk of thromboembolic events or be intolerant, so the other options include the progesterone only pill or insertion of a hormonal IUD. Hormonal IUDs contain progesterone which maintains a thin endometrial lining and since they are an effective contraceptive, they can be used in conjunction with antiandrogens.

Androgenic features

Androgenic features of PCOS (acne, hirsutism and androgenic alopecia) respond to COCPs which are usually the first line agent of choice. However, another option in those not suitable for COCP, those intolerant or where they have proved ineffective is to add an anti-androgen such as spironolactone, provided effective contraception is in place. Others antiandrogens such as cyproterone acetate or finasteride could also be considered but have a more deleterious side effect profile. These inhibit the binding of testosterone to the androgen receptor, thus reducing the features of hirsutism and acne. The recommended starting regime is Spironolactone 25mg once a day increasing up to 100mg once a day.

There are a number of options for mechanical removal of troublesome hair growth. These include shaving, waxing and electrolysis. Laser therapy is another option and often proves superior due its long-term impact. Topical elfornithine 11.5% which targets the hair follicle and slows hair growth may also be beneficial particularly if used in conjunction with mechanical removal. Patients should also be warned this can result in irritation of the skin and can take up to 8 weeks before any benefits are noted.

Treatment for acne should not be forgotten nor delayed during the holistic approach to PCOS. Delay in treatment can lead to unduly emotional and psychological distress as well as increase the risk of long-term scarring. In addition to the standard approach to acne management, women with PCOS should be offered combined oral contraceptives and antiandrogens as targets for the underlying hyperandrogenism.

Metformin and inositol

The use of metformin in PCOS is controversial with many conflicting studies published around its long-term benefits. Metformin undoubtedly reduces insulin resistance and has been shown to reduce visceral fat and overall body weight, however these effects are only significant when used in conjunction with lifestyle modifications. Metformin is also reported to improve ovulatory function, thus aiding fertility, however when compared to ovulation induction with clomiphene/ letrozole or gonadotrophins, metformin alone is inferior. Overall, there seems to be some benefit in the addition of metformin but only in tandem with other targeted therapies and lifestyle optimisation. Inositol supplementation could also be considered in PCOS. Early evidence has shown it can help tackle the metabolic syndrome, however there is limited evidence to suggest it helps with fertility, hyperandrogenism or obesity. It is therefore not recommended ahead of metformin but may be considered in addition to or when metformin is poorly tolerated due to gastrointestinal side effects.

Fertility treatment

70-80% of women with PCOS are reported to experience some degree of infertility, while PCOS is responsible for 75-80% of all infertility cases relating to anovulation. It is therefore very important that clinicians do not delay in referral for fertility support for PCOS patients. Prior to commencing fertility treatment, it is imperative that other causes of subfertility are ruled out. This includes tubal patency testing and semen analysis. As mentioned previously lifestyle improvement is key to fertility optimisation. The cornerstone of this is weight management, ensuring smoking and alcohol cessation as well as commencing high dose 5mg folic acid daily prenatally in obesity. The 2023 international consensus guidelines outline an algorithm for approaching infertility in PCOS (Figure 3). First line medical management of infertility is Letrozole, which is recommended before clomiphene due to the lower risk of multiple pregnancy. Metformin can also be added to clomiphene and is shown to be more effective than clomiphene alone. Further approaches are based on the presence or absence of ovulation. If ovulation is not achieved, ovulation induction with gonadotrophins and follicular tracking is recommended. If ovulation is detected repeated cycles of these medications is recommended before moving to assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) +/- intracytoplasmic sperm injections. Recent research has shown that although more people with PCOS are using fertility treatments (38%) compared to those without PCOS (13%), the birth rate is the same across both groups. Therefore, with careful management and optimisation of fertility treatments PCOS patients can go on to have healthy and successful pregnancies.

Conclusion

Polycystic ovary syndrome is a common and underdiagnosed condition amongst women, resulting in menstrual irregularities, androgenic features, subfertility, and long-term metabolic health complications. Early consideration and workup are imperative for prompt diagnosis and initiation of treatment. PCOS patient’s care needs are very likely to vary and develop throughout their journey, therefore a holistic and flexible management approach is key to ensure these needs are met across each juncture in their lives.

Key further reading:

Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Eur J Endocrinol. 2023 Aug;189 (2):G43-G64. doi: 10.1093/ejendo/lvad096.

References available on request

Written by Dr Rachel Byrne and Dr Niamh Phelan. Department of Endocrinology, St James’s Hospital, Dublin 

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