Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

7. Understanding the Problems of Treating PCOS

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting 5–10 % of women in their reproductive years and is associated with 75 % of all anovulatory disorders causing infertility. It is best diagnosed using the Rotterdam criteria in which any two of the following three are sufficient to confirm the diagnosis: Oligo/anovulation, hyperandrogenism (biochemical or clinical), polycystic ovaries on ultrasound examination. The management of PCOS depends on the presenting symptoms. Whether these are hirsutism or acne, oligo/amenorrhoea, or anovulatory infertility, the first-line treatment for the overweight or frankly obese must be loss of weight. For infertile anovulatory patients, clomiphene citrate is the first-line medication of choice but letrozole is challenging for this position. Metformin is much less successful than clomifene for this purpose. Low-dose FSH therapy is the second-line of treatment but laparoscopic ovarian drilling is also successful particularly for normal weight women with high LH levels. Most women whose cause of infertility is purely anovulatory PCOS will successfully conceive with one of these treatments but for those who have failed (and probably have an additional factor) IVF is a relatively successful ‘last resort’ treatment.

Keywords

Polycystic ovary syndrome PCOSEndocrinopathyAnovulatoryInfertilityAnovulationHyperandrogenismLHFSHAnti-Mullerian hormoneAMHAntral folliclesOvarian androgenHyperinsulinaemiaObesityAnti-oestrogensClomifeneLetrozoleOvulationOestrogenMetforminInsulin sensitisersHypoglycaemiaEuglycaemiaGonadotrophin therapyOvarian hyperstimulation syndromeOHSSHuman menopausal gonadotrophinhMGLaparoscopic ovarian drillingIn-vitro fertilizationIVFHyperandrogenic

Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting 5–10 % of women in their reproductive years and is associated with 75 % of all anovulatory disorders causing infertility. Polycystic ovaries can be found in 20 % of the female population but are not necessarily associated with the typical symptoms.

In 1935 Stein and Leventhal first described the polycystic ovary as a frequent cause of irregular ovulation or anovulation in obese women seeking treatment for subfertility. The initial management of the condition was surgical, with wedge resection of the ovaries resulting in restoration of ovulation in the majority of cases. In the last two decades, the polycystic ovary syndrome (PCOS) has been studied intensely and, although the exact aetiology still escapes us, considerable knowledge of the prevalence, pathophysiology and management of the syndrome has been gained.

7.1 Definition

The ESHRE/ASRM Rotterdam Consensus Meeting (2003) [1] proposed the following definition of PCOS which has been widely adopted.

Any two of the three are sufficient to confirm the diagnosis:

·  Oligo- or anovulation.

·  Hyperandrogenism (biochemical or clinical).

·  Polycystic ovaries on ultrasound examination.

Syndromes with similar presenting features, e.g. congenital adrenal hyperplasia, androgen-secreting tumours or Cushing’s, should be excluded.

·  Oligo- or anovulation

Ovulation occurs at a frequency of less than once in 35 days.

·  Hyperandrogenism

Clinical signs of hyperandrogenism include hirsutism, acne, alopecia (male-pattern balding) and frank virilization. Biochemical indicators include raised concentrations of total testosterone and androstendione, and elevated free androgen index.

·  Polycystic ovaries

The presence of ≥12 follicles in either ovary measuring 2–9 mm in diameter and/or increased ovarian volume (>10 mL).

In practice, the diagnosis of PCOS can be made in almost every case without blood sampling. Although not essential for initial diagnosis or therapeutic decisions, for screening a blood sample for LH, total testosterone, FSH, fasting glucose and fasting insulin may be taken. Although rarely necessary to establish the clinical diagnosis, a serum concentration of anti-Mullerian hormone (AMH) >40 pmol/L will invariably be confirmatory. An oral glucose tolerance test is recommended for the obese, especially for the obese adolescent.

When suggested by the history of a rapid progress of hyperandrogenic symptoms, total testosterone concentration screens for androgen-producing tumours. For 21-hydroxylase deficiency, serum 17-hydroxy-progesterone concentration is an excellent screening test. If suspected, Cushing’s syndrome can be detected using a 24 h urinary cortisol or overnight dexamethasone suppression test.

7.2 Pathophysiology

In order to better understand the principles of management of PCOS, a very brief summary of some of the pathophysiological aspects is presented here.

PCOS is a very heterogeneous syndrome as regards both clinical presentation and laboratory manifestations. While the basic dysfunction seems to lie within the ovary, the clinical expression and severity of the symptoms are dependent on extra-ovarian factors such as obesity, insulin resistance and LH concentrations.

There are four main disturbances which may be involved in the pathophysiology of the syndrome:

·  Abnormal ovarian morphology: 6–8 times more pre-antral and small antral follicles are present in the polycystic ovary compared with the normal ovary. They arrest in development at a size of 2–9 mm, have a slow rate of atresia and are sensitive to exogenous FSH stimulation. The greater the number of small follicles, (also reflected by serum AMH concentrations), the more severe the symptoms [2]. An enlarged stromal volume is invariably present and a total ovarian volume >10 mL is often witnessed.

·  Excessive ovarian androgen production lies at the heart of the syndrome. Almost every enzymatic action within the polycystic ovary which encourages androgen production is accelerated. Both insulin and LH, alone and in combination, exacerbate androgen production.

·  Hyperinsulinaemia due to insulin resistance occurs in 80 % of women with PCOS and central obesity, but also in 30–40 % of lean women with PCOS. This is thought to be due to a post-receptor defect affecting glucose transport and is unique to women with PCOS. Insulin resistance, significantly exacerbated by obesity, is a key factor in the pathogenesis of anovulation and hyperandrogenism. An abnormality of pancreatic B-cell function has also been described.

·  Excessive serum concentrations of LH are detected on single spot blood samples in 40–50 % of women with PCOS. High LH concentrations are more commonly found in lean rather than obese women. Although FSH serum concentrations are often within the low normal range, an intrinsic inhibition of FSH action may be present. Prolactin concentrations may be slightly elevated.

7.3 Management

The management of PCOS depends on the presenting symptoms. Whether these are symptoms of hyperandrogenism such as hirsutism and acne, oligo- or amenorrhoea, or anovulatory infertility, the first-line treatment for the overweight or frankly obese must be loss of weight. Here I will concentrate on the management of anovulatory infertility associated with PCOS.

7.3.1 Weight Loss

Obesity is a common feature in the majority of women with PCOS. Increased truncal–abdominal fat in women with PCOS exacerbates insulin resistance and hyperandrogenism, and, consequently, the severity of the symptoms. Fortunately, the reverse is also true in that diet and exercise (‘lifestyle changes’) are effective treatment. The loss of just 5 % or more of body weight is capable of considerably reducing not only the severity of hirsutism and acne but crucially restoring menstrual regularity and ovulation. A motivation-inducing explanation of these facts should be given at the first consultation and referral to a clinic dedicated to life-style changes is highly desirable.

7.4 Anti-oestrogens

Clomifene citrate has been the first-line medication for the induction of ovulation for the last 50 years. By blocking hypothalamic and pituitary oestrogen receptors, it induces a discharge of FSH which is frequently enough to restore ovulation. Given in a dose of 50–150 mg/day from day four to eight of a spontaneous or progestin-induced menstruation, clomifene will restore ovulation in 75 % and induce pregnancy in 35–40 %. Failure to induce ovulation is more common in the very obese and those with very high serum androgen, insulin or LH concentrations. Failure to respond to 150 mg/day, an endometrial thickness of <7 mm at mid-cycle or failure to conceive following six ovulatory cycles require a change of treatment mode (For a detailed account, see Chap. 8).

Letrozole, a potent aromatase inhibitor, is proving to be as effective, if not more effective than clomifene for the induction of ovulation [3]. By blocking the conversion of androgens to oestrogen, it also induces a discharge of FSH through the negative feedback mechanism and so is capable of restoring ovulation when given at the beginning of the cycle in a dose of 2.5–5 mg/day for 5 days [4]. Letrozole would probably have replaced clomifene were it not for an unfounded suspicion of an increased rate of congenital malformations, later refuted by a number of subsequent series. Unfortunately, the initial suspicion prompted the drug company to contra-indicate its use for ovulation induction and so it is unavailable for this indication in most countries (For further details, see Chap. 8).

7.5 Insulin Sensitisers

Metformin, a well-established oral anti-diabetic agent, is capable of increasing ovulatory frequency in women with PCOS, apparently by decreasing insulin and androgen concentrations, in a dose of 1,500–2,500 mg/day. Its efficacy does not seem to depend on the presence of demonstrable insulin resistance, there is no evidence of teratogenicity and it does not induce hypoglycaemia in women with euglycaemia. Although clomifene is much more efficient and quicker in inducing ovulation and pregnancy as first-line treatment as a mono-agent [5], metformin in combination with clomifene or added to clomifene for women who have proved clomifene resistant may be a worthwhile strategy before having to proceed to the more expensive gonadotrophin treatment (For further details, see Chap. 10).

7.6 Gonadotrophin Therapy

·  Low-dose gonadotrophin therapy—designed to induce ovulation and conception while minimizing the complications due to multifollicular development, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Using a starting dose of 50–75 IU/day of FSH or human menopausal gonadotrophin (hMG) without a change of dose for the first 7–14 days and only small incremental dose rises of 25–37.5 IU for a minimum of 7 days where necessary, pregnancy rates of >20 % per cycle may be expected while OHSS is almost completely eliminated and multiple pregnancy rates are <6 %. Full details can be found in Chap. 9.

7.7 Laparoscopic Ovarian Drilling

Laparoscopic ovarian drilling (LOD) using cautery or laser has proved effective in restoring ovulation and inducing pregnancy, particularly in women of normal weight and with high concentrations of LH. Multiple pregnancy rate is low. Some units employ LOD when clomifene resistance is apparent; most others following failure of gonadotrophin therapy (See Chap. 11).

7.8 In-Vitro Fertilization (IVF)

IVF can be successfully employed for anovulatory women with PCOS when a further infertility-causing factor is involved or when the above methods of ovulation induction have been unsuccessful (See Chap. 18).

A suggested algorithm for the induction of ovulation for women with PCOS is shown in Fig. 8.​2.

7.8.1 Long-Term Health Implications of PCOS

Women with PCOS who are obese, hyperinsulinaemic and hyperandrogenic are at substantial risk for the development of metabolic syndrome (syndrome X). If they remain untreated, the risk of developing diabetes mellitus is seven times greater and hypertension four times greater than in the general population. Both these conditions, and the inevitable dyslipidaemia are all predisposing factors for cardio-vascular disease and demand attention, the earlier the better.

References

1.

Fauser B, Tarlatzis B, Chang J, Azziz R, et al. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–7.CrossRef

2.

Homburg R, Ray A, Bhide P, Gudi A, Shah A, Timms P, Grayson K. The relationship of serum anti-Mullerian hormone with polycystic ovarian morphology and polycystic ovary syndrome: a prospective cohort study. Hum Reprod. 2013;28:1077–83.PubMedCrossRef

3.

Legro R, NIH/NICHD Reproductive Network. Effect of letrozole versus clomiphene on live birth in women with anovulatory infertility due to PCOS: a randomized double-blind multicenter trial. Fertil Steril. 2013;100(3 Suppl):S51, O-167.

4.

Mitwally MF, Casper RF. Aromatase inhibitors for the treatment of inferftility. Expert Opin Investig Drugs. 2003;12:353–71.PubMedCrossRef

5.

Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.PubMedCrossRef