8.1.8 Polycystic ovary syndrome: reproductive aspects

The polycystic ovary syndrome (PCOS) is the most common cause of anovulation and hyperandrogenism in women, affecting between 5 and 10% of women of reproductive age worldwide (1). Although this difficult topic in endocrine gynaecology is under extensive research, controversies still remain about the pathophysiology, diagnosis, and therapy of PCOS.

The PCOS phenotype can be structured in three components: manifestations of anovulation, hyperandrogenism, and the metabolic syndrome (of which hyperinsulinaemia secondary to insulin resistance is the central abnormality). The latter two are addressed in other chapters. Our knowledge about the mechanism of disturbed folliculogenesis in PCOS that is responsible for its reproductive aspects has much increased these last years, thus opening new avenues for the diagnostic and therapeutic approaches.

Ovulation is the endpoint of the follicular growth in mammals. This very complex phenomenon starts from the entry of resting primordial follicles in the basal growth phase, and then continues with progressive maturation to pre-antral, then antral, and ultimately pre-ovulatory stages.

In PCOS, the follicular problem is twofold (2): first, early follicular growth is excessive; second, the selection of one follicle from the increased pool and its further maturation to a dominant follicle does not occur (follicular arrest).

Polycystic ovaries (PCOs) are endowed with an abnormally rich pool of follicles at all stages of development (except the pool of primordial follicles which is normal), exceeding 2–3 times the ones of normal ovaries (3).

With regard to their important effects on the small follicle growth, the intra-ovarian hyperandrogenism, which is the cardinal feature of PCOS, is designated as the main culprit for this follicle excess. In female rhesus monkeys, high doses of systemically administered testosterone or dihydrotestosterone (DHT) induced a sharp increase in the ovarian follicle number, from primary to tertiary follicles within few days, but there was no increase in dominant follicles. Furthermore, GC from those follicles had a lower apoptotic index and a higher mitotic index. These experimental data are reminiscent of the observation of PCOs in female to male trans-sexuals treated with high doses of androgens. Therefore, a local excess of androgens secondary to theca-interstitial cells (TIC) hyperfunction and/or hyperplasia might be an important paracrine factor causing ovaries to be multifollicular in PCOS. A direct effect seems plausible since androgen receptors are highly expressed early in GC, with a progressive decline as follicular growth continues.

Webber et al. (4) also reported a rate of follicle atresia during culture significantly lower in PCO tissue, suggesting a mechanism for maintaining a larger follicle pool. These data are in agreement with Das et al. (5) who reported a decreased expression of apoptotic effectors and an increased expression of a cell survival factors in GC from PCOS patients. Maciel et al. (3) hypothesized that primary follicle growth is abnormally slow in PCOS presumably because of excessive ovarian androgen production, resulting in a stockpiling effect on classic primary follicles.

In PCOS, the follicular arrest has not received yet a clear and unanimous explanation. Several mechanisms can be hypothesized.

FSH is clearly important in the normal selection of a dominant follicle during the early follicular phase. In PCOS, serum FSH levels are not obviously disturbed, but anovulatory patients lack the intercycle FSH rise due to the absence of ovulation and the subsequent absence of corpus luteum and luteolysis during a preceding cycle. Hence, it is rather a secondary phenomenon than a primary defect.

Several experimental and clinical arguments give support to the hypothesis that the follicular arrest is due to an excess of local inhibitor(s) of FSH activity. For example, Coffer et al. (6) reported that the oestradiol response to increasing doses of recombinant FSH occurred at a higher threshold in PCOS subjects compared to normal controls. One of the still unknown factors secreted locally by the selectable follicles and inhibiting the FSH effects could be the anti-müllerian hormone (AMH), secreted by GCs of growing follicles. In numerous studies, it has been shown that women with PCOS have significantly higher AMH levels in both serum and follicular fluid than normal women (5, 7). AMH has been shown to decrease aromatase activity in the fetal ovary and to inhibit granulosaluteal cell proliferation. AMH presumably exerts these effects by decreasing the GC sensitivity to FSH, since follicles from AMH knockout mice are more sensitive to FSH than those from the wild type. Conversely, Baarends et al. (8) previously reported that FSH down-regulates the AMH and AMH type II receptor expression in adult rat ovaries. In line with these experimental data, a negative correlation between AMH and FSH serum, and follicular fluid levels, and between AMH and oestradiol serum, and follicular fluid levels were found in normal and PCOS women (7, 9). These data suggest that the AMH excess is involved in the lack of FSH-induced aromatase activity, which characterizes the follicular arrest of PCOS. Lastly, in anovulatory women with PCOS, mild doses of exogenous FSH gently increase the serum FSH level, with a concomittant and correlated reduction of the AMH excess preceding the emergence of a dominant follicle. This suggests that the inhibition from the latter on aromatase expression by selectable follicles has been relieved by FSH (10).

If the presence of FSH inhibitors (such as AMH) within the cohort is believed to participate in follicular arrest by lessening the FSH effects on GC differentiation, other mechanisms may involve luteinizing hormone.

Elevated serum luteinizing hormone levels are not constant in patients with PCOS and a raised luteinizing hormone level does not seem to be a prerequisite for anovulation. Physiologically, luteinizing hormone affects GC function only in the late follicular phase and during the luteinizing hormone surge, by enhancing the E2 and progesterone production, whereas the multiplication of GCs is inhibited. These effects might occur prematurely in GC from antral follicles in anovulatory patients with PCOS leading to arrested growth, through premature acquisition of luteinizing hormone receptors (11) and/or amplification of luteinizing hormone action by hyperinsulinaemia.

Hyperinsulinism and presumably other factors linked to the metabolic syndrome also impact on follicle dysfunction, as suggested by the close relationship between body mass index (BMI) or waist circumference and menstrual cycle abnormalities (11). However, rather than being the primary cause of anovulation in PCOS, hyperinsulinism and/or insulin resistance may be viewed as a ‘second hit’ that nonspecifically worsens the follicular arrest. The precise target of this hit remains to be ascertained.

While the excess of small follicles appears as the salient and constant feature of PCOs, follicular arrest does not occur constantly in patients with PCOS, since some of them do ovulate monthly (12). Nevertheless, the former influences the latter, as suggested by the strong relationship between the follicle excess and the degree of menstrual disturbances in women with PCOS (13).

With the new Rotterdam definition (14), at least two out of the following three criteria are required to define PCOS: (1) oligo and/or anovulation (OA); (2) clinical and/or biochemical signs of hyperandrogenism (HA); and (3) polycystic ovaries (PCO). Most importantly, other aetiologies have to be excluded before applying these criteria, in particular, congenital adrenal hyperplasia, androgen secreting tumours, Cushing’s syndrome, hypothalamic anovulation, and prolactinoma (see below).

This new definition recognizes four PCOS phenotypes: HA + OA + PCO (full-blown syndrome), HA + OA, HA + PCO (so-called ovulatory PCOS) and OA + PCO (‘nonhyperandrogenic PCOS’). For convenience, they will thereafter be designated as phenotype A, B, C, and D, respectively.

There is, for the moment, good agreement that women with asymptomatic PCOs should not be considered as having PCOS (see below) and, conversely, that ovulatory women with phenotype C do have PCOS. On the other hand, phenotype D is not widely accepted and other definitions of PCOS still exclude this phenotype (15), although data are accumulating to certify that it is a true PCOS phenotype (1).

The clinical and biological features of HA will not be addressed in this chapter devoted to the reproductive outcome of PCOS. Conversely, the features of OA and PCOs have to be described.

OA manifests itself by different symptoms that may vary with time in the same patient.

Primary amenorrhoea is uncommon, but PCOS is still found in about 20% of girls referred for this symptom (16). These patients have no pubertal delay and are frequently overweight. This amenorrhoea is almost always reversible with short courses of progestogen treatment, without having to add oestrogens. This constitutes ‘normo-oestrogenic’ or ‘type 2’ anovulation in the WHO classification.

Oligomenorrhoea (that is, menstrual cycle length more than 3 months) and secondary amenorrhoea are the most typical features of the anovulatory PCOS. They very often date back to menarche. They reappear promptly (3–6 months) after discontinuation of an oral contraceptive. Menstrual irregularity occurring after a history of regular cycles in a woman with PCOs is often associated with weight gain. The best way to identify these symptoms is to ask the patient about her average number of menstrual bleedings per year. The answer ranges from 2 to 6 in most cases.

Infertility is also a major complaint in patients with PCOS, but the practitioner has to keep in mind that other causes of infertility, either female and/or male, are often present in addition to PCOS, especially in cases of longstanding infertility. Indeed, PCOS is not an ‘absolute’ cause of infertility. Providing they do not have other fertility problems, many patients conceive spontaneously, since 2–6 ovulatory cycles can be expected each year.

Irregular and sometimes heavy bleeding can be observed in women with PCOS. These patients must be investigated for endometrial hyperplasia or carcinoma, which traditionally occur in older women, but are not uncommon in 30–40-year-old women with PCOS.

Defining PCOs at ultrasound is an evolving issue, along with technical improvements, such as the use of high frequency probes through the vaginal route and image enhancing software. To define PCOs, the proposal from the Rotterdam consensus conference (17), is ‘either 12 or more follicles measuring 2–9 mm in diameter in the whole ovary and/or increased ovarian volume (>10 cm³)’ (Fig. 8.1.8.1). The priority has to be given to the ovarian volume and to the follicle number because both have the advantage to be physical entities that can be measured in real time conditions and because both are considered as the key and consistent features of PCOs. For instance, a close relationship between serum androgen levels and follicle number has been reported, as well as with AMH (7). In difficult situations, other ultrasound criteria for PCO may be used, although all have not been fully validated. In adolescent girls, the follicle criterion is difficult to use because it is much less reliable by abdominal than by vaginal route, the latter being most often impossible. Only the volume criterion should be used. In such situations, the assay of serum AMH offers an interesting surrogate to the follicle count (18).

In the context of subfertility, making the diagnosis of PCOS may be sometimes a difficult challenge.

About 20% of patients with PCOs report normal menses. However, about 20% of them are in fact anovulatory (12). To document ovulatory cycles, the serum Progesterone assay should yield a value of ≥ 3 ng/ml, 7 days before the expected cycle end, on at least two consecutive cycles. Ovulatory women with PCOs can be considered as having PCOS only if they fulfil phenotype C (see above), i.e. presence of symptoms and/or biochemical evidence of hyperandrogenism.

On the other hand, there is, for the moment, good agreement that women with asymptomatic PCOs should not be considered as having PCOS and in the absence of symptoms it is unnecessary to perform hormonal assays. This is of importance since the incidental discovery of PCOs on ultrasound is frequent (20–30%) in women undergoing investigation for reasons other than symptoms of PCOS, such as pelvic pain, unexplained bleeding, or infertility.

Although it is clear that many women with nonsymptomatic PCOs have normal fertility [19], PCO are not uncommon in the population of regularly cycling women undergoing assisted reproduction techniques (ART) for male, tubal, or unexplained infertility. Although presumably PCOs does not contribute to subfertility in such cases, there is an increased risk of ovarian hyperstimulation syndrome (OHSS) in such cases. Therefore, if PCOs were observed in ovulatory infertile women (in whom PCOS is not the cause of infertility), this information is very important to take into account when designing a ‘superovulation’ protocol for intra-uterine insemination (IUI) or in vitro fertilization (IVF). This finding indicates an enhanced risk for cancellation of the cycle treatment and for OHSS (20).

When PCOs are discovered in a woman who presents with amenorrhea and no symptom of HA, it is certainly safe and cost-effective to schedule a progestin withdrawal test. If it is negative, serum PRL and luteinizing hormone assays, searching for high (>20 ng/ml) and low (<2 IU/l) values, respectively, should be systematically checked in order to exclude a prolactinoma or a hypothalamic anovulation, respectively. Indeed, the incidental association between PCOs and one of these situations is not exceptional.

As already alluded to, PCOS impairs reproductive function by several well-documented mechanisms:

In anovulatory patients with PCOS, ovulation can be induced by various well-established means. A consensus has recently been reached about the management of infertility in this syndrome (21).

Given the strong evidence that hyperinsulinaemia plays a determinant role in the pathogenesis of PCOS, it is reasonable to believe that interventions aiming at reducing circulating insulin levels might also help to restore normal reproductive endocrine function (See Fig. 8.1.8.2).

Lifestyle modification with diet and exercise leading to weight loss should be the first-line treatment of all women with PCOS, especially in case of increased BMI, in order to restore spontaneous ovulation and to optimize the results of clomifene citrate and gonadotropin treatment (see Fig 8.1.8.2). After a 5% to 10% decrease in body weight, spontaneous ovulations may occur in many obese anovulatory women with PCOS (22).

Insulin-sensitizing agents, such as metformin, may increase the rate of spontaneous ovulations, regular menses, and ovulatory response to clomifene citrate in women with PCOS and insulin resistance. However, the first-line treatment for ovulation induction in women with PCOS should be clomifene citrate. Addition of an insulin-sensitizing agent may be considered when treatment with clomifene citrate alone is unsuccessful. Randomized trials have recently well documented that clomifene citrate is superior to metformin alone for inducing ovulation (23). Moreover, the addition of metformin to clomifene citrate does not seem to confer any additional benefit, except possibly in very obese women. In this study, the livebirth rate achieved with clomifene citrate treatment alone (22.5%) was significantly greater than in the group receiving metformin alone (7.2%) and not significantly different from that in women receiving both clomifene citrate and metformin (26.8%). Moreover, in this study, metformin did not reduce the rate of pregnancy loss. Some studies have shown the efficacy of thiazolidinediones (rosiglitazone, pioglitazone) on hyperandrogenism and hyperinsulinaemia. Despite the absence of evidence of teratogenic effects of the thiazolidinediones on animals, information in humans is still inadequate to authorize the use of these molecules for ovulation induction (24).

Clomifene citrate is the first-line treatment for anovulatory patients with PCOS. This anti-oestrogen acts on the hypothalamic–pituitary axis to stimulate the secretion of FSH. This mimics the normal intercycle FSH rise that appears to be defective in PCOS. It is accompanied however by a striking increase in the serum luteinizing hormone (luteinizing hormone) concentration, which, for some authors, may have a deleterious effect. The starting dose is 50 mg/day from days 2 to 6 of the cycle, for 5 days. As the effective dose is variable from one patient to the other, an upgrading adaptation from one cycle to the following, up to 150 mg/day, may be needed. The ovulation rate following clomifene citrate is about 80%, but some studies have stressed that the 6-month-cumulated pregnancy rate is lower than expected, possibly because of the potential anti-oestrogenic effects of clomifene citrate on cervical mucus and endometrium.

Clomifene citrate failure is defined by the absence of conception after six ovulatory cycles and must be distinguished from clomifene citrate resistance, which is the failure of ovulation on maximal doses of clomifene citrate. Clomifene citrate resistance can be improved by weight loss and/or insulin-sensitizing drugs in overweight patients.

In the past, this treatment was considered as highly hazardous in clomifene citrate-resistant patients with PCOS, because of their particular propensity to multifollicular development, with the subsequent risks for OHSS and multiple pregnancies. The design of chronic low-dose regimens in the late 1980s has nowadays facilitated and established the use of exogenous gonadotropins. The rationale for these protocols is the ‘FSH threshold theory’ (see Fig. 8.1.8.3). Briefly, it consists of raising the serum concentrations of FSH, thus allowing only 1–3 follicles to escape from the cohort and to become dominant. In practice, a starting dose of 37.5, 50, or 75 IU of FSH (either recombinant or urinary) or hMG (human menopausal gonadotropin) is injected each day (from day 2), for 2 weeks. This dose is then upgraded by 25 or 37.5 IU at 7-day intervals, if no leading follicle is detected (no follicle more than 10 mm in diameter at ultrasound and/or E2 level below 60 pg/ml and/or endometrial thickness less than 6 mm). Once at least one of these thresholds have been reached, the dose of gonadotropin is maintained until mature pre-ovulatory follicle(s) is (are) obtained (follicle size: 17–20 mm, E2 level: 250 pg/ml/follicle). An ovulatory dose of 5000 IU hCG is then injected intramusculary. This protocol yields a 80% rate of ovulation and a 50% cumulative rate of pregnancy, after 6 months. The prevalence of mild-to-moderate OHSS and multiple pregnancy is low and severe OHSS is exceptional. Obese women need longer treatment and respond to higher doses than nonobese patients. The rate of miscarriage is also increased by overweight and obesity.

This procedure has a long history since bilateral ovarian wedge resection was proposed in the 1930s when clomifene citrate and gonadotropins were not available. Nowadays, operative transvaginal hydrolaparoscopy, also called fertiloscopy, tends to replace laparoscopic procedures because of the reduction of adhesion formation (25). Ovarian surgery initially consisted of either mini-wedge resection, diathermic coagulation, or laser photodiathermy. Nowadays, ovarian drilling consists in an ovarian multiperforation by uni- or bipolar electrode. The mechanism of action of these techniques are still unknown.

So far, no adequately randomized controlled study comparing this treatment with others has been published. Therefore, the place of ovarian surgery within the strategy for ovulation induction in PCOS is still debated. For some authors, ovarian drilling may be interesting as a second-line treatment, and an alternative to gonadotropin regimens (26). For others, ovarian surgery may be more appropriate as a third-line treatment, and an alternative to IVF. Recent studies indicate that this technique is more beneficial in patients with a severe form of PCOS (normal weight, elevated luteinizing hormone, and resistance to treatment) (27, 28).

IVF is an effective therapy for PCOS patients that do not respond to standard ovulation induction or, inversely, that hyper-respond to treatment. Metformin seems to reduce the risk of OHSS in IVF although adequately powered studies are still lacking (29). However, these patients remain at high risk for OHSS and the main interest of IVF here is the control of the number of embryos transferred. Because of its cost and its reduced availability, this procedure must be viewed as the last resort, except if there are indications for IVF other than anovulation (for example, tubal abnormality or male infertility).

Aromatase inhibitors, such as letrozole, used for the treatment of breast cancer, may constitute an alternative option to clomifene citrate. The mechanism of action on ovulation is similar to clomifene citrate without the negative effects on cervical mucus and endometrium. Recent studies have not confirmed the hypothetic risk of teratogenic effects that has been suggested (30, 31), but insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction.

In vitro maturation (IVM) has aroused many hopes, but this technique has not yet proved its superiority over conventional techniques for the treatment of infertility in PCOS.

Lifestyle modification with diet and exercise leading to weight loss should be the first-line treatment of all women with PCOS, especially in case of increased BMI, in order to restore spontaneous ovulation, and to optimize the results of clomifene citrate and gonadotropin treatment. The practitioner should inform the patient about the negative impact of overweight on ovulatory and pregnancy rates.

Once this first measure is ongoing, or in nonoverweight anovulatory women, the first-line treatment for ovulation induction in PCOS should be clomifene citrate. If ovulation fails to occur or if there is no conception after six ovulatory cycles, gonadotropin treatment should be considered, possibly coupled with an intra-uterine insemination in case of associated male factor.

Likewise, if gonadotropin treatment does not yield a satisfactory ovulation rate and/or if it appears too hazardous or too complicated, or if no conception occurs, it should be abandoned after a maximum of six cycles. This applies to about 50% of clomifene citrate-resistant patients.

For these patients, IVF should be then considered. The place of ovarian surgery in the management of infertility in PCOS is still debated (see above).

The use of oral contraceptives, whatever the duration, has not been reported to protect fertility outcome in patients with PCOS, although it appears to have no adverse effect on future fertility. On the other hand, long-term measures that reduce weight in obese women before the patient wishes to conceive are likely to be beneficial.

The risk for OHSS is especially high in young and lean women. The only preventive measure is an extreme caution with the use of ovulation inducers, which should always be precisely tuned and carefully monitored, according to the validated protocols, as detailed above. Also, the decision to trigger ovulation with hCG must be taken after a thorough evaluation of the risks.

The aetiology of recurrent spontaneous abortion in PCOS is not clear. Some authors suggest that excessive luteinizing hormone secretion, whether spontaneously or clomifene citrate-induced, is a risk factor, but this is not supported by other studies. No randomized controlled study have shown that lowering the luteinizing hormone level with a gonadotropin-releasing hormone agonist during ovulation induction with gonadotropin regimens would reduce this risk, although this was suggested by retrospective studies. Furthermore, the use of a gonadotropin-releasing hormone agonist enhances the risk of OHSS.

Conversely, being overweight is a well-recognized risk factor. This stresses again the need for dietary treatment before and during ovulation induction. On the other hand, administration of metformin during pregnancy is not yet recommended, despite the absence of teratogenic effects in animal studies and in the few human data collected so far.

Unopposed oestrogen secretion is believed to be the main determinant of the enhanced risk for endometrial hyperplasia and cancer in PCOS patients. Therefore, treatment with a progestagen is advocated, either by giving an OCP or by the use of cyclical progestagens. The preventive effect of weight reduction must be emphasized again since obesity is a major risk factor for these diseases.

Breast cancer risk is enhanced in obese women, but PCOS by itself is not considered as a risk factor (32).

The physiological decline in the follicle number with age could explain why ovulation and menstrual cycle disorders tend to improve with age in patients with PCOS. These patients undergo menopause at the same age as normal women. However, the ovarian stroma may remain active in some of them, with persisting androgen secretion. Hyperinsulinaemia seems to favour the survival of androgen-secreting tissue in postmenopausal women (33).

The reproductive issues of PCOS have a great impact on the psychological and economical burden of the disease. Our better understanding of the disturbed folliculogenesis of PCOS should now greatly improve our therapeutic strategies in the management of anovulation. It will always remain, however, that our therapeutic interventions would be greatly facilitated and even useless in many patients if lifestyle modification leading to weight loss were implemented as early as possible.