Will emerging pharmacotherapies improve the management of polycystic ovarian syndrome?

1. Background

Polycystic ovary syndrome (PCOS) is the most common metabolic disorder in reproductive aged women, affecting approximately 5–15% of this population.[1]

The Rotterdam Criteria [2] have been accepted by scientific community for PCOS diagnosis in adults [3]; conversely, in adolescent, anovulation and PCO morphology are not sufficient to make a diagnosis, which should be based on the evidence of clinical and/or biochemical signs of hyperandrogenism and oligomenorrhea.[3]

Since 1935,[4] PCOS management confuses clinicians everywhere and neither does benefit of standardized guidelines nor of Food and Drug Administration-approved medications; accordingly, all drugs used in its treatment are still off-label.

Given the heterogeneity of clinical manifestations (hirsutism, oligomenorrhea, infertility, and long-term metabolic and oncologic complications), therapeutic approach for PCOS is not ‘one-size-fits-all’, but depends on patient’s phenotype and reproductive desire.[1]

Anti-Müllerian hormone (AMH) is a glycoprotein released from the granulosa cells of antral follicles in concentrations that are proportional to the number of developing ovarian follicles.[5]

In clinical practice, AMH is employed as a marker of ovarian aging; in this context, its reliability increases by using multimodal methodologies that combine AMH with other hormonal and clinical parameters. An example of this approach is represented by OvAge, a mathematical formula that accounts patient’s biochemical and ultrasonographic parameters as predictor variables and produces a numeric variable, which accurately reflects the ovarian reserve.[6]

Moreover, several authors have investigated the role of basal AMH for the diagnosis of PCOS, since serum AMH is 2–4-fold higher in PCOS (usually >10 ng/ml) than in healthy women, as consequence of the increased number of small antral follicles.[5]

Since AMH concentration correlates with the severity of symptoms,[5] its pretreatment evaluation has been proposed as a novel marker of responsiveness to therapy. Specifically, several authors suggest its clinical implications in identifying women who will benefit of standard therapies or who may require more intensive pharmacological interventions.

By a critical review of literature, no emerging pharmacotherapies for PCOS have been identified; thus, the aim of the editorial is to report all available evidence about AMH involvement in PCOS therapy and to analyze how its evaluation will improve the management of patients, by allowing an individualized approach.

2. Emerging pharmacotherapies in management of PCOS

Given the variety of PCOS phenotypes, each treatment should be tailored to one or more clinical issues, always taking into consideration patient’s age and reproductive desire.

In overweight/obese PCOS population, lifestyle therapy (calorie-restricted diet and exercise) should be always recommended since it improves ovulation and menstrual regularity.[3] Overweight PCOS women who resume ovulation after weight loss have significantly lower pre-diet AMH levels compared to those who experience persistent ovarian dysfunction, suggesting that higher AMH levels are associated with derangement of ovarian function.[7] Hence, the basal measurement of AMH allows to discriminate PCOS women who will benefit from lifestyle intervention from those who may require more intensive or alternative pharmacological regimens.[7]

2.1. Adolescent PCOS population

Since the physiology of ovarian function may mimic PCOS symptoms in the first years after menarche, the principal issue in managing oligomenorrhoic adolescents is to perform a correct diagnosis.[3] Ovulatory disorders should be considered a sign of PCOS only if they persist 2 years beyond menarche. Similarly, acne should not be considered enough for defining hyperandrogenism, as well as the detection of multifollicular ovaries for defining PCO morphology, since they can be a feature of normal puberty.[3]

Irrespective of BMI value, AMH is significantly higher in PCOS adolescents than in unaffected contemporaries.[8] Consequently, elevated AMH values may help as a noninvasive screening or diagnostic test for PCOS,[3] although conflicting data are available [5,8] and there are no well-defined cutoffs.[5]

Combined oral contraceptives (COCs) are the first-line treatment in PCOS adolescents if the therapeutic goal is to treat acne, hirsutism, and anovulation or to prevent pregnancy [3] while metformin is a possible treatment if the goal is to treat impaired glucose tolerance/metabolic syndrome.

2.2. Adult PCOS population

2.2.1. Hirsutism and menstrual disorders

In adult PCOS women, without immediate reproductive desire, hormonal therapy [COCs, antiandrogen] is the first-line treatment for hirsutism and/or menstrual abnormalities.[3]

In women with reproductive desire, metformin, although off-label, is effective in improving hirsutism and is considered a second-line therapy for PCOS women with menstrual irregularity with contraindication for COCs.[3]

Recently, supplementation with myo-inosiol and N-acetyl-cysteine has been demonstrated to ameliorate the metabolic profile of PCOS patients, also improving clinical characteristics, ovarian function, and hormonal parameters.[1,9,10]

2.2.2. Infertility

Although in anovulatory overweight/obese PCOS patients lifestyle interventions are cheap approaches for restoring ovulation,[11] most of these women need also pharmacotherapy to obtain simple or multiple ovulations.

2.2.2.1. Clomiphene citrate (CC)

CC is the gold standard for ovulation induction in PCOS women [11]; with CC therapy, the multiple pregnancy rate is 10%, while ovarian hyperstimulation syndrome (OHSS) is low.[3,11]

If ovulation cannot be induced at the maximum doses allowed, patient is considered ‘clomiphene resistant’, thus alternative regimens and drug combinations have to be attempted.

The ‘extended’ protocol, the ‘luteal phase administration,’ and the ‘stair step protocol’ represent effective strategies employed for enhancing ovarian sensibility.[1]

Compared to CC alone, the combination of CC plus metformin induces higher ovulation and pregnancy rates, representing the most effective strategy in CC resistance.[3]

A modern approach for predicting patient’s sensitivity to CC is represented by the AMH measurement.[12]

Some authors suggest that an AMH cutoff of 1.2 ng/ml could be used to predict CC response in obese PCOS women,[13] whereas Maharam et al. [12] demonstrated that anovulatory women with AMH greater than 3.4 ng/ml are resistant to CC and obtain increased ovulation rate with higher starting dose. Furthermore, patients with very high AMH levels may not be suitable for CC treatment and could therefore be directly switched to more effective treatments, such as gonadotrophin ovarian stimulation.[12]

2.2.2.2. Metformin

Metformin is effective for anovulatory infertility and is associated with restored monofollicular ovulation and low multiple pregnancy rates,[3] but no consensus is available about dose and duration of administration.

Even if the superiority of CC over metformin in achieving live birth has been demonstrated,[3,11] a recent meta-analysis [9] demonstrated that the coadministration of metformin plus CC is superior to CC alone as primary method to induce ovulation and to achieve pregnancy in PCOS, especially in older and viscerally obese patients.[9]

The ability of metformin in increasing the ovarian sensitivity seems to be confirmed by some authors reporting a reduction in AMH levels after 4–6 months metformin treatment,[14,15] especially in obese PCOS subjects,[15] but further data are needed.

2.2.2.3. Gonadotrophins

Gonadotrophins are second-line pharmacological strategy, employed in mono-ovulation protocols in CC-resistant PCOS women or when alternative approaches (such as combination of metformin plus CC) are not effective.[11] Even when the goal of FSH administration is to recruit a single follicle,[11] the insulin-resistant state makes PCOS women susceptible to excessive gonadotrophin response, multiple pregnancies, cancelled cycle, and OHSS.[11]

In mono-ovulation protocols, no significant differences among available gonadotrophins were detected in terms of safety and reproductive outcomes (ovulation rate, live birth, pregnancy, miscarriage, multiple pregnancy, OHSS).[1]

In PCOS women, gonadotrophins can be administered according to the ‘conventional step-up’ protocol but, considering the risk of excessive response, other strategies should be preferred.[1,11]

It is well known that serum AMH level is associated with quantitative response to ovarian stimulation, because AMH decreases the sensitivity of follicles to circulating follicle-stimulating hormone.[16] Therefore, AMH could represent an excellent predictor of ovarian responsiveness to gonadotrophin treatment both in mono-ovulation induction and in in-vitro fertilization (IVF) programs.[16,17] Specifically, above the cutoff value of 4.7 ng/ml, the chances of good ovarian response (defined as ovulation within 20 days of stimulation) are reduced from 100% (in women with lower AMH) to 35%. Thus, pretreatment AMH concentrations may be a valuable predictor of success and may help in determining the gonadotrophins starting dose,[16] even if further studies are necessary to confirm these preliminary results and provide a consensus about the thresholds used for clinical applications, especially in PCOS populations.

IVF cycles are recommended as third-line therapy for the management of infertility in PCOS patients, after failure of first- and second-line strategies [11] or in presence of male indications. The aim of the controlled ovarian hyperstimulation is to achieve multifollicular ovarian development for subsequent egg retrieval, fertilization, and production of embryos for transfer.

In a retrospective cohort study of 134 women,[18] higher rates of OHSS in women with AMH >10 ng/ml compared with women with AMH 5–10 ng/ml suggests that extra caution is required in ovarian stimulation, specifically in women with ultrahigh AMH levels. Consequently, clinicians managing PCOS infertile women should be confident with the new stimulations protocols available for high responders and should be able to offer good prognosis IVF cycles in modern and qualified laboratories, able to ensure high success rates in cycles with thawed blastocysts.

In the past years, the standard protocol for PCOS women consisted in a long-protocol gonadotropin-release-hormone (GnRH) agonist.[19] Recently, live birth and ongoing pregnancy rates resulted similar in GnRH antagonist and long GnRH-agonist protocols in women with PCOS undergoing IVF/intracytoplasmic sperm injection [19]; interestingly, a significant reduction in terms of OHSS rate in GnRH antagonist group was demonstrated,[19] thus it is now accepted as the best choice in PCOS women.

During GnRH antagonist protocols, indeed, oocyte triggering with GnRH agonist instead of human chorionic gonadotropin (hCG) significantly prevents OHSS but also reduces the live-birth rate in fresh cycles.[20]

When an excessive ovarian response is encountered, therefore, clinicians could trigger oocyte maturation with GnRH agonist and supplement the luteal phase with a small bolus of hCG and more intensive E2 and progesterone supplementation. Conversely, it is preferable to trigger with GnRH agonist and freeze all blastocysts available, resulting in a complete elimination of OHSS and high ongoing pregnancy rates in the subsequent frozen-thawed transfer cycles.[20]

3. Expert opinion

It is now recognized that serum AMH correlates with PCOS severity, thus, the ‘PCO-Like’ phenotype [i.e. high antral follicle count (AFC) and/or serum AMH] has been proposed as a surrogate for either oligo-anovulation or hyperandrogenism.[5]

There are sufficient data to support the view that AMH assay might replace (or be an alternative for) AFC in the Rotterdam classification, especially in situations when ultrasound is uninformative or impossible, as in obese women or during childhood.[5]

In PCOS women, the reproductive desire should be always investigated in order to start the most suitable and rapid way to get the result.

Even if further studies are necessary to confirm these data, the evaluation of serum AMH should be prescribed before any treatment, in order to identify women that could take advantage of standard stimulation protocols by those needing further therapeutic regimens.

AMH should be also assessed before scheduling weight loss in overweight/obese PCOS women [7] and the results exploited for determining the starting dose of CC or gonadotrophins,[16,17] or for counseling infertile couples about their risk of OHSS and their clinical pregnancy rates following IVF.[18]

Low-dose therapy with gonadotrophins offers a high rate of ovulation and monofollicular development. However, in women with very high level of AMH or with OvAge significantly lower than chronological age,[6] repeated stimulations could be needed for obtaining mono-ovulation, so that, in qualified centers, IVF may lead to pregnancy faster and safer.

For all these reasons, given the heterogeneity of clinical manifestations and the absence of a standardized ‘one-size-fits-all’ therapeutic approach for PCOS, every clinician has to investigate carefully patient’s phenotypes and reproductive desire before choosing the best and safest strategy. The routine implementation of the AMH measurement in the clinical practice will probably reduce the discretionality about ‘when, why and how to do what’ that still confuses patients, general practitioners, and gynecologists.

Notwithstanding the emerging role of AMH in diagnosis and treatment in PCOS patients, its employment is still limited due to technical difficulties (fluctuations in AMH assays among the kits) and lack of consensus about the thresholds to be used for clinical applications. Currently, only the ‘in-house’ thresholds determined by each center are usable, without it being possible to make a generalization. These difficulties, however, will be quickly overcome by introducing an international standardized assay, which will let to establish a validated AMH cutoff and target future therapy based on its values. Thus, all preliminary AMH thresholds described in literature will be revised when robust and reproducible AMH assays will be available.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.