Targeting infertility in PCOS: Unfolding “Ariadne’s thread”

Introduction

The myth of Ariadne's thread is a fitting analogy for providing a practical and logical algorithm for the management of anovulatory PCOS. The legend tells of King Minos who, after conquering Athens, demanded the annual sacrifice of seven maidens and seven young men to the Minotaur, that inhabited the infamous labyrinth in Crete. Theseus, the son of King Aegeus of Athens, volunteered to take the challenge and be sacrificed. However, Ariadne, the daughter of King Minos had fallen in love with Theseus and so gave him a ball of red thread to help him lay a trail as he penetrated the labyrinth, before killing the Minotaur and returning safely by following the thread back to the entrance. There are many additional strands to this story, just as historically there have been many strands in unraveling both the mysteries of PCOS and the evolution of the various therapies that may be used in its treatment.

Polycystic ovary syndrome (PCOS) is the most common endocrine dysfunction in women and is by far, the most common diagnosable cause of female infertility. The pathophysiological mechanism of infertility in PCOS is anovulation and therefore, logically, the fertility treatment for PCOS revolves around ovulation induction.

From a historical perspective, PCOS was one of the earliest diagnosed conditions causing female infertility, being described in 1935 by Irving Freiler Stein and Michael Leventhal as amenorrhoea associated with polycystic ovaries . Treatment for PCOS has therefore been the earliest medical and surgical treatments available in the sphere of fertility care—namely the use of clomiphene citrate (CC) and ovarian wedge resection, respectively.

The conventional method of ovulation induction for many decades included the triad of clomiphene (an oral ovulation induction agent), gonadotropin therapy (an injectable ovulation induction agent), and laparoscopic ovarian drilling—which was the surgical ovulation induction successor of ovarian wedge resection.

In the past few years, letrozole has emerged as the oral ovulation induction agent of choice after multiple head-to-head trials with clomiphene.

Despite the emergence of many ovulation induction protocols, there remains a significant role for lifestyle changes that can simultaneously restore fertility and improve long-term health outcomes for women with PCOS and also, perhaps, more importantly, lead both to a healthy pregnancy and improved long term outcomes for the baby. Indeed, there is increasing interest in diet, macronutrient balance, and additional supplements in the management of PCOS.

We will cover the established methods of ovulation induction in use at present and describe ongoing research on predictors of response to ovulation induction, which logically leads to the personalization of ovulation induction protocols, including consideration of genetic variations. We will also present a simple and practical algorithm for the ovulation induction pathway based upon the most recent consensus guidelines for its management .

Etiologies for infertility associated with PCOS

Women with PCOS have a smaller family size and are more likely to require fertility treatment to conceive than their peers without PCOS. However, with access to fertility treatment, the incidence of childlessness is no longer different for women with PCOS when compared to women without this condition . Many etiologies have been described for ovarian dysfunction and reproductive failure associated with PCOS which are summarized below and will have been extensively described in other chapters, these comprise the first part of the labyrinth to be untangled by Ariadne's thread.

Ovarian dysfunction in PCOS is primarily related to disruption of the hypothalamic-pituitary-ovarian axis as evidenced by:

• (1)

  Increased Gonadotropin-Releasing Hormone (GnRH) pulse frequency ,

• (2)

  Raised luteinizing hormone (LH) levels, which is particularly evident in the lean PCOS phenotype, and,

• (3)

  Elevated kisspeptin levels as part of the aberrations of a higher control of the hypothalamic activity .

Ovarian dysfunction noted in PCOS is also influenced by:

• (1)

  Elevated levels of Anti-Mullerian Hormone (AMH) produced by the many follicles of the polycystic ovary which exacerbates FSH (follicle-stimulating hormone) resistance, through inhibition of aromatase activity. Failed conversion of androgen to estrogen leads to chronic hyperandrogenemia, interrupting the follicles’ ability to undergo cyclic recruitment.

• (2)

  Hyperandrogenism, including exposure to hyperandrogenism in utero which forms the basis of the androgen circle hypothesis of PCOS .

• (3)

  Insulin resistance, usually but not invariably associated with obesity, including the serine phosphorylation hypothesis, which aims to provide a unifying hypothesis for insulin resistance and hyperandrogenemia in PCOS .

The endometrial environment also appears to be altered in women with PCOS with alterations in progesterone sensitivity, adhesion molecules, cytokines, the inflammatory cascade, and oxidative status all contributing to subfertility in PCOS .

PCOS and its associated hormonal and metabolic disruption, including overt metabolic syndrome, may affect reproductive health not only by affecting implantation, disruption of pregnancy in all three trimesters but also through altering fetal development and thus compromising long-term health of offspring . There is increasing evidence that the in utero environment may have a profound effect on the life course of the child.

There are significant ethnic variations in the prevalence of PCOS and its component parts with different endocrine and metabolic phenotypes affecting symptoms and reproductive health . In addition to the well-known association between PCOS and disturbances in carbohydrate and lipid metabolism, PCOS also appears to be associated with perturbations in micronutrient homeostasis. This is evidenced by either micronutrient deficiencies (such as vitamin D) or through disturbances in micronutrient metabolism, as exemplified by alterations in the Methylenetetrahydrofolate reductase (MTHFR) gene which plays a crucial role in folate metabolism.

Pretreatment health enhancement

Lifestyle changes should be considered the first-line therapy for women with anovulatory PCOS as it is easily accessible, does not require monitoring, and, more importantly, provides the potential for long-term sustained benefit for reproductive health and may lead to natural conception. Furthermore, there may be improvements both in response to any ovulation induction therapies that may be required and also the long-term health risks associated with PCOS.

PCOS is now being increasingly recognized as much more than a condition affecting fertility with irregular cycles showing an association with premature morbidity and mortality . The impact of PCOS on other facets of life has long been recognized, an obvious example being the cosmetic impact of hirsutism. A study indicated that approximately one in four women with PCOS was initially presented to the dermatologist rather than the gynecologist or the infertility specialist and also stressed the importance that all specialist dealing with PCOS should be familiar with all facets of its presentation and management. PCOS appears to have significant impacts on health, long past the reproductive years with increased risks of developing obstructive sleep apnoea, diabetes mellitus, hypertension, endometrial cancer. It might be complacent to consider these risks as confined to beyond the reproductive years as data indicates that up to a third of women with PCOS may have undiagnosed impaired glucose tolerance or type 2 diabetes mellitus . The impact of PCOS on the risk of developing these long-term complications appears to be greatly influenced by the metabolic environment, with women who have obesity having a greater likelihood of developing these chronic conditions.

Delaying ovulation induction with preconceptional weight loss appears to be a more successful strategy than immediate ovulation induction in obese women . Considering the above, international guidelines recommend that women with PCOS should be advised about the impact of lifestyle factors on their diagnosis and the changes they can implement. Such lifestyle changes should include diet, exercise, and behavioral strategies .