The pathogenic role of androgen excess in PCOS

Introduction

Polycystic ovary syndrome (PCOS) is a very common and rather complex endocrine disorder with significant reproductive and metabolic impact . The overproduction of androgens seems to have a role in its development, hence not just being related to the well-known clinical manifestations of the syndrome and its long-term consequences.

There have been many attempts to explain the development of PCOS. In its origin, a suspected genetic basis has been proposed. The more recent evidence indicates that PCOS is probably a complex polygenic disorder with strong environment influences, notably those associated with obesity.

Genomewide association studies (GWAS) have implicated a significant number of genes in the development of PCOS. These include genes for the gonadotropin receptors LHCGR and FSHR, the beta subunit of follicle-stimulating hormone (FSH), insulin receptor (INSR), YAP1, DENND1A , and THADA . After GWAS, the implicated loci and genetic variants need to have their biologic effect and etiologic significance ascertained by functional studies and this process is still going on without illuminating results. Analyses of rarer genetic variants have produced results that on the whole are even more influential than those with higher allelic frequencies identified in GWAS.

Many genes have been suspected (and confirmed) and are referred to as the most plausible candidate genes. These include genes related to gonadotropin secretion, or action, ovarian folliculogenesis, steroidogenesis, insulin secretion or action, and adipose tissue function, among others . These candidate genes will still have to be fully sequenced in appropriately phenotyped PCOS cases and in appropriately dimensioned patient series in order to identify all coding variants that may be contributing to PCOS. Nevertheless, it is already evident that the androgen production by the ovaries and its action through the androgen receptor (AR), together with all of the modulators contributing to the generation of a hyperandrogenic milieu, are at the center of the genetic background that leads to PCOS development.

Under the concept of polycystic ovary syndrome (PCOS) as a complex genetic trait, adrenal androgen (AA) production and excess is also to be considered a relevant factor for the development of the disorder. Data from girls with premature adrenarche and patients with 21-OH deficient CAH support the role of AA excess in the development of the PCOS phenotype in many patients.

In fact, in many PCOS women, a generalized adrenocortical hyperresponsivity is present, particularly in those with overt AA excess, similar to the ovarian hyperfunction seen in the disorder .

Whatever be the origin of androgens, early androgen excess, in particular, prenatal androgen exposure, has been emerging as a possible trigger for PCOS occurrence later in life, being an example of “Developmental Programming” through which hormones acting during the embryonic period contribute to the development of diseases, and in this case PCOS. The evidence, despite still not being absolute, is compelling and seems to guarantee that this is one of the most important initiating factors for PCOS development.

PCOS clinical aspects

PCOS clinical aspects involve many different symptoms and signs going from hirsutism to menstrual irregularities, from insulin resistance to obesity and finally also infertility. One should also not forget the reduced self-esteem, anxiety, and depression that so frequently affect these women. PCOS is associated with increased metabolic morbidity, including increased adiposity, glucose intolerance, and type 2 diabetes mellitus (T2DM). It has also been suspected to have significant cardiovascular consequences.

Since the adoption of the Rotterdam criteria for the definition of PCOS , an added difficulty in identifying its etiology has resulted from the understanding that more than one phenotype exist, taking into consideration the criteria of the new classification.

PCOS is identified by the presence of 2 of the following 3 possible criteria :

• polycystic ovaries confirmed by ultrasonography,

• hyperandrogenism (either clinical or biochemical), and

• ovulatory dysfunction (defined clinically by significant menstrual irregularities and confirmed by biochemical determination of progesterone levels in the supposed luteal phase in women that maintain menstruation cycles).

Consequently, there are currently four recognized phenotypes of PCOS,

• (1)

  hyperandrogenism + oligoanovulation + polycystic ovarian morphology;

• (2)

  hyperandrogenism + oligoanovulation;

• (3)

  hyperandrogenism + polycystic ovarian morphology; and

• (4)

  oligoanovulation + polycystic ovarian morphology,

each with different long-term health and metabolic implications.

Investigating those different phenotypes has made clear to the scientific community that PCOS is not one single disorder but a group of disorders probably with different etiologies or different weights of the diverse etiologic factors.

Besides, definitions have evolved to encompass even cases without hyperandrogenism and at the same time attempted to expand the possibility of identification of the syndrome, to ages that are not restricted to the span between puberty and menopause, hence posing new challenges in the etiologic understanding of PCOS when ovaries are nonfunctioning and sex steroids, including androgens, are at residual levels.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders, affecting approximately 5%–10% of women of reproductive age. If one considers all the phenotypes resulting from Rotterdam, this prevalence increases to 20% of women in that age span . So, PCOS is considered the most important cause of androgen excess and anovulation in women between 18 and 40 years of age.

Hyperandrogenism is considered to be one of the most important symptoms of PCOS because elevated concentrations of androgens, including testosterone, androstenedione, and dehydroepiandrosterone sulphate, are observed in the majority of patients .

Hyperandrogenism is mainly originated in the ovary, with a possibly significant contribution from the adrenal gland and also the adipose tissue .

It has also been shown that abnormally low concentrations of serum SHBG are observed in women with PCOS and that this contributes to the hyperandrogenic symptoms such as hirsutism and acne . A recent meta-analysis involving 62 articles analyzing the potential relationship between serum SHBG concentrations and the occurrence of PCOS demonstrated that lower serum SHBG concentrations were associated with higher risk of PCOS . These results clearly indicate that a down-regulation of SHBG expression plays an important role in the pathogenesis of PCOS and suggests that serum SHBG concentrations could be used as a biomarker or therapeutic target for the diagnosis and treatment of PCOS.

Some experts have argued that hyperandrogenism should be required for a diagnosis of the polycystic ovary syndrome because it best identifies women at risk for coexisting metabolic conditions. As a group, women with only ovulatory dysfunction and polycystic ovaries have lower cardiometabolic risk than women with classic polycystic ovary syndrome .

The next most important sign in PCOS, ovulatory dysfunction, is typically indicated by unpredictable menses that occur at less than 21-day or greater than 35-day intervals. However, having regular menses that occur every 21 to 35 days do not confirm normal ovulatory function in women with hyperandrogenism since 15 to 40% of women with hyperandrogenism and regular menses have anovulatory dysfunction .

Androgens in PCOS

Androgen excess has been identified in most cases of PCOS, a disorder that was in the past considered an Androgen Excess disorder until the consideration of at least one phenotype without elevated androgens and without hirsutism, by the Rotterdam criteria.

Androgen excess in women with PCOS may be primarily ovarian and/or adrenal in origin. Androgen excess has been studied both clinically by analyzing the levels of different androgens in individual patients and in populations and also by dissecting the enzymatic pathways that leads to their production and their effects in different tissues. Various intracellular pathways, mostly implicated in steroidogenesis and various receptors and postreceptor pathways that are related to androgenic action, have been studied. We now know a lot more than we used to, and, in fact, in recent years even new androgens have been identified and their importance in PCOS is well established. Still, we do not know everything.

Clinically, serum total testosterone and free testosterone, or the free androgen index (FAI-calculated as Total Testosterone/SHBG x100), in conjunction with SHBG, are usually evaluated.

Additionally, androstenedione, DHEA and DHEA-s, 17OH progesterone, and dehydrotestosterone (DHT), as well as the newer androgens 17 keto-testosterone and 17 keto-DHT , are also important for the interpretation of androgen excess conditions and should be included in an evaluation of these patients, with research purposes. All of these are, in fact, needed to the best identification of hyperandrogenism in PCOS and understanding of its physiological role, including the etiopathogenetic influence. Not performing a complete androgen assessment only contributes to not being able to understand the correlation between androgen levels and the clinical symptoms.

Androgens, in women, are produced mainly in the ovaries, but the adrenal and the adipose tissue contributions to the complete picture of circulating androgens should not be forgotten. Androgen synthesis involves several enzymes like the microsomal P450c17 with both 17α-hydroxylase and 17,20-lyase activities. A dysfunction in steroidogenesis, mainly in the androgenic pathway, has been pointed out as having a role in PCOS development .

The ovaries, on the other hand, also seem to be hyperresponsive to luteinizing hormone (LH), and since LH is increased in these patients, its effect is even higher . Increased LH secretion seems to result from a hypothalamic defective response to the feedback inhibition of gonadotropin-releasing hormone (GnRH) secretion. This feedback inhibition normally results from the estradiol and progesterone circulating levels, and in PCOS, this process is impaired as a result of the excessive androgen concentrations .

Hyperinsulinemia, a consequence of the insulin resistance that frequently is observed in PCOS, also contributes to the androgen excess either directly, by stimulation of the theca cells, or indirectly, by inhibiting hepatic synthesis of SHBG, consequently increasing the free (active) fraction of circulating androgens.

Insulin also acts at the adrenal level in synergy with ACTH, thus also increasing the secretion of adrenal androgens . It has been demonstrated that adrenal androgens are increased in 20%–36% of PCOS cases. The importance of this adrenal androgen's excess in PCOS has not been completely elucidated. It has been postulated that it may be important by one of two possibilities: Either the production of adrenal androgens starts precociously, a phenomenon known as early adrenarche, and this precocious hyperandrogenic milieu leads to PCOS; or adrenal androgens overproduction is part of a generalized androgen synthesis occurring in all steroidogenic tissues, in PCOS.

Adrenal androgens can, in fact, be secreted prior to puberty as demonstrated in cases of CAH and NCAH but also in the cases of premature adrenarche in which it was demonstrated that 50% come to develop PCOS .

It has also been reported that P450c17 activity is augmented in the adrenals of PCOS patients who have elevated adrenal androgens. It was suggested that an augmented cortisol metabolization would cause reduced cortisol levels and reduce feedback on the hypothalamus-pituitary axis, leading to an increase in ACTH and consequently to hyperproduction of adrenal androgens . However, ACTH is normally not increased in PCOS women, and so, it is more plausible that there is an overresponsiveness of the zona reticularis of the adrenal cortex to normal levels of ACTH in women with PCOS having increased adrenal androgens .

We may conclude that the evidence of a possible participation of adrenal androgens in the development of PCOS was demonstrated in cases of inherited diseases running with adrenal originated hyperandrogenism (CAH and NCAH) as well as in cases in whom an exaggerated adrenarche with elevated adrenal androgens precedes the development of PCOS, thus allowing us to suspect that one situation is causing the other.

Finally, the influence of excessive adipose tissue on androgen levels has also been recognized, and, in fact, obesity is associated with more severe phenotypes while body weight reduction, at the level of 5%, is associated with androgen levels reduction and an overall improvement of their clinical manifestations .