PCOS in adolescence: Pathophysiology, diagnostic challenges, and therapeutic controversies

Pathophysiology of PCOS during adolescence. The PCOS daughters model

Disturbances during intrauterine life have been implicated in the origin of PCOS and may modify the endocrine and metabolic function of a child born to a mother with PCOS . The concept of androgen exposure during pregnancy and further programming of PCOS in the offspring is based on several animal models and lately human evidence showing that daughters of androgenized females express many PCOS features during development .

To understand the sequence of appearance of the pathophysiological components of PCOS, some years ago our group designed a strategy that involved the assessment of daughters born to mothers with PCOS (PCOSd) at different stages of development. In several studies, we have described early metabolic and reproductive markers of the syndrome that may be modified through interventions that improve the adverse pregnancy environment of PCOS and through the control of acquired detrimental factors such as obesity in childhood and puberty . The recognition of these markers of PCOS and their order of appearance is very important to understand this condition during adolescence. We will use the PCOSd model in this section to approach this issue.

For systematizing purposes, we divide the pathophysiological components of PCOS into 4 groups that appear during development:

• (1)

  Ovarian dysfunction : Higher anti-Müllerian hormone (AMH, a marker reflecting the number of ovarian follicles) and increased ovarian volumes are two characteristic features of PCOSd . During early infancy (2–3 months old) and childhood (4–7 years old), PCOSd showed increased AMH levels . This is the first feature that can be recognized and is a very consistent marker in many studies, staying higher from puberty onwards and associated with increased ovarian volumes in PCOSd until adulthood . More importantly, AMH levels at the hypothalamus increase the pulse frequency of gonadotropin releasing hormone (GnRH) neurons leading to higher LH levels as recently shown in a mouse model were the female offspring of mothers treated with AMH during pregnancy showed this neuroendocrine feature , which may be modulated by hyperandrogenism as well as other environmental and genetic factors. These data link ovarian dysfunction with the next component.

• (2)

  Neuroendocrine dysfunction : In adolescents with PCOS, increased LH has been described as an early feature in the establishment of the syndrome . PCOSd exhibit elevated peak LH levels after leuprolide administration during early postnatal life and in late puberty. In Tanner stages IV and V, basal and postleuprolide stimulated LH concentrations are higher in PCOSd compared with control daughters . Similarly, postmenarcheal PCOS daughters exhibit elevated LH levels and LH to FSH ratio indicating that this neuroendocrine defect remains. Although these alterations are not observed in all adult women with PCOS, probably due to the effect of increased BMI, they seem to be a very strong marker during puberty and after menarche. In this regard, it has been observed that LH levels are negatively correlated with BMI and that obesity reduces the amplitude of the LH pulses , which explains why this feature tends to disappear during adulthood. On the other hand, LH levels are positively correlated with AMH levels in PCOSd during puberty , which supports the previously mentioned mechanism of AMH-stimulated GnRH increased pulse frequency as the current main explanation for this neuroendocrine feature in humans.

• (3)

  Hyperandrogenism : PCOSd exhibit higher basal and peak testosterone levels in Tanner stages IV and V compared to control girls . After menarche, basal testosterone levels and free androgen index (FAI) are higher in PCOSd, which is clinically reflected by an increased Ferriman-Gallwey score. Testosterone levels are associated with LH as it drives androgen production in the ovary and diminishes the ovarian-negative feedback regulation of LH . These findings also support data from animal models were the offspring of AMH-treated mothers also show higher testosterone and LH levels .

• (4)

  Hyperinsulinemia : The fourth component is a higher insulin response in the oral glucose tolerance test (OGTT), which may reflect metabolic disruption, one of the main determinants of the severity of PCOS expression. In this regard, insulin resistance, exacerbated by obesity, plays a major role in the metabolic abnormalities of this syndrome. Nevertheless, the relationship between androgens and insulin is reciprocal and there is evidence that androgens can induce insulin resistance . This feature can be observed before the onset of puberty when biochemical and clinical signs of hyperinsulinemia have been shown in PCOSd . Thus, this metabolic component appears early in life and during puberty it is exacerbated . Prepubertal and pubertal PCOSd show higher poststimulated insulin levels in a glucose tolerance test before the onset of hyperandrogenism, suggesting that insulin may play an early and pivotal role in the pathogenesis of PCOS . This feature remains during the postmenarcheal period and, during adulthood, is associated with key metabolic features commonly associated with PCOS, including increased BMI and larger waist circumference . More importantly, insulin resistance can be aggravated by childhood and pubertal obesity, poor eating habits, and lack of exercise, which are important factors that potentiate the expression of PCOS features during development .

  To show the importance of these models of fetal programming of PCOS on the clinical expression of this condition we evaluated the prevalence of PCOS on PCOSd. Using the Swedish Multi-Generational Register and the National Patient Register, daughters born to women with PCOS had a fivefold increased risk of being diagnosed with PCOS compared to daughters born to women without PCOS. Moreover, following up 21 Chilean daughters of women with PCOS until their twenties, 75% met the Rotterdam criteria for PCOS, showing higher BMI, larger waist circumference and higher diastolic blood pressure, demonstrating clinical metabolic dysfunction, and a higher Ferriman-Gallwey score and FAI, which are markers of clinical and biochemical hyperandrogenism along with higher AMH levels indicating an increased number of growing ovarian follicles . Thus, data regarding PCOSd reflect in a very close way the natural history of this condition and the presentation of PCOS during adolescence.