The Significance of Functional Adrenal Hyperandrogenism in Polycystic Ovary Syndrome across the Lifespan

Abstract

Functional adrenal hyperandrogenism is a common feature of PCOS, observed in roughly 20–30% of affected women. The mechanisms of adrenal hyperandrogenism in PCOS require additional clarification, but seem to be related to increased adrenal sensitivity to ACTH at the level of the adrenal gland. Studies in animal models and in girls at risk for PCOS suggest a potential role for early adrenal androgen exposure in development of PCOS during reproductive maturity. Importantly, adrenal androgens may be elevated in at-risk girls from the time of childhood through menopause, suggesting these androgens are clinically relevant over the lifetime. The presence or absence of adrenal hyperandrogenism is just one of a number of clinical phenotypes which vary among women with PCOS. Recent exciting work has focused on defining distinct subtypes of PCOS based on these distinct phenotypes. This will be an important first step toward development of more individualized treatment approaches in affected women.

In Brief

The adrenal glands are an additional source of hyperandrogenemia in a significant proportion of women with polycystic ovary syndrome (PCOS). This review presents the evidence for the role of adrenal hyperandrogenism in the development and clinical manifestations of the syndrome across the lifetime.

Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in women, affecting 10–15% of women of reproductive age (Dumesic et al., 2015). It is defined by a combination of the clinical criteria of 1) hyperandrogenism, 2) oligo/anovulation, and 3) polycystic ovarian morphology (Dumesic et al., 2015). While not a component of the diagnostic criteria, PCOS is also associated with a consistent metabolic phenotype characterized by insulin resistance, adipose tissue dysfunction, and frequently excessive weight gain (Dumesic et al., 2015). Therefore, PCOS often presents as a very heterogeneous syndrome in women and likely arises from several distinct mechanisms.

The clinical criterion for hyperandrogenism in PCOS can be fulfilled by either clinical hyperandrogenism, represented by hirsutism, refractory acne, and/or androgenic alopecia, or biochemical hyperandrogenism in the form of elevated circulating androgens (Teede et al., 2023). While typically the majority of the androgen load arises from an ovarian source, there is evidence for a contribution of adrenal hyperandrogenemia in roughly 30–50% of women with PCOS (Goodarzi et al., 2015). Questions remain regarding the mechanisms involved in the development of functional adrenal hyperandrogenism (FAH) in PCOS and its significance in the presentation of the syndrome. Increased understanding of these distinct mechanisms would be an important first step toward development of more personalized treatment approaches in women with this common but heterogenous syndrome.

Epidemiology of FAH in PCOS

Androgen levels that are commonly measured in PCOS include total and free testosterone, androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). The steroidogenesis pathway is universal in the gonads and adrenal gland and significant portions of testosterone, androstenedione, and DHEA are produced by the ovary (Figure 1). Over 50% of the total testosterone in the circulation is produced from metabolism of androstenedione in the liver, roughly 25–30% is produced by ovarian theca cells, and the remainder originates from the adrenal cortex (Longcope, 1986). In contrast, DHEAS is a more specific measure of adrenal androgen production, as the sulfatase enzyme is nearly exclusive to the adrenal gland (Goodarzi et al., 2015). Additionally, DHEAS has a long half-life in the circulation, allowing for little diurnal variation and more stable serum levels (Goodarzi et al., 2015). Therefore, circulating DHEAS levels are typically used as a proxy for FAH.

Figure 1.

The diagram illustrates the sequential enzymatic conversions leading from cholesterol to the major classes of steroid hormones: progestogens, glucocorticoids, mineralocorticoids, and androgens. Key intermediate metabolites are shown, including pregnenolone, progesterone, and dehydroepiandrosterone (DHEA). Enzymes catalyzing each step are indicated adjacent to their corresponding arrows, including CYP11A1 and CYP17A1, and hydroxysteroid dehydrogenases (3BHSD and 17BHSD). This pathway occurs primarily in the adrenal cortex, testes, and ovaries. (CYP11A1, side chain cleavage enzyme; 3BHSD, 3-beta-hydroxysteroid dehydrogenase; CYP17A1, Cytochrome P450 Family 17 Subfamily A Member 1; CYB5A, cytochrome B5 type A; SULT2A1, DHEA sulfotransferase; AKR1C3, aldo-keto reductase family 1 member C3; SRD5A1, steroid 5-alpha reductase; CYP11B1, 11-beta hydroxylase; 11BHSD, 11-beta hydroxysteroid dehydrogenase)

Estimates have varied widely regarding the prevalence of FAH in women with PCOS, from 15–60% (2). Initial reports suggested higher prevalence estimates of FAH around 50% of women with PCOS (Hoffman et al., 1984). However, more recent studies using race- and age-matched cohorts have reported lower prevalence, in the range of ~20% in White women with PCOS and ~30% in Black women (Kumar et al., 2005). Epidemiologic studies have suggested that circulating DHEAS levels are negatively associated with age, regardless of ethnicity or PCOS status (Kumar et al., 2005). Studies have also established that DHEAS levels are also associated with body weight, and tend to be higher in normal weight PCOS women compared to women with PCOS and obesity (Moran et al., 2015, Morán et al., 1999).

Assessment of Adrenal vs Ovarian Androgen Production

While circulating DHEAS levels have typically been used as a proxy for FAH in epidemiologic studies, mechanistic studies using dynamic testing protocols have provided additional insight into the origins of androgen excess in women with PCOS.

Dexamethasone suppression can be used to isolate ovarian androgens and more accurately assess ovarian vs adrenal sources for androgen excess in women with PCOS. A long dexamethasone suppression test, using dexamethasone 0.6 mg QID for 4–7 days is typically required for suppression of DHEAS, due to its long half-life (Rosenfield et al., 2011). However, Rosenfield et al have established that a short dexamethasone suppression test (SDAST), completed by administering dexamethasone 0.25 mg/m² can be used to measure T from an ovarian source (Rosenfield et al., 2011). Results from the SDAST correlated well with 17-OHP responses to GnRH stimulation, the gold standard for assessment of functional ovarian hyperandrogenism (Mortensen et al., 2009).

In addition to basal DHEAS levels, DHEA responses to low or high dose ACTH have been used to assess for functional FAH (Ehrmann et al., 1995, Ehrmann et al., 1992, Colak et al., 2002). DHEA, androstenedione, and testosterone responses to a low dose ACTH stimulation test are thought to best represent physiologic differences in PCOS vs control women (Colak et al., 2002).

Ontogeny of PCOS: Insights on FAH from Animal Models

Studies in animal models have provided valuable insight into the mechanisms involved in the development of PCOS and support the view that the pathophysiology of PCOS begins early in life. Several have indicated that exposure to androgens or anti-Mullerian hormone (AMH) during critical developmental periods programs the offspring to develop sustained metabolic and reproductive features of PCOS at reproductive maturity (Stener-Victorin et al., 2020). There are differences in the phenotypes produced by this prenatal exposure among different species and depending on the type and dose of prenatal androgen exposure (Stener-Victorin et al., 2020). Importantly, only primates have an androgen-secreting adrenal fetal zone in fetal life and an androgen synthesizing zona reticularis postnatally (Conley and Bird, 1997), an important consideration in selecting an animal model for the study of the physiology of FAH in PCOS (Abbott and Bird, 2009).

Prenatally-androgenized female monkeys are produced by treating the pregnant mother with androgens during early or late gestation, resulting in male-level circulating levels (Abbott et al., 2008). At the time of reproductive maturity, these animals have evidence for FAH based on elevated circulating levels of DHEA and DHEAS (Zhou et al., 2005, Eisner et al., 2002). ACTH-stimulated DHEA and androstenedione levels are also augmented, while 17-OHP and cortisol are not, suggesting increased activity of 17.20-lyase (Zhou et al., 2005). The mechanism for this persistent increased FAH is not fully established, but one hypothesis is that hyperinsulinemia due to insulin resistance is a factor due to increased serine phosphorylation of 17,20 lyase (Zhang et al., 1995).

Developmental Origins of FAH in PCOS

FAH in Childhood Obesity

There is compelling evidence suggesting a link between excessive weight gain during childhood and adrenal androgen production during the peripubertal years. By the peripubertal years, DHEAS levels tend to be higher in children with obesity, who may develop more clinical manifestations of FAH, such as development of pubic or axillary hair or apocrine body odor. One potential mechanism contributing to this phenomenon is reduced 11β-hydroxysteroid dehydrogenase type 1 activity in the liver, which favors the inactivation of cortisol to cortisone (Sandeep and Walker, 2001). The decreased circulating cortisol levels result in increased ACTH secretion, which contributes to greater degrees of hyperandrogenism (Sandeep and Walker, 2001).

Rapid postnatal weight gain may also contribute to increased DHEAS levels in children during later childhood. Interestingly, DHEAS levels during infancy are positively associated with birth weight, being lowest in infants with the lowest birth weights (Dahlgren et al., 1998, Ibáñez et al., 1999, Norman and Joubert, 1982, Tenhola et al., 2002). However, this relationship changes as children develop, and by age 8 years, DHEAS levels are independently negatively associated with birth weight but positively associated with current weight (Ong et al., 2004). These observations suggest that the more rapid catch up weight gain and its associated development of insulin resistance contribute to increased adrenal androgen production by the time of puberty (Ong et al., 2004).

FAH in Daughters of Women with PCOS

PCOS is highly heritable and daughters of affected women have increased risk, with prevalence estimates of up to 70% (Risal et al., 2019). Therefore, several investigators have studied early reproductive and metabolic phenotypes in daughters of affected women in an effort to understand the developmental origins of PCOS. One study reported elevated DHEAS levels in peripubertal PCOS daughters when compared with girls of comparable age and BMI (Maliqueo et al., 2009). In this study, roughly 1/3 of peripubertal PCOS daughters had evidence of exaggerated adrenarche, with DHEAS levels greater than 2 standard deviations above the matched control mean (Maliqueo et al., 2009). A more recent large study using data from the Danish Birth Cohort found that daughters of women with PCOS had earlier adrenarche, developing pubic hair, axillary hair, and acne on average 5 months earlier than daughters of unaffected women (Lunddorf et al., 2022).

Role of Premature Adrenarche/Pubarche

Adrenarche is the developmental period just prior to puberty characterized by an increase in androgen production from the zona reticularis of the adrenal gland (Ibanez et al., 2000). While this process begins in all children around the age of 6 years, only a small portion of children develop early clinical evidence of virilization such as development of pubic or axillary hair. When this occurs prior to 8 years in girls or 9 years in boys, it is considered premature pubarche (Ibanez et al., 2000). This phenomenon is much more common in girls than boys at a ratio of roughly 10:1 (Ibanez et al., 2000).

There is a well-established literature describing an association with premature pubarche and elevation of adrenal androgens during the peripubertal years with later development of PCOS (Ibañez et al., 1993). This association was first reported by Ibanez et al, who completed leuprolide stimulation testing in postpubertal girls with a history of premature adrenarche (Ibañez et al., 1993). These investigators found that baseline DHEAS and androstenedione levels at the time of premature adrenarche diagnosis were positively associated with leuprolide-stimulated 17-OHP post-menarche, indicative of functional ovarian hyperandrogenism (Ibañez et al., 1993). Roughly half of these girls had clinical evidence of PCOS based on the criteria of oligomenorrhea and clinical hyperandrogenism (Ibañez et al., 1993, Ibáñez et al., 1994). This finding may suggest that increased cytochrome P450C17 activity in both the adrenals and ovaries could be a common mechanism for premature adrenarche and PCOS, beginning in the adrenal during adrenarche, and subsequently occurring in the ovary, leading to signs and symptoms of functional ovarian hyperandrogenism (Ibanez et al., 2000). Adrenal androgen production was reassessed post-menarchally in these girls and over half of girls studied had exaggerated responses of 17-OHP, DHEAS, androstenedione to ACTH, suggestive of persistent FAH (Ibáñez et al., 1994). Measures of insulin sensitivity were negatively associated with leuprolide-stimulated 17-OHP levels in these girls, suggesting a role for insulin resistance and hyperinsulinemia in development of functional ovarian hyperandrogenism (Ibanez et al., 1996). The constellation of small for gestational age birth, rapid weight gain during infancy, and exaggerated adrenarche seems to be particularly predictive of later development of FAH and PCOS (Ibáñez et al., 1998, de Zegher et al., 1998).

Congenital Adrenal Hyperplasia (CAH)

Studies investigating the reproductive phenotype of women with 21-hydroxylase deficiency provide more evidence for a relationship between FAH and other features of the PCOS reproductive phenotype. This form of CAH is an autosomal recessive Mendelian genetic disorder resulting in varying degrees of reduced activity of 21-hydroxylase, resulting in relatively reduced production of cortisol and aldosterone and increased production of adrenal androgens (New, 2006). In the milder nonclassic form, affected patients are able to produce normal cortisol levels but at the expense of increased adrenocorticotropic hormone levels, resulting in increased production of adrenal androgens (New, 2006). The standard of care for control of clinically significant FAH in these patients is cortisol replacement with hydrocortisone. However, even in well-managed patients, this regimen is unable to replicate the normal hypothalamic-pituitary-adrenal axis feedback and persistent periods of persistent FAH occur (New, 2006). Some postmenarchal female patients with 21-hydroxylase deficiency develop a similar reproductive phenotype to that observed in PCOS, independent of FAH (Hague et al., 1990, Levin et al., 1991, New, 2006). Reported phenotypes include neuroendocrine differences such as a relative increase in LH:FSH (Levin et al., 1991), and differences in folliculogenesis, resulting in development of polycystic ovarian morphology (Hague et al., 1990, New, 2006). These associated phenotypes suggest a contribution of hyperandrogenemia to development of these extra-adrenal phenotypes.

Mechanisms of FAH in PCOS

Increased sensitivity to ACTH

Several studies suggest that ACTH levels and responsiveness of ACTH to CRH are normal in women with PCOS, suggesting FAH is not related to neuroendocrine factors (Chang et al., 1982, Azziz et al., 1998). Rather, there is evidence that the subset of women with PCOS and elevated DHEAS levels have increased adrenal sensitivity to ACTH. Women with PCOS and FAH have an exaggerated response to ACTH, including the androgens DHEA and androstenedione, as well as pregnenolone, 17-hydroxypregnenolone, 11-deoxycortisol, and cortisol (Goodarzi et al., 2015, Azziz et al., 1998, Carmina and Lobo, 1990, Glintborg et al., 2005).

Hyperinsulinemia

There is a well-recognized relationship between hyperinsulinemia and androgen excess in women. Insulin resistance and compensatory hyperinsulinemia results in reduced hepatic production of sex hormone binding globulin (SHBG), resulting in a proportional increase in biologically active free testosterone (Nestler et al., 1991). Some studies suggest that increased insulin resistance and hyperinsulinemia, along with increased IGF-I activity during puberty, are inducing factors in the development of PCOS (Nobels and Dewailly, 1992). Both insulin and IGF-I can stimulate ovarian thecal-interstitial cells to secrete androgens (Nobels and Dewailly, 1992). Post-pubertally, there continues to be an association between hyperinsulinism and functional ovarian hyperandrogenism (O’Meara et al., 1993), and PCOS (Dunaif et al., 1989) in lean and obese women. In patients with severe forms of insulin resistance such as type A and B insulin resistance, improvement in hyperinsulinism results in resolution of the often severe hyperandrogenism associated with these disorders (DeClue et al., 1991).

The association between insulin resistance/hyperinsulinemia and FAH is less clear. There is in vitro evidence that insulin and IGF-1 can enhance ACTH responsiveness of human adrenocortical cells in culture and augment adrenal androgen production (Lebrethon et al., 1994, Cara and Rosenfield, 1988). In clinical studies, insulin sensitivity measured by frequently-sampled IV glucose tolerance test in prepubertal girls was inversely correlated with ACTH-stimulated levels of 17-OH Preg and the ratio of 17-OH Preg/17-OHP, suggestive of functional FAH (Oppenheimer et al., 1995). Further supporting this association, multiple studies have reproducibly demonstrated decreased adrenal androgen production after improvement in insulin sensitivity with troglitazone (Azziz et al., 2003, Dunaif et al., 1996).

Peripheral conversion of androgen precursors in adipose tissue

In addition to the ovary and adrenal gland, adipose tissue represents another source for androgen production (Figure 2). Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme which is active in adipocytes and catalyzes conversion of weaker androgen precursors into the more potent androgen end products testosterone, dihydrotestosterone (DHT), 11-ketotestosterone (11KT), and 11-keto-5α-dihydrotestosterone (11K-DHT) (Paulukinas et al., 2022). Insulin induces AKR1C3 activity, resulting in increased production of these androgens in women with insulin resistance and resulting hyperinsulinemia (O’Reilly et al., 2017b). Additionally, in vitro studies have suggested that AKR1C3 expression is higher in adipocytes from women with PCOS compared with controls (O’Reilly et al., 2017b).

Figure 2.

This figure outlines glandular sources of androgen production and metabolism. There are multiple complex interactions between these tissues involved in the production of androgens (hormones exported to tissues are highlighted in orange and hormones imported from tissues are highlighted in blue). In the ovaries, LH stimulates ovarian theca cells to produce DHEA, which can be converted to androstenedione and testosterone. The adrenal glands also produce DHEA, androstenedione, and testosterone through various steroidogenic enzymes, and additionally convert DHEA to DHEAS via sulfatase enzyme. In the kidneys, there is conversion of androgen precursors to more active forms of androgen, including 11-oxygenated androgens. Adipose tissue also plays a role in androgen production by promoting conversion of androstenedione to testosterone via aromatase activity. Collectively, these pathways contribute to the hyperandrogenic phenotype seen in PCOS. (LH, luteinizing hormone; FSH, follicle stimulating hormone; DHEA, dehydroepiandrosterone; 11OHA4, 11β-hydroxyandrostenedione; 11OHT, 11β-hydroxytestosterone; 11OHDHT, 11β-hydroxydihydrotesterone; DHT, dihydrotestosterone; 11KA4, 11-ketoandrostenedione; 11KT, 11-ketoterosterone; 11KDHT, 11-ketodihydrotestosterone).

Association of FAH with Metabolic Phenotypes in PCOS

Despite the evidence for an association between FAH in PCOS and hyperinsulinemia/insulin resistance, epidemiologic data suggests that FAH is associated with a more benign metabolic phenotype compared with PCOS women without FAH. A number of studies have reported that PCOS women with FAH tend to be younger, thinner, and more hirsute than women with normal DHEAS levels (Morán et al., 1999). These investigators later reported that the frequency of hyperandrogenemia by increased androstenedione, DHEA, and DHEAS was significantly higher in lean PCOS women compared with those with high BMI (Moran et al., 2015, Carmina and Lobo, 2007). One study reported lower risk for insulin resistance, metabolic syndrome, and impaired glucose tolerance among PCOS women with elevated DHEAS when compared with PCSO women with elevated free T (Lerchbaum et al.). However, more recent studies using hierarchical clustering to characterize phenotypic subtypes of PCOS found that DHEAS did not stratify to either the reproductive or metabolic phenotypes identified (Dapas et al., 2020, van der Ham et al., 2024).

11-Oxygenated Androgens in PCOS

In addition to the more classically measured androgens DHEAS, DHEA, and androstenedione, the adrenals are also the principal source of 11-oxygenated metabolites of androstenedione and testosterone (Figure 2). Through the function of 11β-hydroxylase, androstenedione and testosterone are metabolized to 11β-hydroxyandrostenedione (OHA4) and 11β-hydroxytestosterone (11-OHT), respectively, in the adrenal gland (Turcu et al., 2020). These metabolites are then converted, primarily in peripheral tissues, to 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) (Turcu et al., 2020). In contrast, 11-OHA4 and 11-OHT undergo oxidation primarily in the peripheral circulation through the function of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) (Turcu et al., 2020). In addition, 11KA can be reduced in the periphery to 11KT through the function of AKR1C3 (Rege et al., 2014). Similar to androstenedione, 11OHA4 and 11KA4 have somewhat limited androgenic potency (Rosemberg and Dorfman, 1958). However, 11KT has androgen activity comparable to that of testosterone, suggesting it may be clinically relevant in premature adrenarche, PCOS, CAH, and other androgenic disorders (Rege et al., 2013).

In contrast to gonadal steroids, circulating levels of 11-oxygenated androgens are significant across the lifespan. Prior to puberty, 11KT levels exceed those of testosterone in both sexes (Rege et al., 2018). During the reproductive years, 11KT levels in women are comparable to circulating levels of testosterone (Nanba et al., 2019). During the menopause transition, DHEA and DHEA levels drop significantly. However, 11KT and 11OHA4 levels remain stable or even increase slightly during these years (Nanba et al., 2019). Given its significant circulating levels and bioactive potency, 11KT is likely the primary clinically significant androgen in women during the prepubertal and postmenopausal years in women (Turcu et al., 2016).

Several studies have demonstrated that 11-oxygenated androgens are elevated in women with PCOS, providing additional evidence of an adrenal contribution to the hyperandrogenemia in some of these women (O’Reilly et al., 2017a). However, the clinical significance of these androgens in PCOS remains unclear as one recent study found that elevation of 11-OHT and/or 11-KT was poorly predictive of both clinical hyperandrogenism and elevated circulating levels of classical androgens (Tosi et al., 2022).

As in the case of ovarian androgens, there is some evidence that insulin resistance may potentiate production of 11-oxygenated adrenal androgens. One interesting study compared 11-oxygenated androgen levels in women with severe insulin resistance secondary to lipodystophy compared with insulin receptoropathy (Walzer et al., 2022). These investigators found that 11-oxygenated androgen levels were increased in lipodystrophy but not insulin receptoropathy compared with controls (Walzer et al., 2022). This observation suggests that these adrenal androgens are modulated by post-receptor insulin signaling. This may represent a potential mechanism for the elevated levels observed in PCOS.

Recently, investigators sought to investigate the diagnostic value of elevated 11-oxygenated androgens in PCOS (Mody et al., 2025). Like total testosterone and androstenedione, all four 11-oxyandrogens were elevated in women with PCOS compared to controls, controlling for age and BMI (Mody et al., 2025). Using logistic regression models, these investigators demonstrated that the four 11-oxyandrogens were more predictive of PCOS compared to the classical androgens of testosterone and androstenedione. When considered in isolation, 11KA levels were most predictive of PCOS, again outperforming total testosterone and androstenedione levels (Mody et al., 2025). These findings suggest that measurement of 11-oxygenated androgens may be useful in the diagnosis of PCOS in the clinical setting.

PCOS in Menopause: Role of Adrenal Androgens

In addition to the decline in estradiol levels, natural menopause is associated with a decrease in circulating androgens (Burger et al., 2000). During the menopausal years, the differences in the metabolic and reproductive phenotypes of PCOS women compared with unaffected women become less significant, as reproductively-normal women often develop worsening insulin resistance and both groups develop anovulation (Schmidt et al., 2011). However, there is evidence suggesting that FAH is persistent in women with PCOS following menopause, as basal and ACTH-stimulated androgen levels remain elevated in PCOS compared with control women following the menopausal transition (Markopoulos et al., 2011). However, the clinical significance of these increased adrenal androgens during menopause remains unclear.

Conclusion

In 20–30% of affected women, the adrenal gland is a significant source of hyperandrogenemia, one of the critical components of the PCOS phenotype (Goodarzi et al., 2015). Importantly, these androgens may be elevated in affected women over much of the life course, from the time of adrenarche through menopause (Welt and Carmina, 2013). Many daughters of women with PCOS and girls with premature adrenarche have both early FAH and increased risk for development of PCOS, raising a question regarding a potential mechanistic role for exposure to FAH in the mechanisms of PCOS (Ibanez et al., 2000).

PCOS has significant clinical heterogeneity and recent efforts have sought to characterize specific subgroups within the clinical diagnosis of PCOS (Dapas et al., 2020, van der Ham et al., 2024). These studies have identified discrete metabolic and reproductive subtypes with distinct genetic associations (Dapas et al., 2020, van der Ham et al., 2024). How the finding of FAH contributes to the definition of the PCOS subtypes remains unclear but will be a critical area of investigation. Better characterization of the distinct mechanisms and subtypes of PCOS are a necessary first step towards development of more effective and individualized therapy.