The Landscape of Androgens in Cushing’s Syndrome

Abstract

Hyperandrogenemia in patients with Cushing’s syndrome (CS) presents a diagnostic pitfall due to its rare occurrence and overlapping symptoms with more common conditions like polycystic ovary syndrome (PCOS). This review explores the significance of androgen dysregulation in CS, focusing on both classical and 11-oxygenated androgens. While classical androgens contribute to hyperandrogenism in CS, their levels alone do not fully account for clinical symptoms. Recent research highlights the overlooked role of 11oxC19 androgens, particularly 11OHA4 and 11KT, in driving hyperandrogenic manifestations across all CS subtypes. These adrenal-specific and highly potent androgens offer stable expression throughout the lifespan of a woman, serving as valuable diagnostic biomarkers. Understanding their prominence not only aids in subtype differentiation but also provides insights into the complex nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches and improve clinical management strategies for patients with CS.

 

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Keywords

Cushing’s syndrome - androgens - 11-oxygenated androgens - hyperandrogenemia

Introduction

Cushing’s syndrome (CS) is a rare disease with a prevalence of approximately 0.002% [1]. It is defined as a state of cortisol excess with loss of normal hypothalamic-pituitary-adrenal (HPA) axis feedback loops and disturbed circadian rhythmicity of circulating cortisol levels [2]. The most common form of CS is exogenous glucocorticoid excess. Endogenous CS is, in about 80% of cases, caused by ACTH-dependent CS and about 20% by an ACTH-independent adrenal oversecretion of cortisol. Of those patients with endogenous CS, 70% are due to excessive secretion of adrenocorticotropic hormone (ACTH) by pituitary adenomas, also known as ACTH-dependent CS, and about 10% are due to ectopic ACTH-secreting tumors [3] [4].

Patients with CS usually present with a broad range of clinical symptoms, some of which resemble the clinical phenotype of patients with polycystic ovary syndrome (PCOS) [2] [5] [6] [7] [8]. As PCOS, with a prevalence of up to 18% in women, is far more common, CS is sometimes initially misdiagnosed or the final diagnosis delayed, which can have detrimental effects on morbidity and mortality of the disease [9] [10].

To optimize the diagnostic work-up in these patients with clinical signs of hyperandrogenism, pathogenesis in CS must be properly understood. So far, hyperandrogenism in ACTH-dependent CS has been proposed to be due to several different causes, such as a hypercortisolemic inhibition of gonadotropins production at the pituitary level [11], reduced production of sex hormone binding globulin (SHBG) by the liver resulting in an increased percentage of bioactive available androgens or an actual ACTH-mediated elevation of classical adrenal androgen concentrations [11] [12] [13] [14] [15]. As adrenal androgen synthesis is ACTH-dependent, concentrations of androgen precursors vary depending on the subtype of CS. ACTH-dependent CS and CS due to ectopic ACTH production result in elevations of adrenal androgen concentrations, while levels of androgens in patients with CS due to adrenal cortisol production are low to suppressed [12] [16]. The clinical hyperandrogenic phenotype in patients with CS is, however, not sufficiently explained by just the elevation in classical androgen concentrations, for example, in a comparison of hirsute and non-hirsute females with ACTH-dependent CS, no discernible difference in adrenal androgen concentrations were observed [11]. Just recently, adrenal-specific 11-oxygenated androgens have been shown to play a major role in hyperandrogenemia in patients with ACTH-dependent CS [17]. While the direct stimulation via ACTH was proposed to be responsible for the elevation of this subgroup of androgens, further analysis of different subtypes of CS, however, revealed elevations among all patient subgroups with an inverse relationship between 11-deoxygenated and 11-oxygenated androgens in adrenal CS [17].

This review aims to further elucidate the significance of androgen elevations in patients with CS.

 

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Androgen synthesis in women

In women, the ovaries, adrenal glands, and peripheral tissues are involved in androgen synthesis and metabolism ([Fig. 1]) [18] [19] [20]. Most androgen precursors are 19 carbon (C19) steroids, such as dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4), and are synthesized in the adrenal cortex, more specifically in the zona reticularis (ZR), after stimulation by the pituitary hormone ACTH [21]. Androgen precursors, which do not exhibit high androgenic potency, are further converted to the highly potent androgen testosterone (T) and 5α-dihydrotestosterone (DHT), mainly in the ovaries and peripheral tissues, but to a small extent also in the adrenal gland [21] [22].

Fig. 1 Androgen synthesis in females. Illustration depicting adrenal (orange), ovarian (blue) and peripheral (red) androgen synthesis in females. [rerif]

This implies that DHEA and DHEAS are predominantly of adrenal origin, while A4 production is equally achieved by both ovarian and adrenal steroid synthesis. In the adrenal gland, C19 steroids DHEA and DHEA-S are converted to A4 via the enzyme β-hydroxysteroid dehydrogenase type 2 (HSD3B2) [21] [23].

Ovarian androgen synthesis is regulated mainly by the pituitary production of luteinizing hormone (LH) and takes place in the ovarian thecal cells. As in the adrenal cortex, T, A4, and DHEA result from the conversion of cholesterol and pregnenolone via the cholesterol side-chain cleavage enzyme and 17α-hydroxylase [24].

Adipose tissue is an important peripheral tissue of androgen metabolism. Insulin is also a potent regulator through direct stimulation of thecal cell androgen production, by potentiating the function of LH on the ovaries, stimulating androgen production, and by suppressing hepatic SHBG production, thus increasing free circulating T concentrations [25]. In women with PCOS and simple obesity, insulin was shown to upregulate AKR1C3 expression, promoting peripheral A4 to T conversion [26].

Skin, liver, brain, and breast tissue are further peripheral tissues involved in the conversion of DHEA to A4 via 3βHSD1 and 2 [27] [28]. T can then also further be reduced to DHT via 5α-reductase (5αR), which has the highest androgenic potential [29].

In the same way as in classical androgen synthesis in the adrenal gland, 11-oxygenated androgen (11oxC19) synthesis starts with the Δ⁵-pathway, where pregnenolone is converted to DHEA via cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) [24] [30]. The following synthesis steps are illustrated in [Fig. 1]. Of the A4, which is the result of conversion from DHEA via HSD3B2, some is converted to 11β-hydroxyandrostenedione (11OHA4) via cytochrome P450 11β-hydroxylase (CYP11B1) [31]. 11OHA4 is the most abundant 11oxC19 steroid in the adrenal cortex [32]. To a lesser degree, 11-ketoandrotenedione (11KA4) and 11-ketotestosterone (11KT) are produced via CYP11B1 and mainly result from peripheral conversion of adrenal-derived 11OHA4 [32]. More precisely, 11OHA4 can be converted to 11KA4 by 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), which is highly prevalent in the kidney [33]. Peripheral tissues, such as adipose tissue, express high levels of aldo-keto reductase 1C3 (AKR1C3), which can convert 11KA4 to 11KT [24] [34]. Adipose and other tissues responsive to glucocorticoids produce an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts 11KA4 and 11KT to 11OHA4 and 11β-hydroxytestosterone (11OHT), respectively. 11OHT can be converted to 11KT in mineralocorticoid target tissues in a similar way like 11OHA4 [35]. 11KT can also be converted back to 11OHT by the enzyme HSD11B1 in peripheral tissues [36] [37]. Other oxidative enzymes like 17β-hydroxysteroid dehydrogenases can convert 11KT and 11OHT to 11KA4 and 11OHA4 [34] [37]. Furthermore, 11KT can be further reduced to 11-keto-5α-dihydrotestosterone (11KDHT) [34]. 11KT and 11KDHT are highly potent androgens that activate the androgen receptor with the same affinity as T and dihydrotestosterone (DHT) [38] [39].

Regarding 11oxC19 androgen synthesis, it is important to consider its dependency upon ACTH, which results in circadian patterns of circulating 11oxC19 concentrations, closely resembling cortisol circadian rhythmicity with highest levels in the early morning and declining salivary and serum concentrations over the day [40] [41]. The diagnostic benefit and potential of 11oxC19 androgens originate from their stable expression throughout the lifespan. In contrast to classical adrenal androgens DHEA and DHEA-S, which decline in postmenopausal women due to involution of the ZR [42] [43] [44] [45] [46] [47] [48] [49], 11oxC19 androgen concentrations do not decline with age and are therefore of higher prevalence than T and A4 concentrations in postmenopausal women [50]. In humans, concentrations of DHEA and DHEA-S show a rapid decline right after birth until adrenarche [51]. During adrenarche, between ages 6–10 years, a marked increase in adrenal cortex androgen synthesis is observed [52]. During this period, the distinct ZR forms exhibit a slight alteration in enzyme expression compared to the zona fasciculata (ZF). The expression of cytochrome b5, which facilitates the 17,20-lyase activity of CYP17A1, is upregulated, whereas the expression of 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2) is downregulated [52]. Before the re-discovery of 11oxC19 androgens and investigation of their clinical relevance, adrenarche was attributed to increased synthesis of DHEA and DHEA-S [53]. In 2018, however, one study comparing steroid production in girls during adrenarche compared to premature adrenarche found that 11KT is actually the dominant bioactive androgen in these patients [38]. In postmenopausal women, involution of the ZR results in the ZF containing 3β-hydroxysteroid-dehydrogenase (HSD3B2) and the ZR containing cytochrome B5 type A (CYB5A), to become closely juxtaposed. Consequently, this proximity allows for the conversion of DHEA to A4 and the subsequent formation of 11oxC19 androgens [50]. In reproductive-age women, 11KT and T levels are similar. During postmenopause, the 11KT to T ratio increases, suggesting 11KT as the primary mediator for processes like adrenarche in prepubertal children and postmenopausal women due to its comparable androgenic potency to T [22].

Besides their relevance in premature adrenarche, 11oxC19 androgens have been described as potential diagnostic and therapeutic monitoring tools in other endocrine disorders, such as congenital adrenal hyperplasia (CAH). Owing to their ACTH dependence and adrenal specificity, 11oxC19 androgens have been proposed as biomarkers of androgen excess in CAH due to 21-hydroxylase deficiency (21OHD). In patients with 21OHD, concentrations of 11oxC19 androgens are usually up to fourfold higher than in healthy controls [33] [41]. Especially in male patients with 21OHD, 11KT has been found to better resemble disease control compared to T. Levels of 11KT and 11OHT inversely correlate with T and luteinizing hormone concentrations, suggesting suppression of the hypothalamic-pituitary-gonadal axis and testicular T synthesis in poorly controlled male patients with 21OHD [33] [54]. 11OHT and 11KT concentrations were also significantly higher in patients with testicular adrenal rest tumors (TART) – which results from poor disease control – and also in female patients with menstrual disturbances compared to those patients without [54]. In patients with PCOS and clinical signs of hyperandrogenism, the origin of androgen excess is diverse. While traditionally, the ovaries have been identified as the primary source of heightened androgens in PCOS, emerging clinical and biochemical evidence suggests a nuanced perspective [55] [56] [57] [58] [59] [60] [61] [62]. The 11oxC19 androgens, particularly 11OHA4 and 11KA4, have garnered attention as significant contributors to the androgen pool in this disorder [11] [63] [64]. This, as along with increased DHEA and DHEA-S concentrations in some patients with PCOS, points towards adrenal involvement [60] [61]. Besides elevations in 11oxC19 androgens, studies could also demonstrate correlations to factors, including body mass index, insulin levels, and homeostatic model assessment-insulin resistance, as important evaluation parameters for metabolic risk in these women [11]. Moreover, the adrenal hyper-reactivity to ACTH stimulation also implies a distinct adrenal role in certain PCOS cases, shedding light on the complexity of androgen regulation in this syndrome [62] [65].

 

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Androgens in adrenocorticotropic hormone-dependent Cushing’s syndrome

Signs of hyperandrogenism, such as menstrual disturbances, acne and hirsutism are common in female patients with ACTH-dependent CS. Baseline data from the European Registry on CS (ERCUSYN) on 481 CS patients collected from 36 centres in 23 countries revealed presence of skin alterations in 78% of patients with ACTH-dependent CS, hirsutism and menstrual irregularities in 63% and hair loss in 34% of patients with ACTH-dependent CS [7]. Another study on 45 premenopausal women with ACTH-dependent CS discovered an even higher rate of 80% of menstrual irregularities at the time of disease diagnosis, with amenorrhea being the most prevalent type of menstrual dysregulation [66]. Despite the presence of clinical signs of hyperandrogenism, the cause of hyperandrogenism in these patients was, for a long time, not sufficiently understood, but is most likely of multifactorial origin ([Fig. 2]). One plausible rationale for the extent of hyperandrogenism in these individuals has been postulated to involve heightened concentrations of classical androgens coupled with diminished levels of SHBG. This interplay leads to elevated concentrations of unbound androgens, facilitating efficient binding to androgen receptors. Levels of classical androgens DHEA-S, A4, and T have, however, only rarely been found to be elevated [11]. A study evaluating androgen concentrations in a subset of 36 women with ACTH-dependent CS, mostly due to ACTH-dependent CS (30/36) revealed elevations in DHEA-S in 8/30 patients, A4 elevations in 18/30 and T elevations in 17/30 cases, with normalization of androgen levels after pituitary surgery. In patients with ectopic ACTH secretion, A4 elevations were higher compared to those with ACTH-dependent CS [12]. Another study on 47 patients with ACTH-dependent CS and six patients with ectopic CS also presented elevated levels of androgens and their metabolites compared to a healthy control cohort [15]. In other studies, DHEA-S, A4 and T have been shown to be in the normal reference range mostly [13] [67] or DHEA-S elevations, at least in some patients (11/37) with ACTH-dependent CS, while the majority (70% of patients) however also presented with DHEA-S levels within the reference range [68]. Another retrospective study on 222 patient samples tested for CS with analysis of a panel of 15 plasma steroid hormones via mass spectrometry, identified higher concentrations of adrenal androgens A4, DHEA, and DHEA-S in ACTH-dependent CS compared to adrenal CS. DHEA-S levels were shown to be higher in patients with ACTH-dependent CS compared to healthy patients without hypercortisolism [14]. We have moreover learned from a study on pediatric patients with ACTH-dependent CS that those patients with excessive clinical symptoms of virilization actually go in hand with elevations of classical androgens A4, DHEA-S, and T and also decreased SHBG levels in a direct comparison to those patients with ACTH-dependent CS without clinical signs of virilization [69].

Fig. 2 Multifactorial origin of hyperandrogenism in ACTH-dependent and ACTH-independent Cushing’s syndrome. Hyperandrogenemia in ACTH-dependent Cushing’s syndrome seems to result from multifactorial origin due to hypercortisolemic inhibition of the production of gonadotropins LH and FSH at the pituitary level and inhibition of the release of gonadotropin-releasing hormone synthesis at hypothalamic level (left); due to reduced direct stimulation of adrenal androgen production and decreased SHBG synthesis, which results in increased percentage of bioactive available androgens (middle) and direct stimulation of 11oxC19 androgen synthesis due to increased ACTH concentrations (right). Hyperandrogenemia in ACTH-independent Cushing’s syndrome is most likely the result of the direct conversion of approximately 10% of cortisol to 11oxC19 androgens. ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; 11oxC19, 11-oxygenated androgen. [rerif]

Despite some reports of elevations of classical androgens in patients with ACTH-dependent CS, they do not sufficiently explain the pronounced clinical symptoms as described above. Another contributing factor to menstrual disturbances in patients with ACTH-dependent CS may be attributed to diminished gonadotropin concentrations. Analysis of 45 female patients with ACTH-dependent CS with menstrual irregularities in 80% of these patients revealed positive correlations of menstrual cycle disturbances and cortisol levels as well as inverse correlations with E2 concentrations, while gonadotropin levels were, however, still in the normal range. Therefore, Lado-Abeal et al. suggested at least menstrual irregularities are the results of a hypercortisolemic inhibition of hypothalamic gonadotropin production, rather than high androgen concentrations [66]. White et al. confirmed in 22 patients with CS that gonadotropin levels were only subnormal in patients with the highest elevation in cortisol levels [70]. Instead of increased androgen concentrations, inverse correlations of urinary free cortisol and SHBG, estradiol, and T were also observed in a second study on 13 women with CS, while again, serum E2 levels were similar to those in patients in the early follicular phase of the menstrual cycle and only low in seven of the 13 women with CS [67].

More recent data from our lab revealed the relevance of 11oxC19 elevations for hyperandrogenism in patients with ACTH-dependent CS. We measured elevated levels of 11oxC19 androgens 11OHA4 and 11KT in saliva day profiles of 23 female patients with ACTH-dependent CS compared to healthy controls, while A4, T, and DHEA-S levels were comparable to those of controls and gonadotropin concentrations also in the normal range [17]. We could also demonstrate normalization of salivary 11oxC19 androgen concentrations after successful transsphenoidal surgery in 13 of the patients mentioned above as well as in those medically controlled with Osilodrostat or metyrapone treatment [17]. ACTH-dependence was also confirmed by a positive correlation between the decrease of 11oxC19 steroids in saliva and their urinary metabolites and ACTH concentrations. We, therefore, concluded that ACTH stimulation in ACTH-dependent CS leads to direct adrenal stimulation of 11oxC19 synthesis and that elevated 11oxC19 androgen concentrations are the most relevant factor for hyperandrogenemia in this patient cohort, which could also be supported by correlations of cortisol and cortisone levels and 11OHA4 concentrations as well as cortisol/cortisone and ACTH concentrations. However, disturbances of the HPA axis were not observed in our study cohort; moreover, as 11oxC19 estrogens seem not to be aromatizable in vivo, symptoms of hyperandrogenemia in ACTH-dependent CS seem to rather result from the direct androgenic effect of 11oxC19 steroids on skin, hair, and ovaries, than due to disturbance in the HPG axis [17] [34].

In conclusion, the clinical signs of hyperandrogenism in ACTH-dependent CS appear to be multifactorial, stemming from a combination of dysregulations involving cortisol levels, hypothalamic-gonadotropin inhibition, and altered classical and 11oxC19 androgen concentrations, however, the major relevance of 11oxC19 androgens has so far been neglected as 11oxC19 concentrations have not been routinely measured in patients with ACTH-dependent CS.

 

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Androgens in adrenocorticotropic hormone-independent Cushing’s syndrome

Patients with CS due to adrenal origin of cortisol excess present with similar clinical signs of hyperandrogenism [67], although, to a lower degree in comparison to ACTH-dependent subtypes of CS [71]. In contrast, in all studies comparing concentrations of androgens between the different subtypes of CS, patients with adrenal disease had the lowest concentrations of androgens [14]. Further studies evaluating androgen concentrations in comparison to a healthy control cohort demonstrated significantly lower levels of classical androgens DHEA, DHEA-S, and A4 in both patients with adrenal adenomas and primary bilateral macronodular adrenocortical hyperplasia (PBMAH) [15] [72]. Further studies analyzing the recovery of DHEA-S secretion after achieving remission of CS due to unilateral adrenalectomy in patients with CS due to adrenocortical adenoma revealed persisting suppression of DHEA-S levels for a further two years [68].

Urinary steroid metabolome analysis by gas chromatography-mass spectrometry in a cohort of 168 patients with CS, including 44 patients with ACTH-dependent CS, 18 with adrenal adenoma, and 13 patients with PBMAH as well as 93 healthy controls, revealed a striking increase in excretion rates of all adrenal androgen metabolites in patients with ACTH-dependent CS with 1.5 times higher levels of 11-deoxygenated androgens and 2.7 higher 11oxC19 androgen concentrations compared to the levels in the control group [73]. This resulted in an increased ratio between the 11oxC19 androgens and the 11-deoxygenated adrenal androgen levels. In the same way, 11oxC19 androgen concentrations were elevated 1.6 times in patients with CS due to unilateral cortisol-producing adrenal adenoma, most likely due to the high expression of CYP11B1 in these adrenal adenomas [74]. In those patients however, levels of classical androgens were rather low as expected due to the lack of ACTH-stimulation, resulting in an inverse relation and an even higher ratio of the 11oxC19 androgens and the 11-deoxygenated adrenal androgens. In patients with PBMAH, 11oxC19 androgen concentrations were even further elevated up to 2.3 times those of the control cohort, while classical androgen metabolites were downregulated 0.5 times in comparison to healthy controls, however not as much as in those patients with unilateral adrenal CS [73]. The elevation of 11oxC19 androgens in patients with CS is further exacerbated by the direct conversion of approximately 10% of cortisol to these androgens [75]. As we have demonstrated that these 11oxC19 androgens predominate in all forms of CS, it is most likely that they are also responsible for the clinical signs of hyperandrogenism, such as menstrual disorders, acne, and hirsutism in all subtypes of CS. To distinguish between the two major subtypes of ACTH-dependent and ACTH-independent CS, estradiol and SHBG concentrations, as well as the ratio of 11oxC19 to classical androgen concentrations, should therefore be considered ([Fig. 2]).

 

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Conclusion

In conclusion, a nuanced understanding of androgen dysregulation in CS reveals the multifactorial nature of hyperandrogenism, involving cortisol levels, gonadotropin inhibition, and alterations in both classical and 11oxC19 androgen concentrations. While classical androgens alone do not fully explain the pronounced clinical symptoms, the prominence of 11oxC19 androgens, particularly 11OHA4 and 11KT, so far overlooked in routine assessments, add a crucial dimension to the understanding of hyperandrogenism. These highly potent adrenal-specific androgens demonstrate stable expression throughout a womanʼs lifespan, distinguishing them as valuable diagnostic biomarkers. Their predominant role in all CS subtypes, irrespective of the underlying cause, underscores their pivotal contribution to hyperandrogenic symptoms. The distinct androgen profile provided by 11oxC19 androgens not only aids in subtype differentiation but also offers insights into the multifaceted nature of androgen dysregulation in CS. Recognizing the diagnostic potential of 11oxC19 androgens promises to refine diagnostic approaches, enhancing the precision and effectiveness of clinical management strategies for patients with CS.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

Figures were created using Biorender.com.

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Publikationsverlauf

Eingereicht: 11. April 2024
Eingereicht: 06. Mai 2024

Angenommen: 15. Mai 2024

Accepted Manuscript online:
24. Mai 2024

Artikel online veröffentlicht:
30. Juli 2024