Pasquali R, Pignatelli D (eds): Hyperandrogenism in Women. Beyond Polycystic Ovary Syndrome. Front Horm Res. Basel, Karger, 2019, vol 53, pp 77-91 (DOI: 10.1159/000494904)
Androgens in Cushing’s Syndrome
Giorgio Arnaldi Marianna Martino
Clinica di Endocrinologia e Malattie del Metabolismo, AOU Università Politecnica delle Marche, Ospedali Riuniti Ancona, Ancona, Italy
Abstract
Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing’s Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS find- ings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Be- cause of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum an- drogen assessment is controversial, but the widespread use of high-performance liquid chromatogra- phy and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and an- drostenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-depen- dent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocor- tical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes dis- appearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-con- trolled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.
@ 2019 S. Karger AG, Basel
Introduction
Clinical or biochemical features of androgen excess are observed in 10-15% of women and are predominantly due to polycystic ovary syndrome (PCOS). PCOS is a common disorder presenting with a broad spectrum of reproductive and systemic metabolic man-
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ifestations. Hirsutism is present in approximately in 65-75% of patients with PCOS, the major cause of hirsutism in general population [1].
Conversely to PCOS, endogenous Cushing’s syndrome (CS) is a rare disorder, with an annual incidence of 2-3 cases/million inhabitants. CS comprises a large group of signs and symptoms resulting from prolonged and inappropriately high exposure of tissues to glu- cocorticoids [2, 3]. The most common cause of CS, however, is exogenous CS, which re- sults from taking excessive amounts of corticosteroid drugs for the treatment of many inflammatory, allergic, immunologic, and malignant disorders.
Hirsutism, obesity, insulin resistance, menstrual irregularity, and fertility problems are common findings in women with CS and PCOS. In addition, activation of the hypotha- lamic-pituitary-adrenal (HPA) axis has been documented in women with PCOS. Because of this overlap, the differential diagnosis between these conditions is often difficult and in some cases the diagnosis of CS was initially missed or delayed. Women with PCOS usu- ally consult endocrinologists or gynecologists but, in a survey, surprisingly only 17% of endocrinologists and 6% of gynecologists screened “PCOS referrals” for CS by measuring urinary free cortisol (UFC) [4]. In a recent study, of 26 women with Cushing’s disease (CD), half had previously been diagnosed with and treated initially solely for PCOS [5]. In another recent survey, the gynecologist was the first referring physician for 46% of 176 patients with CD. Furthermore, in 2.5% of the cases the diagnosis was made by the gyne- cologist [6]. For these reasons, screening for hypercortisolism is often required in patients with PCOS whose clinical manifestation share CS.
Cushing’s Syndrome
CS is generally defined as a state of glucocorticoid excess. There are 2 general causes of endogenous CS: adrenocorticotropic hormone (ACTH)-dependent and ACTH-indepen- dent forms. ACTH-dependent CS (70-80%) are generally due to a pituitary corticotroph tumor (which is termed CD, from the first description of neurosurgeon Harvey Cushing in 1932) or, in rare cases, are caused by a neuroendocrine tumor (ectopic ACTH CS). CD occurs predominantly in women (female-to-male ratio ranging from 3:1 to 10:1). ACTH- independent causes (20-30%) are due to unilateral adrenocortical tumors, either benign or malignant, or primary macro-/micronodular hyperplasia [2, 3].
The phenotype of CS is variable, widely differing in severity according to the degree and duration of hypercortisolism and also on individual glucocorticoid receptor sensitiv- ity [7].
Although CS is clinically unmistakable when full blown, the diagnosis can be challeng- ing, particularly in mild cases. Common signs and symptoms include central obesity with supraclavicular fat accumulation, cervical fat pad, thinned skin, easy bruising, purple stri- ae, proximal myopathy, fatigue, hypertension, glucose intolerance and diabetes, acne, hir- sutism, menstrual irregularity, decreased fertility and libido, erectile dysfunction, depres- sion, emotional irritability, sleep disturbances, and cognitive deficits, frequent and im-
paired immune function and opportunistic infections, bone loss, osteoporosis, fractures, and tromboembolism. The clinical presentation in children is characterized by weight gain and impaired growth. Actually, while specific and discriminatory features are few, most of them are unspecific and overlap with more common diseases (like PCOS), often leading to a misdiagnosis and, consequently, a delayed treatment [2, 8]. To note that car- diovascular and fracture risk can persist after cure, early detection of each morbidity could prevent the development of irreversible damage.
Moreover, the evaluation of patients with a suspect of CS could be complex and expen- sive. The biochemical diagnosis is based on the demonstration of inappropriate cortisol secretion with loss of its physiological negative feedback. Measurement of cortisol in more than one 24-h urinary collection and/or the low-dose dexamethasone suppression test (DST) and/or late-night salivary cortisol are recommended as first-line screening test to diagnose hypercortisolism. Once the diagnosis of CS is established, ACTH levels, cortico- troph-releasing hormone stimulation test, high-dose DST, and appropriate imaging (pi- tuitary MRI and adrenal CT or MRI) are the most useful noninvasive procedures for the differential diagnosis of CS. Bilateral inferior petrosal sinuses sampling for ACTH mea- surement is recommended in patients with ACTH-dependent CS whose clinical, bio- chemical, or radiological studies are discordant or equivocal [2, 3, 8].
CS is associated with high cardiovascular risk due to central obesity, hypertension, diabetes, dyslipidemia, cardiac remodeling and dysfunction, venous thrombotic disease, and sepsis leading to an increased mortality rate. The QoL of these patients is often poor and considerably impaired. However, the correction of hypercortisolism does not com- pletely eliminate the comorbidities. Although recent data have shown that in cured pa- tients the survival is similar from that the normal population, other studies have yielded conflicting results [9, 10]. Therefore, particular efforts should be made to diagnose as rap- idly as possible and cure this multisystemic disease and its complications. Although the treatment should be tailored to the patient, surgery is the gold standard treatment for re- moval the responsible tumors (pituitary, ectopic, and adrenal). Treatment options for persistent or relapsed CD include repeat transphenoidal pituitary surgery, radiotherapy, or bilateral adrenalectomy. It is important to note that in a recent study from multiple tertiary referral centers in the United Kingdom, Denmark, the Netherlands, and New Zea- land on 320 patients with CD in remission, patients cured after transsphenoidal surgery alone had long-term survival comparable to that of the general population; on the con- trary, higher mortality was noted with higher number of treatments during a long follow- up (median of 11.8 years) [10].
Medical therapy is an important treatment option for patients with CS who cannot be cured by surgery. Available drugs include inhibitors of ACTH secretion (pasireotide, a multireceptor-targeting somatostatin analogue and cabergoline, a dopamine agonist), ste- roidogenesis inhibitors (ketoconazole, metyrapone, mitotane, etomidate, and the promis- ing osilodrostat and levoketoconazole, an enantiomer of ketoconazole), and glucocorti- coid receptor antagonist (mifepristone) [9, 11].
Cushing’ Syndrome Is Associated with PCOS Phenotype
Menstrual irregularities, hyperandrogenism, acne, hirsutism, and fertility problems are very common in women with CS. These findings, along with obesity and glucose metabo- lism abnormalities, may suggest the diagnosis of PCOS. Approximately 70-80% of wom- en with CS present with menstrual abnormalities, and PCOS findings are found in 46% of these patients. In a study of 45 women with CD, 15 patients had amenorrhea (33.3%), 14 had oligomenorrhea (31.1%), and 4 had polymenorrhea (8.8%). In another 3 patients (6.6%), cycles were irregular and in only 9 patients (20%) the menstrual cycle was regular [12].
Hypercortisolism affects gonadal function at multiple level inhibiting LH and FSH se- cretion at pituitary level and gonadotropin-releasing hormone synthesis and release at hypothalamic level. Besides low gonadotropins, low estradiol, various degrees of adrenal androgen excess, and, in some cases, a slight increase of PRL are also present.
Moreover, hypercortisolism reduces the production of SHBG by the liver and almost all patients have low levels of SHBG, presumably as a consequence of insulin resistance and hyperinsulinemia caused by cortisol excess. The increase in androgen bioavailability could account for the development of hirsutism even in the presence of normal androgen levels.
Interestingly, menstrual alterations in women with CD are closely related to serum cortisol rather than to circulating androgens. In a study by Lado-Abeal et al. [12], amen- orrheic women had higher serum cortisol levels and lower estradiol ones. On the contrary, women with normal menstrual cycles tended to have normal serum cortisol levels and normal estradiol levels. In addition, serum cortisol was significantly inversely correlated with serum estradiol levels, but not with serum androgens. Kaltsas et al. [13] prospective- ly investigated the presence of PCOS defined by strict clinical, biochemical, and ultraso- nographic criteria in a group of 13 CS women of reproductive age. This study confirmed that symptoms and signs of hyperandrogenism are frequently seen in women (all 13 pa- tients), while 70% of this group also developed menstrual irregularity. This clinical phe- notype was similar to that found in patients with PCOS.
In contrast to PCOS, in women with CS menstrual irregularities were mainly related to hypogonadism hypogonadotropic although the cause of menstrual disorder is multi- factorial. In CS, the PCOS phenotype may develop both in the presence of an estradiol- sufficient state and of estrogenic deficiency, with different mechanisms. It has been sug- gested that in the presence of mild hypercortisolism, gonadotropin secretion is still pre- served maintaining ovarian steroid output but this estrogen-sufficient state with or without menstrual disturbance leads to development of a PCOS phenotype. On the con- trary, a severe hypercortisolism causes a state of hypogonadotropic hypogonadism and an estrogen deficiency. In this situation, the PCOS phenotype and hirsutism could be due to low SHBG and to the effect of hyperinsulinemia acting as a co-gonadotropin on ovaries. This double mechanism can also justify why the gonadotropin response to gonadotropin- releasing hormone is so variable in patients with CS [14].
Although very few studies have been systemically analyzed the ovarian morphology, the ovaries of women with CS show fibrosis, reduction of volume, reduction in all phases of primordial follicles, absence of stromal cortical hyperplasia, and luteinization [15].
Finally, hypercortisolism reduces fertility inhibiting normal follicular development and ovulation and thus making pregnancy a rare event in the presence of CS.
Adrenal Androgens Secretion in ACTH-Dependent Hypercortisolism
Adrenal androgens, a variety of C19 steroids, are secreted by the zona fasciculata and re- ticularis under the control of ACTH and in general the secretion of these hormones par- allels that of cortisol. Dehydroepiandrosterone (DHEA), its sulfate conjugate dehydroepi- androsterone sulfate (DHEA-S), and androstenedione (A4) are the major secreted adrenal androgens. DHEA-S is the most abundant adrenal androgen in the circulation with a long half-life of ~17 h. Adrenal androgens have little androgenic activity acting as precursors for the peripheral synthesis of more potent androgens and estrogens (i.e., A4 is readily converted in testosterone [T]).
Although overall adrenal androgen steroid metabolome is incompletely understood, C19 steroids were recently measured by liquid chromatography-tandem mass spectrom- etry (LC-MS/MS) in adrenal vein samples of women before and after ACTH stimulation [16]. This study demonstrated that 3 weak androgens, namely, DHEA, 11b-hydroxyan- drostenedione (11OHA), and A4 are the most abundant unconjugated C19 steroids in the adrenal vein both before and after ACTH infusion. Active androgens, including T and 11b-hydroxytestosterone, are also produced but to a lesser degree. Interestingly, ACTH significantly increased the adrenal output of 9 of the 12 steroids measured, including the active androgens, T and 11b-hydroxytestosterone. ACTH increased the mean adrenal vein concentration of DHEA-S by 5-fold, DHEA by 21-fold, A4 by 7-fold, and 11OHA by 5-fold. The dominant role of ACTH in the regulation of adrenal androgens secretion is confirmed by dexamethasone administration that cause a suppression of androgens. Ad- renal androgens also exhibit a diurnal pattern of secretion although DHEA-S does not have a diurnal rhythm as a consequence of its long half-life. DHEA-S levels increase at the time of adrenarche and decreases after 30 years.
Considering the role of ACTH in the secretion of adrenal androgens, it is not surpris- ing that DHEA, DHEA-S, and A4 levels are generally elevated or in the upper normal range in male and females patients with pituitary and ectopic ACTH-dependent CS. In a study comparing 37 patients with CD to normal subjects of corresponding age, serum DHEA-S levels were elevated in 11 patients and were within the normal range in the re- maining 26 patients [17]. Conversely, DHEA-S was significantly lower in patients with CS due to adrenocortical adenoma. It is interesting that no overlap was found between serum DHEA-S levels of patients with CD and those of patients with adrenocortical adenoma. In another study on 30 women with active CD, DHEA-S, A4, and T were significatively higher than those measured in controls [18]. Elevated androgens were observed in 27% of
Androgens in CS
patients according to previous studies. No difference was found in any androgen value between 22 hirsute and 8 non-hirsute patients. In this study, 7 of the 8 patients with ecto- pic ACTH secretion presented an extremely elevated A4 concentration, and a positive correlation was found between A4 and ACTH and between A4 and cortisol while no cor- relation between DHEA-S, T, and ACTH was found. Notably, an A4 concentration high- er in patients with ectopic ACTH than in CD was observed. In contrast with these data, Kaltsas et al. [13] showed that despite the presence of symptoms/signs of hyperandrogen- ism, all 13 women with CS had androgen levels (T, androstendione, and DHEA-S) within the normal reference range, but as a group they were significantly lower than those ob- served in women with PCOS, even after excluding the 2 patients with ACTH-independent CS. In these patients, the UFC showed a statistically significant inverse correlation with SHBG, estradiol, and also T. It is interesting that T production rates measured using a stable-isotope dilution technique and mass spectrometry are subnormal or low-normal in 4 male patients, but not in 12 women patients with CS [19].
More recently, plasma and urine steroid metabolomics using LC-MS/MS and gas chromatography-mass spectrometry have become the choice method for characterizing the steroid secretion of patients with CS and or adrenal masses. The simultaneous mea- surement by LC-MS/MS of 15 adrenal steroids in plasma demonstrated that among the steroid examined, 11-deoxycortisol and 11-deoxycorticosterone were consistently high- er (p <0.0001) in all subtypes of CS [20]. The adrenal androgens (A4, DHEA and DHEA- S) showed lower concentrations in adrenal CS than in pituitary CS and ectopic ACTH- secreting tumors. As expected, DHEA-S was higher in patients with pituitary CS than in patients without hypercortisolism. Whereas, plasma DHEA and DHEA-S concentra- tions were also lower in the adrenal CS group than in normal subjects. It is interesting to note that using a combination of 10 plasma steroids (11-deoxycortisol, cortisol, corti- sone, corticosterone, 11-deoxycorticosterone, A4, 18-oxocortisol, DHEA, DHEA-S, and aldosterone) in a stepwise variable selection, it was possible to distinguish the 3 subtypes of CS.
The clinical consequences of androgens excess are different in men and females. Wom- en present a dysregulation of gonadotropins that impacts the normal ovarian and men- strual cycles, as well normal follicular development and fertility, growth of facial and body hair, acne and in the more severe cases, male-pattern baldness. In the European Registry on Cushing’s syndrome, hirsutism was found in 92% of women with ectopic ACTH CS and its prevalence was significantly higher compared with that in the other groups (63% in the CD and 37% in the patients with adrenal CS) [21]. Patients with CD showed sig- nificantly more skin alterations, menstrual irregularities, and hirsutism compared with those with adrenal CS (78 vs. 64% for skin alterations, 63 vs. 43% for menstrual irregu- larities, and 63 vs. 37% for hirsutism; p < 0.01 for all comparisons).
In men, hypercortisolism determines hypogonadism hypogonadotropic (50-70%) with reduced T and libido (69%) and lower frequency of sexual activity. It is interesting to note that reduced libido was more frequently reported in men than in women (69 vs. 40%; p < 0.01 for both comparisons). Considering the role of androgens in influencing
sexual behavior in women, it is possible that the increase of adrenal androgens may jus- tify the libido decrease, although this symptom is often overlooked and underreported in female patients.
Adrenal Androgens Secretion in ACTH-Independent Hypercortisolism
According to the level of ACTH, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. It is interesting to note that also patients with subclinical hypercortisolism have A4 and DHEA levels lower than patients with nonse- creting adrenocortical adenomas and controls [22]. In addition, DHEA is lower in pa- tients with nonsecreting adrenocortical adenomas than in controls; females with subclin- ical hypercortisolism also show significantly lower T levels than controls. By analyzing the serum steroid profile by LC-MS/MS in patients with adrenocortical adenomas, Di Dalmazi et al. [22] showed that DHEA and A levels were reduced in basal condition and after stim- ulation with 1-24 ACTH in subclinical hypercortisolism in both sexes. They suggested that androgen reduction could be a marker of subclinical hypercortisolism. More recent- ly, 2 further independent studies confirmed lower plasma and urinary androgens in ACTH-independent CS than in ACTH-dependent forms of CS [23, 24].
However, androgen-secreting adrenal tumor (adenoma and carcinoma) can be also associated with hyperandrogenism (mainly T, DHEA-S, and steroid precursors) and vir- ilization (clitoris enlargement, deepening of the voice, male-pattern baldness, and muscle hypertrophy). Adrenal carcinoma is a rare tumor (incidence between 0.7 and 2.0 per mil- lion per year) and in most cases steroid hormone-producing tumor (50-60%) with vari- able prognosis [25]. CS or mixed Cushing and virilizing syndromes are observed in the majority of these patients. Pure androgen excess is less frequent (10%), while estrogen or mineralocorticoid excess is very rare. In several cases, patients with adrenal carcinoma present nonspecific symptoms (abdominal or flank pain, nausea, vomiting) or they may be asymptomatic showing an incidentally discovered adrenal tumor.
A tumoral hyperandrogenism could be suspected in the presence of T levels greater than 7.3 nmol/liter although the ovaries are key glands to T synthesis and when there is rapid onset and evolution of symptoms or virilization. However, this value was observed in only 41% of patients with adrenal tumors, whereas the majority had only mild T levels overlap- ping with those observed in patients with functional hyperandrogenism [26, 27]. Therefore, the measurement of serum T alone presents several limitations in identifying patients with virilizing tumors. It has been suggested that the combination of an elevated basal serum T and a less than 40% suppression of serum T during the low-dose DST offer a good sensitiv- ity and specificity for distinguishing tumorous from nontumorous hyperandrogenism [26].
A recent systematic review and meta-analysis regarding 19 publications with 3,814 pa- tients demonstrated that cortisol-secreting adrenal carcinomas are associated with a worse overall survival showing a weighted relative risk of 1.71 (95% CI 1.18-2.47) com- pared to nonsecreting carcinoma) [28]. Similarly, these tumors have a higher recurrence
risk. Of all adrenocortical carcinomas, 18.5% produced androgens (with or without other hormones). Interestingly, androgen secretion was not clearly associated with a worse prognosis (the weighted RR was 0.82; 95% CI 0.60-1.12). However, the authors state that data on androgen-secreting adrenal cancer are very limited. It is not clear if the presence of hypercortisolism indicates a more aggressive cancer subtype or whether cortisol is merely a prognostic marker. Moreover, most carcinomas present an immature steroido- genesis producing a large amount of steroid precursors. It is not surprising that 17-OH progesterone is elevated in more than half of adrenal carcinoma. However, this parameter has low sensitivity and specificity (it is increased in 6-10% of benign lesions).
It has been demonstrated that plasma and 24-h urine steroid metabolome profiling by LC-MS/MS is a useful tool to discriminate adrenal carcinomas from other adrenal tumor lesions.
In 2011, a proof-of-concept study carried out on 45 patients with cancer and 102 pa- tients with adenoma demonstrated a characteristic steroid profile of carcinoma with 90% sensitivity and specificity [29]. Three steroid metabolites were most informative in distin- guishing cancer from adenoma: the tetrahydro-11-deoxycortisol (THS), the main urinary metabolite of 11-deoxycortisol, and the adrenal androgen precursors pregnenediol and pregnenetriol derived from pregnenolone and 17-hydroxypregnenolone, respectively. Moreover, urinary steroid profile did not differ in patients with metastatic cancer. In an independent study on a small cohort of patients, urinary THS was confirmed the best in- formative steroid to distinguish carcinoma from adenoma with a cutoff value of 2.35 umoL/24 h [30]. Velikanova et al. [31] confirmed the importance of urinary androgens and glucocorticoid precursors (pregnanediol, 5-pregnanetriol, and 5-pregnanediol), DHEA, and THS determination by gas chromatography-mass spectrometry for differen- tiation of adrenal cancer and adenoma.
In a recent study performed on 71 patients with adrenal diseases of which 5 with car- cinoma and 61 with adenoma (4 with cortisol-producing adenoma and 57 with nonfunc- tioning adenoma) urinary steroid profile showed significant differences in patients with carcinoma for 11 steroids, most notably again in THS [24]. Finally, a recent study con- firmed that the circulating cortisol precursor 11-deoxycortisol is most discriminating for differentiating 10 adrenal carcinomas from other 38 adrenal lesions suggesting a critical change in 11b-hydroxylase activity in adrenal carcinoma due to dedifferentiation and mu- tational changes [23]. Similarly, the increase of the androgen precursor steroids 5-preg- nanetriol and 5-pregnanediol indicates a relative inefficiency of 17,20 lyase activity in converting 17-hydroxypregnenolone to DHEA.
How to Distinguish a Patient with CS from a Patient with PCOS?
Patients with CS present variable clinical manifestations depending on the degree and duration of hypercortisolism and probably on glucocorticoid receptor sensitivity [7]. The florid phenotype is generally easy to recognize, but in many cases, the picture is much less
clear and can be misleading especially in patients with mild and cyclic hypercortisolism [2, 8]. Therefore, the diagnosis is often difficult and time consuming.
Before biochemical screening, it should be excluded a long history of alcohol intake or exogenous glucocorticoids (oral, parenteral, rectal, inhaled, or topical). Easy bruising, fa- cial plethora, and proximal myopathy are the most sensitive clinical features of CS.
As we have seen above, differentiating between CS and PCOS is still challenging, par- ticularly in case of mild hypercortisolism. Although hyperandrogenism in women is pre- dominantly due to PCOS, this diagnosis should be established upon exclusion of other causes of hyperandrogenism and anovulation but unfortunately only a minority of pa- tients are evaluated for CS. Recently, a retrospective analysis conducted by Brzana et al. [5] showed that 50% of reproductive age women with histologically proven CS were ini- tially diagnosed with isolated PCOS.
Current guidelines recommend using two of the following tests to demonstrate the cortisol excess and the impairment of physiological feedback of the HPA axis: at least 2 measurements of 24-h UFC or late-night salivary cortisol, 1-mg overnight DST, or longer low-dose DST [2, 3]. Although an increase of UFC (4 times the upper limit of normal) is suggestive of CS, none of these tests have proven fully capable of identifying all cases of CS and all provide false-positive results in patients with Pseudo-Cushing where an over- activity of the HPA axis occurs without true CS. With this in mind, it should be remem- bered that PCOS is a possible condition of Pseudo-Cushing as reflected by mild increase of UFC (25-50% of patients) and high midnight serum cortisol concentrations (20% of patients) and apparent lack of cortisol suppression after DST (5-15% of patients), both in normal weight and obese women with PCOS [2, 32, 33]. Moreover, serum corticosteroid- binding globulin was significantly decreased in patients with PCOS. In addition, obesity is also associated with multiple alterations of the HPA axis activity in both sexes, with or without PCOS [34].
Pseudo-CS is caused by a heterogeneous group of conditions (i.e., depression, other psychiatric disorders, alcoholism, severe obesity, poor controlled diabetes mellitus other than PCOS), which share many of the clinical and biochemical features but in the absence of a true CS. The “functional hypercortisolism” that characterize these conditions is usu- ally mild, disappears when the underlying disorder disappears. However, patients with functional hypercortisolism usually present systemic complications associated with cor- tisol excess (e.g., hypertension, insulin resistance, diabetes, obesity, cardiovascular dis- ease, etc.). It is plausible to hypothesize that a harmful cortisol action could take place in every state of functional hypercortisolism [35].
Negative effects of functional hypercortisolism in PCOS have not been extensively studied, but some reports suggest a role for cortisol in the onset of hyperglycemia and im- paired secretion of gonadotropins. The cortisol levels were higher in women affected by PCOS and diabetes than levels observed in women with normal glucose tolerance [36]. Furthermore, cortisol increase after ACTH test was positively correlated with glucose lev- els during oral glucose tolerance test. It is also worth noting that cortisol was found to be one of the factors involved in conditioning the broad insulin peaks observed in PCOS [37].
In addition, the normal daytime correlation between the amount of pulsatile ACTH and cortisol release as observed in the controls was lost in PCOS patients [34]. Moreover, dur- ing a nocturnal pulsar analysis study, a positive correlation between circulating cortisol and FSH/LH pulse time lag suggesting the existence of multifaceted dysregulation of the HPA axis in PCOS. Unfortunately, there are no other studies on this topic, and further work needs to be done to know the role of cortisol in developing of PCOS.
According to the current guidelines, the diagnosis of PCOS is based on the presence of clinical and biochemical hyperandrogenism [1]. An important point is that an androgen profile, rather than the evaluation of T alone, may be a more appropriate way to define hyperandrogenemia in women with PCOS. In other words, androgen excess in PCOS is not restricted to the contribution of the ovaries, but also that of adrenal, adipose tissue, and skin, which leads to varying degrees of hirsutism [38, 39]. In particular, new data have highlighted that 11-oxygenated androgens represent the majority of circulating andro- gens in women with PCOS, with close correlation to markers of metabolic risk [40].
In a recent study, Elhassan et al. [41] assessed simultaneously by LC-MS/MS serum concentrations of DHEA-S, A4, and T in 1205 women with a suspect of androgen excess over a period of 5 years. Unsurprisingly, PCOS was the most common diagnosis in pre- menopausal (89%) and postmenopausal women (29%). It is interesting to note that only 49% of premenopausal and 27% of postmenopausal women with PCOS had isolated in- crease of serum T. A4 was the more sensitive marker of PCOS-related androgen excess than serum T (isolated increase was observed in 41.3% of postmenopausal women). In- creased DHEA-S was the most prevalent finding in the premenopausal women with PCOS (high DHEA-S with normal A4 and normal T in 37.3% of cases). This shift in androgen pattern at menopause may be due to the age-related decline in adrenal DHEA-S produc- tion. Other causes of androgen excess included: congenital adrenal hyperplasia (CAH; 4.8%), ACC (4.0%, the next most cause in postmenopausal women), ovarian hypertheco- sis (1.9%), CD (1.6%), adrenocortical adenoma (ACA; 1.3%), and ovarian tumors (0.5%). Increase of all 3 serum androgens was observed in cases of ACC and in some women with CAH and ovarian hyperthecosis. A4 was increased in all ACCs. There were only 4 cases of ACC among the premenopausal women, all with severe androgen excess. Although, in premenopause severe DHEA-S excess was predominantly due to PCOS, in postmeno- pausal women all cases of severe DHEA-S and A4 excess were caused by ACC and severe T excess equally by ACC and ovarian hyperthecosis. In conclusion, the diagnostic workup should include the measurement of all 3 androgens to evaluate the pattern and severity of androgen excess.
Therefore, hypercortisolism should be excluded in patient presenting with obesity, hir- sutism, menstrual abnormalities, and/or suspected of PCOS. Frequently overlapping clin- ical and biochemical findings from the screening evaluation require additional tests and follow-up (time as additional diagnostic tool) [2, 3, 42, 43]. DST-corticotroph-releasing hormone test and DDAVP test have been used to distinguish patients with true hypercor- tisolism who typically respond from those with functional hypercortisolism. Interpretive criteria to differentiate between CS from pseudo-Cushing are different and there is not a
Table 1. Cinical and hormone features in different causes of hirsutism
a Clinical features in different causes of hirsutism
| Disease | Hirsutism | Menstrual abnor- malities | Over- weight/ obesity | Hyper- tension | Impaired glucose metabolism | Trombo- embolism | Osteo- porosis |
|---|---|---|---|---|---|---|---|
| CS | + | + | + | + | + | + | + |
| Virilizing adrenal tumors | ++ | + | -/+ | -/+ | – | – | – |
| Congenital adrenal hyperplasia (21-OH deficiency)ª | + | + | + | – | – | – | – |
| Glucocorticoid resistance | + | + | – | + | – | – | – |
| PCOS | + | + | -/+ | – | -/+ | – | – |
b Hormone features in different causes of hirsutism
| Disease | 17-OHP | E2 | Testo- sterone | 44 Andro- stenedione | DHEAS | LH | FSH | SHBG |
|---|---|---|---|---|---|---|---|---|
| Cushing's ☐ syndrome | Normal | Normal/ low | Normal/ high | Normal/high | Low/ normal/ high | Low/ normal | ☐ Normal/ low | ☐ Low |
| Virilizing adrenal tumors | High | Normal/ high | Very high | High | Very high | Normal/ high | Normal/ low | Low/ normal |
| Congenital adrenal hyperplasia (21-OH deficiency) | Very high | ☐ High | High | High | High | High | Normal/ low | Normal/ low |
| Glucocorticoid resistance | High | Normal/ high | High | High | igh | Low/ normal/ high | Normal/ low | Normal/ high |
| PCOS | Normal | Normal/ low | Normal/ high | Normal/high | Normal/ high | Normal/ high | Normal/ low | ☐ Low |
c Hormone features in different causes of hirsutism
| Disease | Cortisolb | ACTH | PRA | ☐ Aldosterone |
|---|---|---|---|---|
| CS | High or very high | Low (ACTH-independent); normal/high (ACTH-dependent) | ☐ Normal/low | ☐ Normal/low |
| Virilizing adrenal tumors | Normal/high | Low/normal | ☐ Normal/low | ☐ Normal/low |
| Congenital adrenal hyper- plasia (21-OH deficiency) | Normal (salt wasting: low) | Normal/high | ☐ Normal (salt ☐ wasting: high) | Normal (salt ☐ wasting: low) |
| Glucocorticoid resistance | ☐ High | ☐ High | ☐ Low | ☐ Low |
| PCOS | ☐ Normal/high | ☐ Normal/high | ☐ Normal | ☐ Normal |
a Consider overlapping with Cushing’s syndrome if overtreated. b ≥1 among: 24-h urinary free cortisol (2 samples), late night salivary cortisol (2 samples), Dexamethasone Suppression Test 1 mg.
CS, Cushing’s syndrome; PCOS, polycystic ovary syndrome; ACTH, adrenocorticotropic hormone.
ACT H
Cholesterol
Feedback loop malfunctioning in Cushing’s
X KETOCONAZOLE
LEVOKETOCONAZOLE
Pregnenolone
LEVOKETOCONAZOLE
Progesterone
☒ X
KETOCONAZOLE
11-Deoxycorticosterone
LEVOKETOCONAZOLE
☒ X
KETOCONAZOLE
METYRAPONE
METYRAPONE
X
17-OH pregnenolone
Dehydroepiandrosterone (DHEA)
LCI699
Corticosterone
17-OH progesterone
KETOCONAZOLE
Androstenedione
Estrone
LEVOKETOCONAZOLE
18-OH-corticosterone
METYRAPONE
11-Deoxycortisol
Testosterone
KETOCONAZOLE
KETOCONAZOLE
Estradiol
METYRAPONE
X
LEVOKETOCONAZOLE
LCI699
X
METYRAPONE
Aldosterone
Cortisol
LCI699 OSILODROSTAT
clear cutoff. Using an increase of plasma ACTH of >6 pmol/L (>27 pg/mL) as criterion, the DDAVP test showed a sensitivity between 75 and 87% and specificity between 90 and 91%. Our group identified new combined criteria for interpreting the DDAVP tests [44]. The pair of interpretative criteria that we identified for the DDAVP test is constituted by basal serum cortisol >331 nmol/L (>12.0 µg/dL) and a rise in plasma ACTH >4 pmol/L (>18 pg/mL). This combined criterion in a cohort of 111 subjects (52 CS, 28 Pseudo- Cushing and 31 controls) yielded a sensitivity of 90.3% and a specificity of 91.5% for the diagnosis of true CS. It is important to note that in this study, we evaluated 28 patients with pseudo-Cushing including 9 women with PCOS: the prevalence of obesity, hirsut- ism, acne, and menstrual alterations were similar in CS and pseudo-Cushing patients, whereas osteoporosis occurred with greater prevalence in true hypercortisolism. There- fore, assessment of bone mineral density (BMD) could be a useful additional tool for the differential diagnosis between CS and PCOS: indeed, hypercortisolism leads to impaired BMD and increased risk of fractures, while women with PCOS have a preserved BMD, which at least partially has been hypothesized as a consequence of prolonged exposure to androgen excess [45].
Clinical and biochemical characteristics to differentiate CS from other conditions of hirsutism are summarized in Table la-c.
Androgens and Treatment of CS
As a general rule, when treating CS, symptoms and signs of androgen excess progressive- ly disappear alongside control of hypercortisolism; a reappearance of menstrual irregular- ity, hirsutism, acne, and/or alopecia may underpin disease recurrence. It is interesting to note that there is dissociation of cortisol and DHEA-S secretion in patients with CS due to ACC after adrenalectomy: serum DHEA-S remains suppressed for months or years af- ter the recovery of cortisol and ACTH [17].
The disappearance of signs and symptoms of androgen excess also occurs during med- ical treatment with pituitary-directed drugs (Pasireotide, Cabergoline) resulting from normalized ACTH production, as well as during treatment with some adrenal steroido- genesis inhibitors, such as Ketoconazole, as a consequence of blocked cholesterol side- chain cleavage and 17 hydroxylase/C17-20 lyase activities [46] (Fig. 1).
For these reasons, ketoconazole has antiandrogenic properties, which can have favor- able effects on women with hirsutism but may be disturbing for male patients causing hypogonadism and gynecomastia [9].
Conversely, up to one-third of women treated with steroidogenesis inhibitors primar- ily acting against 110/18-hydroxylase enzyme (Metyrapone and the novel Osilodrostat, LCI699) decreases cortisol secretion but the compensatory rise of ACTH levels (3- to 4-fold) increases 11-deoxycortisol, 11-deoxycortisone, and androgens levels with worsen- ing of hyperandrogenism [47, 48] (Fig. 1). ACTH levels increased at least 2- to 3-fold in approximately two-thirds of CD patients treated with the glucocorticoid receptor antago- nist mifepristone. This drug has showed its efficacy in improving clinical and metabolic features of hypercortisolism, but no clinical or androgen data are reported in the SEISMIC studies [49, 50]. Mifepristone also binds competitively to androgen and progestin recep- tors, and it is possible that the androgen effects are blocked.
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Giorgio Arnaldi
Clinica di Endocrinologia e Malattie del Metabolismo, AOU Università Politecnica delle Marche Ospedali Riuniti Ancona, via Conca 71 IT-60126 Ancona (Italy) E-Mail gioarnaldi@gmail.com
Androgens in CS
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