Cushings Syndrome: All variants, detection, and treatment

Susmeeta T. Sharma, MBBS

a
and Lynnette K. Nieman, MD
b
Program on Reproductive and Adult Endocrinology, National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, MD
Synopsis
Cushings syndrome is caused by prolonged exposure to excess glucocorticoids. Diagnosis of
Cushings syndrome involves a step-wise approach and establishing the cause can be challenging
in some cases. Hypertension is present in about 80% of patients with Cushings syndrome and can
lead to significant morbidity and mortality. Several pathogenic mechanisms have been proposed
for glucocorticoid-induced hypertension including a functional mineralocorticoid excess state, up-
regulation of the renin angiotensin system and deleterious effects of cortisol on the vasculature.
Surgical excision of the cause of excess glucocorticoids remains the optimal treatment for
Cushings syndrome. Anti-glucocorticoid and antihypertensive agents and steroidogenesis
inhibitors can be used as adjunctive treatment modalities in preparation for surgery, and in cases
where surgery is contraindicated or has not led to cure.
Keywords
Cushings syndrome; hypertension; glucocorticoids; ectopic ACTH secretion; 11-beta
hydroxysteroid dehydrogenase; hypercortisolemia
Introduction
Cushings syndrome is a rare disorder that results from prolonged and pathological exposure
to excess glucocorticoids. The incidence of Cushings syndrome varies depending on the
population studied, anywhere from 2 to 3 cases per million population per year (13). More
recent data suggests that this is probably an underestimate and Cushings syndrome may be
more common than previously thought (45). Iatrogenic Cushings syndrome caused by the
administration of supraphysiologic doses of glucocorticoids is probably much more common
(although underreported) than endogenous causes.
The clinical presentation of Cushings syndrome varies widely. Although the diagnosis is
straightforward in full-blown cases, establishing the diagnosis can be difficult in mild
hypercortisolism especially as none of the signs or symptoms is pathognomonic of the
syndrome (Table 1). However, some of the signs that have been reported to better
distinguish Cushings syndrome from simple obesity include proximal muscle weakness,
easy bruising, violaceous striae greater than 1 cm, and hypertension (6-7). The clinical
presentation differs in children, in whom weight gain and growth retardation are more
prominent (8).
a
Coauthor address: Bldg 10/CRC 1East Rm3140 10 Center Dr Bethesda, MD 20892-1109 (301) 496-5800 (301) 402-0884 (fax)
[email protected] .
b
Corresponding author for proof and reprints: Bldg 10/CRC 1East Rm3140 10 Center Dr Bethesda, MD
20892-1109 (301) 496-8935 (301) 402-0884 (fax) [email protected] .
NIH Public Access
Author Manuscript
Endocrinol Metab Clin North Am. Author manuscript; available in PMC 2011 J une 1.
Published in final edited form as:
Endocrinol Metab Clin North Am. 2011 June ; 40(2): 379391. doi:10.1016/j.ecl.2011.01.006.
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When the clinical presentation suggests Cushings syndrome, biochemical confirmation of
hypercortisolism is necessary. According to the 2008 Endocrine Society guidelines, any of
the following tests can be used for the initial diagnosis of Cushings syndrome: 24 hour
urinary free cortisol, late-night salivary cortisol, or a dexamethasone suppression test (DST,
either as a 1 mg overnight test or the longer low-dose test using 2mg/day over 48 hours) (9).
After two different abnormal tests establish the diagnosis, the cause of Cushings syndrome
must be determined. Endogenous Cushings syndrome can be divided into
adrenocorticotropin (ACTH) dependent and independent forms. ACTH-independent
Cushings syndrome (15%) results from increased autonomous production of cortisol from
adrenal tumors (adenoma or carcinoma) or hyperplasia. Corticotropin-dependent causes of
Cushings syndrome include ACTH production from pituitary (Cushings disease, 70%) or
other tumors (ectopic Cushings syndrome, 15%) and rarely, corticotropin-releasing
hormone (CRH)-producing tumors (10-11).
In all forms of Cushings syndrome the normal secretion of CRH and ACTH are suppressed
by the excessive cortisol levels. Thus, the first step in the differential diagnosis strategy is
measurement of a plasma ACTH level. A low normal or undetectable value points to an
adrenal source of hypercortisolemia, the so-called ACTH-independent forms. Imaging of the
adrenal glands with computerized tomography (CT) or magnetic resonance imaging (MRI)
should be performed to identify the site(s) of abnormality.
An elevated or inappropriately normal ACTH level reflects a pituitary or an ectopic source
of ACTH as a cause of excessive cortisol. Differentiating between these two etiologies can
be challenging. Pituitary MRI should be obtained first. If a pituitary mass larger than 6mm is
found, and biochemical testing with CRH stimulation test and high-dose 8 mg DST are
consistent with Cushings disease, no further testing is necessary. If the biochemical testing
is discordant and the pituitary MRI is normal or equivocal (mass less than 6 mm), bilateral
inferior petrosal sinus sampling (IPSS) should be strongly considered. Alternatively, IPSS
may be obtained without additional biochemical testing, as it has the highest diagnostic
accuracy. A significant central-to-peripheral ACTH gradient during IPSS (more than 2
before, and more than 3 after CRH administration) indicates Cushings disease. In the
absence of a gradient, a search for an ectopic source should be performed using various
imaging modalities (3,10).
Hypertension in Cushings syndrome
The increased mortality of Cushings syndrome is caused in part by an increased risk of
vascular disease up to five times the population average (2,12). In one prospective study,
ultrasound identified atherosclerotic plaques in both carotid arteries in eight of 25 patients
with active Cushings disease and two of 32 age, sex, and BMI matched controls (13).
Hypertension, impaired glucose tolerance, diabetes, dyslipidemia and visceral obesity are
common cardiovascular risk factors in patients with Cushings syndrome. Hypertension,
although not invariable, is a frequent feature of endogenous Cushings syndrome with a
prevalence of approximately 80% in adults. It is even more common (95%) in ectopic
Cushings syndrome (14), whereas in children and adolescents, it is less common (about
47%) (15). By contrast, hypertension is present in only about 20% of patients with
iatrogenic Cushings syndrome, where it correlates with the daily dose of glucocorticoid
(1617).
Studies have clearly shown that in the general population, the chance of myocardial
infarction, heart failure, stroke, and kidney disease increases as blood pressure increases
(18). In a meta-analysis of 61 prospective studies of individuals aged 40 69 years,
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Lewington et al. reported that for every 20 mmHg systolic or 10 mm Hg diastolic increase in
blood pressure, there is a two-fold increase in mortality from ischemic heart disease and
stroke (19).
Because of the potential impact of hypertension on morbidity and mortality, it is important
to understand its cause(s) and to treat it. The purpose of this article is to review the various
possible mechanisms leading to hypertension in Cushings syndrome and its treatment.
Physiology of Blood Pressure in Cushings Syndrome
Healthy adults have a diurnal variation in blood pressure, with a decrease in blood pressure
during sleep. This decrease parallels that of cortisol, and may reflect decreased sensitivity to
catecholamines. The absence of sleep-related decrease in blood pressure is found in a
number of pathological conditions including glucocorticoid-induced hypertension (20-21).
In 2004, Zacharieva and colleagues performed 24-hour ambulatory blood pressure
monitoring in 100 patients with Cushings syndrome (80 with Cushings disease and 20 with
adrenal causes) and 40 patients with essential hypertension. They found that the nighttime
decrease in blood pressure in patients with each type of Cushings syndrome was
significantly reduced compared to patients with essential hypertension. However, the
nocturnal fall in heart rate was preserved in both groups of patients. The blunted decrease in
nighttime blood pressure improved with treatment of Cushings syndrome and the degree of
improvement was negatively correlated with the duration of hypercortisolism (22).
Administration of supra-physiologic doses of exogenous glucocorticoids leads to a similar
loss of the nocturnal fall in blood pressure (23).
Pathogenesis of Hypertension in Cushings Syndrome
Glucocorticoids play an important role in blood pressure regulation. Several mechanisms
have been postulated to explain how hypercortisolism leads to hypertension in Cushings
syndrome. These include mineralocorticoid effects of cortisol, activation of the renin
angiotensin system and the action of cortisol on peripheral and systemic vasculature (17,24).
Mineralocorticoid Effects of Cortisol: Role of 11-betahydroxysteroid
dehydrogenase
Cortisol binds to both type 1 (mineralocorticoid) and type 2 (glucocorticoid) receptors. It is
likely that glucocorticoid induced hypertension is mediated through effects of cortisol on
both receptors. At the cellular level, cortisol availability is modulated by the two isoforms of
the enzyme 11-betahydroxysteroid dehydrogenase (II- HSD) (25).
11- HSD-1 is a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme
that is most abundantly expressed in liver and adipose tissue. It has bidirectional activity and
catalyzes both dehydrogenation (conversion of cortisol to cortisone) and reduction
(conversion of cortisone to cortisol) reactions. In vivo, it predominantly functions as a
reductase, converting inactive cortisone to active cortisol. This reductase activity relies on
high NADPH concentrations, which in turn are dependent on the activity of hexose-6-
phosphate dehydrogenase within the endoplasmic reticulum.
11- HSD-2 is an NAD-dependent enzyme and predominantly acts as a dehydrogenase to
convert cortisol into inactive cortisone. It is abundantly expressed in the classical
mineralocorticoid target tissues including the renal cortex, colon, and salivary glands
(17,25). Both 11- HSD-1 and -2 are present in vascular endothelial cells, coronary artery
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cells and vascular smooth muscles thereby modulating local access of cortisol to the
vasculature (26,27).
In vitro, the mineralocorticoid receptor has similar binding affinity for both cortisol and
aldosterone. However, the circulating levels of cortisol in healthy individuals are about 100-
to 1000- times higher than aldosterone levels. The in vivo selectivity of the renal
mineralocorticoid receptor for aldosterone requires conversion of cortisol to cortisone by 11-
HSD-2, rendering it unable to bind to the mineralocorticoid receptor (2829).
The global activity of 11- HSD can be assessed by measurement of urinary steroid
metabolites. Both cortisol and cortisone undergo A-ring reduction by 5 - and 5 -reductases
and 3 -hydroxysteroid dehydrogenase, yielding 5 -tetrahydrocortisol (THF), 5 -
tetrahydrocortisol (allo-THF) and 5 -tetrahydrocortisone (THE). The overall 11- HSD-1
and 2 activity in the body is reflected in the ratio of urinary cortisol and cortisone
metabolites (THF +allo-THF/THE). Alternatively, urine free cortisol-to-cortisone ratio or
plasma cortisol-to-cortisone ratio can also help in the evaluation (25,30).
One potential etiology for hypertension in Cushings syndrome is decreased renal
conversion of cortisol to cortisone, which would increase mineralocorticoid action. In
Cushings syndrome, the urinary THF +allo-THF/THE ratio is elevated, especially in
patients with the highest UFC. These findings suggest that high cortisol levels can
overwhelm the 11- HSD-2 enzyme due to substrate saturation leading to spillover of
cortisol to the mineralocorticoid receptor. This may cause a functional mineralocorticoid
excess state with hypokalemia, increased renal tubular sodium reabsorption, intravascular
volume expansion, and hypertension (14,31). These findings are similar to those in patients
with inactivating mutations of 11- HSD-2 who have a syndrome of apparent
mineralocorticoid excess (SAME) (25). However, in SAME, THE, aldosterone and renin
levels are suppressed in comparison to those seen in Cushings syndrome.
Other studies suggest that cortisol induced hypertension is not primarily mediated via
sodium retention. Connell and colleagues gave ACTH (1 mg/day) to healthy volunteers on a
sodium restricted diet (15mmol/day). They noted that systolic blood pressure rose
significantly from a mean value of 116 mm Hg to 125 mmHg and plasma volume rose from
a mean of 2.8 liters to 3.6 liters. The level of increase in blood pressure was less than that
seen in previous studies in which ACTH was given to subjects on a normal sodium diet,
suggesting that dietary sodium restriction lessens but does not prevent the rise in blood
pressure with hypercortisolemia (32). Williamson et al. demonstrated that mineralocorticoid
blockade with spironolactone (400 mg/day) did not affect the increased blood pressure seen
in patients given cortisol (80 and 200 mg/day), even though it completely blocked salt and
water retention (33). In another study, Whitworth and colleagues showed that administration
of synthetic glucocorticoids with little or no mineralocorticoid activity increased blood
pressure without salt and water retention (34). Finally, the glucocorticoid antagonist
mifepristone can normalize blood pressure in Cushings syndrome but does not bind to the
mineralocorticoid receptor (35). These findings indicate that a functional mineralocorticoid
excess state is not the sole pathogenic mechanism, and the glucocorticoid receptor is
involved in the development of hypertension in Cushings syndrome.
Glucocorticoid effects on vasculature
Enhanced action of the renin angiotensin system (RAS)
In rodent models, glucocorticoids increase angiotensinogen production (36). Despite this
potential increase in substrate, plasma angiotensin II levels and renin activity are usually
normal or suppressed in patients with Cushings syndrome. However, animal studies have
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shown that glucocorticoids increase angiotensin II receptor type 1 concentration in brain and
peripheral tissue. They also enhance angiotensin II stimulated inositol phosphate-3
production in vascular smooth muscle cells (37-38) and its central pressor effects (39).
Patients with Cushings syndrome show an increased pressor response to angiotensin II,
suggesting increased sensitivity to the agent. These data support the concept that the RAS
may play a role in the pathophysiology of glucocorticoid-induced hypertension through
upregulation of central and peripheral angiotensin II receptors.
Inhibition of vasodilators
In addition to enhancing RAS activity, glucocorticoids impair vasodilation (40). Although
circulating levels of the vasodilator atrial natriuretic peptide (ANP) are increased in
experimental and clinical conditions of glucocorticoid excess, in vitro studies show that
glucocorticoids decrease its biological activity (41). Sala and colleagues administered
physiological doses of ANP to normotensive healthy volunteers, and patients with Cushings
disease or essential hypertension. Despite a 4-fold increase in ANP levels in all groups, the
biological response, increase in plasma and urine cGMP, was much lower in patients with
Cushings disease (40).
Glucocorticoids also decrease production of nitric oxide synthase, which is responsible for
the synthesis of another vasodilator, nitric oxide (42). Glucocorticoids also inhibit
production of other potent vasodilators like prostacyclin, prostaglandin E2 and kallikrein
(4344). This in turn may increase blood pressure by decreasing peripheral vasodilation.
Enhanced vascular reactivity to vasopressors
Glucocorticoids increase the vascular sensitivity to the effects of catecholamines. Studies in
healthy volunteers demonstrate that glucocorticoids increase the sensitivity to infusions of
phenylephrine, angiotensin II, and norepinephrine resulting in an increase in peripheral
vascular resistance and mean arterial blood pressure (44-46). Although plasma
concentrations of various vasopressor hormones are normal in patients with Cushings
syndrome, an increase in beta-adrenergic receptor sensitivity has been documented (45).
Endothelin-1 (ET-1) is a potent vasoconstrictor produced by vascular smooth muscle cells
and endothelial cells. Plasma levels of ET-1 are significantly elevated in patients with
Cushings syndrome (47). However, studies looking at the role of ET-1 in glucocorticoid
induced hypertension have conflicting results. On one hand, dexamethasone decreases
endothelin receptors in the kidney and the nonselective endothelin antagonist bosentan has
no effect on ACTH-induced hypertension in rats. On the other hand, in animal studies,
chronic use of endothelin type-A receptor antagonist normalizes blood pressure in 11- HSD
inhibitor induced hypertension (48). Therefore, the contribution of the endothelin-1 pathway
to glucocorticoid-induced hypertension requires further study.
Glucocorticoids also appear to down regulate the expression of the sodium-calcium
exchanger in vascular smooth muscle cells, which in turn increases the cytoplasmic
concentration of calcium, and leads to vasoconstriction (49). Plasma levels of erythropoietin,
another vasoconstrictor, have also been shown to increase with glucocorticoids and may
play a role in glucocorticoid induced hypertension (50).
Other Indirect Factors
Obstructive sleep apnea has been reported in patients with Cushings syndrome (51). As
OSA is associated with hypertension, this represents an additional etiology. Moreover,
obesity-associated hypertension may occur irrespective of cortisol levels and also may also
contribute to hypertension in Cushings syndrome.
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Management of Hypertension in Cushings Syndrome
As hypertension is mediated by excess cortisol levels in Cushings syndrome, the
therapeutic goal is to find and surgically remove the cause of excess glucocorticoids. While
this may lead to resolution or improvement of hypertension, in some cases complete
normalization is not achieved. In patients with occult ACTH-secreting tumors, as well as in
those awaiting surgery, antihypertensive agents and anti-glucocorticoid agents are useful
adjunctive therapies.
Medical Management
Although the optimal therapy for Cushings syndrome is surgical, medical treatment of
hypercortisolism is often required while awaiting surgery and also when surgery is
contraindicated or a tumor cannot be found. Medical agents include compounds that
modulate ACTH release (dopamine and somatostatin agonists), inhibit steroidogenesis
(metyrapone, ketoconazole, and mitotane), or block glucocorticoid action at its receptor
(mifepristone). Normalization of cortisol is generally associated with improved blood
pressure, although metyrapone may exacerbate hypertension by increasing mineralocorticoid
production.
The steroidogenesis inhibitors metyrapone and ketoconazole have a rapid onset of action.
However, due to an escape phenomenon, where ACTH secretion overrides control of
hypercortisolemia, these drugs are usually not effective as the sole long-term treatment for
Cushings disease. They are usually used as adjunctive agents after surgery or radiotherapy,
or in preparation for surgery. The escape phenomenon is less likely with very high doses of
mitotane, presumably because of its adrenolytic effects. The choice of agent is
individualized depending on the side effect profile and other factors (Table 2). One of the
main concerns with all medical agents is overtreatment that can render the patient adrenally
insufficient. Therefore, all patients receiving such treatment should be educated in the use of
glucocorticoids in emergency.
Agents evaluated for inhibition of ACTH secretion include bromocriptine, cabergoline,
octreotide, and the investigational somatostatin-dopamine chimeric drug SOM230 (52).
Successful normalization or control of hypercortisolemia leads to better control of
hypertension. However, these agents are not uniformly effective and their role in treatment
of ACTH-dependent Cushings syndrome is not defined. Despite early promise, peroxisome
proliferator activated receptor (PPAR ) agonists are not effective (53-54).
In addition to anti-glucocorticoid agents, antihypertensive agents should be used. Patients
usually require more than one agent to reach the target blood pressure levels recommended
by J NC 7. Since upregulation of RAS may be involved in glucocorticoid induced
hypertension, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor
blockers (ARB) are recommended. ACEIs and ARBs ameliorate hypertension in almost
50% of hypertensive patients with Cushings disease (55-57). While adrenergic blockade
and calcium channel blockers may be ineffective alone, they may be useful in combination
therapy (58).
Hypertension can be difficult to control with antihypertensive agents without normalization
of hypercortisolemia. Fallo and colleagues conducted a retrospective study of 40 patients
with hypertension in Cushings syndrome; 28 had received conventional antihypertensive
therapy while 12 were treated with ketoconazole. Blood pressure normalized in only 4 of the
28 patients on conventional treatment. Twelve of the remaining 24 patients were placed on
ketoconazole, with normalization of blood pressure in all but one patient. In the second
group, 11 of the 12 patients achieved normal blood pressure with ketoconazole alone (59).
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Whether this reflects bias in allocation to either treatment or suboptimal use of
antihypertensive medications is not known. Specific treatment of hypertension and
normalization of cortisol levels is essential in Cushings syndrome.
Surgical treatment of Cushings syndrome
Surgical excision of cortisol or ACTH producing tumors remains the optimal treatment of
Cushings syndrome. Worldwide, transsphenoidal resection of pituitary adenoma for
Cushings disease has immediate post-operative cure rates of 78 to 97%, with best results
with microadenomas and experienced neurosurgeons. Unilateral or bilateral adrenalectomy
is used for primary adrenal disease, depending on its location. Localization and surgical
excision of non-metastatic ectopic ACTH-secreting tumors leads to cure. Bilateral
adrenalectomy can be considered when a tumor cannot be localized or other treatments have
failed (10).
Even after curative surgery for Cushings syndrome, not all patients become normotensive.
Studies have shown that about one-third of adult patients after surgery continue to have
hypertension (60-62). Persistent hypertension after surgery correlates with the duration, but
not the severity, of preoperative hypertension. These findings are similar to rates of
persistent hypertension after treatment of other forms of secondary hypertension in adults,
and probably reflect irreparable damage or remodeling of the vasculature from long-standing
hypertension. By contrast, children and adolescents show complete resolution of
hypertension within one year after surgical cure (15). The exact reason for this is not known
but it may be related to the shorter duration of hypercortisolemia and/or vascular protective
factors in younger patients.
Conclusion
Cushings syndrome results from chronic pathological exposure to glucocorticoids.
Hypertension is present in almost 80% of patients with Cushings syndrome and if left
uncontrolled can lead to an increased cardiovascular risk and mortality. Although the exact
pathophysiology leading to hypertension in Cushings syndrome is still not known, several
possible mechanisms have been proposed (Figure 1). These include the presence of a
functional mineralocorticoid excess state secondary to substrate saturation of the 11- HSD
2 enzyme, upregulation of the renin angiotensin system, inhibition of vasodilators, and an
enhanced vasoreactivity to vasopressors. Control of hypercortisolemia is important for blood
pressure control. Normalization of hypercortisolemia via surgical resection of the source of
excess glucocorticoids adrenal pathology, pituitary adenoma or an ectopic tumor remains
the therapeutic goal. Anti-glucocorticoid drugs and antihypertensive agents should be used
as adjunctive modes of treatment to normalize blood pressure.
Acknowledgments
This work was supported by the intramural programof the National Institute of Child Health and Human
Development, National Institutes of Health
On part of the NIH, Dr. Nieman participates in a Cooperative Research and Development Agreement (CRADA
with HRA-Pharma to evaluate mifepristone treatment of ectopic ACTH secretion. Dr. Sharma has nothing to
disclose.
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Figure 1.
Pathogenesis of hypertension in Cushings Syndrome. Text and arrows in red show the
effect of excess glucocorticoids on the renin-angiotensin system and other pathways
involved. =Increased, =decreased, Nl =normal.
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Table 1
Signs and symptoms of Cushings syndrome
Hypertension
Adipose
Weight gain
Increased centripetal, supraclavicular, temporal, and/or
dorsocervical fat
Skin
Hirsutism
Striae (especially is >1 cmdiameter and purple)
Easy bruising
Plethora
Reproductive System
Menstrual irregularity
Amenorrhea
Decreased libido
Psychiatric and Cognitive
Depression
Emotional lability
Irritability
Decreased memory
Decreased concentration
Skeleton and Muscle
Proximal muscle weakness
Reduced bone mineral density
Fractures
Metabolism
Impaired glucose tolerance
Diabetes
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Table 2
Steroidogenesis inhibitors and glucocorticoid antagonist for treatment of hypercortisolism
Name Mechanism of
action
Time to
onset of
action
Side-effects Other concerns
Metyrapone Inhibits CYP11B1 Days Hirsutism,
hypertension,
gastrointestinal
effects
In US, available only
fromthe manufacturer
as of 2010
Ketoconazole Inhibits CYP11B1
and CYP11A1
Days Gastrointestinal,
gynecomastia, rarely
hepatic dyscrasia
Enzyme inhibition leads
to decreased
testosterone;
requires gastric acidity
for bioavailability
Mitotane Adrenolytic; inhibits
CYP11B1 and
CYP11A1; possibly
other actions
Months Gastrointestinal
(common); CNS
(lethargy, dizziness)
Hepatic enzyme
inducer; teratogenic; fat
soluble
Mifepristone Reversible blockade
of glucocorticoid
receptor
Days Risk of adrenal
insufficiency
Also antagonizes
androgen and
progesterone receptor
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