Key words
primary pigmented nodular adrenocortical disease (PPNAD) - adrenocorticotropin hormone
(ACTH)-independent Cushing’s syndrome
(CS) - hypercortisolemia - Carney complex (CNC) - adrenalectomy
Introduction
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of
adrenocorticotropin hormone (ACTH)-independent Cushing’s syndrome (CS) and
is characterized by small, black and brown pigmented micronodules in adrenal cortex.
PPNAD mainly occurs in children and young adults. The incidence of PPNAD is unknown
at present [1]. PPNAD accounts for only about
1.1–1.8% of all causes of CS [2]
[3]. It may be isolated or
associated with Carney complex (CNC). About 10% of patients with PPNAD
without familial history or other manifestations of CNC, are generally termed as
isolated PPNAD (i-PPNAD) [4]. CNC is a rare
autosomal dominantly inherited multiple neoplasia syndrome characterized by spotty
skin pigmentation, multiple endocrine neoplasia, and myxomas [5]. It is most frequently caused by mutations
in the type 1a regulatory subunit gene of protein kinase A (PKA) (PRKAR1A),
and approximatively 30% of cases occur sporadically. Clinical manifestations
of CNC include lentigines, blue nevus, myxomas in the heart, skin, and breast,
pituitary tumors, adrenocortical tumors, and thyroid neoplasms. PPNAD and the
consequent ACTH-independent Cushing’s syndrome is one of the most common
endocrine manifestations of CNC, accounting for about 25–60% of CNC
patients [6]
[7].
Hypercortisolism in PPNAD can be overt, subclinical, cyclic or atypical. And adrenal
imaging is also often non-specific, which makes the diagnosis and treatment of the
disease difficult [8]
[9]
[10]
[11]. In the last two decades,
much progress has been made in describing the various forms, clinical
manifestations, and pathogenesis of PPNAD. However, there is still controversy
regarding the treatment of the disease. Treatment options with proven clinical
efficacy for PPNAD included adrenalectomy (bilateral or unilateral adrenalectomy)
and drug treatment to control hypercortisolemia. The preferred treatment is surgery.
Bilateral adrenalectomy is the universal recommended option, which will cause
permanent adrenal insufficiency and require a life-long hormone replacement therapy
[12]. In recent years, some authors
considered that unilateral adrenalectomy or subtotal adrenalectomy can also let
selected patients to obtain long-term remission without hormone replacement therapy,
so that patients have a better quality of life [13]
[14]
[15]. As PPNAD often leads to mild, occult or
atypical Cushing’s syndrome, drug therapy may be a good candidate. In
medical treatment, Ketoconazole, Metyrapone, Mitotane and other drugs can be used
to
treat hypercortisolemia for patients who have severe hypercortisolemia before
surgery and refuse to undergo further surgery or who have surgical contraindications
[16]. In addition, a number of promising
drugs are being studied and may be used in the clinic in the future. Along with the
basic research of PPNAD, scholars found that there were several alternative drugs
associated with the possible mechanism targets of the disease: tryptophan
hydroxylase inhibitor, 5-hydroxytryptamine receptor antagonist, COX2 inhibitor
celecoxib and somatostatin, etc. [17]
[18]
[19].
These drugs are promising, but most of them only are proven in animal studies, and
further research is needed to illustrate whether they can be used in the clinic.
PPNAD is now better recognized, an increasing number of endocrinologists and
urologists were aware of its numerous manifestations and the need for effective
management. Furthermore, the management of some special groups, such as children and
pregnant women, need multidisciplinary cooperation. Appropriate treatment strategy
and follow-up management are important to prognosis of disease. In this review, we
will summarize the update of diagnosis and treatment of PPNAD, including treatment
experience on patients during gestation, and results of studies on new type drugs
acting on new molecular targets.
Clinical Characteristics of PPNAD
Clinical Characteristics of PPNAD
PPNAD patients are generally younger. The age of PPNAD patients associated with CNC
appeared to be bimodally distribution, with a few appearing in the first 2–3
years and most in the twentieth and thirtieth decades [20]. Among a total of 212 patients with PPNAD,
the prevalence was significantly higher in women than in men (71 vs. 29%).
The median age of PPNAD diagnosis was 34 years, and women were diagnosed at a
younger age than men (30 years vs. 46 years). Such gender difference became apparent
after puberty [21].
CS usually starts insidiously, and the main features are hypertension, weight gain,
and growth restriction in children, although it is not seen in all patients. Typical
features also include osteoporosis, proximal muscle weakness, wide purple striae,
full moon face, central obesity, irregular menstruation in women, hirsutism, acne,
decreased cognitive function, and so on [22]
[23]. According to previous
literature, hypercortisolism in PPNAD can be overt, subclinical, cyclic or atypical
[8]
[9]
[10]
[11]. Due to the variable Cushing’s
syndrome phenotypes of PPNAD, its symptoms and signs may not be obvious. Patients
always visit doctors repeatedly until the diagnosis of ACTH-independent CS can be
clearly diagnosed [12]. Whether these
different CS phenotypes are related to the genotype of PPNAD remains to be further
explored.
Osteoporosis and osteoporotic fractures are more common in patients with PPNAD
compared with other causes of Cushing’s syndrome. In a 10-year retrospective
study of 1652 Chinese Cushing’s syndrome patients, osteoporotic fractures
were observed more frequently in PPAND than in adrenocortical adenoma (ADA) and
primary bilateral macronodular adrenal hyperplasia (PBMAH) patients (26.7 vs. 9.0
vs. 4.9%) [3]. In another Chinese
PPNAD cases (25 patients), PPNAD patients are more likely to develop osteoporosis
than ADA patients (78.3 vs. 48.0%), while there are no differences between
PPNAD and PBMAH patients [9]. In addition,
some patients are accompanied by hyperandrogenemia, with hirsutism and irregular
menstruation as the main symptoms [8]
[24]
[25].
In a case series of 6 patients from India, one patient had CS associated with
symptoms of hyperandrogenism (hirsutism and irregular menses) [8].
Since the majority of PPNAD patients are associated with CNC, patients usually have
clinical manifestations associated with CNC, such as spotty skin pigmentation, heart
myxoma, skin myxoma. And many patients have a family history of CNC or PPNAD [7]
[26].
Although CS is rare in children, it can lead to significant morbidity and even
mortality. CS should be diagnosed early by clinician [27]. PPNAD mainly occurs in late childhood or
youth, and is very rare in infancy, the reported youngest patients are only 15
months [8]. Bilateral adrenal resection and
replacement therapy were the most common treatment strategies [28]
[29],
Ketoconazole and other drugs can be used for transition before surgery [8]. They always showed catch-up growth and
improvement in the BMI after adrenalectomy [8]
[28]
[30]. PPNAD may be a signal of CNC, so patients
with dominant CS at a younger age may requires genetic testing and long-time
follow-up.
PPNAD is very rare in infancy, whereas CS associated with McCune – Albright
syndrome (MAS) is usually in infancy. MAS is a sporadic heterogeneous disorder
caused by an activating mutation in GNAS, which encodes the alpha subunit of
the Gs G-coupled protein receptor [31]. It is
characterized by congenital polyostotic fibrous bone dysplasia, café-au-lait
skin plaques, precocious puberty and other endocrine disorders. About 7.1%
of patients can present with CS, which is usually severe, and is also associated
with other endocrine dysfunction, such as hyperthyroidism and precocious puberty
[32].
Adrenal causes of CS, such as PBMAH and adrenal cortical adenoma, may be closely
associated with anomalous adrenal hormone receptors, especially G-coupled protein
receptors, such as the gastric inhibitory polypeptide (GIP) receptor, the
luteinizing hormone/human chorionic gonadotropin (LH/HCG) receptor,
vasopressin (AVP) receptor, and the beta-adrenergic receptor [33]. These aberrant adrenal hormone receptors
are functionally associated with steroidogenesis. Although less reported in PPNAD,
aberrant 5-HT receptors have recently been found to be expressed in PPNAD [17]. The detection of abnormal adrenergic
hormone receptors provides a new target for treatment.
Diagnosis of PPNAD
The diagnosis of PPNAD is challenging, especially for patients without other
manifestations of CNC or family history due to: 1) clinical manifestations may not
be obvious, atypical, and progress slowly; 2) laboratory tests can be normal during
the non-secretory period of periodic CS; 3) those without CNC-related clinical
manifestations (skin pigmentation, myxoma, etc.) and family history which effect
judgement; and 4) it is difficult to accurately find small nodules on CT.
First, the diagnosis of CS should be established. After excluding exogenous
glucocorticoid exposure, initial screening tests include urine free cortisol (UFC),
late night salivary cortisol, 1 mg overnight dexamethasone suppression test
(DST) and 2 mg/d for 48 hours DST [34]. The dexamethasone-CRH test or the midnight
serum cortisol test can be used as subsequent evaluation to establish the cause of
CS in patients with concordantly positive results from two different initial tests
[34].
Adrenal imaging should be evaluated in patients with suspicious adrenal cause CS.
In
PPNAD, computed tomography (CT) imaging examinations may show normal size adrenal
glands and several small bead-like nodules [22]
[35]. But
‘normal’ imaging is often reported too [10]. CT with slice thickness of 3 mm or
less may be helpful for diagnosis [36].
Single-photon emission computed tomography (SPECT-CT) with the use of
iodomethyl-norcholesterol (I-131) showed bilateral glands uptake was increased [25]. It supported the diagnosis of PPNAD. In
addition, adrenal cortical imaging with (6–131I) iodomethyl-19
cholesterol-lowering (NP-59) also can be an optional imaging examination. Vezzosi
et
al. compared CT scans and adrenal cortical imaging with (6–131I)
iodomethyl-19 cholesterol-lowering (NP-59) in 17 patients with diagnosed PPNAD.
NP-59 imaging showed bilateral adrenal uptake in all patients, and asymmetric uptake
was observed in 59% of patients [37].
Besides, bone scintigraphy will help identify bone lesions associated with MAS [38].
Laboratory examination often show that patients with overt CS have ACTH-independent
cortisol secretion hypercortisolism unrelated to ACTH and lack of cortisol diurnal
rhythm. However, laboratory tests may be normal during the non-secretory period of
periodic CS. It is worth noting that patients with PPNAD often appear an abnormal
increase in urinary free cortisol during the Liddle test [39]. This increase in urinary glucocorticoid
excretion following dexamethasone administration is one of the diagnostic criteria
for CNC. But recently, a prospective study showed that only 39 percent of patients
with confirmed or probable PPNAD had an abnormally elevated UFC [40]. In 2018, for the first time Chen et al.
proposed to distinguish PPNAD from bilateral macronodular adrenal hyperplasia and
adrenal cortical adenoma (ADA) by using the ratio of UFC to pre-HDDST
24 hours after high-dose dexamethasone inhibition test (HDDST). When 24-hour
UFC (post-H-DEX)/UFC (pre-H-DEX) was>1.08, the sensitivity and
specificity were 84.0 and 75.6%, respectively [9]. In addition, adrenal tissue ACTH
immunohistochemistry will help identify the presence of ACTH paracrine secretion
[41].
ACTH is a regulator of androgen secretion from the adrenal cortex. Due to the
inhibitory effect of excessive cortisol secretion on ACTH, the
dehydroepiandrosterone (DHEAS) of adrenal CS patients were often lower than those
of
healthy individuals [17]. According to
previous reports of patients with PPNAD, laboratory results showed frequent
decreases in serum DHEAS levels [18], and some
patients showed overproduction of testosterone and normal DHEAS [6]. Overproduction of androgens by
PPNAD-associated adenomas leading to virilization and infertility has also been
reported in the literature [19].
ACTH is a regulator of androgen secretion from the adrenal cortex. Due to the
inhibitory effect of excessive cortisol secretion on ACTH, the
dehydroepiandrosterone (DHEAS) of adrenal CS patients were often lower than those
of
healthy individuals [42]. According to
previous reports of patients with PPNAD, laboratory results showed frequent
decreases in serum DHEAS levels [25], and some
patients showed overproduction of testosterone and normal DHEAS [24]. Overproduction of androgens by
PPNAD-associated adenomas leading to virilization and infertility has also been
reported in the previous literature [43].
Both CNC and PPNAD can be associated with inactivating mutations of the
PRKAR1A gene. In 353 patients with PPNAD or CNC, 73% carried 80
different PRKAR1A mutations [21]. Such
inactivating PRKAR1A germline mutations are also common in i-PPNAD [24]
[44].
In addition, mutations in PDE11A
[45]
and PDE8B
[46] are described for PPNAD.
Somatic defects in PRKAR1A gene [47],
and β-catenin gene (CTNNB1) [48] have been also observed in PPNAD patients, which has potential
clinical and genetic significance. The study of genetic mutations in adrenal tissue
will help to identify such somatic mutations. And genetic testing may be of great
help in diagnosing PPNAD.
Adrenalectomy
Bilateral adrenalectomy
Bilateral adrenalectomy is the universal recommended surgical type for PPNAD
treatment because of its feature for involvement of bilateral adrenal glands
[8]
[12]
[49]
[50]
[51]. Clinical Practice Guidelines for the treatment of CS from
Endocrine Society suggested that laparoscopic bilateral adrenalectomy is the
definite treatment for PPNAD [52].
Laparoscopic surgery can be performed as transabdominal or retroperitoneal
approach, both of which have significant advantages over open surgery, including
a clear field of vision, small incisions, less bleeding, and shorter hospital
stays. The retroperitoneal approach, which can avoid abdominal stimulation has
shorter operative time, fewer complications and less postoperative pain. But it
has a smaller workspace and may increase intraocular pressure due to the need
for prone position [53]. The advantages of
bilateral adrenalectomy are that it rapidly cures CS, has low risk of
recurrence, and is suitable for patients of all ages [8]
[28]
[54]. Bilateral
adrenalectomy was performed in most patients presenting with overt CS. According
to the current literatures, most of patients have biochemical remission after
bilateral adrenalectomy, and the corresponding symptoms can disappear. The
children always catch-up with growth, and the weight of patients can return to
normal, and the Cushing appearance can disappear. Most of the patients were
followed up for a short period of time. It is conceivable that bilateral
adrenalectomy will cause permanent adrenal insufficiency and require a life-long
careful glucocorticoid and mineralocorticoid replacement therapy. Such patients
are prone to acute adrenal crisis as a complication especially under stress or
infection, and may have a lower quality of life, so they have to be good
compliance [8]
[12]
[15]
[35]. Unilateral total
adrenalectomy associated with contralateral partial adrenal (adrenal-sparing
surgery) has been observed to achieve good treatment results in PBMAH [55]. This approach avoids the need for
lifelong steroid replacement in most cases and has a low rate of adrenal
insufficiency and recurrence [56]. It may
be a potential surgery approach for PPNAD.
In 31 patients with adrenal hyperplasia (MAH) or PPNAD who underwent bilateral
adrenalectomy, 30 (97%) patients are cured biochemically [12]. These patients had complete resolution
for Cushing’s syndrome symptoms at 9 to 12 months postoperatively. Six
patients in their cases presented with hypertension, and all were cured or
improved after surgery. Five of them were able to discontinue all
antihypertensive drugs, and the remaining one required only one antihypertensive
drug. In the case series of Memon et al. on a mean age of 8.2 years, 5 patients
are cured after bilateral adrenalectomy, and 1 of them die about 2 years after
surgery probably caused by an adrenal crisis. All patients showed improvement in
height post-surgery [8]. Two adolescent
brothers with complaints of weight gain and growth retardation had typical
Cushing’s syndrome manifestations: hypertension, moon-shaped face,
facial plethora, centripetal obesity, and red-purple skin striae. One month
after bilateral adrenalectomy, they lost 5–6 kg of weight their
skin textures fades and there was a reduction in the facial plethora. And their
blood pressure, lipids and heart ejection fraction were improved [28]. A 20-year-old woman presenting with
overt CS had bilateral avascular necrosis of the femoral heads. After bilateral
adrenalectomy, her presentation of cortisol excess improved, and her femoral
head necrosis resolved without orthopedic intervention with 1-year follow-up
[57].
Unilateral adrenalectomy
In recent years, more studies have shown that unilateral adrenal resection can
achieve remission of long-term symptoms and biochemical for some patients
without adrenal insufficiency [51]. Some
case reports [58]
[59] and cases series proved the feasibility
and effectiveness of unilateral adrenalectomy [10]
[13]
[60]. Most patients acquired biochemical
remission and disappearance of clinical symptoms after unilateral adrenalectomy.
But some patients reappear with symptoms of hypercortisolism after surgery,
usually less severe than at the time of presentation. And most patients with
recurrence undergo contralateral resection, while some are treated with
medication.
A 16-year-old female patient with complaints of weight gain and irregular
menstruation had a preoperative iodocholesterol scintigraphy showing unilateral
uptake of the left adrenal gland. She underwent left adrenalectomy. After 10
months of follow-up, she had significant weight loss, disappearance of the
features of CS and biochemical remission [51]. Xu et al. reviewed 13 PPNAD patients who underwent unilateral
adrenalectomy, of whom only 1 patient recurred with a requirement of
contralateral adrenal resection, while the rest achieved remission (Median
follow-up time: 47 months) [13]. Kyrilli
et al. summarized the patients with unilateral adrenal resection in the
literature. There were 24 cases with unilateral adrenalectomy, followed by
contralateral resection in 5 cases, with the duration of contralateral resection
ranging from 2 months to 25 years [14].
Cohen et al. reported a case of successful pregnancy after unilateral adrenal
resection without adrenal hypofunction during pregnancy, indicating that
unilateral adrenal resection may be considered as an option for women with
fertility needs [59]. There were two
15-year-old patients with complaints of weight gain and growth retardation, with
typical manifestations of hypercortisolism on examination (central obesity,
hirsutism, purplish streaks, facial acne). They underwent unilateral
adrenalectomy. 5–6 months postoperatively, they had significant clinical
and biochemical improvement, weight loss, accelerated growth, and regression of
skin streaks and acne. One required HC replacement for a short period of time
and one not required HC replacement. Then they reappeared with CS symptoms and
laboratory tests suggesting loss of cortisol circadian rhythm, so contralateral
adrenalectomy was performed at 8 and 10 months postoperatively [61].
Bilateral adrenocortical hyperplasia (BAH) mainly includes Primary Bilateral
Macronodular adrenocortical hyperplasia (PBMAH) and PPNAD [62]. Studies have shown that unilateral
adrenalectomy improves clinical symptoms and biochemical status successfully for
PBMAH for adult patients, particularly for patients with asymmetric hyperplasia
and mildly phenotypes [62]
[63]
[64]. Similar to PBMAH, PPNAD is often manifested as mild to moderate
CS. That suggested that unilateral resection for PPNAD may also be a feasible
approach.
Some patients have bilateral adrenal nodular hyperplasia with the presence of
macronodules. Research studies of Vezzosi et al. about Adrenal
[6β-131I]-iodomethyl-19-norcholesterol] (NP-59)
scintigraphy revealed that asymmetrical adrenal uptake associated with
macronodules in 10 of 17 patients (59%) [37]. In those patients with unilateral greater nodular hyperplasia,
selective resection of the side with greater nodules may be a good option. There
are twins female patients with PPNAD from Belgium who under unilateral
adrenalectomy have ongoing clinical and biochemical remissions without any
adrenal insufficiency after 3 years and 18 months follow-up after surgery,
respectively [14]. Unilateral
adrenalectomy was chosen because the symptoms were mild and asymmetric bilateral
adrenal uptake or size was shown on imaging (131I
iodomethyl-norcholesterol scintigraphy coupled with single-photon emission
computed tomography (SPECT)/CT Adrenal CT scan) [14].
It seems unilateral adrenalectomy can relieve the symptoms of mild to moderate CS
without causing adrenocortical insufficiency. When NP-59 scintigraphy or
(SPECT)/CT scan revealed asymmetrical adrenal uptake [37], selective resection of the side with
prevalent uptake may be a good option [14]. But scintigraphy is not available in many countries. Adrenal volume
measurement, adrenal vein sampling are also modalities that can substitute
scintigraphy. Clinicians should also consider the possibility that unilateral
resection may not be a complete cure and may require a second operation. There
is also a case showed that adrenal crisis occurred during a viral infection 3
weeks after unilateral adrenalectomy [50].
But we thought the probability for adrenal crisis of unilateral adrenalectomy is
much lower than bilateral resection. Most adrenalectomies are performed by
laparoscopy with less trauma. For patients who have the possibility of remission
after resection of one side, they and their doctors may prefer to remove one
side first and then remove the other side after recurrence. Compared with
permanent adrenal insufficiency caused by bilateral adrenal resection, it may be
better to selectively remove one side of the adrenal gland for patients with
atypical or mild symptoms. In addition, genotypic - phenotypic correlation
indicated that some gene mutation sites were associated with milder phenotypes,
which may be a basis for determining surgical approaches, but further studies
are needed [21]. Therefore, we suggested
that clinicians should select unilateral or bilateral adrenal resection based on
a comprehensive evaluation of the degree of increased cortisol, symptoms,
preoperative imaging evaluation, and the patient’s willingness, to
choose the surgical procedure with the best benefit. Due to the rarity of PPNAD,
clinical studies about the treatment were limited, the indication and long-term
efficacy of unilateral adrenal resection remained to be studied. If further
studies could confirm the indications for unilateral adrenal resection, it may
greatly improve the quality of life of patients without long-term hormone
replacement on the basis of disease control.
Drug Therapy
Drugs that inhibit steroid production and action
There are several kinds of drugs to treat hypercortisolism as conservative
managements. These include steroidogenic inhibitors (Metyrapone, Mitotane,
Etomidate, LCI699) and glucocorticoid receptor antagonists (Mifepristone) [65]. They can be used as preoperative
transition for patients with severe hypercortisolemia or maintenance therapy for
patients who refuse surgery [65].
Medication is also needed for patients who are not cured completely after
surgery [44].
If patients have severe hypercortisolemia preoperatively, they should receive
adrenolytic medications for weeks preoperatively [12]. In the literature, Ketoconazole can as
a bridge therapy before surgery [8]
[25]. It is worth noting that Ketoconazole
has potential side effects such as liver enzyme elevation, gastrointestinal
discomfort, androgen reduction and pruritus [66]. Therefore, it is not generally preferred for men, and it should
be used under liver enzyme monitoring [67]. Ketoconazole treatment has been used successfully in several cases
of CS pregnancy and did not cause birth defects to the fetus [68]
[69]. Fluconazole has been considered as an alternative to
Ketoconazole [70]. Navarro et al. reported
case series in which a patient showed a significant decrease in urinary cortisol
after 3 months of Fluconazole treatment. But he discontinued due to the side
effects of pruritus and facial rash; Another patient remained on low-dose
Metyrapone as maintenance therapy after unilateral adrenalectomy [44].
As for a patient who refused surgery, long-term and low-dose mitotane therapy
(from 0.5 g/d to 4 g/d) was an effective method
to correct hypercortisolism. The typical symptoms of Cushing’s syndrome
and hyperandrogenism gradually subsided at two months from the beginning of the
treatment. The size of the adrenal glands appeared to be reduced after 7 months
adrenolytic treatment. The patient was still in remission after 122 months
follow-up [16].
Besides, Osilodrostat as an oral 11β-hydroxylase (CYP11B1) inhibitor,
catalyzes the final step of cortisol synthesis. And it is administered less
frequently than conventional drugs, with fewer adverse effects and fewer
interactions with other drugs [71]
[72]. Phase III clinical trial results have
confirmed its safety and efficacy in adult CS patients, and it may be a new
option for the treatment of PPNAD.
New drugs targeting possible pathogenic mechanisms
The pathogenic mechanisms of PPNAD are still not clear up to now, a possible
mechanism is that genetic events lead to structural activation of
cAMP/PKA (cyclic adenosine monophosphate/protein kinase A)
signal pathway [73]
[74]. The PKA consists of two molecules of
regulatory (R) subunits bound to two molecules of catalytic (C) subunits.
PRKAR1A as a tumor-suppressor gene located at 17q22–24
encodes the type 1a regulatory subunit of cAMP-dependent PKA [73]
[75]. Inactivation mutation of PRKAR1A cause premature stop
codons through the nonsense-mediated mRNA decay (NMD). This process would lead
to a truncated protein product which contributes to increased signal by PKA
[[76]. In addition, mutations in the
phosphodiesterase PDE11A
[45] and
PDE8 and the PKA catalytic subunit PRKACA gene [77] are also detected in patients with
PPNAD, and all of these gene events lead to structural activation of the
cAMP/PKA signaling pathway, resulting in high glucocorticoid secretion
independent of ACTH.
There are a number of drug candidates currently under study that target possible
mechanisms of the disease, such as Rapamycin, Celecoxib, tryptophan hydroxylase
inhibitors ([Fig. 1]). These drugs have
been proven in animal or in vitro tests, but there are no clinical studies have
been reported.
Fig. 1 Drug candidates under study that target possible mechanisms
of PPNAD. One of pathogenic mechanisms of PPNAD is that genetic events
lead to structural activation of cAMP/PKA signal pathway, resulting in
high glucocorticoid secretion independent of ACTH. The mTORC1 pathway
was activated by PKA signaling. Rapamycin is a mTOR inhibitor that acts
on the PKA/mTOR pathway. Activated PKA signal leads to FLACs cannot be
clear out and then morbid hyperplasia of adrenal cortical. Celecoxib can
effectively reduce the proliferation of adrenal cortical cells induced
by FLACs and thereby reduce glucocorticoid production. There is an
illicit serotonergic stimulatory loop associated with hypercortisolemia
because of cAMP/PKA pathway activation in adrenal tissues. Tryptophan
hydroxylase inhibitors can reduce the stimulatory effect of 5-HT.
Somatostatin analogs can reduce intracellular cAMP production and thus
may reduce cortisol secretion in PPNAD. PPNAD, Primary pigmented nodular
adrenocortical disease; cAMP/PKA, cyclic adenosine monophosphate/protein
kinase A; mTORC1, the mammalian target of Rapamycin sensitive complex 1;
FLACs, Fetal-like adrenal cortical cells; 5-HT, 5-hydroxytryptamine.
Rapamycin
The mammalian target of Rapamycin sensitive complex 1 (mTORC1) pathway was
activated by PKA signaling in adrenal glands of specific PRKAR1A knockout
mouse and human PPNAD tissues, leading to increased cell survival. PKA/mTOR
activation was correlated with BAD (a member of the BCL-2 apoptotic family)
hyperphosphorylation which may lead to apoptosis resistance and tumor formation.
Rapamycin is an effective and selective mTOR inhibitor that acts on the PKA/mTOR
pathway. Treatment with Rapamycin specifically sensitized ADKO adrenal cortical
cells to dexamethasone-induced apoptosis in animal experiments, indicating its
potential efficacy in the treatment of adrenal hyperplasia [78]
[79].
Celecoxib
In specific PRKAR1A knockout mice, Sahut et al. observed that the atypical
hyperplasia of fetal-like cortex at the corticomedullary junction. And such
hyperplasia extended to the periphery over time. Fetal-like adrenal cortical
cells (FLACs) caused by the lack of R1a cannot be clear out and then morbid
hyperplasia of adrenal cortical [80].
Celecoxib is a prostaglandin peroxidase synthase 2 (PTGS2) [also known as
cyclooxygenase 2 (COX2)] inhibitor that is currently used to inhibit the growth
of certain tumors. It is mainly related to the inhibition of prostaglandinE2
(PGE2), and the reduction of stem cell-like cells induced by this molecule [19]. Celecoxib can effectively reduce the
proliferation of adrenal cortical cells induced by FLACs and thereby reduce
glucocorticoid production, which has been verified in mice and human adrenal
cells in vitro [81].
Somatostatin analogues
Somatostatin (SST) analogues (SSA) like Octreotide can reduce intracellular cAMP
production and thus may reduce cortisol secretion in PPNAD and other
ACTH-independent CS patients. A short-term preliminary clinical study on the
application of Octreotide in patients with PPNAD showed that the expression
levels of somatostatin receptors (SSTRs) in PPNAD tissues were significantly
higher than those in normal adrenal glands. But short-acting SSA Octreotide had
no significant effect on cortisol secretion in patients with PPNAD. However,
because of the sample size of this study was small, only Octreotide was used and
further SSA-related studies with larger sample sizes may be possible in the
future to further explore its effect on PPNAD [18].
Tryptophan hydroxylase inhibitor
Bramet et al. found that adrenal tissues removed from PPNAD patients overexpress
the key enzyme tryptophan hydroxylase type 2 (TPH2) and the 5-hydroxytryptamine
receptors (5-HT4R, 5-HT6R and 5-HT7R) because of cAMP/PKA pathway
activation, leading to an illicit serotonergic stimulatory loop associated with
hypercortisolemia [17]. Later, Le Mestreet
al. confirmed this by studying adrenal tissues exposed to high plasma ACTH
levels for a long time and found that TPH and/or
5-HT4/6/7 receptors were overexpressed in tissues of different
disease types. In addition, they found that 5-HT4R antagonists can reduce the
stimulatory effect of 5-HT in vitro. It is suggested that tryptophan hydroxylase
inhibitors may also be a promising drug for the treatment of PPNAD [82].
Drug therapy is commonly used as a transition treatment preoperatively for
patients with severe hypercortisolemia currently [65]. The drugs targeting the specific
mechanism of PPNAD are very promising. But they only have been proven in animal
or in vitro tests. We expect these drugs to be proven clinically and look
forward to the clear indications for drug therapy. Although there are still many
problems to be solved in the treatment of PPNAD, we proposed a brief treatment
strategy for PPNAD by summarizing the literature ([Fig. 2]). We look forward to more studies
that will tell us more about specific treatments.
Fig. 2 treatment strategy for PPNAD.
Management of PPNAD During Gestation
Management of PPNAD During Gestation
Using “PPAND” and “pregnancy” as key words, we
searched English literature published before May 2021 in PubMed database and found
3
cases with PPNAD during pregnancy [83]
[84]
[85].
There are 2 patients received Metyrapone to control hypercortisolemia during
pregnancy [83]
[84]. All the 3 patients were successfully delivered by cesarean section,
and the causes of delivery included preeclampsia and recurrent vaginal bleeding. All
the infants survived after birth, and two infants developed respiratory distress
syndrome and transient hyponatremia ([Table
1]).
Table 1 Published reports of PPNAD during pregnancy.
Authors [Ref]
|
Patient age
|
Period
|
Therapy
|
Medication using during pregnancy
|
Perinatal morbidity
|
Birth weight (g)
|
Apgar scores (1 min, 5 min)
|
Fetal complications
|
Spaniol et al. [84]
|
24
|
18–26 weeks
|
drug therapy, bilateral adrenalectomy 4 months postpartum
|
Metyrapone (500 mg/day)
|
preeclampsia
|
650
|
2, 6
|
NS
|
Schulz et al. [85]
|
31
|
32 weeks
|
bilateral adrenalectomy postpartum
|
None
|
severe preeclampsia
|
1700
|
4, 8
|
moderate respiratory distress syndrome
|
Ralser et al. [83]
|
31
|
26–31 weeks
|
drug therapy, remission at 6 weeks postpartum
|
Metyrapone (1000 mg/day)
|
recurrent vaginal bleeding
|
1740
|
8, 10
|
transient hyponatremia
|
IUGR: Intrauterine fetal growth restriction; NS: Not stated.
Hypercortisolism in PPNAD may be related to the high estradiol level during
pregnancy. Catichaet.al. observed that estradiol can stimulate cortisol secretion
in
a dose-dependent manner with the absence of ACTH in vitro of PPNAD cells [86]. Most drugs in the hypercortisolism
treatment are contraindicated during pregnancy [87]
[88]. Metyrapone is an
11β-hydroxylase inhibitor that has been used safely during pregnancy [65]
[89].
It can reduce serum cortisol levels, but adrenocorticotropic hormone (ACTH) is
stimulated with the decreased cortisol levels, which increases the production of
mineralocorticoid, possibly leading to hypertension. This point should be vigilant
in clinical practice [89]. Due to the limited
evidence reported in the literature, it should be used cautiously.
Due to high blood pressure, diabetes, weight gain and skin purple lines may also
associate with pregnant, the diagnosis of CS during pregnancy is challenging. In
addition, the physiological changes during pregnancy can also include the increase
of serum cortisol and urine free cortisol [89]. However, the loss of circadian rhythm of cortisol secretion and the
significant increase of 24-hour urine free cortisol level are still helpful for the
diagnosis of CS. If severe preeclampsia is diagnosed and blood pressure is difficult
to control, pregnancy or delivery may need to be terminated promptly. In patients
with a history of bilateral adrenal resection, hormone replacement must be
monitored, and a stress dose of glucocorticoids administered at delivery.
Unfortunately, there is no data on long-term follow-up of mothers and fetuses after
completion of delivery of PPNAD. We have no idea about long-term remission. In
conclusion, the pregnancy decision of PPNAD patients requires multidisciplinary
cooperation. Due to the genetic characteristics of PPNAD and CNC, the fetus should
be screened for genetic diseases after birth and a detailed follow-up strategy
should be developed to detect and manage the possible related diseases at an early
stage.
Conclusion
PPNAD is a rare disease with atypical symptoms and difficult clinical diagnosis. And
the exact mechanism remains unclear. Surgery is the treatment of PPNAD, while the
appropriate surgical methods should be selected according to individual
circumstances. For patients who cannot receive surgical treatment or only have mild
hypercortisolemia, drug treatment can be candidate. The drugs that may have
therapeutic potential for PPNAD, such as tryptophan hydroxylase inhibitor, 5-HT
receptor antagonist, COX2 inhibitor celecoxib and somatostatin, still need further
clinical studies to confirm. Furthermore, we should pay attention to the management
of PPNAD in children and pregnancy, strengthen interdisciplinary teamwork, and
long-term follow-up should be conducted no matter what treatment plan is
selected.