referate generale

Ref: Ro Med J. 2019;66(4)

DOI: 10.37897/RMJ.2019.4.2

Hyperpigmentation and ACTH –

an overview of literature
Florica Sandru1,2, Mihai Cristian Dumitrascu2,3, Simona Elena Albu2,3,
Mara Carsote2,4, Ana Valea5,6
1Elias
Emergency University Hospital, Bucharest, Romania
2“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
3 Emergency University Hospital, Bucharest, Romania
4“C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania
5Clinical County Hospital, Cluj-Napoca, Romania
6“Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania

ABSTRACT
Introduction. ACTH (adrenocorticotropic hormone) is a key regulator of adrenal production involving cortisol
as an essential hormone for life. The melanin is a pigment which is produced by melanocytes at the level of
melanosomes (the melanogenesis). Both MSH and ACTH are generated by the cleavage of POMC (proopi-
omelanocortin) after CRF (corticotropin-releasing factor) stimulation and then MSH acts on the skin causing
hyperpigmentation.
Aim. To introduce clinical data of literature that link hyperpigmentation with ACTH excess. Three main topics
are introduced: Addison’s disease, ectopic Cushing’s syndrome, and Nelson’s syndrome.
Method. This is a short overview of literature including papers that have been mostly published within last 5
years.
General data. Hyperpigmentation in relationship to ACTH includes its high levels in addition to low cortisol in
Addison’s disease and Nelson’s syndrome and high non-suppressible cortisol in ectopic Cushing’s disease.
ACTH has a pituitary origin in first two situations and malignancy in the third one. A pituitary tumour is found
in cases with Nelson’s syndrome. An autoimmune background may be associated with Addison’s disease. An
iatrogenic component is brought by Nelson’s syndrome. All three situations are severe and life threatening of
different scenarios.
Conclusion. Hyperpigmentation may be the clue to connect dermatology to endocrine pathologies and
ACTH massive release by a pituitary or a non-pituitary origin involves a complex panel of conditions.

Keywords: hyperpigmentation, ACTH, Nelson’s syndrome, Addison’s disease,

ectopic Cushing’s syndrome

Abbreviations
ACTH = adrenocorticotropic hormone MSH = melanocyte stimulating hormone
ASP = Agouti signalling protein MC1R = melanocortin receptor type 1
CRF = corticotropin-releasing factor PET = positron emission therapy

Introduction the adrenal glands may produce ACTH as the pitu-

itary gland does (1,2). ACTH acts not only as a hor-
ACTH (adrenocorticotropic hormone) is a key mone at the level of adrenal glands but also at the
regulator of adrenal production involving cortisol level of blood vessels and a local mediator at
as an essential hormone for life (1,2). The steroid adrenals (1,2). ACTH also has a role as an acute
secretion is normally the effect of a complex frame regulator of aldosterone production as well as sero-
that also includes autocrine and paracrine factors tonin (2,3).
(1,2). Even chromaffin cells from medullary part of

Corresponding author: Article History:

Lecturer Mara Carsote, MD, PhD Received: 20 November 2019
E-mail: [email protected] Accepted: 11 December 2019

Revista Medicală Română – Volumul lXVi, Nr. 4, An 2019 309

310 Revista Medicală Română – Volumul lXVI, Nr. 4, An 2019

Beyond endocrine and cardiovascular connec- and mucosa is one of the main clinical features (9).
tions, ACTH is also linked to the skin and melano- Others skin conditions like vitiligo may be associ-
genesis and this goes through MSH (melanocyte ated in cases with polyglandular autoimmune syn-
stimulating hormone) interplay (4,5). Alpha-MSH drome (10). Primary adrenal insufficiency may be
is a regulator of pigmentation in normal humans lethal if adequate substitution is not provided (9).
(5,6). This is done in association with other mel- More than 30 causes are described, including ge-
anocortins whose roles are more or less understood netic types (9).
until present time (5,6). Alpha-MSH as well as ASP
(Agouti signalling protein) acts on melanocortin re- Ectopic Cushing’s syndrome
ceptor type 1 (MC1R) of melanocytes displaying Cushing’s syndrome is the excess of glucocorti-
melanogenic effects, but also mitogenic actions coid of either endogenous or exogenous cause
(5,6). Skin melanocytes are activated by paracrin (11,12). Endogenous sources includes the adrenal
and autocrin factors, for instance, in case of pro- itself and ACTH derivate forms like corticotropino-
longed sun exposure (5,6). The melanin is a pig- ma and ectopic Cushing’s syndrome (also called
ment which is produced by melanocytes at the level ACTH-dependent types) (11,12). This last men-
of melanosomes (the melanogenesis) (6). Both tioned type comprises between 10% and 20% of all
MSH and ACTH are generated by the cleavage of ACTH-dependent cases (11,12). The cause of
POMC (proopiomelanocortin) after CRF (corti- ACTH is a non-pituitary tumour despite the fact
cotropin-releasing factor) stimulation (6,7). The that a concomitant pituitary incidentaloma might
acquired hyperpigmentation it comes with an ab- be registered due to the high prevalence in general
normal ACTH in parallel with high MSH as it hap- population (13,14,15,16). The most frequent forms
pens in ACTH tumour-derivate secretion of pitui- of cancer causing ectopic Cushing’s syndrome are
tary and non-pituitary origin (5,6,7). located in thorax-abdominal region (12,17). Among
them we mention small cell lung carcinoma, med-
Aim ullary thyroid cancer, neuroendocrine tumours of
the lung and gastro-intestinal tract (17,18,19,20).
To introduce clinical data of literature that link The typical endocrine assessment includes the con-
hyperpigmentation with ACTH effects at the level firmation of persistent cortisol secretion which is
of the skin. Three main topics are introduced: Addi- not suppressible at high-dose dexamethasone sup-
son’s disease, ectopic Cushing’s syndrome, and pression test (18,19). The imaging tests are com-
Nelson’s syndrome. All these conditions are associ- plex from computed tomography, magnetic reso-
ated with high levels of ACTH of either pituitary or nance imaging up to PET (positron emission
non-pituitary tumour as cause, benign or malign, therapy) imaging (18,19). The therapy targets the
and this goes with hyperpigmentation. specific profile of the causing tumour and, in cases
with unknown/unidentified cause, bilateral adre-
Material and method nalectomy might be necessary to control the dam-
age due to Cushing’s syndrome (21). In these cases
This is a short overview of literature including the CRF but mostly the ACTH excess associates
papers that have been mostly published within last with hyperpigmentation even in a relative short pe-
5 years regarding medical data that involves high riod of time (19).
ACTH and skin hyperpigmentation. A selection of
30 papers is done. Nelson’s syndrome
Nelson’s syndrome represents another particular
General data situation where ACTH increase is part of the path-
ogenic loop and its values can get extremely high
Addison’s disease (22,23,24). This happens after bilateral adrenalec-
Addison’s disease is a rare, heterogeneous con- tomy for Cushing’s disease and it represents a rath-
dition where the destruction of the adrenal glands is er atypical option nowadays due to others several
done mainly based on an autoimmune or tubecur- medical and surgical therapeutical resources which
culosis background (8). Low cortisol causes an are preferred (22,25,26). The complication is rare;
ACTH increase based on a feedback mechanism it involves high ACTH with known complications
between pituitary and adrenal glands while hyper- including the skin,and corticotropinoma enlarge-
pigmentation at the level of skin (including scars) ment (26,27). Prior radiotherapy might be protec-
Revista Medicală Română – Volumul lXVI, Nr. 4, An 2019 311

FIGURE 1. Conditions with high ACTH and hyperpigmentation

tive, yet the general data are inconclusive (26,27). Discussion

There is not general guideline as approach but radi-
otherapy, neurosurgery of the pituitary gland an Overall, hyperpigmentation in relationship to
and potential use of somatostatin analogues and/or ACTH includes its high levels in addition to low
dopamine agonists are the therapy lines (26,27). A cortisol in Addison’s disease and Nelson’s syn-
study published in 2019 showed that 38% of the drome and high non-suppressible cortisol in ectop-
subjects with Nelson’s syndrome displayed some ic Cushing’s disease. ACTH has a pituitary origin
level of progression during a follow-up of 10 years in first two situations and malignancy in the third
(28). The risk of progression is higher if complex one. A pituitary tumour is found in cases with
therapies are applied to Cushing’s disease but this Nelson’s syndrome. An autoimmune background
may also be correlated with a more severe form of may be associated with Addison’s disease. An iat-
disease (28). Nelson-Salassa syndrome has been rogenic component is brought by Nelson’s syn-
revealed in half of the persons with Cushing’s dis- drome. All three situations are severe and life
ease treated with bilateral adrenal removal associ- threatening of different scenarios (Figure 1).
ating a mild evolution (29). A few cases are de-
scribed actually underling a pituitary ACTH- Conclusion
producing carcinoma (29). This is suspected in rap-
idly growing tumours and ACTH increase with Hyperpigmentation may be the clue to connect
suggestive symptoms (29). Despite this potential dermatology to endocrine pathologies and ACTH
severe complication, difficult cases of Cushing’s massive release by a pituitary or a non-pituitary or-
disease should still be treated with synchronous bi- igin involves a complex panel of conditions.
lateral adrenalectomy (30).

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