Pseudoacromegaly induced by the long-term use

of minoxidil
Kari H. Nguyen, MD, and James G. Marks, Jr, MD
Hershey, Pennsylvania

Acromegaly is an endocrine disorder caused by chronic excessive growth hormone secretion from the
anterior pituitary gland. Significant disfiguring changes occur as a result of bone, cartilage, and soft tissue
hypertrophy, including the thickening of the skin, coarsening of facial features, and cutis verticis gyrata.
Pseudoacromegaly, on the other hand, is the presence of similar acromegaloid features in the absence of
elevated growth hormone or insulin-like growth factor levels. We present a patient with pseudoacromegaly
that resulted from the long-term use of minoxidil at an unusually high dose. This is the first case report of
pseudoacromegaly as a side effect of minoxidil use. (J Am Acad Dermatol 2003;48:962-5.)

accentuated, which gives prominence to creases on

A cromegaly is a rare endocrine disorder that is

caused by chronic excessive growth hor-
mone (GH) secretion from the anterior pitu-
itary. More than 95% of cases are due to GH-secret-
ing pituitary adenomas.1 Other causes include
pituitary carcinoma, which can be associated with
multiple endocrine neoplasia type 1, and ectopic
GH-releasing hormone-secreting tumor that stimu-
lates GH secretion from the pituitary.2
The striking clinical manifestations of acromegaly
are due to excessive insulin-like growth factor
(IGF-1; also known as somatomedin C) production
by the liver in response to GH stimulation.3 The
growth-promoting properties of IGF-1 trigger bone,
cartilage, and soft tissue hypertrophy and viscero-
megaly that are seen characteristically in acromeg-
aly. The disease is insidious; most patients have
symptoms for 5 to 10 years before the diagnosis is
made. The 2 most sensitive confirmatory tests are
plasma IGF-1 level and the oral glucose tolerance
test.4 Unlike IGF-1, GH level is unreliable because of
its short half-life, pulsatile secretion, and circadian
variation. A normal response in the oral glucose
tolerance test is a suppression of the GH level to less
than 2 ␮g/L. In acromegaly, this suppression of GH
does not take place.
Significant disfiguring cutaneous changes occur
in acromegaly, most markedly on the face and ex-
tremities.3 The skin is thickened and has a doughy
texture. Facial features coarsen as skin folds become
From the Department of Dermatology, Pennsylvania State Univer-
sity College of Medicine.
Reprints not available from authors.
Copyright © 2003 by the American Academy of Dermatology, Inc.
0190-9622/2003/$30.00 ⫹ 0
doi:10.1067/mjd.2003.325
the forehead, nose, chin, and nasolabial folds. Pa-
tients appear to wear a permanent scowling expres-
sion. Overgrowth of the dermis leads to the furrow-
ing of the scalp (cutis verticis gyrata), the thickening
of the eyelids, and the enlargement of the lower lip,
tongue, and nose to give it a distinct triangular
shape. Fingers elongate and thicken and assume a
blunted appearance. The pads of the digits become
fleshy, and the nails become thick and hard. Skin
pores enlarge, and the skin becomes oily from in-
creased sebum secretion. Other features include ec-
crine and apocrine hyperhidrosis, hypertrichosis
(not affecting the beard area), and generalized hy-
perpigmentation. Bone and cartilage changes pri-
marily affect the face and skull. The calvaria thick-
ens, and the frontal sinuses enlarge, which leads to
prominent supraorbital ridges. Anterior and inferior
growth of the mandible results in prognathism and
widely spaced teeth. These characteristic changes
enable the diagnosis to be made on the basis of ap-
pearance in a person with “late-stage” acromegaly.
We report a case of pseudoacromegaly, which is
defined as the presence of acromegaloid features in
the absence of elevated GH or IGF-1 levels, that
most likely resulted from the long-term use of mi-
noxidil. This is the first time to our knowledge that
such a side effect has been reported for minoxidil.
More commonly, pseudoacromegaly occurs in the
context of severe insulin resistance.5-8 In these pa-
tients, a postreceptor defect impairs the insulin’s
ability to stimulate glucose transport although its
mitogenic signaling pathway remains intact. The un-
opposed mitogenic and anabolic actions that are
mediated by hyperinsulinemia would result conse-
quently in pseudoacromegaly.5,6 Of further interest,
pseudoacromegaly has also been associated with an

962
J AM ACAD DERMATOL Nguyen and Marks 963
VOLUME 48, NUMBER 6

autosomal recessive syndrome of skin ulceration,

arthro-osteolysis, keratitis, and oligodontia.9

CASE REPORT
A 58-year-old white man was referred to our
clinic for exuberant soft tissue growth over an un-
certain period of time. Two years earlier, he had
undergone surgical reduction of an excessive skin
fold across his forehead that interfered with his vi-
sion. Since then, he noticed gradual soft tissue en-
largement of the earlobes, nose, and eyelids. These
recurring changes were impairing his respiration
and vision. He also noted the development of skin
folds and deep furrows on his scalp and face. His
review of systems was remarkable for a weight gain
of 10 to 15 pounds over a 1-year period, an increase
in ring size by one-half size without any change in
shoe size, increased moist and oily skin, and in-
creased generalized hair growth. He attributed these
changes to the minoxidil he had been taking for the
past 10 years for hypertension. His medical history
was notable for coronary artery disease status after
coronary artery bypass graft of 3 vessels, peripheral
vascular disease status after a right femoropopiteal Fig 1. Marked coarse facial features from redundant skin
bypass, and severe hypertension. His medications folds and deep furrows.
included minoxidil 50 mg daily, labetalol 400 mg
daily, furosemide 320 mg daily, potassium 80 mEq
daily, quinapril 20 mg daily, spironolactone 100 mg
daily, simvastatin 40 mg daily, lansoprazole 30 mg diographs of the chest and long bones (femora and
daily, and aspirin 81 mg twice a week. humeri) were all normal.
On physical examination, the patient had longi-
DISCUSSION
tudinal folds and furrows in the scalp (cutis verticis
Minoxidil is a piperidinopyrimidine derivative
gyrata) with abundant hair. His earlobes and nose
that was approved initially in oral form for the treat-
were enlarged markedly and soft, with prominent ment of patients with severe or organ-damaging
auricular and nasolabial folds. He had coarse facial hypertension that does not respond to other antihy-
features from redundant skin folds and deep fur- pertensive medications.10 The active metabolite, mi-
rows, with hyperpigmentation of the temples (Fig noxidil sulfate, opens adenosine triphosphate–mod-
1). There was generalized erythema of the forehead ulated potassium channels in smooth muscle to
and cheeks and enlargement of facial pores, and the cause an efflux of potassium, which leads to the
nose was studded with multiple small papules. relaxation of smooth muscle and, subsequently, to
Laboratory data revealed normal routine chemis- vasodilation.11 One adverse effect of minoxidil is
tries, complete blood cell count, triiodothyronine hypertrichosis, which is assumed to be a conse-
level, and tyroid-stimulating hormone. Hemoglobin quence of increased blood flow to the skin as the
and hematocrit levels were slightly depressed. A result of vasodilation of cutaneous blood vessels.
shave biopsy of the left posterior ear showed dermal Hypertrichosis occurs predominantly on the face,
edema, increased mucin deposition, and an in- back, arms, and legs. It is sometimes accompanied
creased number of fibroblasts with connective tissue by coarsening of facial features. Although hypertri-
deposition around adnexal structures and at the der- chosis is undesirable in women and children, it led
moepidermal junction. Proliferation of blood vessels to the marketing of topical minoxidil (Rogaine) for
and a prominent folliculosebaceous unit were also androgenetic alopecia. Other reported side effects
noted (Fig 2). These histologic findings were felt to include fluid retention and increased cardiac sym-
be consistent with acromegaly, pachydermoperios- pathetic responses (increased heart rate, myocardial
tosis, or other causes of connective tissue hyperpla- contractility, and myocardial oxygen consumption)
sia. However, IGF-1 and GH levels along with ra- that require the concurrent use of a loop diuretic and
964 Nguyen and Marks
Fig 2. Hyperplasia of the follicular sebaceous apparatus along with the surrounding adventitial
connective tissue. (Hematoxylin-eosin stain; original magnification ⫻52.)
a beta-blocker, respectively. Rare side effects in-
clude rashes, bullous eruptions, Stevens-Johnson
syndrome, thrombocytopenia, the formation of an-
tinuclear antibodies, and glucose intolerance. These
effects are reversible and resolve after the discontin-
uation of the drug.
Our patient had been taking large doses (50 mg
daily; the typical dose is 10 mg daily) of minoxidil
for approximately 10 years. It was during this time
that his cardiologist began to notice a gradual in-
crease in generalized hair and soft tissue growth,
especially of the face. We considered the diagnosis
of acromegaly versus pachydermoperiostosis be-
cause of his marked soft tissue hypertrophy and
extreme coarsened facial features. However, labora-
tory tests and radiologic studies ruled out these di-
agnoses. This led us to believe that the patient may
have pseudoacromegaly that had been induced by
the long-term use of minoxidil. We believe the large
dose of minoxidil exaggerated the coarsening of
facial features, an already recognized side effect, and
caused pseudoacromegaly. Minoxidil-induced
pseudoacromegaly has not been observed by Phar-
macia & Upjohn, a manufacturer of minoxidil (Mon-
te S. Cohen, PharmD, personal correspondence),
nor has it ever been reported as an adverse reaction
in the clinical studies that examined the long-term
use of minoxidil. The patient’s other medications are
unlikely to be the cause of his cutaneous changes
because they have never been demonstrated to have
significant impact on skin or soft tissue growth.
In the basic science literature, however, minoxidil
has been reported to have profound effects on both
epidermal and dermal cells. In keratinocytes, mi-
J AM ACAD DERMATOL
JUNE 2003
noxidil promotes cell proliferation and glycosamino-
glycan biosynthesis.12 In skin fibroblasts, minoxidil
stimulates elastin synthesis and increases its messen-
ger RNA level.13 Also in skin fibroblasts, minoxidil
exerts inhibitory effects on cell proliferation during
the growth phase, decreases the activity of lysyl
hydroxylase (a key enzyme in collagen production
pathway),14 and decreases the secretion of glycos-
aminoglycan.15,16 Thus, minoxidil can have signifi-
cant impact on the cellular and soft tissue composi-
tion of the skin.
The histopathologic finding in acromegaly is in-
creased deposition of glycosaminoglycan (primarily
hyaluronic acid, chondroitin sulfate, and dermatan
sulfate) in the papillary and reticular dermis, which
promote water retention within the skin and con-
tribute to the thickening and hardening of the skin.17
Priestley et al15,16 reported that minoxidil inhibits
glycosaminoglycan secretion by fibroblasts. This
would seem to contradict our presumption that the
drug was responsible for this patient’s pseudoacro-
megaly. However, the studies were done in vitro,
and the fibroblasts were exposed to minoxidil for
just 3 days. Thus, the effects of minoxidil that were
observed are only short-term effects. It is possible
that, over a long period of time (ie, 10 years) and
with large doses, minoxidil influences other aspects
of cell proliferation and/or cell function such that
the initial inhibitory effects on the fibroblasts dimin-
ish. It is possible that over time, minoxidil may exert
some selection pressure to cause a shift in the fibro-
blast population to favor those fibroblasts that are
resistant to the inhibitory effect of minoxidil and are
thus able to thrive and flourish even with continual
J AM ACAD DERMATOL
VOLUME 48, NUMBER 6
drug exposure. There has been no study to examine
the long-term effects of minoxidil on keratinocytes
and fibroblasts.
The patient and his family have noticed at least an
arrest, if not a gradual reversal, in the soft tissue and
hair overgrowth 5 months after the discontinuation
of minoxidil. This strongly suggests that minoxidil
was the cause of the pseudoacromegaly.
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