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

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- noxidil promotes cell proliferation and glycosamino-
clude rashes, bullous eruptions, Stevens-Johnson glycan biosynthesis.12 In skin fibroblasts, minoxidil
syndrome, thrombocytopenia, the formation of an- stimulates elastin synthesis and increases its messen-
tinuclear antibodies, and glucose intolerance. These ger RNA level.13 Also in skin fibroblasts, minoxidil
effects are reversible and resolve after the discontin- exerts inhibitory effects on cell proliferation during
uation of the drug. the growth phase, decreases the activity of lysyl
Our patient had been taking large doses (50 mg hydroxylase (a key enzyme in collagen production
daily; the typical dose is 10 mg daily) of minoxidil pathway),14 and decreases the secretion of glycos-
for approximately 10 years. It was during this time aminoglycan.15,16 Thus, minoxidil can have signifi-
that his cardiologist began to notice a gradual in- cant impact on the cellular and soft tissue composi-
crease in generalized hair and soft tissue growth, tion of the skin.
especially of the face. We considered the diagnosis The histopathologic finding in acromegaly is in-
of acromegaly versus pachydermoperiostosis be- creased deposition of glycosaminoglycan (primarily
cause of his marked soft tissue hypertrophy and hyaluronic acid, chondroitin sulfate, and dermatan
extreme coarsened facial features. However, labora- sulfate) in the papillary and reticular dermis, which
tory tests and radiologic studies ruled out these di- promote water retention within the skin and con-
agnoses. This led us to believe that the patient may tribute to the thickening and hardening of the skin.17
have pseudoacromegaly that had been induced by Priestley et al15,16 reported that minoxidil inhibits
the long-term use of minoxidil. We believe the large glycosaminoglycan secretion by fibroblasts. This
dose of minoxidil exaggerated the coarsening of would seem to contradict our presumption that the
facial features, an already recognized side effect, and drug was responsible for this patient’s pseudoacro-
caused pseudoacromegaly. Minoxidil-induced megaly. However, the studies were done in vitro,
pseudoacromegaly has not been observed by Phar- and the fibroblasts were exposed to minoxidil for
macia & Upjohn, a manufacturer of minoxidil (Mon- just 3 days. Thus, the effects of minoxidil that were
te S. Cohen, PharmD, personal correspondence), observed are only short-term effects. It is possible
nor has it ever been reported as an adverse reaction that, over a long period of time (ie, 10 years) and
in the clinical studies that examined the long-term with large doses, minoxidil influences other aspects
use of minoxidil. The patient’s other medications are of cell proliferation and/or cell function such that
unlikely to be the cause of his cutaneous changes the initial inhibitory effects on the fibroblasts dimin-
because they have never been demonstrated to have ish. It is possible that over time, minoxidil may exert
significant impact on skin or soft tissue growth. some selection pressure to cause a shift in the fibro-
In the basic science literature, however, minoxidil blast population to favor those fibroblasts that are
has been reported to have profound effects on both resistant to the inhibitory effect of minoxidil and are
epidermal and dermal cells. In keratinocytes, mi- thus able to thrive and flourish even with continual
J AM ACAD DERMATOL Nguyen and Marks 965
VOLUME 48, NUMBER 6

drug exposure. There has been no study to examine hypertriglyceridemia, and pseudoacromegaly. J Clin Endocrinol
the long-term effects of minoxidil on keratinocytes Metab 1996;81:3456-8.
8. Flier JS, Moller DE, Moses AC, O’Rahilly S, Chaiken RL, Grigorescu
and fibroblasts. F, et al. Insulin-mediated pseudoacromegaly: clinical and bio-
The patient and his family have noticed at least an chemical characterization of a syndrome of selective insulin re-
arrest, if not a gradual reversal, in the soft tissue and sistance. J Clin Endocrinol Metab 1993;76:1533-41.
hair overgrowth 5 months after the discontinuation 9. Kozlova SI, Altshuler BA, Kravchenko VL. Self-limited autosomal
of minoxidil. This strongly suggests that minoxidil recessive syndrome of skin ulceration, arthroosteolysis with
pseudoacromegaly, keratitis, and oligodontia in a Kirghizian
was the cause of the pseudoacromegaly. family. Am J Med Genetics 1983;15:205-10.
10. Anonymous. Minoxidil (Loniten). Med Lett Drugs Ther 1980;22:
21-2.
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