PHARMACOTHERAPY CASE REPORTS
DRUG-INDUCED HYPERrRICHOSIS: CASE REPORT AND REVIEW OF THE LITERATURE Linda J. Miwa, Mark S. Shaefer, Robert J. Stratta, R. Patrick Wood, Alan M. Langnas, and Byers W. Shaw, Jr.
ABSTRACT: Hypertrichosis is a well-recognized adverse effect of therapy with either cyclosporine or minoxidil. We present a case of extreme hypertrichosis in an eight-year-old male liver transplant recipient who received concurrent cyclosporine and minoxidil therapy. A review of drug-induced hypertrichosis is presented.
Dlep Ann Pharmacother 1990;24:365-8. HAIR IS COSMETICALLY IMPORTANT in our society. Most of the human body is covered by short, fine-textured, unpigmented hair called vellus hair. Longer, coarser, pigmented hair, such as scalp hair and eyebrows, is called terminal hair. During puberty, vellus hairs on selected parts of the body, e.g., pubic and axillary areas, convert to terminal hairs in response to androgens. Hence, some hair follicles are known to be androgen sensitive.' Hypertrichosis and hirsutism both refer to excessive hair growth. Hypertrichosis is used to describe an increase in nonsexual, i.e., nonandrogen-dependent hair. Hirsutism is used to describe excessive growth of androgen-dependent terminal hair in females." Administration of exogenous androgens or any pathological process that increases endogenous androgen activity can cause hirsutism. 2 Drug-induced hypertrichosis is not commonly associated with an increase in androgen production and the pathophysiology is poorly understood. 3 We present a case of extreme hypertrichosis associated with concurrent cyclosporine and minoxidil therapy. Druginduced hypertrichosis is also reviewed.
CASE REPORT An eight-year-old white boy was admitted on December 8, 1988 for adjustment of antihypertensive medications and control of hypertrichosis. The patient's past medical history was significant for orthotopic liver transplantation performed August 22, 1988 for endstage liver disease secondary to a1pha,-antitrypsin deficiency. The patient had an uncomplicated posttransplant course except for hypertension. He was discharged September 3 on proLINDA J. MIWA, Phann.D.• and MARK S. SHAEFER, Phann.D., are Assistant Professors of Pharmacy Practice, Department of Pharmacy Practice; ROBERT J. STRATTA, M.D., is an Assistant Professor of Surgery; R. PATRICK WOOD, M.D., is an Associate Professor of Surgery; ALAN M. LANGNAS, 0.0., is an Assistant ProfessorofSurgery; and BYERS W. SHAW,Jr., M.D., is a Professor of Surgery, Department of Surgery, University of Nebraska Medical Center, 42ndand Dewey Ave., Omaha, NE 68105. Reprints: Mark S. Shaefer. Pharm.D.
pranoIoI 10 mg po qid, hydralazine 25 mg po qid, and prazosin 3 mg po q8h for control of his blood pressure. He was also receiving nystatin 250000 units po qid, Mylanta II 5 mL po q4h, aspirin 81 mg/d po, sucralfate 0.5 gpo ac and hs, cyclosporine 200 mg po bid, and prednisone 15 rng/d po. He was readmitted the next day with moderate graft rejection which was managed with rapidly tapering intravenous methylprednisolone boluses (25 mg q6h x 4 doses, 20 mg q6h x 4 doses, 15 mg q6h x 4 doses, 10 mg q6h x 4 doses, 10 mg ql2h x 2 doses, then started on pre-taper oral dose). During the second hospitalization, minoxidil 5 mg po bid was initiated on September 10 to control labile blood pressure. The minoxidil dose was increased on September 17 to 7.5 mg po bid. He was discharged three days later on oral cyclosporine 150 mg bid, furosemide 20 mg bid, propranolol 10 mg qid, minoxidil 7.5 mg bid, prednisone 20 mg q d, Mylanta II 5 mL pc and hs, aspirin 81 rng/d, and nystatin 250000 units qid. Physical examination on December 5 revealed a 28.2-kg child who was pleasant and cooperative. Vital signs were temperature 35. 9°C, pulse 115beats/min, respirations 24 breaths/min, and BP 123/55 mrn Hg. Marked hair growth was present over the face, extremities, and trunk. On the face, there was hair growth on the cheeks to the temples bilaterally with frontal hair growth to the eyebrows (Figures I and 2). The rest of his physical examination was unremarkable, Laboratory values were also unremarkable with the exception of moderately elevated lactic dehydrogenase (236 UlL) and alkaline phosphatase (167 U/L). His cyclosporine whole blood trough concentration on admission was 722 ng/rnl, (normal target range is 800-1200 ng/mL by whole blood TDx assay). Upon admission the minoxidil dose was decreased to 5 mg bid, 2.5 mg bid on December 6, 2.5 mg qd on December 7, and was discontinued December 8. Captopril was initiated at a dose of 6.25 mg po tid on December 5. The patient's BP remained stable with systolic BP in the 110-120 mrn Hg range and diastolic BP in the 50-60 mrn Hg range. His BP at the time of discharge was 120/69 with a pulse rate in the 80s. There wasminimal resolution of the patient's hypertrichosis at discharge, at which time the patient's mother removed the hair by shaving. After four months she reported that it had not recurred.
Iatrogenic hypertrichosis or hirsutism has been reported with many drugs (Table I). Hirsutism by definition is excessive hair growth associated with increased androgen activity and is therefore a common adverse effect of anabolic steroids (e.g., stanozolol, danazol, nandrolone). Testosterone and its metabolite dihydrotestosterone are primarily responsible for endogenous androgen activity. Its
DICP, The Annals of Pharmacotherapy
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precursors dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione are useful markers of increased androgen production. 3 Increased androgen activity can also occur in association with decreased concentrations of sex hormone-binding globulin (SHBG), the protein to which androgens are bound in serum. Androgens inhibit production of SHBG resulting in increased free androgen and increased androgen activity.i -' Corticosteroids may cause hirsutism by this effect. 41 A discussion of drugs commonly associated with iatrogenically induced hair growth follows. MinoxidiJ
Hypertrichosis associated with minoxidil therapy has a reported frequency of 24-100 percent. 4 Increased hair growth has been reported to occur as soon as two to three weeks after initiating therapy" and to be completely reversible after discontinuing the drug .4,5 Frequently described as severe, the hair growth may occur on the trunk and is prominent on the limbs and face , particularly the forehead, eyebrows, and cheeks. The effect is not dose-related and frequently requires discontinuation of the drug. 5,6 The pattern of hair growth, lack of virilizing effects, and laboratory evidence indicate the effect is not androgen-mediated." It has been proposed that minoxidil induces growth by increasing cutaneous blood flow, similar to diazoxide ." However, cutaneous blood flow measurements after cutaneously applied minoxidil have provided conflicting results and some authors have questioned the validity of this mech-
anisrn." Cyclosporine
months and then remaining constant. IO,U This observation may be related to tapering of cyclosporine doses over time and may indicate that the effect on hair growth is doserelated. U Other authors have reported that the effect may respond to dose reduction ." However, no direct relationship between the degree of hypertrichosis and cyclosporine serum concentrations has been established.P:" Some authors have suggested that patients who do not exhibit hypertrichosis within the first three months of therapy are unlikely to do so. 10 Reversal of the effect occurs over one to several months after discontinuation of the drug. IO•11 The mechanism of cyclosporine-induced hypertrichosis is unknown . As cyclosporine is highly lipophilic and may accumulate in the skin it is not surprising that it would exert an effect on skin structures . Animal data have shown an increased uptake of cystine into hair with cyclosporine administration. 11 It is also possible that the effect is due to a drug interaction of cyclosporine with corticosteroids, which are usually administered concomitantly. 11 Cyclosporine-induced hair growth does not appear to be an androgen-mediated effect. It occurs independent of other androgen effects (e.g., virilization) and the hair grows in nonandrogen-dependent sites . 10 Two studies have failed to show an effect of cyclosporine on serum androgens . A comparison of 16 renal transplant recipients (5 female , II male) with cyclosporine-induced hypertrichosis with a control group of age-matched renal transplant recipients receiving azathioprine found no differences between serum testosterone, 17-hydroxyprogesterone (an androgen precursor), and DHEA sulfate, all of which were below normal. SHBG was within the normal range." Another study of renal transplant recipients compared pre- and posttransplant serum concentrations of testosterone, SHBG ,
Hypertrichosis is a common adverse effect of cyclosporine therapy with an occurrence rate of 95 percent in one report. 10 Increased hair growth occurs over the trunk, back, neck, shoulders, arms, legs, scalp, forehead, cheeks, eyebrows, earlobes, nose, and fingers. 10.11 Children and adolescents may be at greater risk for hypertrichosis than adults. Sex of the patient does not appear to correlate with this adverse effect. 10 Increased hair may appear within the first month of therapy, 11 increasing over the first six
Figure 1. Excessive hair growth over the face and shoulders.
366
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Figure 2. Marked hair growth over the trunk .
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1990 April, Volume 24
Case Reports
DHEA, DHEA sulfate, and 17-hydroxyprogesterone and found no significant differences."
Oral Contraceptives It has been reported that 0.1 percent of women taking oral contraceptives experience facial hypertrichosis. 15 Hirsutism is the more appropriate term as this is an androgenmediated effect. The progestin component of all available oral contraceptives are derivatives of 19-nortestosterone. Their relationship to testosterone is thought to be responsible for the androgenic and antiestrogenic effects of these drugs. The potential for a specific oral contraceptive to cause hirsutism in a susceptible woman is dependent on the effects of the specific progestogen on SHBG production, its binding affinity to SHBG and androgen receptors, and the estrogenic effects of the estrogen component of the contra-
ceptive."
Psoralens Hypertrichosis following use of systemic methoxsalen and exposure to ultraviolet-A light" or sunlight" (PUVA therapy) has been reported in patients treated for vitiligo, psoriasis, and alopecia areata. The incidence has ranged from 217 to 65 percent" although in the latter report all the subjects were female. Increased hair growth in exposed areas (face and extrernitiesj'
DRUG-INDUCED HYPERrRICHOSIS: CASE REPORT AND REVIEW OF THE LITERATURE Linda J. Miwa, Mark S. Shaefer, Robert J. Stratta, R. Patrick Wood, Alan M. Langnas, and Byers W. Shaw, Jr.
ABSTRACT: Hypertrichosis is a well-recognized adverse effect of therapy with either cyclosporine or minoxidil. We present a case of extreme hypertrichosis in an eight-year-old male liver transplant recipient who received concurrent cyclosporine and minoxidil therapy. A review of drug-induced hypertrichosis is presented.
Dlep Ann Pharmacother 1990;24:365-8. HAIR IS COSMETICALLY IMPORTANT in our society. Most of the human body is covered by short, fine-textured, unpigmented hair called vellus hair. Longer, coarser, pigmented hair, such as scalp hair and eyebrows, is called terminal hair. During puberty, vellus hairs on selected parts of the body, e.g., pubic and axillary areas, convert to terminal hairs in response to androgens. Hence, some hair follicles are known to be androgen sensitive.' Hypertrichosis and hirsutism both refer to excessive hair growth. Hypertrichosis is used to describe an increase in nonsexual, i.e., nonandrogen-dependent hair. Hirsutism is used to describe excessive growth of androgen-dependent terminal hair in females." Administration of exogenous androgens or any pathological process that increases endogenous androgen activity can cause hirsutism. 2 Drug-induced hypertrichosis is not commonly associated with an increase in androgen production and the pathophysiology is poorly understood. 3 We present a case of extreme hypertrichosis associated with concurrent cyclosporine and minoxidil therapy. Druginduced hypertrichosis is also reviewed.
CASE REPORT An eight-year-old white boy was admitted on December 8, 1988 for adjustment of antihypertensive medications and control of hypertrichosis. The patient's past medical history was significant for orthotopic liver transplantation performed August 22, 1988 for endstage liver disease secondary to a1pha,-antitrypsin deficiency. The patient had an uncomplicated posttransplant course except for hypertension. He was discharged September 3 on proLINDA J. MIWA, Phann.D.• and MARK S. SHAEFER, Phann.D., are Assistant Professors of Pharmacy Practice, Department of Pharmacy Practice; ROBERT J. STRATTA, M.D., is an Assistant Professor of Surgery; R. PATRICK WOOD, M.D., is an Associate Professor of Surgery; ALAN M. LANGNAS, 0.0., is an Assistant ProfessorofSurgery; and BYERS W. SHAW,Jr., M.D., is a Professor of Surgery, Department of Surgery, University of Nebraska Medical Center, 42ndand Dewey Ave., Omaha, NE 68105. Reprints: Mark S. Shaefer. Pharm.D.
pranoIoI 10 mg po qid, hydralazine 25 mg po qid, and prazosin 3 mg po q8h for control of his blood pressure. He was also receiving nystatin 250000 units po qid, Mylanta II 5 mL po q4h, aspirin 81 mg/d po, sucralfate 0.5 gpo ac and hs, cyclosporine 200 mg po bid, and prednisone 15 rng/d po. He was readmitted the next day with moderate graft rejection which was managed with rapidly tapering intravenous methylprednisolone boluses (25 mg q6h x 4 doses, 20 mg q6h x 4 doses, 15 mg q6h x 4 doses, 10 mg q6h x 4 doses, 10 mg ql2h x 2 doses, then started on pre-taper oral dose). During the second hospitalization, minoxidil 5 mg po bid was initiated on September 10 to control labile blood pressure. The minoxidil dose was increased on September 17 to 7.5 mg po bid. He was discharged three days later on oral cyclosporine 150 mg bid, furosemide 20 mg bid, propranolol 10 mg qid, minoxidil 7.5 mg bid, prednisone 20 mg q d, Mylanta II 5 mL pc and hs, aspirin 81 rng/d, and nystatin 250000 units qid. Physical examination on December 5 revealed a 28.2-kg child who was pleasant and cooperative. Vital signs were temperature 35. 9°C, pulse 115beats/min, respirations 24 breaths/min, and BP 123/55 mrn Hg. Marked hair growth was present over the face, extremities, and trunk. On the face, there was hair growth on the cheeks to the temples bilaterally with frontal hair growth to the eyebrows (Figures I and 2). The rest of his physical examination was unremarkable, Laboratory values were also unremarkable with the exception of moderately elevated lactic dehydrogenase (236 UlL) and alkaline phosphatase (167 U/L). His cyclosporine whole blood trough concentration on admission was 722 ng/rnl, (normal target range is 800-1200 ng/mL by whole blood TDx assay). Upon admission the minoxidil dose was decreased to 5 mg bid, 2.5 mg bid on December 6, 2.5 mg qd on December 7, and was discontinued December 8. Captopril was initiated at a dose of 6.25 mg po tid on December 5. The patient's BP remained stable with systolic BP in the 110-120 mrn Hg range and diastolic BP in the 50-60 mrn Hg range. His BP at the time of discharge was 120/69 with a pulse rate in the 80s. There wasminimal resolution of the patient's hypertrichosis at discharge, at which time the patient's mother removed the hair by shaving. After four months she reported that it had not recurred.
Iatrogenic hypertrichosis or hirsutism has been reported with many drugs (Table I). Hirsutism by definition is excessive hair growth associated with increased androgen activity and is therefore a common adverse effect of anabolic steroids (e.g., stanozolol, danazol, nandrolone). Testosterone and its metabolite dihydrotestosterone are primarily responsible for endogenous androgen activity. Its
DICP, The Annals of Pharmacotherapy
•
1990 April, Volume 24
•
365
precursors dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione are useful markers of increased androgen production. 3 Increased androgen activity can also occur in association with decreased concentrations of sex hormone-binding globulin (SHBG), the protein to which androgens are bound in serum. Androgens inhibit production of SHBG resulting in increased free androgen and increased androgen activity.i -' Corticosteroids may cause hirsutism by this effect. 41 A discussion of drugs commonly associated with iatrogenically induced hair growth follows. MinoxidiJ
Hypertrichosis associated with minoxidil therapy has a reported frequency of 24-100 percent. 4 Increased hair growth has been reported to occur as soon as two to three weeks after initiating therapy" and to be completely reversible after discontinuing the drug .4,5 Frequently described as severe, the hair growth may occur on the trunk and is prominent on the limbs and face , particularly the forehead, eyebrows, and cheeks. The effect is not dose-related and frequently requires discontinuation of the drug. 5,6 The pattern of hair growth, lack of virilizing effects, and laboratory evidence indicate the effect is not androgen-mediated." It has been proposed that minoxidil induces growth by increasing cutaneous blood flow, similar to diazoxide ." However, cutaneous blood flow measurements after cutaneously applied minoxidil have provided conflicting results and some authors have questioned the validity of this mech-
anisrn." Cyclosporine
months and then remaining constant. IO,U This observation may be related to tapering of cyclosporine doses over time and may indicate that the effect on hair growth is doserelated. U Other authors have reported that the effect may respond to dose reduction ." However, no direct relationship between the degree of hypertrichosis and cyclosporine serum concentrations has been established.P:" Some authors have suggested that patients who do not exhibit hypertrichosis within the first three months of therapy are unlikely to do so. 10 Reversal of the effect occurs over one to several months after discontinuation of the drug. IO•11 The mechanism of cyclosporine-induced hypertrichosis is unknown . As cyclosporine is highly lipophilic and may accumulate in the skin it is not surprising that it would exert an effect on skin structures . Animal data have shown an increased uptake of cystine into hair with cyclosporine administration. 11 It is also possible that the effect is due to a drug interaction of cyclosporine with corticosteroids, which are usually administered concomitantly. 11 Cyclosporine-induced hair growth does not appear to be an androgen-mediated effect. It occurs independent of other androgen effects (e.g., virilization) and the hair grows in nonandrogen-dependent sites . 10 Two studies have failed to show an effect of cyclosporine on serum androgens . A comparison of 16 renal transplant recipients (5 female , II male) with cyclosporine-induced hypertrichosis with a control group of age-matched renal transplant recipients receiving azathioprine found no differences between serum testosterone, 17-hydroxyprogesterone (an androgen precursor), and DHEA sulfate, all of which were below normal. SHBG was within the normal range." Another study of renal transplant recipients compared pre- and posttransplant serum concentrations of testosterone, SHBG ,
Hypertrichosis is a common adverse effect of cyclosporine therapy with an occurrence rate of 95 percent in one report. 10 Increased hair growth occurs over the trunk, back, neck, shoulders, arms, legs, scalp, forehead, cheeks, eyebrows, earlobes, nose, and fingers. 10.11 Children and adolescents may be at greater risk for hypertrichosis than adults. Sex of the patient does not appear to correlate with this adverse effect. 10 Increased hair may appear within the first month of therapy, 11 increasing over the first six
Figure 1. Excessive hair growth over the face and shoulders.
366
•
DICP, The Annals of Pharmacotherapy
Figure 2. Marked hair growth over the trunk .
•
1990 April, Volume 24
Case Reports
DHEA, DHEA sulfate, and 17-hydroxyprogesterone and found no significant differences."
Oral Contraceptives It has been reported that 0.1 percent of women taking oral contraceptives experience facial hypertrichosis. 15 Hirsutism is the more appropriate term as this is an androgenmediated effect. The progestin component of all available oral contraceptives are derivatives of 19-nortestosterone. Their relationship to testosterone is thought to be responsible for the androgenic and antiestrogenic effects of these drugs. The potential for a specific oral contraceptive to cause hirsutism in a susceptible woman is dependent on the effects of the specific progestogen on SHBG production, its binding affinity to SHBG and androgen receptors, and the estrogenic effects of the estrogen component of the contra-
ceptive."
Psoralens Hypertrichosis following use of systemic methoxsalen and exposure to ultraviolet-A light" or sunlight" (PUVA therapy) has been reported in patients treated for vitiligo, psoriasis, and alopecia areata. The incidence has ranged from 217 to 65 percent" although in the latter report all the subjects were female. Increased hair growth in exposed areas (face and extrernitiesj'
