Persistent Gynecomastia due to Short-term Low-dose Finasteride for Androgenetic Alopecia

Abstract

We report a case of persistent gynecomastia in a healthy 20-year-old man after 1 month of low-dose finasteride. Finasteride was discontinued after 2 months, and gynecomastia was unchanged 5 months after drug withdrawal. The gynecomastia regressed but did not resolve after 6 months of treatment with raloxifene, a selective estrogen receptor modulator. One year later, bilateral mammoplasty was performed to remove the remaining breast tissue. Finasteride, a 5-alpha-reductase inhibitor, is widely used for the treatment of androgenetic alopecia. Gynecomastia is an expected side effect of this therapy given its mechanism of action. However, only 8 cases of gynecomastia have been reported with low-dose (1 mg daily) finasteride treatment since its approval for androgenetic alopecia in 1997. This raises the concern that gynecomastia resulting from low-dose finasteride is significantly underreported, causing inadequately informed patients. Further, because of the risk of gynecomastia, it is important for prescribing physicians to counsel patients regarding this complication and to consider early intervention when finasteride-induced gynecomastia first arises to prevent fibrosis and thus irreversible gynecomastia.

Introduction

Topical minoxidil and oral finasteride are currently Food and Drug Administration (FDA)-approved for the treatment of androgenetic alopecia (AGA), an androgen-dependent form of hair loss. Topical minoxidil, approved in 1986, promotes hair regrowth. Its mechanism of action is not fully understood. Finasteride, approved for benign prostatic hyperplasia (BPH) in 1992 and for AGA in 1997, is a 5-alpha reductase inhibitor. It functionally inhibits the 5-alpha reductase enzyme, which converts testosterone to dihydrotestosterone (DHT), a more potent androgen. Blocking 5-alpha reductase reduces serum DHT levels, resulting in prostate gland reduction in most males with BPH and induction of hair growth and reduction of hair loss in most males with AGA.

There are three 5-alpha reductase isozymes (types 1, 2, and 3). Type 2 is expressed in the breast, prostate gland, and other tissues, and type 3 is highly expressed in skin and breast tissue, suggesting that types 2 and 3 play a significant role in conversion of testosterone to DHT in these tissues. Types 2 and 3 are both potently inhibited by finasteride [1, 2], whereas type 1 is not.

Topical minoxidil can be purchased without a prescription. Adverse events resulting from minoxidil are rare and mild, and most involve local reaction at the site of medication application. Low-dose (1 mg daily) finasteride is prescribed by dermatologists for ∼200 000 AGA patients yearly [3]. Adverse event data from studies leading to FDA approval of finasteride in 1997 for this indication demonstrated that gynecomastia did not differ between patients receiving active drug and those receiving placebo. However, postmarketing reports led to modification of the FDA package insert, which now states that breast enlargement and breast cancer have been reported [4].

A recent systematic review of studies involving the treatment of BPH with high-dose finasteride (5 mg daily) focused on adverse events related to breast disease. This analysis demonstrated a 2-fold greater risk of gynecomastia (3.30% vs 1.84%, P < .00001) in men treated with high-dose finasteride compared with those treated with placebo after an average treatment duration of 6 months [5].

Few cases of gynecomastia with low-dose finasteride treatment have been reported in the literature. Given the evidence demonstrating occurrence of gynecomastia with high-dose finasteride and the drug's mechanism of action, gynecomastia is an expected adverse effect of low-dose finasteride and may be underreported. Counseling patients regarding the risk of gynecomastia with finasteride treatment is important, and early recognition of gynecomastia is necessary so that rapid intervention can be considered to prevent the breast tissue from becoming irreversible because of fibrosis.

Case Presentation

A 20-year-old healthy male with AGA was started on low-dose finasteride, 1 mg daily, and noted unilateral, tender gynecomastia after 1 month of treatment. The prescribing dermatologist decreased the finasteride to 0.5 mg daily, but the gynecomastia persisted, so after 2 months, finasteride was stopped. Five months after finasteride discontinuation, gynecomastia was unchanged. Breast ultrasound showed mild gynecomastia, right greater than left.

Diagnostic Assessment

Endocrinologist evaluation revealed a healthy young adult male. Pertinent medical history included transient bilateral pubertal gynecomastia in high school, which completely resolved by the end of puberty. There was no history of chest wall injury. The patient exercised several times per week, including weightlifting, but not excessively. His weight and height were unchanged since starting finasteride. There was no history of exposure to products containing androgens, estrogens, or phytoestrogens. He ate a well-balanced diet. He denied use of any amphetamines or antipsychotic medications. He was started on fluoxetine and bupropion for anxiety, depression, and posttraumatic stress disorder approximately 6 months after the onset of gynecomastia. He reported a history of marijuana use but had not used it in any form during the year before starting finasteride. He denied tobacco use and reported social alcohol consumption (approximately 3-4 beers twice weekly). No other medications were used to treat his AGA before finasteride initiation.

Physical examination by the endocrinologist demonstrated bilateral gynecomastia (4-cm diameter breast tissue). Testicular volume was 25 mL bilaterally, and there was no hypospadias. The remainder of his examination was unremarkable. Body mass index was 26.5.

Laboratory (blood) tests at the time of initial endocrine evaluation, 5 months after finasteride discontinuation, were within the normal range (Table 1).

Table 1.

Laboratory values at initial endocrine diagnosis

Laboratory test	Measured value, conventional units	Normal range, conventional units
Sodium	139 mmol/L (139 mmol/L)	136-145 mmol/L (136-145 mmol/L)
Potassium	4.3 mmol/L (4.3 mmol/L)	3.5-5.1 mmol/L (3.5-5.1 mmol/L)
Chloride	100 mmol/L (100 mmol/L)	98-107 mmol/L (98-107 mmol/L)
Total carbon dioxide	30 mmol/L (30 mmol/L)	22-29 mmol/L (22-29 mmol/L)
Urea nitrogen	18 mg/dL (6.43 mmol/L)	9-21 mg/dL (3.21-7.50 mmol/L)
Creatinine	1.12 mg/dL (99.01 μmol/L)	0.73-1.18 mg/dL (64.53 μmol/L)
Glucose	91 mg/dL (5.05 mmol/L)	70-99 mg/dL (3.89-5.49 mmol/L)
Alkaline phosphatase	88 U/L (88 U/L)	40-150 U/L (40-150 U/L)
Alanine aminotransferase	32 U/L (32 U/L)	<55 U/L (<55 U/L)
Aspartate aminotransferase	26 U/L (26 U/L)	5-34 U/L (5-34 U/L)
Bilirubin, total	0.7 mg/dL (11.97 μmol/L)	0.2-1.2 mg/dL (3.42-20.52 μmol/L)
Bilirubin, direct	0.3 mg/dL (5.13 μmol/L)	< 0.5 mg/dL (<8.55 μmol/L)
Free thyroxine	1 ng/dL (12.9 pmol/L)	0.7-1.5 ng/dL (9.0-19.4 pmol/L)
TSH	3.09 mIU/mL (3.09 mIU/mL)	0.35-4.94 mIU/mL (0.35-4.94 mIU/mL)
Testosterone, total	477 ng/dL (16.55 nmol/L)	240-871 ng/dL (8.33-30.22 nmol/L)
SHBG	26 nmol/L (26 nmol/L)	11-78 nmol/L (11-78 nmol/L)
Albumin	5 g/dL (50 g/L)	3.5-5.2 g/dL (35.0-52.0 g/L)
Testosterone, free, calculated	10.3 ng/dL (357.1 pmol/L)	5.0-21.0 ng/dL (173.4-728.1 pmol/L)
Dihydrotestosteronea	232 pg/mL (798 pmol/L)	112-955 pg/mL (385-3285 pmol/L)
LH	3.2 U/L (3.2 IU/L)	0.6-12.1 U/L (0.6-12.1 IU/L)
FSH	4.3 U/L (4.3 IU/L)	1.0-12.0 U/L (1.0-12.0 IU/L)
Estradiol	11 pg/mL (40.37 pmol/L)	11-44 pg/mL (40.37-161.48 pmol/L)
Prolactin	19.4 μ/L (19.4 μ/L)	3.5-19.4 μ/L (3.5-19.4 μ/L)

Values in parenthesis are International System of Units (SI)

^a All laboratory tests were performed at the National Institutes of Health Clinical Center except for dihydrotestosterone, which was performed at the Mayo Clinic Laboratory.

Treatment

The patient was treated with raloxifene (60 mg daily), a selective estrogen receptor modulator (SERM), for 6 months, resulting in partial resolution of the gynecomastia. One year later, he underwent bilateral reduction mammoplasty for removal of the remaining breast tissue.

Outcome and Follow-up

All breast tissue was successfully removed during mammoplasty without complications and with minimal scarring. Pathologic study of the resected specimens revealed that it contained glandular breast tissue. The patient's gynecomastia had not recurred as of 19 months after reduction mammoplasty.

Discussion

There are very few reported cases of gynecomastia resulting from low-dose finasteride (Table 2). Review of the literature revealed only 8 cases [6-9]. When combined with the present case, 7 of 9 cases occurred in young adult males (aged 18-29 years) and the other 2 cases occurred in men aged 53 and 65 years. Seven of the 9 cases were unilateral and 2 were bilateral. For all cases, finasteride was discontinued when gynecomastia developed (or shortly afterward). Gynecomastia resolved spontaneously in 5, persisted in 3, and resolution could not be assessed in 1 because the tissue was surgically removed at diagnosis; therefore, 38% of the reported cases had persistent gynecomastia.

Table 2.

Reported cases of gynecomastia resulting from low-dose finasteride

Source	Number	Age	Finasteride indication	Dose of finasteride	Duration of finasteride treatment at gynecomastia onset/total duration of finasteride treatment	Medical treatment	Outcome
Wade et al, 2000 [6]	1 case	20 years	“Androgenetic alopecia”	1 mg/day	2 months/4 months	None	Incomplete resolution of gynecomastia 7 months after finasteride discontinuation
Zimmerman et al, 2000 [7]	1 case	53 years	“Alopecia”	1 mg/day	2 months/2 months	Surgical excision	Resolution of gynecomastia following surgical excision
Ferrando et al, 2002 [8]	4 cases	18 years	“Male androgenic alopecia”	1 mg/day	2 months/2 months	None	Resolution of gynecomastia 10 months after finasteride discontinuation
		23 years	Not specified	1 mg/day	6 months/6 months	None	Resolution of gynecomastia 2 months after finasteride discontinuation
		29 years	“Male androgenic alopecia”	1 mg/day	3 months/3 months	None	Resolution of gynecomastia 3 months after finasteride discontinuation
		25 years	Not specified	1.25 mg/day	11 months/12 months	None	Resolution of gynecomastia between 2 and 10 months after finasteride discontinuation
Ramot et al, 2009 [9]	2 cases	21 years	“Androgenetic alopecia”	1 mg/day	4 months/4 months	None	No resolution of gynecomastia 10 months after finasteride discontinuation
		65 years	“Androgenetic alopecia”	Not specified	2 months/2 months	None	Incomplete resolution of gynecomastia 6 years after finasteride discontinuation
Current case	1 case	20 years	“Androgenetic alopecia”	1 mg/day for 1 month, then 0.5 mg/day for 1 month	1 month/2 months	Raloxifene 60 mg/day for 6 months followed by mammoplasty	No resolution of gynecomastia 5 months after finasteride discontinuation, partial resolution of gynecomastia 6 months after raloxifene treatment, resolution of gynecomastia after surgical excision

In 1992, before low-dose (1 mg) finasteride was approved for AGA, high-dose (5 mg) finasteride was approved by the FDA for treatment of BPH. A comprehensive meta-analysis of studies of BPH treatment with high-dose finasteride demonstrated a 2-fold greater risk of gynecomastia in finasteride-treated men compared with placebo (3.30% vs 1.84%, P < .00001) [5]. In contrast, there are no published data on the rate of gynecomastia in men treated with low-dose finasteride for AGA, presumably because this adverse effect is rarely reported and neither prospective nor retrospective evaluation has been performed. Pharmacokinetic studies comparing finasteride doses demonstrated that for both 1 and 5 mg, decreases in serum and scalp skin DHT were comparable (71.4% vs 72.2% for serum, 64.1% vs 69.4% for scalp skin, 1 mg vs 5 mg). However, increases in serum and scalp skin testosterone were greater for 1 mg compared with 5 mg (12.5% vs 3.7% for serum, 41.4% vs 29.7% for scalp skin, 1 mg vs 5 mg, both P < .01) [10]. This is significant because the underlying cause of gynecomastia with finasteride treatment is the increase in serum testosterone, which is subsequently converted to estradiol by aromatase in peripheral tissues, thus increasing serum and breast estrogen concentrations and resulting in breast development [10, 11]. Because the 1-mg dose of finasteride raises testosterone levels in the serum and scalp skin more than the 5-mg dose, there is every reason to believe that gynecomastia is at least as prevalent in men treated with 1 mg compared with those treated with 5 mg. Of note, a carefully conducted prospective study looking at the duration of serum testosterone elevation secondary to high-dose (5 mg) finasteride administration in healthy men showed that testosterone increased by about 25% after starting finasteride and then returned to baseline by weeks 4 to 12 of treatment. In addition, no changes were noted in serum gonadotropins, estradiol, or sex hormone binding globulin [12]. For individuals who develop gynecomastia while on finasteride in the first several months of treatment and experience resolution following rapid drug discontinuation, these data suggest that the gynecomastia might have resolved without stopping finasteride.

An interesting consideration is the lack of gynecomastia in individuals with 5-alpha reductase deficiency, an autosomal recessive genetic condition that typically presents with ambiguous genitalia at birth. Most cases of 5-alpha reductase deficiency are due to a mutation in the gene encoding the type 2 5-alpha reductase isozyme [13]. Although the type 2 isozyme is expressed in the breast, prostate gland, and other tissues, the type 3 isoenzyme is highly expressed in skin and breast tissue. Because both the type 2 and type 3 isozymes are potently inhibited by finasteride, it might be expected that the effects of loss of 5-alpha reductase activity because of the medication would be more pronounced in skin and breast tissues than in individuals with 5-alpha reductase deficiency.

Early intervention can be important with finasteride-induced gynecomastia. Although gynecomastia is often self-limited and resolves spontaneously once the causative medication is removed, this is not always the case. In addition, gynecomastia present for greater than 1 year is unlikely to completely regress because of fibrosis of the ductal tissue, and once this occurs, surgical intervention is the only effective treatment [14]. It is important for prescribers to inform finasteride-treated patients about early recognition of gynecomastia because if it develops and the breast tissue does not completely regress shortly after drug discontinuation, the condition may quickly become irreversible. Reviews evaluating strategies to treat gynecomastia caused by nonsteroidal antiandrogens (such as finasteride) demonstrate that certain SERMs (such as tamoxifen) are safe and effective as adjunct therapy for gynecomastia treatment, as was seen (partial regression) in the case reported here [15, 16].

Limitations of this analysis include that the current case report is an anecdotal observation with no definitive proof of a cause-and-effect relationship. In addition, the actual rate of gynecomastia remains unknown for men treated with low-dose finasteride, although based on the drug's mechanism of action, it is likely comparable to that seen with high-dose finasteride. Also, many studies evaluating rates of gynecomastia rely on patient self-report rather than physical examination by a skilled clinician, possibly resulting in underdiagnosis of this condition. Last, although pharmacokinetic studies showed that serum and scalp skin testosterone were higher with the 1-mg finasteride dose compared with the 5-mg dose, it is not possible to know the actual hormone levels in the breast tissue, where the testosterone is presumably being converted by aromatase to estrogen. This information would have been extremely helpful with respect to understanding the pathophysiology of this adverse effect.

Very few cases of gynecomastia associated with low-dose finasteride have been reported in the literature. Finasteride's mechanism of action is consistent with the risk for development of gynecomastia, and it is likely that this adverse drug effect is underreported for low-dose finasteride given its prevalence in patients treated with high-dose finasteride for BPH. It is important for finasteride prescribers to discuss the risk of gynecomastia with patients in advance of treatment. Patients should be assessed at baseline for preexisting gynecomastia and then examined by a trained clinician at least monthly during the first year of treatment for evidence of breast tissue development. If the clinician is unable to distinguish gynecomastia from lipomastia, a breast ultrasound should be obtained to make the distinction. If gynecomastia develops during therapy, discontinuation of finasteride and treatment with an appropriate SERM should be immediately considered to prevent the breast tissue from fibrosing, making the gynecomastia irreversible.

Learning Points

• Patients treated with finasteride should be educated regarding the risk of gynecomastia as well as other adverse effects related to resulting hormonal aberrations.

• Gynecomastia resulting from low-dose finasteride is probably much more common than is reported.

• Gynecomastia from low-dose finasteride does not always resolve when the drug is discontinued, regardless of treatment duration.

• Early intervention for gynecomastia should be strongly considered in individuals treated with low-dose finasteride.

• Failure to treat persistent gynecomastia early in its course can result in irreversible fibrosis of the breast tissue.

Abbreviations

AGA

androgenetic alopecia

BPH

benign prostatic hyperplasia

DHT

dihydrotestosterone

FDA

Food and Drug Administration

SERM

selective estrogen receptor modulator

Contributors

All authors made individual contributions to authorship. Y.H.J. and V.S. were responsible for patient diagnosis and management, patient data validation, and extensively involved in manuscript revisions and finalization. H.S.F. and E.W.L. performed the literature search, drafted the manuscript, and were extensively involved in manuscript revisions and finalization. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

There are no conflicts of interest or disclosures for any of the authors of this manuscript.

Informed Patient Consent for Publication

Signed informed consent was obtained directly from the patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.