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Open Journal of Internal Medicine, 2016, 6, 69-71
Published Online September 2016 in SciRes. http://www.scirp.org/journal/ojim
http://dx.doi.org/10.4236/ojim.2016.63011
How to cite this paper: Shaikh, S. and Shaikh, S. (2016) Gynecomastia in a Rheumatoid Arthritis Patient; a Rare Side Effect
of Methotrexate Therapy. Open Journal of Internal Medicine, 6, 69-71. http://dx.doi.org/10.4236/ojim.2016.63011
Gynecomastia in a Rheumatoid Arthritis
Patient; a Rare Side Effect of Methotrexate
Therapy
Soorih Shaikh, Sarwan Shaikh
The Indus Hospital, Karachi, Pakistan
Received 23 June 2016; accepted 25 July 2016; published 28 July 2016
Copyright © 2016 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
We are reporting a case of a 51-year-old male patient with 3-year history of Rheumatoid Arthritis
who developed gynecomastia 2 - 3 months after starting Methotrexate (MTX) therapy, without fo-
late supplementation. Two months after stopping MTX therapy and initiating folate supplementa-
tion, gynecomastia started resolving. Very few cases of gynecomastia due to MTX therapy have been
reported worldwide, although it is a rare yet a significant occurrence and should always be consi-
dered in male patients with Rheumatoid Arthritis.
Keywords
Rheumatoid Arthritis, Gynecomastia, Methotrexate, Folate
1. Case Report
A 51-year-old male patient, with no known co-morbidities, came with complaint of painful progressive deforma-
tion of joints. Symptoms started 3 years ago with moderate to severe pain in the small joints of hands, wrist & an-
kle, morning stiffness for more than 45 minutes and decreased range of motion. Overtime, he noticed progressive
deformation of the respective joints. On examination, he had deformed interphalangeal, wrist and ankle joints, bi-
laterally with marked ulnar deviation of wrist joints. Radiographs of both wrist and ankle joints showed osteopenia,
decreased joint space and other features of Rheumatoid Arthritis (Figure 1). His lab studies showed positive RA
factor (qualitatively and high-quantitatively) and Anti-CCP antibodies, confirming the severe course of RA.
On the basis of above findings, he was started on Naproxen (Synflex) 550 mg once daily, Methotrexate (Imutrex)
10 mg once weekly (without folate supplementation) and Calcium/Vitamin D supplements once daily; in response to
the medications, joint deformation slowed down but he developed gynecomastia within a period of 2 - 3 months.
S. Shaikh, S. Shaikh
70
Figure 1. Gynecomastia and deformed wrist joints in a patient with rheumatoid arthritis.
This patient in particular was prescribed MTX therapy without folate supplementation, hence, he developed
gynecomastia earlier as compared to previously known cases. A thorough work-up for gynecomastia was per-
formed. It was found that the patient did not have any other co-morbidities that could lead to the development of
gynecomastia, hence, MTX was considered to be the cause. So MTX therapy was discontinued and folate sup-
plementation initiated. About 2 months after stopping MTX and starting folate, gynecomastia started to resolve.
2. Discussion
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic, progressive, inflammatory de-
struction of joint lining that results in erosion of bone and leading ultimately to the deformed joint. RA usually
affects the small joints of hands and feet but large joints of body can also be affected. Although there is no cure
for RA, multiple treatment options including NSAIDs, Steroids and DMARDs have been known to decrease
symptoms, slow disease progression and significantly improve overall functioning.
Methotrexate (MTX) is the most commonly used drug in DMARD (Disease-Modifying Anti-Rheumatic
Drugs) therapy. It is an anti-folate and antimetabolite drug; it inhibits the enzyme dihydrofolate reductase
(DHFR) and enzymes involved in purine metabolism. MTX is used as a treatment for cancer, medical abortions
(in ectopic pregnancy etc.) and Rheumatoid Arthritis. It is recommended to be taken once or twice a week only.
MTX therapy, even in low doses [1]-[3] causes multiple side effects; Hepatic toxicity, bone marrow suppres-
sion, pneumonitis & lung fibrosis, hypersensitivity and rarely gynecomastia and sexual dysfunction [4] [5].
Gynecomastia is a rare side effect of MTX therapy [1] [3] [6] [7]; so far, only 8 to 10 cases have been re-
ported. Out of many proposed mechanisms for development of gynecomastia with methotrexate therapy, most
supported yet unproven theory is, methotrexate being an antimetabolite drug damages leydig cells in testicles,
leading to azoospermia and decreased testosterone production. This in turn stimulates Luteinizing hormone (LH)
production which leads to increased production of estrogen from testicles, disturbing estrogen to testosterone ra-
tio and formation of breast tissue in males.
Folate supplementation with MTX therapy is essential to reduce and delay the side effects [2]. It is seen that
patients usually develop gynecomastia and other side effects when they skip folate therapy. In previously known
cases, patients developed gynecomastia after about 3 - 4 months of MTX therapy (with folate supplementation),
about a month or two later than this patient. This clearly shows MTX is the cause of developing gynecomastia
and folate has an important delaying and preventing effect on development of gynecomastia caused by MTX
therapy. It is also seen that gynecomastia caused by MTX is reversible; once Methotrexate is stopped and Folate
supplements initiated, gynecomastia resolves itself.
S. Shaikh, S. Shaikh
71
3. Conclusion
We suggest that folate should be prescribed as a part of methotrexate therapy in Rheumatoid Arthritis to lessen
frequency and severity of the side effects. It is also suggested that further studies be conducted to understand the
phenomenon behind development of gynecomastia with MTX therapy; it is MTX itself that causes gynecomas-
tia or its chemotherapeutic effect that damages leydig cells leading to disturbed estrogen-testosterone ratio or its
effect on liver that leads to decreased estrogen metabolism and development of gynecomastia.
References
[1] Abe, K., Mitsuka, T., Kanamori, S., Yamashita, K. and Yamaoka, A. (2007) Gynecomastia Associated with Low-Dose
Methotrexate Therapy for Rheumatoid Arthritis. Modern Rheumatology, 17, 511-513.
http://dx.doi.org/10.3109/s10165-007-0619-2
[2] Fukushi, J., Nakashima, Y. and Iwamoto, Y. (2010) Gynecomastia Associated with Low-Dose Methotrexate Therapy
for Rheumatoid Arthritis Ameliorated by Folate Supplement. Rheumatology International, 30, 1371-1372.
http://dx.doi.org/10.1007/s00296-009-1062-9
[3] Del Paine, D.W., Leek, J.C., Jakle, C. and Robbins, D.L. (1983) Gynecomastia Associated with Low-Dose Methotrex-
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[5] Schmutz, J.L., Barbaud, A. and Techot, P. (2004) Gynecomastia and Sexual Disorders Induced by Methotrexate. An-
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[6] Thomas, E., Leroux, J.L. and Blotman, F. (1994) Gynecomastia in Patients with Rheumatoid Arthritis Treated with
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[7] Finger, D.R. and Klipple, G.L. (1995) Gynecomastia Following Low Dose Methotrexate Therapy for Rheumatoid
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