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Treatment of gynecomastia with tamoxifen: A double-blind crossover study
Treatment
of Gyne~omastja
With Tamoxifen:
A Double-Blind
Crossover
Study
Lawrence N. Parker, David R. Gray, Michael K. Lai, and Ellis R. Levin Benign asymptomatic or painful enlargement of the male breast is a common problem, postulated to be due to an increased estrogen/testosterone ratio or due to increased estrogenic or decreased androgenic stimulation via estrogen or androgen receptor interactions. Treatment at present consists of analgesic medication or surgery. However, treatment directed against the preponderance of estrogenic simulation would seem to represent a more specific form of therapy. In the present double-blind crossover study, one-month courses of a placebo or the antiestrogen tamoxifen (IO mg given orally bid) were compared in random order. Seven of ten patients experienced a decrease in the size of their gynecomastia due to tamoxifen (P < 0.005). Overall, the decrease for gynecomastia for the whole group was significant (P < 0.01). There was no beneficial effect of placebo fP > 0.1 I. Additionally. all four patients with painful gynecomastia experienced symptomatic relief. There was no toxicity. The reduction of breast size was partial and may indicate the need for a longer course of therapy. A followup examination was performed in eight out of ten patients nine months to one year after discontinuing placebo and tamoxifen. There were no significant changes from the end of the initial study period except for one tamoxifen responder who developed a recurrence of breast tenderness after six months, and one nonresponder who demonstrated an increase in breast size and a new onset of tenderness after ten months. Therefore, antiestrogenic treatment with tamoxifen may represent a safe and effective mode of treatment for selected cases of cosmetically disturbing or painful gynecomastia. Q 1966 by Grune & Stratton, Inc.
M
ANY physiologic and pathologic conditions are considered to be associated with enlargement of the male breast. For example, commonly encountered conditions in clinical practice include liver disease, aging, or use of the drugs cimetidine, spironolactone, or digoxin. There is evidence that the gynecomastia seen in these situations is due to an increased estrogen/testosterone ratio or due to increased estrogenic or decreased androgenic stimulation via estrogen or androgen receptor interactjons.‘-5 At present, analgesics are used to treat painful gynecomastia, and surgery is usually recommended for gynecomastia that is cosmetically or psychologically disturbing. However, if estrogenic mechanisms are primarily responsible for most cases of gynecomastia, a trial of antiestrogenic therapy would seem to be indicated as a more specific method of therapy. In the present report, we describe a double-blind crossover trial of placebo and the antiestrogen tamoxifen in ten men with gynecomastia of diverse etiology. MATERIALS AND METHODS
Subjects The subjects with gynecomastia gave their informed consent for the study, which was approved by the Research and Development and Human Studies Committees of the VAMC. The average age was 63.2 years and the range was 54 to 80 years of age. The factors alleged to be associated with gynecomastia that were present in these patients are listed in Table 1. No patients were taking estrogenic medications, and none had the stigmata of Klinefelter’s syndrome or a positive buccal smear. All patients had normal serum thyroxine levels and none had elevated serum beta-human chorionic gonadotropin concentrations. Pretreatment ~ncent~tions of prdactin, testosterone, and estradiol were determined by radioimmunoassay by Microanalytic Research Laboratories (Laguna Hills, Calif), Radioassay Systems Laboratories (Carson, Calif), and Nichols Institute (San Clemente, Calif), respectively. Normal ranges are: prolactin, less than 18 ng/mk testosterone, 250 to 1,000 ng/dL; and estradiol, 10 to 50 pg/mL. Pain or tenderness due to gynecomastia was the chief complaint in three subjects while all ten complained of cosmetic deformity. Ten out of 13 patients completed the study. Two dropped out before the crossover point due to problems unrelated to the study, and one was Meiaboiism, Vol35,
No 8 (August), 1986: pp 705-708
lost to followup before the crossover. These patients are not included in Table I. Protocol Inifial study. Patients were randomized into a two-month double-blind crossover study in which they took tamoxifen 10 mg orally and placebo one month each in random order (phases I and II). Tamoxifen and placebo were enclosed in identical appearing capsules and given twice daily. The study was conducted double blind. No other changes in the medication regimen of the patients were made. Patients had normal renal and liver function as measured by serum creatinine, SGOT, and bilirubin, except for patient 6, who was being treated with hem~ialysis for chronic renal failure, and patient 7, who had mild hepatitis with a slight elevation of SGOT to 43 (nL 8 to 40 mU/mL). Measurements of the palpable diameter of each patient’s concentric subareolar glandular tissue’ were made by a single experienced observer (L.N.P.) before the study and after tamoxifen and placebo using a flexible centimeter ruler bent over the curvature of the breast. Changes of less than 0.5 centimeters were found by repeated measurements to be within the error of the method. The presence of tenderness was noted. Due to occasional reports of leukopenia or thrombocytopenia associated with tamoxifen when used for treatment for breast carcinoma, complete blood counts and platelet counts were obtained three times during the study. Follow-up. Follow-up breast examinations were performed between nine months and one year following cessation of tamoxifen and placebo. Two patients were lost to followup. Follow-up measurements were also made by the same observer. Analysis ofdak The change in diameter of gynecomastia was considered to represent unilateral change if the gynecomastia was primarily unilateral, while an average of both breasts was used for calculations if gyn~mastia was bilateral. M~surements of gyneco-
From the Medicine and Pharmacy Services, University of California at Irvine, Long Beach Medical Program, Veterans Administration Medical Center, Long Beach, Calif. Address reprint requests to Lawrence N. Parker, MD. Endocrinology Section, Vererans Administration Medical Center, 5901 E. 7fh St, Long Beach, CA 90822. o 1986 by Grune & Stratton, Inc. 0026-0495/86/350&0004$03.00/0
705
2.0
Rwmd= Dioo*n
29
271
3.0
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50.0 + 7.1
49.6 * 5.3
435.3 t 126.9
465.8 + 64.5
1.8 + 0.2
2.2 * 0.4
36
684
2.0
AbhObSm
Group mem
56
356
1.5
owr‘all mean
58
267
2.0
Akahdism. cimk tidine
66
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507.4 + 79.8
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2.4 f 0.6
Akohdism
NOtWespanderS
Groupmesn
Hepatitis
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Renal failure. time-
dactone. digoxin 39
26
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527
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0.5
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Akddim
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502
(VI
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T Ins/al
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-
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Tamoxifen Before
(cm)
Chanae
Diameter of Gynacomastia
Tabie 1. Tamoxifen Y Placebo: Double-Blind Crossover Study
t 0.3
-2.14
+ 0.5
0.2 * 0.2
0
0
-0.5
2.9t
-3.0
-1.5
-3.0
-3.5
-4.0
- 2.5
-2.5
ChIlIlge
WA
N/A
N/A
WA
“Dne
WA
N/A
P!acabo
N/A
N/A N/A
N/A yes
lies
N/A
1amohifan
in Pain 01 Tenderness
lmprowmmt
to.5
-0.5
i
-0.5
Size Changs
Fdbww
-
6mo
after
-enca
0
WXM
-
Pai” or TSndanKs
(S- 12 mol
707
GYNECOMASTIA AND TAMOXIFEN
mastia before and after placebo or tamoxifen were compared by paired t-test. RESULTS
Gynecomastia Size. The code was broken following completion of the study. Five patients received placebo for the first month and, likewise, five patients initially received tamoxifen. Of the ten men who completed the study, seven had an objective decrease in the size of their gynecomastia. The measurements of all subjects are shown in Table 1. The overall change in breast diameters was -2.1 cm with tamoxifen (P < 0.01) and +0.2 cm with placebo (P c 0.10) in the whole group. The average duration of gynecomastia was 2.4 years in the responders and 1.8 years in the nonresponders. There was no clear difference in the hormonal status or the initial breast diameter between the responders and the nonresponders (Table 1). There was also no significant difference between the age of the responders (64.5 + 4.4 yr) and the nonresponders (58.3 + 2.6). No responders were obese, while two nonresponders were more than 20% over ideal body weight. In the followup study, one nonresponder developed an increase in breast size ten months after the initial study. No patient underwent surgery. Tenderness. Of the four men with painful or tender gynecomastia, all three experienced pain relief within 2 weeks of beginning tamoxifen. In the followup study, one responder developed a recurrence of tenderness after six months. Toxicity
Information from the manufacturer of tamoxifen (Nolvadex; Stuart Pharmaceuticals, Wilmington, Del) lists nausea, vomiting, skin rashes, and hematologic changes (leukopenia and thrombocytopenia) as possible side effects. None of these adverse clinical effects were noted or reported. Complete blood and platelet counts demonstrated no leukopenia or thrombocytopenia. DISCUSSION
Although breast tissue in most men is rudimentary, there is glandular hypertrophy in a significant fraction. In a survey of 306 US Air Force reservists, age 17 to 58 years old, 36% had palpable gynecomastia.6 The great majority of gynecomastia is benign.’ While other hormones can stimulate breast tissue, estrogens have the single strongest influence. Adolescents and adult men with gynecomastia often have an elevated free or total estradiol to testosterone ratio, if not an absolute elevation of serum estradiol concentrations.‘*2q8-‘o The hyperestrogenic stimulus may occur from direct testicular secretion
of estradiol, especially in hypergonadotrophic hypogonadal states, or from increased peripheral conversion of androstenedione to estrone. Ingestion of estrogens, or production of estrogens by adrenal or testicular neoplasms can also result in gynecomastia, sometimes occurring in a time period as short as one to six months.“*‘* Since estrogenic mechanisms underlie the seemingly unrelated etiologies of gynecomastia, including those in the present study, treatment with antiestrogens would seem to be a rational mode of therapy in an attempt to treat gynecomastia without surgery. Antiestrogen treatment of adolescent gynecomastia with clomiphene has been reported to be successful in two studies.“*r4 However, these studies were not controlled, and some toxicity was reported. Since clomiphene is a significant estrogen receptor agonist as well as antagonist, the drug itself may occasionally cause gynecomastia. 15.16 Due to its relative lack of estrogenic agonist effects or toxicity,“-” tamoxifen at an oral dosage of 10 mg bid was selected for the present study. Previously, the successful use of tamoxifen for painless or symptomatic gynecomastia has been reported in four uncontrolled cases.21*22In these cases, clinical improvement was reported in less than one month, which influenced the design of the present study. Our results are in agreement with these reports in that gynecomastia decreased in size and pain or tenderness decreased or disappeared within several weeks. There was no significant difference in our study between the testosterone:estradiol ratios of the tamoxifen responders compared with the nonresponders. This could be due to many factors, including variations in sex hormone binding, receptor sensitivity, or intracellular steroid conversion.23 Another possible factor could be sampling error of pulsatile hormone secretion, but this is probably not a significant source of error since it has been shown that a single testosterone measurement, for example, has a 68% probability of being within 20% of the true mean.24 There was no toxicity in the present study, and a relatively long duration of gynecomastia did not preclude clinical and objective benefit. However, our use of only one course of one month of tamoxifen therapy may be less than optimal in view of the recurrence of breast tenderness after six months in a tamoxifen responder. Also, it is possible that larger reductions in breast size could be achievable by use of a longer course of therapy. Problems with efficacy or patient acceptance have been reported with testosterone or danazol therapy for gynecomastia.2.25 In the present study, tamoxifen in a dose of 10 mg twice daily was superior to placebo in reducing both the tenderness and cosmetic deformity associated with nonmalignant gynecomastia. We propose that tamoxifen may represent a safe and effective method of therapy for selected cases of cosmetically disturbing or symptomatic gynecomastia in adults.
REFERENCES 1. Wilson JD, Alman J, MacDonald PC: The pathogenesis of gynecomastia, in Schwartz T (ed): Advances in Internal Medicine. Chicago, Yearbook, 1980, pp 2-32
2. Carlson HE: Gynecomastia. N Engl J Med 303:795-799, 1980 3. Rose LI, Underwood RH, Newmark SR, et al: Pathophysiol-
708
ogy of spironolactone-induced gynecomastia. Ann Intern Med 87:398403, 1977 4. Morley JE, Melmed S: Gonadal dysfunction in systemic disorders. Metabolism 28:1051-1073, 1979 5. Rifka SM, Pita JC, Vigersky RA, et al: Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrino1 Metah 48:338-344, 1977 6. Nuttal FQ: Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 48:338-340, 1979 7. Dexter CJ: Benign enlargement of the male breast. N Engl J Med 254:996-997.1956 8. Lee PA: The relationship of concentrations of serum hormones in pubertal gynecomastia. J Pediatr 86:212-215, 1975 9. Lafranchi SH, Parlow AF, Lippe BM, et al: Pubertal gynecomastia and transient elevation of serum estradiol level. Am J Dis Child 129:927-931, 1975 10. McFayden IJ, Bolton AE, Cameron EHD, et al: Gonadalpituitary hormone levels in gynecomastia. Clin Endocrinol 13:77-88, 1980 11. Gabrilove JL, Nicolis GL, Mitty HA, et al: Feminizing interstitial cell tumor of the testis: Personal observations and a review of the literature. Cancer 35:1184-1202, 1975 12. Waterfall NB, Glasser MG: A study of the effects of radiation on prevention of gynecomastia due to estrogen therapy. Clin Oncol5:257-260,1979 13. Stepanas AV, Burnet RB, Harding PE, et al: Clomiphene in the treatment of pubertal-adolescent gynecomastia: A preliminary report. J Pediatr 90:651-653, 1977 14. Leroith D, Sobel R, Glick SM: The effect of clomiphene citrate on pubertal gynecomastia. Acta Endocrinol 95:177-180, 1980
PARKER ET AL
15. Check JH, Murdock MG, Caro JF, et al: Case report: Cystic gynecomastia in a male treated with clomiphene citrate. Fertil Steril 30:713-715.1978 16. Cathro DM, Saez JM, Bertrand J: The effect of clomiphene on the plasma androgens of prepubertal and pubertal boys. J Endocrinol 50:387-396, 1971 17. Calabres P, Parks R: Antiproliferative agents and drugs used for immunosuppression, in Goodman A, Gilman A (eds): The Pharmacological Basis of Therapeutics, (ed 6). New York, Macmillan, 1980, pp 1304-l 305 18. Tamoxifen for breast cancer. Med Lett 20:41-42, 1978 19. Willis KJ, London DR, Bevis MA, et al: Hormonal effects of tamoxifen in oligospermic men. J Endocr 73:171-178, 1977 20. Patterson JS: Clinical aspects and development of antiestrogen therapy: a review of the endocrine effects of tamoxifen in animals and man. J Endocrinol 89:67-75, 1981 21. Fairlamb D, Boesen E: Gynecomastia associated with gonadotrophin carcinoma of the lung. Postgrad Med J 53:269-27 1, 1977 22. Jeffreys DB: Painful gynecomastia treated with tamoxifen. BrMedJ1:1119-1120,1979 23. Rajendran K, Shah P, Bagli N, et al: Steroid biosynthetic potential of gynecomastia tissue in man. Horm Res 6:329-335, 1975 24. Goldzieher J, Dozier T, Smith K, et al: Improving the diagnostic reliability of rapidly fluctuating plasma hormone levels by optimized multiple sampling techniques. J Clin Endocrinol Metab 43:824-830, 1976 25. Buckle R: Danazol in the treatment of gynecomastia. Drugs 19:356-361,198O
of Gyne~omastja
With Tamoxifen:
A Double-Blind
Crossover
Study
Lawrence N. Parker, David R. Gray, Michael K. Lai, and Ellis R. Levin Benign asymptomatic or painful enlargement of the male breast is a common problem, postulated to be due to an increased estrogen/testosterone ratio or due to increased estrogenic or decreased androgenic stimulation via estrogen or androgen receptor interactions. Treatment at present consists of analgesic medication or surgery. However, treatment directed against the preponderance of estrogenic simulation would seem to represent a more specific form of therapy. In the present double-blind crossover study, one-month courses of a placebo or the antiestrogen tamoxifen (IO mg given orally bid) were compared in random order. Seven of ten patients experienced a decrease in the size of their gynecomastia due to tamoxifen (P < 0.005). Overall, the decrease for gynecomastia for the whole group was significant (P < 0.01). There was no beneficial effect of placebo fP > 0.1 I. Additionally. all four patients with painful gynecomastia experienced symptomatic relief. There was no toxicity. The reduction of breast size was partial and may indicate the need for a longer course of therapy. A followup examination was performed in eight out of ten patients nine months to one year after discontinuing placebo and tamoxifen. There were no significant changes from the end of the initial study period except for one tamoxifen responder who developed a recurrence of breast tenderness after six months, and one nonresponder who demonstrated an increase in breast size and a new onset of tenderness after ten months. Therefore, antiestrogenic treatment with tamoxifen may represent a safe and effective mode of treatment for selected cases of cosmetically disturbing or painful gynecomastia. Q 1966 by Grune & Stratton, Inc.
M
ANY physiologic and pathologic conditions are considered to be associated with enlargement of the male breast. For example, commonly encountered conditions in clinical practice include liver disease, aging, or use of the drugs cimetidine, spironolactone, or digoxin. There is evidence that the gynecomastia seen in these situations is due to an increased estrogen/testosterone ratio or due to increased estrogenic or decreased androgenic stimulation via estrogen or androgen receptor interactjons.‘-5 At present, analgesics are used to treat painful gynecomastia, and surgery is usually recommended for gynecomastia that is cosmetically or psychologically disturbing. However, if estrogenic mechanisms are primarily responsible for most cases of gynecomastia, a trial of antiestrogenic therapy would seem to be indicated as a more specific method of therapy. In the present report, we describe a double-blind crossover trial of placebo and the antiestrogen tamoxifen in ten men with gynecomastia of diverse etiology. MATERIALS AND METHODS
Subjects The subjects with gynecomastia gave their informed consent for the study, which was approved by the Research and Development and Human Studies Committees of the VAMC. The average age was 63.2 years and the range was 54 to 80 years of age. The factors alleged to be associated with gynecomastia that were present in these patients are listed in Table 1. No patients were taking estrogenic medications, and none had the stigmata of Klinefelter’s syndrome or a positive buccal smear. All patients had normal serum thyroxine levels and none had elevated serum beta-human chorionic gonadotropin concentrations. Pretreatment ~ncent~tions of prdactin, testosterone, and estradiol were determined by radioimmunoassay by Microanalytic Research Laboratories (Laguna Hills, Calif), Radioassay Systems Laboratories (Carson, Calif), and Nichols Institute (San Clemente, Calif), respectively. Normal ranges are: prolactin, less than 18 ng/mk testosterone, 250 to 1,000 ng/dL; and estradiol, 10 to 50 pg/mL. Pain or tenderness due to gynecomastia was the chief complaint in three subjects while all ten complained of cosmetic deformity. Ten out of 13 patients completed the study. Two dropped out before the crossover point due to problems unrelated to the study, and one was Meiaboiism, Vol35,
No 8 (August), 1986: pp 705-708
lost to followup before the crossover. These patients are not included in Table I. Protocol Inifial study. Patients were randomized into a two-month double-blind crossover study in which they took tamoxifen 10 mg orally and placebo one month each in random order (phases I and II). Tamoxifen and placebo were enclosed in identical appearing capsules and given twice daily. The study was conducted double blind. No other changes in the medication regimen of the patients were made. Patients had normal renal and liver function as measured by serum creatinine, SGOT, and bilirubin, except for patient 6, who was being treated with hem~ialysis for chronic renal failure, and patient 7, who had mild hepatitis with a slight elevation of SGOT to 43 (nL 8 to 40 mU/mL). Measurements of the palpable diameter of each patient’s concentric subareolar glandular tissue’ were made by a single experienced observer (L.N.P.) before the study and after tamoxifen and placebo using a flexible centimeter ruler bent over the curvature of the breast. Changes of less than 0.5 centimeters were found by repeated measurements to be within the error of the method. The presence of tenderness was noted. Due to occasional reports of leukopenia or thrombocytopenia associated with tamoxifen when used for treatment for breast carcinoma, complete blood counts and platelet counts were obtained three times during the study. Follow-up. Follow-up breast examinations were performed between nine months and one year following cessation of tamoxifen and placebo. Two patients were lost to followup. Follow-up measurements were also made by the same observer. Analysis ofdak The change in diameter of gynecomastia was considered to represent unilateral change if the gynecomastia was primarily unilateral, while an average of both breasts was used for calculations if gyn~mastia was bilateral. M~surements of gyneco-
From the Medicine and Pharmacy Services, University of California at Irvine, Long Beach Medical Program, Veterans Administration Medical Center, Long Beach, Calif. Address reprint requests to Lawrence N. Parker, MD. Endocrinology Section, Vererans Administration Medical Center, 5901 E. 7fh St, Long Beach, CA 90822. o 1986 by Grune & Stratton, Inc. 0026-0495/86/350&0004$03.00/0
705
2.0
Rwmd= Dioo*n
29
271
3.0
Akoholism. s&m-
50.0 + 7.1
49.6 * 5.3
435.3 t 126.9
465.8 + 64.5
1.8 + 0.2
2.2 * 0.4
36
684
2.0
AbhObSm
Group mem
56
356
1.5
owr‘all mean
58
267
2.0
Akahdism. cimk tidine
66
49.4 + 7.3
426
507.4 + 79.8
3.0
2.4 f 0.6
Akohdism
NOtWespanderS
Groupmesn
Hepatitis
tidine
Renal failure. time-
dactone. digoxin 39
26
680
1.0
Digoxin
527
73
861
2.0
0.5
67
265
5.0
Diixin.
Akddim
cimetidnw
46
502
(VI
E, WmL)
T Ins/al
PredisposingFscfwe
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6.5
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Phase’
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-
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TIEI Ratio
PlWXZt”X
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Tamoxifen Before
(cm)
Chanae
Diameter of Gynacomastia
Tabie 1. Tamoxifen Y Placebo: Double-Blind Crossover Study
t 0.3
-2.14
+ 0.5
0.2 * 0.2
0
0
-0.5
2.9t
-3.0
-1.5
-3.0
-3.5
-4.0
- 2.5
-2.5
ChIlIlge
WA
N/A
N/A
WA
“Dne
WA
N/A
P!acabo
N/A
N/A N/A
N/A yes
lies
N/A
1amohifan
in Pain 01 Tenderness
lmprowmmt
to.5
-0.5
i
-0.5
Size Changs
Fdbww
-
6mo
after
-enca
0
WXM
-
Pai” or TSndanKs
(S- 12 mol
707
GYNECOMASTIA AND TAMOXIFEN
mastia before and after placebo or tamoxifen were compared by paired t-test. RESULTS
Gynecomastia Size. The code was broken following completion of the study. Five patients received placebo for the first month and, likewise, five patients initially received tamoxifen. Of the ten men who completed the study, seven had an objective decrease in the size of their gynecomastia. The measurements of all subjects are shown in Table 1. The overall change in breast diameters was -2.1 cm with tamoxifen (P < 0.01) and +0.2 cm with placebo (P c 0.10) in the whole group. The average duration of gynecomastia was 2.4 years in the responders and 1.8 years in the nonresponders. There was no clear difference in the hormonal status or the initial breast diameter between the responders and the nonresponders (Table 1). There was also no significant difference between the age of the responders (64.5 + 4.4 yr) and the nonresponders (58.3 + 2.6). No responders were obese, while two nonresponders were more than 20% over ideal body weight. In the followup study, one nonresponder developed an increase in breast size ten months after the initial study. No patient underwent surgery. Tenderness. Of the four men with painful or tender gynecomastia, all three experienced pain relief within 2 weeks of beginning tamoxifen. In the followup study, one responder developed a recurrence of tenderness after six months. Toxicity
Information from the manufacturer of tamoxifen (Nolvadex; Stuart Pharmaceuticals, Wilmington, Del) lists nausea, vomiting, skin rashes, and hematologic changes (leukopenia and thrombocytopenia) as possible side effects. None of these adverse clinical effects were noted or reported. Complete blood and platelet counts demonstrated no leukopenia or thrombocytopenia. DISCUSSION
Although breast tissue in most men is rudimentary, there is glandular hypertrophy in a significant fraction. In a survey of 306 US Air Force reservists, age 17 to 58 years old, 36% had palpable gynecomastia.6 The great majority of gynecomastia is benign.’ While other hormones can stimulate breast tissue, estrogens have the single strongest influence. Adolescents and adult men with gynecomastia often have an elevated free or total estradiol to testosterone ratio, if not an absolute elevation of serum estradiol concentrations.‘*2q8-‘o The hyperestrogenic stimulus may occur from direct testicular secretion
of estradiol, especially in hypergonadotrophic hypogonadal states, or from increased peripheral conversion of androstenedione to estrone. Ingestion of estrogens, or production of estrogens by adrenal or testicular neoplasms can also result in gynecomastia, sometimes occurring in a time period as short as one to six months.“*‘* Since estrogenic mechanisms underlie the seemingly unrelated etiologies of gynecomastia, including those in the present study, treatment with antiestrogens would seem to be a rational mode of therapy in an attempt to treat gynecomastia without surgery. Antiestrogen treatment of adolescent gynecomastia with clomiphene has been reported to be successful in two studies.“*r4 However, these studies were not controlled, and some toxicity was reported. Since clomiphene is a significant estrogen receptor agonist as well as antagonist, the drug itself may occasionally cause gynecomastia. 15.16 Due to its relative lack of estrogenic agonist effects or toxicity,“-” tamoxifen at an oral dosage of 10 mg bid was selected for the present study. Previously, the successful use of tamoxifen for painless or symptomatic gynecomastia has been reported in four uncontrolled cases.21*22In these cases, clinical improvement was reported in less than one month, which influenced the design of the present study. Our results are in agreement with these reports in that gynecomastia decreased in size and pain or tenderness decreased or disappeared within several weeks. There was no significant difference in our study between the testosterone:estradiol ratios of the tamoxifen responders compared with the nonresponders. This could be due to many factors, including variations in sex hormone binding, receptor sensitivity, or intracellular steroid conversion.23 Another possible factor could be sampling error of pulsatile hormone secretion, but this is probably not a significant source of error since it has been shown that a single testosterone measurement, for example, has a 68% probability of being within 20% of the true mean.24 There was no toxicity in the present study, and a relatively long duration of gynecomastia did not preclude clinical and objective benefit. However, our use of only one course of one month of tamoxifen therapy may be less than optimal in view of the recurrence of breast tenderness after six months in a tamoxifen responder. Also, it is possible that larger reductions in breast size could be achievable by use of a longer course of therapy. Problems with efficacy or patient acceptance have been reported with testosterone or danazol therapy for gynecomastia.2.25 In the present study, tamoxifen in a dose of 10 mg twice daily was superior to placebo in reducing both the tenderness and cosmetic deformity associated with nonmalignant gynecomastia. We propose that tamoxifen may represent a safe and effective method of therapy for selected cases of cosmetically disturbing or symptomatic gynecomastia in adults.
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