Of interest, in reference [ 52 ], spontaneous resolution occurred in 20 of 21 patients monitored for more than 1 year in spite of continuing the HAART regimen. Also, two cases have been reported in HIV-infected men that were not attributed to medications [ 53 ]. There were several publications of an association of gynecomastia with ketoconazole. However, only two publications of the same three patients who met our criteria were found.
The examination technique was not specified. Hormonal studies were done in two patients and were within normal limits. A rechallenge was not done. Later, the same authors reported data on 60 patients, but there was no further increase in patients with gynecomastia [ 73 ]. In a carefully done prospective study of 38 men being treated with imatinib for chronic myeloid leukemia, breast mass changes were determined by direct sequential measurement [ 63 ]. Seven patients developed palpable breast tissue equal to or greater than 2 cm in diameter.
The treatment itself tended to be associated with reduction in the free and total testosterone concentration in all of the subjects, but the decrease was in general greater in those who developed breast enlargement. Estradiol data apparently were obtained but not reported. The number reporting pain or tenderness was not indicated, but it was stated to have occurred often.
Also, whether the breast enlargement was unilateral or bilateral was not stated. However, in at least one case, it was unilateral. Testosterone was within the reference range, but the estradiol was modestly elevated in three patients. There are several reports of an association of cimetidine with gynecomastia. Only three are reviewed here as typical of the data. In the first study [ 11 ], cimetidine, 1. After treatment for 4—9 months, five patients reported soreness of one or both nipples, associated with breast swelling.
How gynecomastia was confirmed was not indicated. Testosterone and estradiol were within the reference range. Nine complained of breast changes, 8 of which noted increased nipple sensitivity or breast pain.
Gynecomastia was reported in 5. However, how the diagnosis was documented is unclear. Hormonal studies were not done. New onset gynecomastia was reported in The gynecomastia was attributed exclusively to the use of cimetidine and was dose dependent.
Information for 80 of these cases was available. In this group, 67 were self-reported, and 11 were incidental findings. Data were not available in two cases. Whether the patients presented with mastodynia was not stated. Thirty-four were unilateral, 38 were bilateral, and in 8, this information was lacking.
In 37, there was complete regression, and it was partial in The gynecomastia was attributed to a cimetidine induced increase in estradiol due to impaired conversion to the inactive 2-hydroxy-estradiol product, as reported by Galbraith and Michnovicz [ ].
However, as indicated above, hormone data were not obtained and based on the data obtained in reference [ 11 ], this explanation is unlikely. Cimetidine is not commonly used at present, particularly in the doses used in the past.
It is available over the counter in smaller dose sizes in the USA, and to our knowledge, an association of gynecomastia with cimetidine has not been reported in the last 10 or more years. In summary, although cimetidine is rarely used in USA at the present time, data obtained in the past suggest that cimetidine in high doses can induce nipple tenderness, mastodynia, and transient breast swelling. Here, the relative odds ratio for omeprazole exposure showed a statistically significant elevation in comparison to those with no exposure.
However, how the gynecomastia was diagnosed and characterized was not reported. The presence or development of gynecomastia has been reported in several publications. Only representative reports are included here. In a prospective study [ 91 ], 9 subjects received mg of spironolactone for 24 weeks. Six developed gynecomastia.
In none was the diameter more than 2 cm. In the same report, nine additional subjects received mg for 4 weeks, then mg for another 4 weeks. In none of these subjects did gynecomastia develop.
Whether the breast enlargement regressed is unknown. One subject dropped out because of painful gynecomastia. In the second prospective study [ 92 ], spironolactone or potassium canrenoate a product of spironolactone metabolism was administered to 44 subjects with liver cirrhosis and ascites. All of those receiving spironolactone developed gynecomastia. Gynecomastia developed in 16 of the 30 who received potassium canrenoate.
Here, gynecomastia was defined as a palpable, discrete button of firm subareolar tissue at least 2 cm in diameter. In this study, the testosterone, dialyzable testosterone, estradiol, LH, FSH did not change significantly.
In a case control study [ 93 ], 16 subjects were studied, 6 of whom received spironolactone and 10 were matched controls. All had been on — mg of spironolactone for 4 to 13 months before the study. Gynecomastia did not develop in the ten controls. The blood testosterone levels were significantly less and blood estradiol levels significantly greater in the spironolactone group, suggesting that spironolactone does alter peripheral metabolism of testosterone in some men and results in changes in the ratio of testosterone to estradiol.
It should be noted that the doses of spironolactone used in the above studies were greater than those commonly used clinically. The presence or development of gynecomastia also has been reported retrospectively in several large studies. Unfortunately, how the gynecomastia was detected and defined was not stated [ 95 ].
Again, how gynecomastia was diagnosed was not stated. Finally, in a retrospective study of 13, hospitalized medical patients monitored in a drug surveillance program, of whom received spironolactone during 1 or more admissions, gynecomastia as an adverse reaction was reported in only 1.
The mechanism by which spironolactone induces modest gynecomastia remains unknown. It is speculated that spironolactone or a metabolic product of spironolactone [ ] binds to the androgen receptors and displaces testosterone.
Thus, spironolactone may act as a competitive inhibitor of androgen action. Indeed, it is used to reduce sexual hair growth in hirsute women with and without the polycystic ovary syndrome [ ].
However, Stripp et al. In this retrospective study [ 20 ], during —, nine patients diagnosed with myeloma were treated with a cyclophosphamide, prednisolone, and melphalan regimen. Four patients who developed gynecomastia were considered to be cases, whereas 5 who did not were considered to be controls.
Gynecomastia was predominantly bilateral. How the gynecomastia was diagnosed was not indicated. An increase in free estradiol and a relative decrease in testosterone were only present in those with gynecomastia. Gynecomastia as a side effect of this regimen has not been reported since. This review of the literature documents an extraordinary number and assortment of drugs reported to be associated with the diagnosis of gynecomastia.
Most are only single case reports or small series. In the great majority of cases, the initial observation was by the patient and consisted of a painful or tender breast followed by a reported enlargement of the breast.
Also, most commonly only a single breast was involved, although in some, it became bilateral later in the course. Indeed, the breast enlargement was often described as disappearing completely. When determined, a hormonal etiology generally could not be documented, although speculated on frequently.
However, these data generally only indicate the presence or absence of detectible breast tissue. Whether it is new or not cannot be readily determined.
The latter issue also is a limitation in interpreting breast histology. In addition, in some reports, an inflammatory component has been mentioned [ , , ]. An increase in hyaluronic acid also is commented on, suggesting the presence of stromal edema [ ].
As reviewed above, mastodynia with the subsequent observation of breast swelling has been reported to be associated with numerous medications. Kruss DM, Littman A. Safety of cimetidine. Gastroenterology ; Hyperprolactinemia in response to antipsychotic drugs; characterization across comparative clinical trials. Psychoneuroendocrinology ;28 Suppl 2 :S H1 and H2 receptors antagonists and induced release prolactin in male rats. Neuroendocrinology ; Plasma prolactin and cimetidine.
Rojdmark S, Andersson DE. Cimetidine effect of Dopaminergic modulation of prolactin release in healthy woman. Metabolism: ; Drug-induced hyperprolactinemia: A case-non-case study from the national pharmacovigilance database.
Therapie ; Hypothamic H1 and H2 receptors: A tool to investigate the neoroendocrine role of histamine. Pharmacol Res Commun ; Serum prolactin response to acute and chronic cimetidine administration in man. Acta Hepatogastroenterol Stuttg ; Despite not being a health-threatening condition, gynecomastia can cause psychological distress due to physical-appearance alterations.
Mammary glandular tissue proliferation is physiologically stimulated by oestrogens and inhibited by androgens. The majority of gynecomastia cases are physiological in nature neonatal, pubertal and senile gynecomastia. Many drugs can cause gynecomastia see Table 1 as much as several active principles, which have been associated to this condition. Antiandrogens such as bicalutamide and flutamide can cause gynecomastia by antagonist action to testosterone and dihydrotestosterone on mammary glands.
Spironolactone, an aldosterone antagonist used for high blood pressure treatment, presents both anti-androgenic and oestrogenic activities. This drug can induce gynecomastia after one month only of treatment, with a dose-dependent incidence. Main outcome measures: New occurrences of idiopathic gynaecomastia diagnosed by general practitioner.
Results: The relative risk of gynaecomastia for current users of cimetidine compared with non-users was 7. Relative risks for misoprostol, omeprazole, and ranitidine were 2.
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