madman
Super Moderator
Summary
Objective: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering, and psychotropic drugs.
Material and methods: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class.
Results: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed-gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs were available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found.
Conclusions: Antiandrogens and to a lesser extent 5 alpha-reductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such an effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated with the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.
INTRODUCTION
Gynecomastia is a condition in which the male breast is enlarged due to an increase in ductal tissue, stroma, or fat. Histological observation shows a proliferation of the mammary ducts embedded in a fibroconnective tissue stroma. Gynecomastia is associated with medical conditions such as extreme obesity, hypogonadism, liver, and kidney failure. In addition, the administration of certain drugs is a known risk factor for gynecomastia. According to Food and Drug Administration (FDA) Adverse Event Reporting System, gynecomastia is most frequently reported after administration of inhibitors of 5alpha-reductase (dutasteride, finasteride), spironolactone, antipsychotics, lipid-lowering agents (rosuvastatin, atorvastatin, and simvastatin), and antiandrogens (1).
Other drugs causing gynecomastia include antiretrovirals (protease inhibitors and nucleoside reverse transcriptase inhibitors), histamine2-receptor blockers (cimetidine), antimycotics (long-term use of ketoconazole), calcium channel blockers, and chemotherapeutic agents. Gynecomastia was also reported after intake of exogenous hormones (estrogens) or steroids (in adolescent boys), and after environmental exposure to phenothrin or intake of phytoestrogens (e.g., large quantities of phytoestrogen containing soy products).
There are numerous reports on the association between the intake of certain drugs and gynecomastia, but no meta-analysis has so far assessed the extent of the risk of gynecomastia linked to specific classes of drugs.
The aim of this work was to review the scientific evidence on the risk of gynecomastia after administration of the drugs that are most frequently associated with the occurrence of this side effect.
DISCUSSION
Mechanisms regulating the growth of the breast tissue are complex and not fully elucidated (36, 37).
The breast tissue expresses receptors for both estrogens and androgens, which can induce the proliferation or inhibition of the growth and differentiation of the mammary gland, respectively. Gynecomastia can be caused either by an overt reduction of circulating estrogen levels or by an increase in androgen serum levels. In addition, imbalances between estrogen and androgen levels, which may retain serum concentrations within the normal ranges, may cause such effects.
Furthermore, the activity of estrogens and androgens can be locally modulated in the breast tissue (i) by increased local production of estrogens or decreased inactivation of estrogens, (ii) by decreased local production of androgens, or (iii) by changes in the number and/or activity of androgen or estrogen receptors. Besides androgens and estrogens, other hormones can interfere with the growth of men’s breast tissue, which presents receptors for prolactin, progesterone, insulin-like growth factor (IGF)-1, IGF-2, luteinizing hormone (LH), and/or human chorionic gonadotropin (hCG). Our meta-analysis confirmed that antiandrogens are associated with the highest risk of gynecomastia.
In conclusion, our study confirmed the high risk of gynecomastia in patients taking antiandrogens for the treatment of prostate cancer. The frequent occurrence of gynecomastia is a limiting factor of this treatment and ablation of the breast tissue by ionizing radiation is sometimes used to prevent this effect. The risk of gynecomastia is lower but significantly higher than placebo in patients receiving spironolactone, 5-alpha-reductase inhibitors, and atypical antipsychotics (risperidone vs. quetiapine). The potential risk of gynecomastia associated with the use of statins should be better assessed with studies evaluating the long-term side effects of these drugs. In clinical practice, the possible additive or synergic interaction of several drugs predisposing to the onset of gynecomastia must be cautiously considered.
Objective: To review the evidence concerning treatment-related gynecomastia in patients taking spironolactone, antiandrogens, 5 alpha-reductase inhibitors, lipid-lowering, and psychotropic drugs.
Material and methods: A search of Medline and EMBASE was performed up to 30 June 2021. We included randomized controlled trials comparing the effects of a drug belonging to these classes versus placebo or versus a drug of the same class.
Results: A total of 32 randomized controlled trials were included in the final review. There was an increased odds of gynecomastia in men receiving antiandrogens (OR = 17.38, 95% CI: 11.26 to 26.82; 6 trials, 9599 participants) and 5 alpha-reductase inhibitors compared to controls (OR = 1.77, 95% CI: 1.53 to 2.06; 7 series out of 6 trials, 34860 participants). The use of spironolactone in mixed-gender populations was characterized by significantly higher odds of having gynecomastia compared to controls (OR = 8.39, 95% CI: 5.03 to 13.99; 14 trials, 3745 participants). No placebo-controlled trials focusing on the risk of gynecomastia in patients taking antipsychotic drugs were available, although there was a significant difference in the odds of having gynecomastia in a comparison between risperidone and quetiapine (OR = 4.32, 95% CI: 1.31 to 14.27; 3 trials, 343 participants). Limited evidence about the effects of statins on mammary glands was found.
Conclusions: Antiandrogens and to a lesser extent 5 alpha-reductase inhibitors and spironolactone are associated with an increased risk of developing gynecomastia. Such an effect can be explained by a modification of the testosterone to estradiol ratio. Gynecomastia (and galactorrhea) associated with the use of conventional and certain atypical antipsychotics can be related to high prolactin levels.
INTRODUCTION
Gynecomastia is a condition in which the male breast is enlarged due to an increase in ductal tissue, stroma, or fat. Histological observation shows a proliferation of the mammary ducts embedded in a fibroconnective tissue stroma. Gynecomastia is associated with medical conditions such as extreme obesity, hypogonadism, liver, and kidney failure. In addition, the administration of certain drugs is a known risk factor for gynecomastia. According to Food and Drug Administration (FDA) Adverse Event Reporting System, gynecomastia is most frequently reported after administration of inhibitors of 5alpha-reductase (dutasteride, finasteride), spironolactone, antipsychotics, lipid-lowering agents (rosuvastatin, atorvastatin, and simvastatin), and antiandrogens (1).
Other drugs causing gynecomastia include antiretrovirals (protease inhibitors and nucleoside reverse transcriptase inhibitors), histamine2-receptor blockers (cimetidine), antimycotics (long-term use of ketoconazole), calcium channel blockers, and chemotherapeutic agents. Gynecomastia was also reported after intake of exogenous hormones (estrogens) or steroids (in adolescent boys), and after environmental exposure to phenothrin or intake of phytoestrogens (e.g., large quantities of phytoestrogen containing soy products).
There are numerous reports on the association between the intake of certain drugs and gynecomastia, but no meta-analysis has so far assessed the extent of the risk of gynecomastia linked to specific classes of drugs.
The aim of this work was to review the scientific evidence on the risk of gynecomastia after administration of the drugs that are most frequently associated with the occurrence of this side effect.
DISCUSSION
Mechanisms regulating the growth of the breast tissue are complex and not fully elucidated (36, 37).
The breast tissue expresses receptors for both estrogens and androgens, which can induce the proliferation or inhibition of the growth and differentiation of the mammary gland, respectively. Gynecomastia can be caused either by an overt reduction of circulating estrogen levels or by an increase in androgen serum levels. In addition, imbalances between estrogen and androgen levels, which may retain serum concentrations within the normal ranges, may cause such effects.
Furthermore, the activity of estrogens and androgens can be locally modulated in the breast tissue (i) by increased local production of estrogens or decreased inactivation of estrogens, (ii) by decreased local production of androgens, or (iii) by changes in the number and/or activity of androgen or estrogen receptors. Besides androgens and estrogens, other hormones can interfere with the growth of men’s breast tissue, which presents receptors for prolactin, progesterone, insulin-like growth factor (IGF)-1, IGF-2, luteinizing hormone (LH), and/or human chorionic gonadotropin (hCG). Our meta-analysis confirmed that antiandrogens are associated with the highest risk of gynecomastia.
In conclusion, our study confirmed the high risk of gynecomastia in patients taking antiandrogens for the treatment of prostate cancer. The frequent occurrence of gynecomastia is a limiting factor of this treatment and ablation of the breast tissue by ionizing radiation is sometimes used to prevent this effect. The risk of gynecomastia is lower but significantly higher than placebo in patients receiving spironolactone, 5-alpha-reductase inhibitors, and atypical antipsychotics (risperidone vs. quetiapine). The potential risk of gynecomastia associated with the use of statins should be better assessed with studies evaluating the long-term side effects of these drugs. In clinical practice, the possible additive or synergic interaction of several drugs predisposing to the onset of gynecomastia must be cautiously considered.
