Long-term use of attenuated androgens may increase health risks

Patient data over 43 years from two angioedema centers were analyzed

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A rope begins to fray in this illustration, signifying increased risk.

Long-term use of attenuated androgens — male hormones used as a preventive treatment — may increase the risk for other disorders in hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE), a retrospective analysis suggests.

Disorders linked with their use included high blood pressure, high cholesterol, diabetes, and benign liver tumors.

“The results of this study warrant an extensive work-up for comorbidities in patients with angioedema due to C1-INH deficiency, in particular in those on LTP [long-term treatment] with attenuated androgens,” the clinicians wrote in “Comorbidities in Angioedema due to C1-inhibitor deficiency: an Italian survey,” which was published in The Journal of Allergy and Clinical Immunology: In Practice. The study was funded by CSL Behring, which is developing garadacimab, a preventive treatment candidate for hereditary angioedema.

C1-INH-HAE is a rare genetic disorder characterized by sudden and recurrent swelling attacks in the deeper layers of the skin, namely the mucosal linings of the respiratory and digestive tracts. It’s caused by low levels or a dysfunctional C1 inhibitor, a protein that blocks the activity of other proteins involved in producing the hormone bradykinin.

When C1-INH levels  are low or the protein malfunctions, bradykinin levels can get too high, causing fluid to leak from the bloodstream into nearby tissues and triggering an attack. C1-INH also helps regulate other bodily functions, including the complement system, a part of the immune system that helps defend against infections,  coagulation, and preventing blood clots.

As such, C1-INH deficiency may cause additional disorders, or comorbidities, in C1-INH-HAE patients. To see if standard long-term preventive treatment (prophylaxis) can reduce them, clinicians in Italy retrospectively analyzed data from adult C1-INH-HAE patients who were followed at angioedema centers in Milan and Padua between 1979 and 2021. Both were part of the Italian Network for Hereditary and Acquired Angioedema (ITACA). Prophylactic treatment was limited to attenuated androgens, either Danocrine (danazol) or Winstrol (stanozolol), or tranexamic acid.

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Analyzing data on use of attenuated androgens

Data from 446 patients (mean age 52.5) were analyzed. More than a third (37.4%) had attacks that affected the larynx, mostly women (43.9% vs. 30.5% men). Of the 446 patients, 63 died, although the cause of death was not specified in the analysis. Almost half (48.9%) the patients received one or more than one long-term prophylaxis (LTP) for at least a year.

Attenuated androgens were the most commonly prescribed medications for long-term prophylaxis, Danocrine by 80.3% of patients, followed by Winstrol by 31.6%. Tranexamic acid was used by 22.5%. Several patients switched from one to another LTP due to lack of efficacy or side effects.

When compared with the general Italian population, certain comorbidities seemed to affect more C1-INH-HAE patients, in particular heart diseases (4.8% vs. 9.6%). The prevalence of heart attacks was higher (5.6%) in C1-INH-HAE patients over the general population (1.4%). So was the prevalence of infection by the hepatitis C virus (10.5% vs. 2.5%) and removal of the appendix (15.9% vs. 4.3%).

Patients who received LTP were older (mean age, 56.5 vs. 48.7) and had experienced more attacks in the larynx over the nonprophylatic group (51.4% vs. 46.1%).

Among those treated with a LTP, 83.9% initially received attenuated androgens. Among these, 7.6% were later treated with tranexamic acid. A total of 16% of patients were first treated with tranexamic acid, after which 60% were later treated with attenuated androgens.

Attenuated androgens are a risk factor for high blood pressure (hypertension), high cholesterol, diabetes, hepatic angioma (a noncancerous growth of blood vessels in the liver), and focal nodular hyperplasia, a noncancerous tumor that forms in the liver, statistical analyses suggested. On the other hand, attenuated androgens seemed to protect against the need for surgery to remove the appendix. No association was seen between comorbidities and tranexamic acid.

Overall, “in this large patient population with a rare disease followed for up to a 43-year period, we found a greater prevalence of comorbidities hitherto unreported in the literature and an association between comorbidities and LTP [long-term treatment] with” attenuated androgens, the researchers said.