What are the cardiac side effects of progesterone?

From the Guidelines

Progesterone, particularly natural micronized progesterone, has a relatively favorable cardiac side effect profile compared to synthetic progestins, with minimal impact on cardiovascular risk when used in hormone replacement therapy 1. The most common cardiac side effects of progesterone include:

• Fluid retention leading to edema
• Slight blood pressure changes
• Occasional palpitations Some women may experience a small increase in blood pressure while taking progesterone, particularly synthetic progestins found in hormonal contraceptives. Progesterone can also affect lipid metabolism, potentially increasing LDL cholesterol and decreasing HDL cholesterol, which could theoretically increase cardiovascular risk with long-term use. However, natural micronized progesterone has been shown to minimize hormonal-related cardiovascular risks when compared to synthetic progestogens 1 and has a neutral or beneficial effect on blood pressure 1. In rare cases, progesterone therapy has been associated with thromboembolism (blood clots), which can lead to serious cardiac events like pulmonary embolism or stroke, especially in women with pre-existing risk factors such as smoking, hypertension, or previous clotting disorders. The risk of these serious side effects is higher with synthetic progestins than with natural progesterone, as evidenced by the Women's Health Initiative study 1. Patients with existing cardiovascular disease, history of thromboembolism, uncontrolled hypertension, or liver disease should use progesterone with caution and under close medical supervision. These effects occur because progesterone influences sodium and water retention in the kidneys and affects vascular tone and coagulation factors in the blood. The European Society for Human Reproduction and Embryology (ESHRE) recommends natural micronized progesterone as a preferred progestogen in hormone replacement therapy due to its safer pharmacological profile 1.

From the FDA Drug Label

WARNINGS See BOXED WARNING. 1. Cardiovascular disorders An increased risk of pulmonary embolism, deep vein thrombosis (DVT), stroke, and myocardial infarction has been reported with estrogen plus progestin therapy. Serious, but less common side effects include: Risk to the Fetus: Cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects. Abnormal Blood Clotting: Stroke, heart attack, pulmonary embolus, visual loss or blindness PRECAUTIONS A. General 1. Addition of a progestin when a woman has not had a hysterectomy ... 2. Fluid Retention Progesterone may cause some degree of fluid retention Women with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation.

The cardiac side effects of progesterone include:

• Increased risk of pulmonary embolism
• Deep vein thrombosis (DVT)
• Stroke
• Myocardial infarction
• Abnormal blood clotting
• Fluid retention, which may be a concern for women with cardiac or renal dysfunction 2, 2, 2

From the Research

Cardiac Side Effects of Progesterone

The cardiac side effects of progesterone are a topic of ongoing research and debate. Several studies have investigated the effects of progesterone on cardiovascular health, with varying results.

• The study published in Nature clinical practice. Cardiovascular medicine 3 suggests that progesterone may have a positive effect on cardiovascular function, potentially reducing the risk of microvascular cardiac ischemia.
• A study published in the International journal of fertility and women's medicine 4 found that progestin therapy can affect arterial function, but the impact on cardiovascular health is still unclear.
• Research published in Menopause (New York, N.Y.) 5 highlights the importance of selecting progestogens with minimal androgenic properties to avoid attenuating the beneficial effects of estrogens on the lipid profile and vasomotion.
• A study published in Climacteric : the journal of the International Menopause Society 6 found that micronized progesterone has a neutral effect on the vasculature and may reduce the incidence of new-onset diabetes when combined with transdermal estrogen.
• A review published in Reviews in cardiovascular medicine 7 notes that not all progestational agents are alike in their cardiovascular properties, and that progesterone may have different effects on cardiac vessels compared to other progestins like medroxyprogesterone.

Key Findings

• Progesterone may have a positive effect on cardiovascular function, particularly when used in conjunction with estrogen 3, 6.
• The choice of progestogen is important, as some progestins may attenuate the beneficial effects of estrogens on cardiovascular health 4, 5.
• Micronized progesterone may be a good option for reducing cardiovascular risk, as it has a neutral effect on the vasculature and may reduce the incidence of new-onset diabetes 6.
• Further research is needed to fully understand the cardiac side effects of progesterone and to determine the optimal hormone replacement therapy regimen for reducing cardiovascular risk 3, 7.