Estrogen, Progesterone, Testosterone: Side Effects & Safety

A look at safety of each hormone:

Estradiol: When taken as a pill, any type of estrogen (yes, bioidentical as well) slightly increases the risk of blood clots, which can lead to thrombosis, stroke, or pulmonary embolism. This is because after the hormone is absorbed by the stomach, it is transported directly to the liver, where it will be handled similar to a toxin (only because the liver is not accustomed to dealing with a large amount of this hormone ingested as “food”). The extensive metabolism that ensues results in the liver increasing production of blood clotting and inflammatory factors. However, research has shown that when estradiol is absorbed slowly (by using a patch, topical cream, or subcutaneous pellet) there is not elevated risk of blood clot, because the hormone is delivered gradually into the bloodstream through capillaries, rather than first passing through the liver all at once.

For the same reason, oral estrogen slightly increases the risk of gallbladder disease, which also can be avoided with use of transdermal or subcutaneous pellet therapy.

Bottom line: The safest way to receive estradiol supplementation is by a non-oral route.

Testosterone. Bio-identical testosterone for those assigned female at birth has been used off-label for decades, and there is a growing body of data regarding its safety for hormone replacement. Most adverse health risks you may have seen referenced would likely be related to the synthetic pill methyltestosterone, which is subject to the first pass liver effect described above. Current data specifically regarding bio-identical testosterone formulations have not shown increased risk in cancer, cardiovascular disease, or other serious condition. However, I always screen a person for baseline increased hemoglobin and hematocrit, because testosterone can increase these, which can in turn put one at increased risk for clot. I continue to monitor these levels when my patients are taking testosterone.

According to the NW Menopause Society, “oral testosterone therapy is associated with adverse lipid profiles with negative effects on high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol levels, and is not recommended.”

Studies of non-oral testosterone therapies (gel, cream, pellets, injectable), in doses that approximate physiological testosterone concentrations for premenopausal cis women, have shown no statistically significant adverse effects on lipid profiles over the short term.

Available data suggest that short-term transdermal testosterone therapy does not impact breast cancer risk .There are no data to support the use of testosterone therapy to prevent breast cancer.

Caution is recommended for testosterone use in those with hormone-sensitive breast cancer.

Testosterone therapy for postmenopausal people, in doses that approximate physiological testosterone concentrations for premenopausal cis women, is not associated with serious adverse reactions or effects.

When an appropriate approved female testosterone preparation is not available, off-label prescribing of an approved cis male formulation is reasonable, provided hormone concentrations are maintained in the physiologic cis female range.

According to the NW Menopause Society, any testosterone preparation that results in supraphysiologic concentrations of testosterone, including pellets and injections, is not recommended. That being said, pellet therapy remains a popular option by many providers. They further state “compounded “bioidentical” testosterone therapy cannot be recommended”-of note, they recommend against all compounded hormones due to lack of data on safety and testing.

Should a trial of testosterone therapy be given, a repeat level 3–6 weeks after treatment initiation

Patients should be tested for serum total testosterone level every 6 months, to screen for overuse.

If no benefit is experienced by 6 months, treatment should be ceased.

Monitoring of hematocrit and lipid levels are recommended for patients taking testosterone.


There is no known medical or clinical risk of using bio-identical progesterone, by oral or other route of delivery. Anyone who mentions risk associated with progesterone therapy is confusing it with a synthetic progestin, such as Provera (medroxyprogesterone) or norethindrone. It can make one sleepy, so we usually prescribe it to be taken at bedtime.

Does HT increase risk of cancer?

The only cancer conclusively shown to be increased by estrogen therapy is uterine cancer, and the proper use of progesterone eliminates the increase in risk. As stated above, use of unopposed estrogen can cause over-stimulation of the cells of the uterine lining, but when properly balanced with progesterone, uterine lining growth is limited, and there is no increase in uterine cancer risk.

The cancer risk of HT that draws the most attention is the possible link to breast cancer. Many who are hesitant to use hormone therapy cite this as their main concern. Hundreds of studies have examined estrogen therapy and breast cancer, and though some show a small increase in risk, others show no increase, and still others show a decrease in breast cancer for women on estrogen therapy.

Evidence does suggest that a pre-existing breast cancer will grow in response to estrogen.

What are the side effects of HRT?

Depending on the type of treatment, side effects may include:




breast tenderness

swelling in the breasts or other parts of the body

abdominal or back pain

leg cramps




vaginal bleeding

mood changes


These side effects usually disappear after a few weeks.

Some of those treated with HRT have side effects such as breast tenderness, fluid retention and mood swings. In most cases, these side effects are mild and do not require you to stop HRT therapy.

For patients taking any of the estrogens by mouth or by injection:

Nausea may occur during the first few weeks after you start taking estrogens. This effect usually disappears with continued use. If the nausea is bothersome, it can usually be prevented or reduced by taking each dose with food or immediately after food.

In some patients using estrogens, tenderness, swelling, or bleeding of the gums may occur. Brushing and flossing your teeth carefully and regularly and massaging your gums may help prevent this.

If you have bothersome side effects from HRT, please let us know! We can often reduce these side effects by changing the type and dosage of estrogen and/or progestin