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:
swelling in the breasts or other parts of the body
abdominal or back pain
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
If your menstrual periods have stopped, they may start again. This effect will continue for as long as the medicine is taken. However, monthly bleeding usually stops within 10 months.
Also, if you are still having cycles, vaginal bleeding between your regular menstrual periods may occur during the first 3 months of use.
It is not uncommon to experience breast tenderness and/or mild vaginal bleeding upon initiation of HT. These side effects might occur after a few days or weeks, and are usually limited to the first few weeks of treatment. If breast tenderness is severe or persistent, you should decrease your estrogen dose, at least for a while.
Some individuals will experience some fluid weight gain for a few weeks-- this usually resolves.
Most people using HT for perimenopause or menopause have relief of symptoms with no side effects. Of those who report side effects, the most common are short-term breast tenderness and uterine bleeding. Both of these are usually limited to the first few weeks after initiation of treatment, and they are due to the breast and uterine tissue being “re-exposed” to estrogen after a period of estrogen depletion.
Testosterone therapy is well tolerated generally. A small number will experience facial hair or acne, both of which can be managed by reducing the dose or another solution. Very few may experience unwanted increased libido (sex drive), sleep difficulty, anxiety or aggression. Others may find it helps them sleep better and enjoy the increased sex drive. Side effects also include may include increased cholesterol, increased red blood cells, hair loss, and masculinization-- but this usually only occur when testosterone is used in supraphysiologic doses (such as transgender doses, not doses used for other purposes).
Those who could become pregnant should avoid testosterone therapy, because its use during pregnancy introduces the risk of the development of male traits in a female fetus. Testosterone therapy should also be avoided in women who have or have had breast or uterine cancer, have high cholesterol or heart disease, or have liver disease.
A study using combined estrogen and testosterone preparations for treatment showed uncommon side effects of alopecia, acne, and hirsutism, although these side effects are dependent on dosage and duration. Low incidence rates of deep voice, oily skin, acne, and male-pattern hair loss were found in a few controlled studies. Virilization can occur with higher-than-normal dosing of testosterone, but it is uncommon and reversible. Cis-women using the lowest effective dosage of testosterone have not been shown to experience side effects or adverse events. Increased dosages inevitably result in the aforementioned adverse effects, as well as increased hair growth.
Most women who take progesterone at bedtime enjoy a good night’s sleep and don’t feel sleepy the next day. However, some are more sensitive than others to the side effect of sleepiness with oral progesterone. In these cases, it may be preferable to use a vaginal progesterone suppository or progestin-containing IUD as the progesterone component of their HT, to avoid the sleepiness side effect. Additionally, progesterone in larger doses can cause uterine cramping and light vaginal bleeding.
About 10% of people cannot tolerate oral progesterone. They may experience sleepiness, dizziness, mood depression, or abdominal bloating.
Additional Safety Concerns:
If you are using topical hormones, please note:
1. If you are using any cream, gel, or spray hormone product on your arms and then blood levels are tested, the blood specimen can become contaminated with some of the product from your skin. Therefore, please have blood drawn from the opposite arm, or use hormone product on your legs the day of the blood test.
2. Topical hormones can transfer to other people (rubbing the arm) or pets (licking the arm). This is particularly important to remember if you care for a small child, infant, or pet because they can actually absorb enough from your arms to affect their small bodies. If this is a possibility, you may choose to wear long sleeves, or use the topical hormone product on your legs – inner thighs and behind knees are acceptable locations
Is it necessary to check hormone levels?
Monitoring hormone levels can be of use in specific situations, though it is not necessary in all cases. Some women ask about saliva testing of hormones, which has been advocated by certain books (often co-authored by those who have a stake in saliva-testing laboratories). Despite very convincing arguments in these books, there is no scientific validity in the practice of monitoring saliva levels of ovarian hormones. Monitoring hormone levels in the blood is scientifically based, and if hormone monitoring is indicated, serum (blood) testing is the most reliable method.
When are hormones unsafe?
Typically, the older a woman is, the greater the overall risk. The data is becoming clearer that women over age 60 should be aware of the increased risk of starting hormones because their risk of stroke starts to increase. Younger women who start BHT within five years of menopause may have more benefits with less risk. One prominent study by the World Health Initiative (WHI), revealed that women from age 50-59 taking estrogen were no more likely to have a heart attack or die of heart disease than those taking a placebo. Researchers even suggested that the risk for heart disease in this group might have been slightly reduced. Some risks associated with hormones include blood clots, stroke, and breast cancer. These complexities make it important f to consult with your provider and tailor each treatment to the individual risks and benefits.
One important thing to remember is you do not have to “just live with” the symptoms of aging!!!
For those who are unable or unwilling to use estrogen therapy, many non-hormonal medications, including selective serotonin reuptake inhibitors, complementary and alternative medicine and supplements, are available that may effectively relieve symptoms or prevent or treat disease.
To learn more about perimenopause/menopause symptoms and treatment with HRT or to learn about natural options, check out our blogs:
About the Authors
Havilah Brodhead is a board-certified family nurse practitioner and chief medical officer of Hearthside Medicine Family Care in Bend, Oregon, an integrative medical practice. Havilah loves incorporating natural, plant-based medicine and alternative medicine into her conventional medicine training. She and her fellow NP provider Marie Mency love to care for the whole family and share a special interest in Women's Health. Havilah loves to mountain bike, practice yoga, and spend time with her husband and two young daughters exploring Oregon. Marie specializes in women's health and has two young daughters as well. Both providers are accepting new patients in person or via telehealth throughout Oregon. Marie is also able to offer telehealth to patients in California.
Marie Mency, FNP
Havilah Brodhead, FNP
Havilah Brodhead, FNP and Marie Mency, FNP/Women's Health are accepting new patients of all ages and take most insurances.