Hormonal Treatment for Endometriosis: What You Need to Know

Why Hormonal Treatment?

Endometriosis management typically begins with pain control medications (such as anti-inflammatory drugs like ibuprofen) and hormonal treatment. While pain medications help manage symptoms in the short term, hormonal treatments target the root of the problem by reducing the effect of estrogen, the hormone that fuels endometriosis growth, causing the tissue to shrink and become less active over time. Hormonal therapy is usually one of the first steps because it is effective for most women and can be used long-term. Several hormonal options are available, including birth control pills, progestin-only medications, and newer oral therapies. Here is a summary of current evidence on hormonal treatment for endometriosis.

Types of Hormonal Treatment

1. Birth Control Pills, Patches, and Vaginal Rings (Combined Hormonal Contraceptives)

These contain a combination of estrogen and progestin. They work by preventing ovulation (the release of an egg) and thinning the uterine lining, which also shrinks endometriosis tissue.

• How they are used: Often taken continuously (skipping the placebo or "sugar" pills) to prevent monthly periods altogether, which tends to provide better pain relief than the standard cyclical schedule.
• Success rate: Studies show an average pain reduction of about 15 points on a 100-point pain scale compared to no treatment. Most women notice meaningful improvement in their symptoms. About two-thirds of patients respond well to these first-line treatments.
• Common side effects: Headache, mood changes, breast tenderness, and nausea (each occurring in up to 10% of users). These side effects often improve after the first few months. Breakthrough bleeding (spotting) can occur, especially with lower-dose formulations.
• Important safety note: These are not suitable for women with a history of blood clots, migraine with visual disturbances (aura), smokers over 35 years, or for patients with certain liver conditions.

2. Progestin-Only Treatments

Progestins are a type of hormone similar to the body’s natural progesterone. They come in several forms:

• Pills (norethindrone acetate, dienogest, medroxyprogesterone acetate)
• Injection (depot medroxyprogesterone acetate, given every 3 months)
• Implant (a small rod placed under the skin of the arm)
• Hormonal IUD (a small device placed in the uterus that releases levonorgestrel)

These work by thinning and shrinking endometriosis tissue, reducing inflammation, and in some cases preventing ovulation.

• Success rate: The hormonal IUD showed one of the largest pain reductions in studies, about 18 points on a 100-point scale. Oral progestins and other forms show similar overall effectiveness.
• Common side effects:
  • Pills: Irregular bleeding (more than 10% of users), weight gain (up to 10%), and mood changes (up to 10%).
  • Injection: Headache, weight changes, and stomach upset (each in more than 10% of users); depression and decreased sex drive (up to 10%). Long-term use may cause some bone density loss, and it can take up to 12 months for fertility to return after stopping.
  • Implant: Irregular bleeding, weight gain, headache, and acne (each in more than 10% of users). About 1 in 10 women discontinue due to unpredictable bleeding.
  • Hormonal IUD: Irregular bleeding is common initially (affecting about 65% of users) but usually improves over time. It has fewer body-wide side effects (like mood changes) compared to pills or injections because the hormone acts mostly locally in the uterus.

3. GnRH Agonists (e.g., Leuprolide, Nafarelin, Goserelin)

These medications work by temporarily "turning off" the hormonal signals from the brain that tell the ovaries to produce estrogen. This creates a temporary menopause-like state, causing endometriosis tissue to shrink significantly.

• How they are used: Given as injections or nasal sprays, usually for up to 6 months. Typically prescribed with a low-dose "add-back" hormone pill to take alongside the medication to reduce side effects while keeping the treatment effective.
• Success rate: Pain reduction is comparable to other hormonal treatments, about 16 points on a 100-point scale.
• Common side effects: Because estrogen levels drop very low, side effects resemble menopause and may include hot flashes (more than 10% of users), headache, difficulty sleeping, vaginal dryness, and mood changes. The most important concern is bone density loss, which is why add-back therapy is recommended from the start and treatment duration is usually limited.

4. GnRH Antagonists (Newer Medications)

These are a newer class of oral medications that block estrogen production more quickly and with more precise control than GnRH agonists. Two options are currently available:

• Elagolix (Orilissa): Available in two doses.
  • Low dose (150 mg once daily): About 43–46% of women experienced meaningful relief from period pain at 6 months. Common side effects include hot flashes (24%), headache (17%), and nausea (11%). Can be used for up to 24 months.
  • High dose (200 mg twice daily): About 75–77% of women experienced meaningful relief from period pain. However, hot flashes are more common (46%), and use is limited to 6 months due to greater bone density effects.
• Relugolix Combination Therapy (Myfembree): This is a single daily pill that combines a GnRH antagonist with low-dose add-back hormones built right in, which helps reduce side effects. About 75% of women experienced meaningful relief from period pain at 6 months, with benefits lasting up to 2 years. Common side effects include headache (33%), hot flashes (13%), mood changes (9%), irregular bleeding (about 7%), and nausea (6%). Bone density changes were minimal (less than 1%). Most women experience lighter periods or no periods at all while on this medication.
  • Important safety note: Myfembree carries a warning about a small increased risk of blood clots, so it is not recommended for women over 35 who smoke, or those with uncontrolled high blood pressure.

What to Expect Overall

• Most women notice improvement in pain within the first 1-3 months of starting hormonal treatment.
• About two-thirds of patients respond well to first-line options (birth control pills or progestins).
• If the first medication tried does not work well or causes bothersome side effects, there are several other options to try. Finding the right fit sometimes takes patience.
• Symptoms may return after stopping treatment. About 25–34% of women experience pain recurrence within 12 months of stopping hormonal therapy, so long-term management plans are common.

Long-Term Health Outcomes: What Research Shows

Beyond controlling pain, hormonal treatments used for endometriosis may have important long-term effects on cancer risk. Here is what current research says:

Ovarian Cancer

Women with endometriosis have a slightly higher risk of developing ovarian cancer compared to women without endometriosis, but the overall risk remains low.

The good news is that long-term use of combined oral contraceptives (birth control pills) has been shown to substantially reduce this risk. Research shows:

• Women with endometriosis who used oral contraceptives for more than 10 years had about an 80% lower risk of ovarian cancer.
• This protective effect lasts for more than a decade after stopping the pill and may even bring the risk below that of the general population.
• The protection appears to be related to suppressing ovulation over time. About one-third of all ovarian cancers may be prevented by ever using hormonal contraceptives, and 15 years of use may reduce the risk by about 50%.
• The hormonal IUD (levonorgestrel-releasing intrauterine system) has also been associated with a reduced risk of ovarian cancer in several large studies, though the evidence is less established than for oral contraceptives.

Endometrial (Uterine) Cancer

Women with endometriosis also have a modestly increased risk of endometrial cancer. Hormonal treatments, particularly those containing progestins, appear to be protective:

• Ten years of oral contraceptive use has been associated with a reduction in the absolute risk of endometrial cancer from about 2.3 to 1.3 cases per 100 women before age 75.
• The hormonal IUD has been associated with a 20-50% lower risk of endometrial cancer in large population studies.
• Depot medroxyprogesterone acetate (the injection) has been associated with up to a 70-80% reduced risk of endometrial cancer, with the benefit increasing with longer duration of use.
• The etonogestrel implant has also been associated with a substantially reduced risk of endometrial cancer.
• This protective effect of oral contraceptives lasts for up to two decades after stopping use.

Colorectal Cancer

Oral contraceptive use has been associated with a modest reduction in colorectal cancer risk. A large systematic review found that ever use of oral contraceptives was associated with about a 14% lower risk of colorectal cancer. Some studies have shown even greater reductions with longer duration of use.

Breast Cancer

The relationship between hormonal treatments and breast cancer is more complex:

• Combined oral contraceptives are associated with a small increase in breast cancer risk (about 8% higher than non-users), but this increase is modest and appears to diminish after stopping.
• The hormonal IUD has been associated with a small increase in breast cancer risk (about 13–26% higher) in some large studies, though other studies found no increased risk.
• Depot medroxyprogesterone acetate does not appear to significantly increase breast cancer risk except possibly with very long-term use (5 or more years).

It is important to put these numbers in perspective: the absolute risk changes are small, and the protective effects against ovarian, endometrial, and colorectal cancers may offset the small potential increase in breast cancer risk for many women.