Certain Progestogens Linked to Higher Risk of Brain Tumors, Study Finds

Commonly used progestogens may increase the risk of developing meningioma, a brain tumor sometimes requiring surgery.

An MRI finding of meningioma. April stock/Shutterstock

Prolonged use of certain progestogen hormone drugs, including a common injectable contraception, is associated with an increased risk of developing intracranial meningioma tumors.

In a recently published study in The BMJ, French researchers found that medrogestone, promegestone, and injectable medroxyprogesterone acetate—a widely used contraceptive known by the brand name Depo-Provera—increase the risk of intracranial meningiomas requiring surgery.

Progestogens are progestogenic drugs that produce effects similar to natural progesterone in the body and include both plant-derived bioidentical progesterones and synthetic forms. They are often prescribed to women to treat gynecological conditions, such as infertility, endometriosis, menopausal symptoms, and polycystic ovarian syndrome; to prevent miscarriages or preterm births; and as contraceptives.

The Study

Researchers used data from the French national health data system for women of all ages who underwent surgery for intracranial meningioma between Jan. 1, 2009, and Dec. 31, 2018, to determine whether progestogens increased the risk of developing meningiomas.

Out of 108,366 women, 18,061 with a mean age of 57.6 had intracranial surgery for meningioma during the selected period and were used as the case group. Each case was matched to five controls (90,305 total) with the same birth year and area of residence.

The researchers examined various administration routes of progestogen exposure, including intravaginal, percutaneous, intramuscular, and oral progesterone, dydrogesterone (with or without estrogen), hydroxyprogesterone, promegestone, medrogestone, the injectable contraceptive medroxyprogesterone acetate, dienogest (with or without estrogen), and intrauterine systems of levonorgestrel.

They also looked at three modes of exposure to progestogens:

• The first mode was exposure to the progestogen of concern.
• The second mode was an exposure to high doses of at least one of the three progestogens already known to increase the risk of meningiomas, such as chlormadinone acetate, nomegestrol acetate, and cyproterone acetate.
• The third mode was the absence of exposure to any progestogen (used as the reference for the analyses).

The researchers also considered a wide range of sociodemographic factors and medical characteristics of the participants.

The study found that long-term use of promegestone, medrogestone, and the injectable contraceptive medroxyprogesterone acetate increased the risk of developing an intracranial meningioma. However, researchers found no increased risk of meningioma for progestogens used for less than a year, progesterone, dydrogesterone (commonly used for miscarriages), and levonorgestrel intrauterine systems such as Skyla and Mirena that slowly release the hormone into the uterus.

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Additionally, there wasn’t a significant association between an increased risk of intracranial meningioma surgery and oral, intravaginal, or percutaneous progesterone, dydrogesterone, or spironolactone. By contrast, an increased risk of meningioma was associated with the use of medrogestone, promegestone, and medroxyprogesterone acetate—which is the only one currently available in the United States.

Intracranial Meningiomas

An intracranial meningioma is a typically benign tumor (meaning that it won’t spread) that grows from the membranes surrounding the brain and spinal cord called meninges. Meningiomas account for 40 percent of central nervous system primary tumors and affect roughly 9.5 per 100,000 people in the United States each year.

Even though most are not cancerous, meningiomas can cause potentially debilitating symptoms, such as confusion, seizures, personality changes, hearing loss or ringing in the ears, compression of adjacent brain tissue, neurological deficits, and muscle weakness. Because of this, surgery is usually the first line of treatment.

Although meningiomas are rare before the age of 35, there are recognized risk factors, including being female, intracranial exposure to ionizing radiation, neurofibromatosis type 22, and prolonged exposure to high doses of the three recognized progestogens known to cause meningiomas: cyproterone acetate, chlormadinone acetate, and nomegestrol acetate.

According to the study, the link between female sex hormones—namely progesterone and intracranial meningioma—is “biologically plausible,” as 60 percent of meningiomas have progesterone receptors, and the magnitude of these tumors appears to increase during pregnancy, when progesterone levels are elevated, and decrease postpartum. Additionally, studies have suggested a link between breast cancer and meningiomas.

“This is an important article showing an increased likelihood of meningioma surgery with previous exposure to certain progesterone products, including medroxy progesterone, which is a common injectable contraception,” British geneticist Dr. Gareth Evans said in a rapid response published in The BMJ.

“The most likely explanation is that the exposure [to progestogens] accelerates growth in very small meningiomas that would never present clinically to tumors that required surgery. This is plausible, as many women are diagnosed with meningioma [that] are asymptomatic when [they are] scanned for other symptoms, and most meningiomas have progesterone receptors and can be driven by progesterone,” he said.

Dr. Evans also said this would explain the increased incidence of meningiomas in women diagnosed with tumors in adulthood despite boys being at higher risk than girls of developing a meningioma.

“Whilst these results need validation, women with NF2-related schwannomatosis should avoid injectable medroxy progesterone acetate, and both sexes cyproterone acetate.”

NF2-related schwannomatosis is a genetic disorder that results in the growth of benign tumors along the nerves and in the skull. Cyproterone acetate is a steroid used in anti-androgen therapy to lower levels of testosterone in the body. It is also used in combination with ethinyl estradiol to treat women with severe acne and symptoms of androgenization.

Depo-Provera is the fourth most prevalent contraceptive in the world, with an estimated 74 million users. In the United States alone, there were more than 2 million prescriptions for the injectable contraceptive in 2020, and more than one in five sexually active U.S. women reported having used the contraception.

The authors of the BMJ paper suggest that the number of meningiomas attributable to the progestogen found in Depo-Provera may be “potentially high” in countries with a large number of people using the contraceptive. Additionally, medroxyprogesterone (non-acetate) is used orally at lower doses in some countries, “notably the U.S.,” for which no data currently exists on the risks of developing meningioma.