The pharmaceutical maker Upjohn had begun the New Drug Application (NDA) for DMPA approval in the U.S. as early as 1968, and the drug was introduced in New Zealand in 1969. Concerns nevertheless existed regarding studies showing that Depo-Provera caused mammary tumours in beagles and later studies showing a two-fold increased risk of breast cancer in certain sub-groups of women, including those with current or recent use within the previous five years.

By the late 1970s, DMPA was in use in some 70 countries worldwide, having been endorsed by the International Planned Parenthood Federation and the World Health Organization for use in less developed countries, despite existing safety concerns. By 2019, Depo/DMPA was described as “one of the most commonly used hormonal contraceptive methods in the world,” particularly in Sub-Saharan Africa. With increasing use of DMPA worldwide came increasing numbers of studies with ominous findings about the drug, including its association with increased risk of bone density loss, cervical cancer, and HIV transmission. Despite numerous findings of these and other adverse effects throughout the 1980s and 1990s, it would take until 2004 before the FDA would add a Black Box Warning for Depo-Provera — and then, only for bone density loss.

Indeed, as early as the mid to late 1980s, data were emerging from Mexico, Thailand, Costa Rica and elsewhere that suggested long-term users of Depo-Provera were up to twice as likely as non-users to develop cervical dysplasia and invasive cervical cancer, especially women who began using DMPA before the age of 30. This included data from large studies such as the World Health Organization’s Collaborative Study of Neoplasia and Steroid Hormone Contraceptives.

By the mid to late 1990s, research on monkeys suggested that the 2.5 million American women then taking progestin-containing contraceptives, such as oral pills, Norplant, and Depo-Provera — could be at substantially higher risk of contracting HIV-AIDS through sexual contact. In a study published in 1996, researchers Preston A. Marx and colleagues from the Aaron Diamond AIDS Research Center in Tuxedo, New York, found that female rhesus macque monkeys that were administered progesterone were eight times as likely as controls to contract Simian immunodeficiency virus (SIV), a monkey version of AIDS. These scientists found that subcutaneous progesterone implants, which could mimic hormonally based contraceptives such as Depo-Provera, thinned the vaginal epithelium and enhanced SIV vaginal transmission 7.7-fold. Subsequent studies have likewise shown that progestin-containing contraceptives induce hyperplasia of the vaginal epithelium, with thinning of the vaginal lining and altered local leukocytes (immune cells) rendering women more susceptible to disease transmission.

As already noted, it wasn’t until 2004 that the FDA added a Black Box Warning for Depo-Provera for bone density loss. As early as 1991 — prior to FDA approval of Depo-Provera for contraceptive use — a study published in the British Medical Journal showed that DMPA had adverse effects on women’s bone density, potentially placing young women at risk of osteoporosis. A 1991 study compared 30 users of DMPA with a minimum of five years previous use with two control groups, 30 pre-menopausal controls and 30 post-menopausal controls. When compared with the pre-menopausal controls matched for age, race, and body mass index, DMPA users had significantly reduced bone density in the lumbar spine (mean difference 7.5%) and in the femoral neck (mean difference 6.6%).

A study launched at a community health center in Durham, North Carolina, in 1997 found that teen DMPA users were soon presenting with the sort of low estrogen levels and bone density loss typically seen in older, post-menopausal women. That study (a slide presentation personally communicated to the author) followed sexually active teens ages 13 through 17, with average exposure to DMPA among the injectable users being 17 months. The study found that differences in bone marrow apparent density (BMAD) in the lumbar spine was statistically significant between users and non-users, with spine BMAD being particularly affected after 15 months of use. Bone density measurements were particularly low for teens who began DMPA use sooner after menarche and who used DMPA for a longer time. Analysis of serum estradiol levels among DMPA users further revealed quite low levels of estrogen in these girls (7 to 22.4 pg/mL), where a level of 30 would be considered post-menopausal. In other words, while still teens, many of these young women were presenting with the estrogen levels and bone density loss associated with elderly women.

Bone density issues remained debated through the 1990s, but by the year 2000, a study was published in the journal Obstetrics & Gynecology using findings from a multi-center, cross-sectional study in an international population. The WHO Study of Hormonal Contraception and Bone Health collected data on 2,474 women from seven facilities in three regions of the developing world from April 1994 to June 1997. For users of DMPA and levonorgestrel implants, adjusted mean bone mineral density (BMD) was significantly lower in short-term current DMPA users compared with women who never used hormonal contraceptives. These authors downplayed the clinical significance of such findings, however, as they argued that such bone mineral density losses are “reversible.” The authors did not point out that bone fractures are “reversible,” too, or that women might not welcome either such outcome. As George Thorogood and the Destroyers might sing, it is overdue, long overdue, for the FDA to officially recognize that Depo-Provera is “bad to the bone.”

The history of Depo-Provera and the FDA reveals the failings of a federal agency that, for too long and especially in the realm of women’s reproductive health, has listened to drug manufacturers and the International Planned Parenthood Federation versus women themselves. Studies of many thousands of Depo-Provera users are cited here, but there are also many thousands of women who have “voted with their feet,” so to speak, after exposure to the drug and its immediate side effects.

For example, a 1996 study followed for one year 536 women who received an injection of DMPA from any of 17 clinical settings in southeast Texas. Users complained most frequently of amenorrhea, irregular bleeding, and weight gain, with reports of amenorrhea, weight gain, and acne or skin problems increasing over time. Users’ continuation rate at one year dropped to 28.6%, meaning that more than 70% of women rejected DMPA within 12 months. Similarly, another 1996 study reported that, of 5,178 women who obtained the DMPA injectable from Planned Parenthood of the Rocky Mountains between January 1993 and March 1995, more than three-fourths (77%) of users discontinued DMPA entirely within one year. Difficulty tolerating side effects was the main reason for terminating use.

The current multi-district litigation against Pfizer on behalf of more than 1,200 American women who contend that Depo-Provera caused them to develop brain tumors underscores the FDA’s egregious failure to protect women who have not been so wise or fortunate as to reject the contraceptive drug immediately themselves. Ironically, contraceptive programs for felids and canids (wild cats and dogs) in North American zoos began in the 1970s with implants such as medroxyprogesterone acetate (DMPA) or melengestrol acetate (MGA), but DMPA use was soon shunned because it was associated with changes in glucocorticoid levels. (Glucocorticoid levels are very important in regulating the body’s immune system and response to stress and inflammation.) Indeed, the Association of Zoos and Aquariums (AZA) Wildlife Contraception Center avoided use of medroxyprogesterone acetate after Munson and colleagues reported that long-term use of progestin contraceptives was associated with higher rates of uterine and mammary pathologies such as endometrial hyperplasia, endometrial cancer, and breast cancer.

In other words, more than 45 years after the emergence of studies showing an association between medroxyprogesterone acetate and mammary tumors in beagles, millions of American women are still receiving a drug deemed unsuitable for even wild dogs or cats in our nation’s zoos.

The insult and harm to women are exacerbated by the fact that Depo-Provera and other contraceptive drugs do not treat or prevent disease — unless one considers female fertility and children to be pathologies — thus obliterating any attempt to continue to defend the drug through some sort of “Risk-Benefit” analysis. Certainly, the more than 1,200 victims who have incurred intracranial meningiomas after using Depo-Provera represent many millions more women who deserve accountability from, and major internal reform at, the FDA.

Teresa A. Donovan, MPH, is an Associate Scholar of the Washington, D.C.-based Charlotte Lozier Institute and former Senior Writer and Editor of Presidential Messages & Correspondence for President George H.W. Bush (GB41). She has served more recently in higher education, including work focused on environmental and public health sciences at University of Kentucky and the University of Cincinnati College of Medicine|UC Center for Environmental Genetics.