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Depo-Provera: The Quarterly Contraceptive
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Depo-Provera: The Quarterly Contraceptive

The Food and Drug Administration (FDA) approved Depo-Provera (manufactured by The Upjohn Co., Kalamazoo, MI) for contraception in October 1996. The active ingredient in Depo-Provera is a synthetic hormone similar to the natural hormone progesterone.

"I was not happy with other methods," says Becky Schroder, of Jacksonville, FL. "I was a poor pill taker. I forgot. And I thought that barrier methods were inconvenient and messy."

Schroder, 31, started Depo-Provera when its use as a contraceptive was still in the investigational stages. (The FDA had previously approved the drug for treating endometrial and renal cancers.)

Depo-Provera inhibits the production of another hormone, gonadotropin. This, in turn, prevents ovulation. Depo-Provera also causes changes in the lining of the uterus that make pregnancy less likely to occur. Depo-Provera's estimated effectiveness in preventing pregnancy is 99%, on a par with Norplant, the contraceptive implant. Norplant contains another synthetic progestin hormone called levonorgestrel.

Timing Is Critical

The amount of Depo-Provera in the bloodstream is at the highest level just after injection. Over time, the level drops and after three months, the level may no longer offer enough protection against conception.

"Go back on time for the next injection," says Ridgely Bennett, MD, the FDA medical officer responsible for reviewing the new drug application for Depo-Provera. That should be made abundantly clear.

He adds that if the time between injections is greater than 14 weeks, the physician should make sure the woman isn't pregnant before giving her the next injection.

Getting Started

A woman should get her first injection of Depo-Provera within five days after the start of her menstrual period. The drug is effective immediately, so no other birth control is necessary.

Because Depo-Provera is not a barrier contraceptive, however, it offers no protection against sexually transmitted diseases such as AIDS, herpes, chlamydia, and gonorrhea. For optimum protection from both disease and pregnancy, couples may choose to use both Depo-Provera and a condom.

A woman who has just had a baby and wants to wait before having another should get her shot within five days after the birth if she is not breastfeeding, and six weeks after the baby is born, if she is.

Although numerous studies by the World Health Organization (WHO) have shown that Depo-Provera does not have any adverse effects on breast milk production or composition, or on the health of the nursing infant, it's best not to expose a newborn to the drug in the first six weeks, according to Philip Corfman, MD, a supervisory medical officer in the FDA's division of metabolism and endocrine drug products. It's just a precaution, he says.

If a woman decides at the end of three months that she wants to get pregnant, she simply doesn't get the next injection. But because the length of time between the last injection and becoming pregnant varies widely, any woman starting Depo-Provera should be sure she doesn't want to become pregnant for the next year or two, says Susan Wysocki, executive director of the National Association of Nurse Practitioners in Reproductive Health.

According to the approved physician's label, the median time to conception for those who do conceive is 10 months following the last injection with a range of 4-31 months. Since Depo- Provera does not accumulate in the body, the return to fertility is independent of the number of injections received, but may be affected by a woman's age or weight.

A woman should not take Depo-Provera if she has acute liver disease; unexplained vaginal bleeding; breast cancer; or blood clots in the legs, lungs, or eyes.

Side Effects

Change in the menstrual cycle is the most common side effect of Depo-Provera. At first there may be irregular bleeding or spotting, but that usually diminishes and eventually disappears after several injections. After a year on Depo-Provera, menstruation will stop completely in approximately half of the women.

Normal menstruation will usually return within a few months once the injections stop.

Women who continue to menstruate while on Depo-Provera may have decreased blood flow, which, in turn, reduces the chance of anemia. There may also be a decrease in menstrual cramps and pain, as well as ovulatory pain.

Schroder, who had very painful premenstrual symptoms before starting Depo-Provera, says she thinks of these side effects as benefits.

After menstrual changes, the most common side effect is weight gain. It's not clear whether the weight gain is due to water retention or a metabolic effect that increases appetite and body fat, says David Grimes, MD, a professor with the department of obstetrics and gynecology at the University of Southern California School of Medicine. But it is real, and women should know about it. African American adolescents may be at greater risk of weight gain than are Whites, and they apparently do develop increased body fat while on Depo-Provera. Women who are overweight when beginning Depo-Provera may also be at higher risk of progressive weight gain.

In addition, some patients may experience headache, nervousness, abdominal pain, dizziness, weakness, or fatigue.

Breast Cancer Concerns

The possibility of a link between Depo-Provera and breast cancer was first considered in the early 1970s, after breast cancers were found in beagles treated for more than three years with a dose of Depo-Provera equivalent to 25 times that of the human contraceptive dose. However, those studies were eventually discounted at an October 1981 meeting of the World Health Organization. Experts at that meeting concluded, and the FDA later agreed, that beagles were not appropriate animal models for determining what the potential effects of Depo-Provera would be on women.

Ten years later, WHO presented the results of a study of over 11,000 women who used Depo-Provera, mainly in Thailand and New Zealand. (The drug has been approved for contraception in about 90 countries.) Based on the study, published in the October 5, 1991 issue of the Lancet, WHO concluded that, overall, women on Depo-Provera are not at increased risk of breast cancer. In addition, breast cancer risk did not increase the longer a woman stayed on the injectable contraceptive. The WHO position on Depo-Provera in 2007 remains that there is no evidence of a causation link between Depo-Provera and breast cancer.

The study did find a slight increase in the risk of breast cancer during the first four years of use, primarily in women under 35. That increase, however, is statistically weak and comparable to the risk associated with oral contraceptives, according to the researchers.

But the National Women's Health Network disagrees with the researchers' conclusion. In testimony presented to the FDA's Fertility and Maternal Health Drugs Advisory Committee, Cindy Pearson, a representative of the National Women's Health Network, said that the WHO studies were conducted in countries with breast cancer rates less than half that of the United States and therefore can't be accurately applied to women in this country.

She adds that comparing the breast cancer risk to that associated with oral contraceptives is also misleading. These disturbing data are emerging from much smaller groups of women than was the case with oral contraceptives, she said. Only three epidemiologic studies have been done on Depo-Provera and breast cancer, and all three raise a red flag.

However, to Dr. Grimes, that increased risk in younger women isn't a link to Depo-Provera. Instead, It suggests that women who start taking Depo-Provera may be coming into the healthcare system for the first time and having preexisting tumors discovered.

It should be noted, says the FDA's Bennett, that more data on breast cancer risk is now available for Depo-Provera than has been required for any other drug prior to marketing.

The results of the WHO study also indicated that Depo-Provera use did not increase the overall risk of cancer of the liver or cervix. WHO reports that there is now substantial evidence that Depo-Provera protects against endometrial cancer, ovarian cancer, acute pelvic inflammatory disease, recurrent vaginal candidiasis, and endometriosis.

Osteoporosis Risk?

Depo-Provera use is associated with a decrease in bone mineral density (BMD). This decrease appears to be most rapid in the first two years of use. The loss of BMD appears to be largely reversible once Depo-Provera is discontinued. This does not seem to lead to reduced bone mineral density at the age of menopause. Depo-Provera is associated with a decrease in bone mineral density in adolescents during a critical period of bone increase. BMD decrease during adolescence may result in ultimately lower peak bone mass. For this reason, the FDA placed a Black Box Warning on Depo-Provera regarding the risk of bone density loss in adolescents, and in all women after extended years of use.

Available data do not support the routine use of bone density testing in Depo-Provera users. In selected patients with significant risk factors, bone density testing may be appropriate. Healthcare providers should inform patients of the potential effects of Depo-Provera on BMD and counsel them on “bone health,” including calcium and vitamin D supplementation, smoking cessation, weight-bearing exercise, and decreased alcohol and caffeine consumption. The WHO recommends that “there should be no restriction on the use of DMPA, including no restriction on duration of use, among women aged 18-45 who are otherwise eligible to use the method".

Depo-Provera should not be the first line choice of contraception in adolescents under 18 and should only be used after due consideration of other alternatives and informed choice. In women of all ages, careful re-evaluation of the risks and benefits of treatment should be carried out in those who wish to continue use for more than two years. This evaluation should involve traditional clinical history-taking and lifestyle assessment. On the basis of current evidence available, no routine laboratory tests or imaging procedures are required.

Best Candidates

Depo-Provera has been a godsend for women who've been unable or unwilling to use other methods, says Grimes.

Becky Schroder's plans to have a baby in the next two or three years made her decide against Norplant. Although the implant can be removed at any time, it isn't cost effective if it's taken out early, she says.

But Pearson, of the National Women's Health Network, is concerned that Depo-Provera will be forced on poor women. She told the FDA's advisory committee that the women's health movement has already documented many cases of coercion even while Depo-Provera was not approved as a contraceptive.

Wysocki acknowledges Pearson's concern. That concern stems from some very real things that happened in the 1960s, particularly with sterilization, but there's no reason to believe that because the technology is available that it will be abused. The problem itself should be addressed, not the drug.

Wysocki adds that Depo-Provera is a safe, low-cost method of contraception that requires little attention. No one method of contraception is perfect for all women at all times during their reproductive years, she says. However, additional options increase the likelihood that a method of contraception that matches each woman's need will be found.

The original article was published by the Consumer Information Center, of the US General Services Administration. Dori Stehlin is a staff writer for FDA Consumer.

RESOURCES:

The Alan Guttmacher Institute
http://www.agi-usa.org

Planned Parenthood
http://www.plannedparenthood.org

References:

Bonny AE, Britto MT, Huang B, Succop P, Slap GB. Weight gain, adiposity, and eating behaviors among adolescent females on depot medroxyprogesterone acetate (DMPA). J Pediatr Adolesc Gynecol. 2004 Apr;17(2):109-15.

Chilvers C. Breast cancer and depot medroxyprogesterone acetate: a review: Contraception. 1994;49:211-22.

Dennerstein GJ. Depot provera in the treatment of recurrent vulvo-vaginal candidiasis. J Reprod Med. 1986;31:801-3.

Hickey M, Fraser IS. Contraceptive use of depotmedroxyprogesterone acetate. Clinical Obstet Gynecol. 1995;38 (4):849-58.

Mangan SA, Larsen PG, Hudson S. Overweight teens at increased risk for weight gain while using depot medroxyprogesterone acetate. J Pediatr Adolesc Gynecol. 2002 Apr;15(2):79-82.

Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM. Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception. Arch Pediatr Adolesc Med. 2005 Feb;159(2):139-44.



Last reviewed May 2007 by Jeff Andrews, MD, FRCSC, FACOG

Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.


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