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Medroxyprogesterone Acetate (Depo-Provera)

It is a popular hormonal contraceptive or birth control product which is injected every 3 months. Depo-Provera is the brand name for medroxyprogesterone acetate manufactured by Pfizer Inc. Depo-Provera contains pregnane (17α-hydroxyprogesterone derivative) progestin, medroxyprogesterone acetate, without estrogen, and is administered to women in the form of an intramuscular injection once every 11 to 13 weeks. Depo-Provera causes the ovaries to stop releasing eggs.

Mechanism of action

The mechanism of action of progestin-only contraceptives depends on the progestin activity and dose. High dose progestin-only contraceptives, such as injectable Depo-Provera, completely inhibit follicular development and ovulation. Like all progestin-only contraceptives, Depo-Provera also increases cervical mucus viscosity, thereby inhibiting sperm penetration. In anovulatory cycles using progestin-only contraceptives, the endometrium is thin and atrophic. If the endometrium was also thin and atrophic during an ovulatory cycle, this could theoretically interfere with implantation of a blastocyst (embryo).

Benefits

• Near 100% effective at preventing pregnancy. Injected every 3 months.

• The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to insure that they do not require medical attention.

• 80% reversible within 12 months and 95% reversible within 18 months

• Depo-Provera reduces the risk of endometrial cancer by 80%.The reduced risk of endometrial cancer in Depo-Provera users is thought to be due to both the direct anti-proliferative effect of progestogen on the endometrium and the indirect reduction of estrogen levels by suppression of ovarian follicular development.

Pregnancy and breastfeeding

Depo Provera may be used by breast-feeding mothers. Heavy bleeding is possible if given in the immediate postpartum time and is best delayed until six weeks after birth. It may be used within five days if not breast feeding. While a study showed "no significant difference in birth weights or incidence of birth defects" and "no significant alternation of immunity to infectious disease caused by breast milk containing DMPA", a subgroup of babies whose mothers started Depo Provera at 2 days postpartum had a 75% higher incidence of doctor visits for infectious diseases during their first year of life.

A larger study with longer follow-up concluded that "use of DMPA during pregnancy or breastfeeding does not adversely affect the long-term growth and development of children". This study also noted that "children with DMPA exposure during pregnancy and lactation had an increased risk of suboptimal growth in height," but that "after adjustment for socioeconomic factors by multiple logistic regression, there was no increased risk of impaired growth among the DMPA-exposed children." The study also noted that effects of DMPA exposure on puberty require further study, as so few children over the age of 10 were observed.

Disadvantages and side effects

• Depo Provera can require up to fourteen days to take effect. This means pregnancy can occur within fourteen days of the first Depo injection.

• Takes seven days to take effect if given after the first four days of the period cycle. Effective immediately if given during the first four days of the period cycle.

• Offers no protection against Sexually transmitted diseases (STDs).

• Depo Provera can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhoea; after 2 years, the rate rises to 68%. In the first months of use "irregular or unpredictable bleeding or spotting, or rarely, heavy or continuous bleeding" was reported.

• Return to fertility may be slow. Fifty percent of women may be able to conceive in about 10 months from the last injection, but fertility may be totally suppressed in some women for up to 18 months or more.

• Long-term studies of users of Depo-Provera have found slight or no increased overall risk of breast cancer. However, the study population did show a slightly increased risk of breast cancer in recent users (Depo use in the last four years) under age 35, similar to that seen with the use of combined oral contraceptive pills.

• Infants born to women exposed to Depo during pregnancy in one study had an 80% greater chance of dying in the first year of life.

Black box warning

While it has long been known that Depo-Provera causes bone loss, it has recently been discovered that the osteoporotic effects of the injection grow worse the longer Depo-Provera is administered, may remain long after the injections are stopped, and may be irreversible. For this reason, on November 17, 2004 the United States Food and Drug Administration and Pfizer agreed to put a "black box warning" on Depo-Provera's label.However, the World Health Organization (WHO) advises that the use of Depo Provera should not be restricted

It is unclear whether the bone density loss associated with Depo-Provera use is reversible, and if so, how completely. Three studies have suggested that bone loss is reversible after the discontinuation of Depo-Provera, although one notes that bone loss was not reversible in long-term users of Depo-Provera. Other studies have suggested that the effect of Depo-Provera use on post-menopausal bone density is minimal, perhaps because Depo users experience less bone loss at menopause. However, as of 2006, no study has directly examined fracture risk in post-menopausal women who have used Depo-Provera; therefore, the risk is unknown. Pfizer and the FDA recommend that Depo-Provera not be used for longer than 2 years, unless there is no viable alternative method of contraception, due to concerns over bone loss.

Side effects

Depo-Provera may have side effects, in order of greatest frequency:  menstrual irregularities (irregular bleeding, amenorrhoea absence of bleeding or metrorrhagia constant bleeding) nausea, vomiting, headaches, dizziness, breast swelling and tenderness, depression, skin disorders (rash, hot flushes, acne, alteration hair growth), alteration in appetite, altered weight and changes in libido. Other possible associated side effects are set out in the product licensing and patient labelling with some rare but potentially serious effects being: convulsions, jaundice, urinary tract infections, allergic reactions, fainting, paralysis, osteoporosis, lack of return to fertility, deep vein thrombosis and pulmonary embolus.

Contraindications

Women with the following conditions should not use Depo Provera

• stroke

• currently pregnant

• current or past breast cancer

• liver problems or liver disease

• blood clots

Other uses

Depo-Provera is also used with male sex offenders as a form of chemical castration as it has the effect of drastically reducing sex drive in males.

Controversy over Approval of Depo-Provera

There is a long, controversial history regarding the approval of Depo Provera by the FDA. The original manufacturer, Upjohn, applied repeatedly for approval, which was repeatedly denied. Points in the controversy include:

• Animal testing for carcinogenicity. Depo Provera caused breast cancer tumors in dogs. Critics of the study claimed that dogs are more sensitive to artificial progesterone, and that the doses were too high to extrapolate to humans. The FDA pointed out that all substances carcinogenic to humans are carcinogenic to animals as well, and that if a substance is not carcinogenic it does not register as a carcinogen at high doses. Levels of Depo Provera which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal luteal phase progesterone level for dogs. (Which is lower than the pregnancy level of progesterone for dogs, and is species-specific.) Depo Provera caused endometrial cancer in monkeys—2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys. However, subsequent studies have shown that in humans, Depo Provera actually reduces the risk of endometrial cancer by approximately 80%. Speaking in comparative terms regarding animal studies of carcinogenicity for drugs, a member of the FDA's Bureau of Drugs testified at an agency Depo hearing, "...Animal data for this drug is more worrisome than any other drug we know of that is to be given to well people."

• Bias of OB-GYN committee. The OB-GYN Committee, which advised the FDA to approve Depo on the two occaisons when it was not approved, was not capable of objectivity according to senior FDA officials/a former director of the FDA bureau of drugs, because members of the committee were in "the population control business." Cervical cancer in Upjohn/NCI studies.

• Cervical cancer was found to be increased as high as 9-fold in the first human studies recorded by the manufacturer and the National Cancer Institute. However, numerous larger subsequent studies have shown that Depo Provera use does not increase the risk of cervical cancer.

• Coercion and lack of informed consent. Testing/use of Depo was focused almost exclusively on women in developing countries and poor women of color in the US, raising serious questions about coercion and lack of informed consent, particularly for the illiterate and for the mentally retarded, who in some reported cases were given Depo long-term for reasons of "menstrual hygiene", in spite of the fact that they were not sexually active.

• Atlanta/Grady Study. Upjohn studied the effect of Depo for 11 years in Atlanta, mostly on black women who were receiving public assistance, but did not file any of the required follow-up reports with the FDA. Investigators who eventually visited noted that the studies were disorganized. "They found that data collection was questionable, consent forms and protocol were absent; that those women whose consent had been obtained at all were not told of possible side effects. Women whose known medical conditions indicated that use of Depo would endanger their health were given the shot. Several of the women in the study died; some of cancer, but some for other reasons, such as suicide due to depression. Over half the 13,000 women in the study were lost to followup due to sloppy record keeping." Consequently, no data from this study was usable.

• WHO Review. In 1992, the WHO presented a review of Depo in four developing countries to the FDA. The National Women's Health Network and other women's organizations testified at the hearing that the WHO was not objective, as the WHO had already distributed Depo Provera in developing countries. Depo was approved for use in US on the basis of the WHO review of previously submitted evidence from countries such as Thailand, evidence which the FDA had deemed insufficient and too poorly designed for assessment of cancer risk at a prior hearing. The Alan Guttmacher Institute has speculated that US approval of Depo may increase its availability and acceptability in developing countries.

Aftermath

• In 1995, several women's health groups asked the FDA to put a moratorium on Depo Provera, and to institute standardized informed consent forms.

• In 1994, when Depo was approved in India, India's Economic and Political Weekly reported that "The FDA finally licensed the drug in 1990 in response to concerns about the population explosion in the third world and the reluctance of third world governments to license a drug not licensed in its originating country."  Some scientists and women's groups in India continue to oppose Depo Provera. In 2002, Depo was removed from the family planning protocol in India.

• One in five black teenagers using birth control in the US uses Depo Provera, a far higher rate of use than for white teenagers. Activists claim this is because black teenagers are disproportionately targeted for the least safe contraceptives.

• The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of Depo in Canada. Since the approval of Depo in Canada in 1997, a $700 million class-action lawsuit has been filed against Pfizer by users of Depo who developed osteoporosis. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of Depo Provera with the Canadian medical community.