Depo-Provera

Depot medroxyprogesterone acetate (DMPA) is a progestogen-only hormonal contraceptive birth control drug which is injected every 3 months.

Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension for depot injection of the pregnane 17α-hydroxyprogesterone-derivative progestin medroxyprogesterone acetate.

Depo-Provera Contraceptive Injection is the brand name for a 150 mg aqueous suspension of medroxyprogesterone acetate for depot intramuscular injection every 3 months (12–13 weeks) manufactured by Pfizer.

depo-subQ provera 104 is the brand name for a 104 mg aqueous suspension of medroxyprogesterone acetate for depot subcutaneous injection every 3 months (12–14 weeks) manufactured by Pfizer.

depo-subQ provera 104 was approved in the United States by the FDA for contraceptive use on December 17, 2004, and for management of endometriosis-related pain on March 25, 2005.

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Mechanism of action

The mechanism of action of progestogen-only contraceptives depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as injectable DMPA, inhibit follicular development and prevent ovulation as their primary mechanism of action.^[1][2]

The progestogen decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.^[3][4]

A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.^[5]

Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophic. These changes in the endometrium could, theoretically, prevent implantation. However, because DMPA is highly effective in inhibiting ovulation and sperm penetration, the possibility of fertilization is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.^[5]

Effectiveness

The life-table first-year failure rates for 8,183 women using Depo-Provera in seven prospective clinical trials were: 0%, 0%, 0.1%, 0.2%, 0.2%, 0.3%, and 0.7%, with a weighted average of 0.3%.^[6]

The Pearl Index first-year failure rates for 2,042 women using depo-subQ 104 in three prospective clinical trials were: 0%, 0%, and 0%, with a weighted average of 0%.^[7]

The first-year failure rate for 209 women using Depo-Provera in one retrospective survey was: 2.6%.^[8][9]

• the 1995 National Survey of Family Growth (NSFG) — a retrospective survey based on a woman's recall, during a 90-minute interview, of her month-by-month contraceptive use during the preceding 4 to 5 years^[8][10]

Perfect use

Trussell's estimated perfect use first-year failure rate for Depo-Provera is the weighted average of failure rates in seven clinical trials: 0.3%.^[6][11]

• considered perfect use because the clinical trials measured efficacy during actual use of Depo-Provera
  • defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection)

Typical use

Prior to 2004, Trussell's typical use failure rate for Depo-Provera was the same as his perfect use failure rate: 0.3%.^[12]

• Depo-Provera estimated typical use first-year failure rate = 0.3% in:
  • Contraceptive Technology, 16th revised edition (1994)^[13]
  • Contraceptive Technology, 17th revised edition (1998)^[14]
    • adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance^[15]

In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for Depo-Provera from 0.3% to 3%.^[6][11]

• Depo-Provera estimated typical use first-year failure rate = 3% in:
  • Contraceptive Technology, 18th revised edition (2004)^[6]
  • Contraceptive Technology, 19th revised edition (2007)^[16]

Trussell did not use 1995 NSFG failure rates as typical use failure rates for the other two then newly available long-acting contraceptives, the Norplant implant (2.3%) and the ParaGard copper T 380A IUD (3.7%), which were (as with Depo-Provera) an order of magnitude higher than in clinical trials. Since Norplant and ParaGard allow no scope for user error, their much higher 1995 NSFG failure rates were attributed by Trussell to contraceptive overreporting at the time of a conception leading to a live birth.^[6][9][11]

Benefits

Depo-Provera has several advantages:^{[3][4][17][18]}

• Highly effective at preventing pregnancy.
• Injected every 12 weeks. The only continuing action is to book subsequent follow-up injections every twelve weeks, and to monitor side effects to ensure that they do not require medical attention.
• No estrogen. No increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction.
• Culturally acceptable. Some cultures believe injections are especially efficacious. Injections also afford privacy because use is not detectable.
• Minimal drug interactions (compared to other hormonal contraceptives).
• Decreased risk of endometrial cancer. Depo-Provera reduces the risk of endometrial cancer by 80%.^[19][20][21] 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.^[22]
• Decreased risk of iron deficiency anemia, pelvic inflammatory disease (PID), ectopic pregnancy, and uterine fibroids.
• Decreased symptoms of endometriosis.
• Decreased incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts.
• Decreased incidence of seizures in women with epilepsy. Additionally, unlike most other hormonal contraceptives, Depo-Provera's contraceptive effectiveness is not affected by enzyme-inducing antiepileptic drugs.^[23]
• Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.^[17]

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.^[24]

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.^[25]

Disadvantages and side effects

Warnings and precautions

• 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.^[26]
• Delayed return of fertility. The average return to fertility is 9 to 10 months after the last injection. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods^[3][4]
• 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.^[26]
• A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to Depo-Provera during pregnancy had a higher risk of low birth weight and an 80% greater-than-usual chance of dying in the first year of life.^[27]

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.^[28] However, the World Health Organization (WHO) advises that the use of Depo-Provera should not be restricted.^[29][30]

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.^[31][32][33] Other studies have suggested that the effect of Depo-Provera use on post-menopausal bone density is minimal,^[34] perhaps because Depo users experience less bone loss at menopause.^[35] 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.^[28]

Side effects

In the largest clinical trial of Depo-Provera, the most frequently reported adverse reactions (which may or may not be related to the use of Depo-Provera) were: menstrual irregularities (bleeding or amenorrhea or both), abdominal pain or discomfort, weight changes, headache, asthenia (weakness or fatigue), and nervousness. Other, less frequently reported adverse reactions are listed in the patient and physician label information for Depo-Provera.^[26][36]

Related studies

• A study of 819 women in one city found an association between using Depo-Provera and higher incidence of chlamydia and gonorrhea.^[37] A second prospective study in 948 Kenyan women found that Depo-Provera use was associated with higher rates of chlamydial infection, but lower rates of trichomoniasis and pelvic inflammatory disease, when compared to women using no contraception.^[38]
• Primate studies of medroxyprogesterone have suggested that it may increase the risk of transmission of simian immunodeficiency virus (SIV), an animal model of HIV.^[39][40] At least one study in humans has suggested an increased rate of HIV infection in Depo-Provera users,^[41] while a number of other studies have found no such association.^[42][43][44] A large prospective clinical trial addressing the issue of Depo-Provera and HIV susceptibility is currently ongoing.^[45]

Contraindications

The WHO Medical Eligibility Criteria for Contraceptive Use and RCOG Faculty of Family Planning & Reproductive Health Care (FFPRHC) UK Medical Eligibility Criteria for Contraceptive Use list the following as conditions where use of Depo-Provera is not usually recommended or should not be used because of an unacceptable health risk or because it is not indicated:^[46][47]

Conditions where the theoretical or proven risks usually outweigh the advantages of using Depo-Provera:

• Multiple risk factors for arterial cardiovascular disease
• Current deep vein thrombosis (DVT) or pulmonary embolus (PE)
• Migraine headache with aura while using Depo-Provera
• Before evaluation of unexplained vaginal bleeding suspected of being a serious condition
• Past history of breast cancer and no evidence of current disease for 5 years
• Active liver disease: (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumours)
• Conditions of concern for hypo-estrogenic effects and reduced HDL levels theoretically increasing cardiovascular risk:
  • Hypertension with vascular disease
  • Current and history of ischemic heart disease
  • History of stroke
  • Diabetes for > 20 years or with nephropathy/retinopathy/neuropathy or vascular disease

Conditions which represent an unacceptable health risk if Depo-Provera is used:

• Current or recent breast cancer (a hormonally sensitive tumour)

Conditions where use of Depo-Provera is not indicated and should not be initiated:

• Pregnancy

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.[1]

Controversy over Approval of Depo-Provera in the United States

There was a long, controversial history regarding the approval of Depo-Provera by the U.S. Food and Drug Administration. The original manufacturer, Upjohn, applied repeatedly for approval. FDA advisory committees unanimously recommended approval in 1973, 1975 and 1992, as did the FDA's professional medical staff, but the FDA repeatedly denied approval. Ultimately, on October 29 1992, the FDA approved Depo-Provera, which had by then been used by over 30 million women since 1969 and was approved and being used by nearly 9 million women in more than 90 countries, including the United Kingdom, France, Germany, Sweden, Thailand, New Zealand and Indonesia.^[48] Points in the controversy included:

• 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.)[2]
  Depo-Provera caused endometrial cancer in monkeys—2 of 12 monkeys tested, the first ever recorded cases of endometrial cancer in rhesus monkeys.^[49] However, subsequent studies have shown that in humans, Depo-Provera actually reduces the risk of endometrial cancer by approximately 80%.^[19][20][21]
  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."
• 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.^[50] However, numerous larger subsequent studies have shown that Depo-Provera use does not increase the risk of cervical cancer.^{[51][52][53][54][55]}
• 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,^[56] raising serious questions about coercion and lack of informed consent, particularly for the illiterate^[57] and for the mentally challenged, 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.^[58]
• 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.^[56]
• 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.[3]The Alan Guttmacher Institute has speculated that US approval of Depo may increase its availability and acceptability in developing countries.[4]^[59]

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.^[60]
• 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." ^[61] Some scientists and women's groups in India continue to oppose Depo-Provera.^[62] In 2002, Depo was removed from the family planning protocol in India.^{[citation needed]}
• 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.^[63]
• The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of Depo in Canada.^[64] 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.^[65]