Depot medroxyprogesterone acetate

Depo-Provera
Background
Birth control type Hormonal
First use 1967
Failure rates (first year)
Perfect use 0.2%[1]
Typical use 6%[1]
Usage
Duration effect 3 months
(12–14 weeks)
Reversibility 3–18 months
User reminders Maximum interval is just under 3 months
Clinic review 12 weeks
Advantages and disadvantages
STD protection no
Period disadvantages Especially in 1st injection may be frequent spotting
Period advantages Usually no periods from 2nd injection
Benefits Especially good if poor pill compliance.
Reduced endometrial cancer risk.
Risks Reduced bone density, which may reverse after discontinuation
Medical notes
For those intending to start family, suggest switch 6 months prior to alternative method (e.g. POP) allowing more reliable return fertility.

Depot medroxyprogesterone acetate (DMPA) is a long-acting reversible hormonal contraceptive birth control drug that is injected every three months. It is a progestin-only contraceptive. It is marketed under the brand name Depo-Provera.

It is an aqueous suspension for depot injection of the pregnane 17α-hydroxyprogesterone-derivative progestin medroxyprogesterone acetate. It is also used for chemical castration.

Effectiveness

Estimates of first-year failure rates are about 0.3%.[2]

Perfect use

Trussell's estimated perfect use first-year failure rate for Depo-Provera as the average of failure rates in seven clinical trials at 0.3%.[2][3] It was 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%.[4]

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%.[2][3]

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.[2][9][3]

Benefits

Depo-Provera has several advantages:[10][11][12][13]

The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive use since 2008, particularly for young people;[20] following on from the October 2005 National Institute for Health and Clinical Excellence guidelines.[21] Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework "good practice" for primary care.[22]

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:[23][24]

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

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

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

Side effects

Warnings and precautions

Black box warning

On November 17, 2004 the United States Food and Drug Administration put a black box warning on the label, indicating that there were potential adverse effects of loss of bone mineral density.[27][28] While it causes temporary bone loss, most women regain their bone density after discontinuing use. The World Health Organization (WHO) recommends that the use not be restricted.[29][30] The American College of Obstetricians and Gynecologists notes that the potential adverse effects on BMD be balanced against the known negative effects of unintended pregnancy using other birth control methods or no method, particularly among adolescents.

Three studies have suggested that bone loss is reversible after the discontinuation 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] Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.[36]

The FDA recommends 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] However, a 2008 Committee Opinion from the American Congress of Obstetricians and Gynecologists (ACOG) advises healthcare providers that concerns about bone mineral density loss should neither prevent the prescription of or continuation of Depo-Provera beyond 2 years of use.[37]

HIV risk

There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk, others do not.[38] The World Health Organization issued statements in February 2012 and July 2014 saying the data did not warrant changing their recommendation of no restriction—Medical Eligibility for Contraception (MEC) category 1—on the use of DMPA in women at high risk for HIV.[39][40]

Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015.[41] They found a 1.4 to 1.5 fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use.[42][43] In January 2015, the Faculty of Sexual & Reproductive Healthcare of the Royal College of Obstetricians and Gynaecologists issued a statement reaffirming that there is no reason to advise against use of DMPA in the United Kingdom even for women at 'high risk' of HIV infection.[44]

A large, four-year randomized controlled trial of hormonal contraception and HIV in sub-Saharan Africa (to provide better evidence than currently available observational studies) that is planned to begin in 2015[45] has been controversial.[46][47][48][49][50]

Pregnancy and breastfeeding

The steroid hormone Progesterone is produced in increasingly larger amounts over the course of a pregnancy. The main ingredient in Depo-Provera, medroxyprogesterone acetate, is similar to Progesterone USP but does not support pregnancy. Women who learn they are pregnant should discontinue use of Depo-Provera and visit with her doctor for appropriate health care.

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.[51]

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.[52]

Other uses

Depo-Provera is also used with male sex offenders as a form of chemical castration as it has the effect of reducing sex drive in males.[53]

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.[54][55] 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.[10][11]

A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration by changes in the cervical mucus.[56]

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.[56]

Society and culture

Commercial products

Depo-Provera is the brand name for a 150 mg aqueous injection of DMPA depot medroxyprogesterone acetate. It is applied in the form of an intramuscular injection. The shot must be injected into the thigh or buttocks or deltoid four times a year (every 11 to 13 weeks) and provides pregnancy protection instantaneously after the first injection.[57] It was approved in the United States by the FDA for contraceptive use on 29 October 1992,[58] and for management of endometriosis-related pain on 25 March 2005. Depo-subQ Provera 104, also manufactured by Pfizer, is a variation of the original Depo Shot that is instead a 104 mg subcutaneous injection. It contains 69 percent of progestin found in the original Depo-Provera shot. This can be injected using a smaller injection needle inserting the hormone just below the skin, instead of into the muscle, in either the abdomen or thigh. This subcutaneous injection claims to reduce the side effects of the progestin while still maintaining all the same benefits of the original Depo shot.

Controversy

Outside the United States

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.[58] Points in the controversy included:

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