Depo Provera
Encyclopedia
Depo-Provera is a branded progestogen-only contraceptive, depot medroxyprogesterone acetate (DMPA) long acting reversible
hormonal contraceptive
birth control
drug that is injected every 3 months. It is an aqueous suspension
for depot injection of the pregnane 17α-hydroxyprogesterone
-derivative progestin
medroxyprogesterone acetate.
by the FDA
for contraceptive use on 29 October 1992, <55> 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 reduces the side effects of the progestin while still maintaining all the same benefits of the original Depo shot.
and prevent ovulation
as their primary mechanism of action.
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.
A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm
penetration by changes in the cervical mucus.
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.
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%.
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%.
The first-year failure rate for 209 women using Depo-Provera in one retrospective survey was: 2.6%.
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%.
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.
The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive
use since 2008, particularly for young people; following on from the October 2005 National Institute for Health and Clinical Excellence
guidelines. Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework
"good practice" for primary care.
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.
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:
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:
, 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 these reasons, 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. 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. Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density. 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. 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.
as it has the effect of drastically reducing sex drive in males.
. 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
. Points in the controversy included:
Long Acting Reversible Contraceptive
Long-acting reversible contraceptive methods are birth control methods that provide effective contraception for an extended period of time without requiring user action.-LARC methods:Available LARC methods include:* Intrauterine device...
hormonal contraceptive
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
birth control
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
drug that is injected every 3 months. It is an aqueous suspension
Suspension (chemistry)
In chemistry, a suspension is a heterogeneous fluid containing solid particles that are sufficiently large for sedimentation. Usually they must be larger than 1 micrometer. The internal phase is dispersed throughout the external phase through mechanical agitation, with the use of certain...
for depot injection of the pregnane 17α-hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
-derivative progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
medroxyprogesterone acetate.
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 medicine must be injected into the thigh or buttocks or deltoid four times a year (every 11 to 13 weeks) and provides pregnancy protection starting a week after the first injection. It was approved in the United StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for contraceptive use on 29 October 1992, <55> and for management of endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
-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 reduces the side effects of the progestin while still maintaining all the same benefits of the original Depo shot.
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 developmentFollicular phase
The follicular phase is the phase of the estrous cycle, during which follicles in the ovary mature. It ends with ovulation. The main hormone controlling this stage is estradiol....
and prevent ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
as their primary mechanism of action.
The progestogen decreases the pulse frequency of gonadotropin-releasing hormone
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
(GnRH) release by the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, which decreases the release of follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) and luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH) by the anterior pituitary
Anterior pituitary
A major organ of the endocrine system, the anterior pituitary, also called the adenohypophysis, is the glandular, anterior lobe of the pituitary gland...
. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
levels. Progestogen negative feedback
Negative feedback
Negative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
and the lack of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
positive feedback
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
on LH release prevent a LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation.
A secondary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm
Spermatozoon
A spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
penetration by changes in the cervical mucus.
Inhibition of ovarian function during DMPA use causes the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
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
Human fertilization
Human fertilization is the union of a humanoid egg and sperm, usually occurring in the ampulla of the uterine tube. The result of this union is the production of a zygote, or fertilized egg, initiating prenatal development...
is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.
Effectiveness
The life-tableDecrement table
Decrement tables, also called life table methods, are used to calculate the probability of certain events.-Birth control:Life table methods are often used to study birth control effectiveness...
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%.
The Pearl Index
Pearl Index
The Pearl Index, also called the Pearl rate, is the most common technique used in clinical trials for reporting the effectiveness of a birth control method.-Calculation and usage:...
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%.
The first-year failure rate for 209 women using Depo-Provera in one retrospective survey was: 2.6%.
- 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
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%.- 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%.- Depo-Provera estimated typical use first-year failure rate = 0.3% in:
- Contraceptive Technology, 16th revised edition (1994)
- Contraceptive Technology, 17th revised edition (1998)
- adopted in 1998 by the FDAFood and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for its current Uniform Contraceptive Labeling guidance
- adopted in 1998 by the FDA
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%.
- Depo-Provera estimated typical use first-year failure rate = 3% in:
- Contraceptive Technology, 18th revised edition (2004)
- Contraceptive Technology, 19th revised edition (2007)
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
Norplant
Norplant is a form of birth control developed by the Population Council that was first approved in 1983 in Finland, where it was manufactured by Leiras Oy Pharmaceuticals...
implant (2.3%) and the ParaGard copper T 380A IUD
Intrauterine device
A copper IUD is a type of intrauterine device. Most IUDs have a plastic T- or U-shaped frame which is wrapped in copper wire, with the exception of Gynefix, which is a plastic string with several copper beads, affixed to the fundus of the uterus...
(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.
Benefits
Depo-Provera has several advantages:- 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 estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
. No increased risk of deep vein thrombosis (DVT)Deep vein thrombosisDeep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
, pulmonary embolism (PE)Pulmonary embolismPulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
, strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, or myocardial infarctionMyocardial infarctionMyocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. - Minimal drug interactionDrug interactionA drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s (compared to other hormonal contraceptives). - Decreased risk of endometrial cancerEndometrial cancerEndometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
. 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. - Decreased risk of iron deficiency anemiaIron deficiency anemiaIron-deficiency anemia is a common anemia that occurs when iron loss occurs, and/or the dietary intake or absorption of iron is insufficient...
, pelvic inflammatory disease (PID)Pelvic inflammatory diseasePelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
, ectopic pregnancyEctopic pregnancyAn ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...
, and uterine fibroidsUterine fibroidsA uterine fibroid is a benign tumor that originates from the smooth muscle layer and the accompanying connective tissue of the uterus.Fibroids are the most common benign tumors in...
. - Decreased symptoms of endometriosisEndometriosisEndometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
. - Decreased incidence of primary dysmenorrheaDysmenorrheaDysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...
, ovulation painMittelschmerzMittelschmerz is a medical term for "ovulation pain" or "midcycle pain". About 20% of women experience mittelschmerz, some every cycle, some intermittently.-Symptoms and diagnosis:...
, and functional ovarian cystsOvarian cystAn ovarian cyst is any collection of fluid, surrounded by a very thin wall, within an ovary. Any ovarian follicle that is larger than about two centimeters is termed an ovarian cyst. An ovarian cyst can be as small as a pea, or larger than an orange....
. - Decreased incidence of seizures in women with epilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. Additionally, unlike most other hormonal contraceptives, Depo-Provera's contraceptive effectiveness is not affected by enzyme-inducingEnzyme induction and inhibitionEnzyme induction is a process in which a molecule induces the expression of an enzyme.Enzyme inhibition can refer to* the inhibition of the expression of the enzyme by another molecule...
antiepileptic drugs. - Decreased incidence and severity of sickle cell crisesSickle-cell diseaseSickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...
in women with sickle-cell disease.
The United Kingdom Department of Health has actively promoted Long Acting Reversible Contraceptive
Long Acting Reversible Contraceptive
Long-acting reversible contraceptive methods are birth control methods that provide effective contraception for an extended period of time without requiring user action.-LARC methods:Available LARC methods include:* Intrauterine device...
use since 2008, particularly for young people; following on from the October 2005 National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
guidelines. Giving advice on these methods of contraception has been included in the 2009 Quality and Outcomes Framework
Quality and Outcomes Framework
The Quality and Outcomes Framework is a system for the performance management and payment of general practitioners in the National Health Service in England, Wales, Scotland and Northern Ireland...
"good practice" for primary care.
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.
Contraindications
The WHOWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
Medical Eligibility Criteria for Contraceptive Use and RCOG
Royal College of Obstetricians and Gynaecologists
The Royal College of Obstetricians and Gynaecologists is a professional association based in the UK. Its members, including people with and without medical degrees, work in the field of obstetrics and gynaecology, that is, pregnancy, childbirth, and female sexual and reproductive health...
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:
Conditions where the theoretical or proven risks usually outweigh the advantages of using Depo-Provera:
- Multiple risk factors for arterial cardiovascular diseaseCardiovascular diseaseHeart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
- Current deep vein thrombosis (DVT)Deep vein thrombosisDeep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
or pulmonary embolus (PE) - Migraine headache with auraAura (symptom)An aura is a perceptual disturbance experienced by some migraine sufferers before a migraine headache, and the telltale sensation experienced by some people with epilepsy before a seizure. It often manifests as the perception of a strange light, an unpleasant smell or confusing thoughts or...
while using Depo-Provera - Before evaluation of unexplained vaginal bleedingVaginal bleedingVaginal bleeding refers to bleeding in females that is either a physiologic response during the non-conceptional menstrual cycle or caused by hormonal or organic problems of the reproductive system. Vaginal bleeding may occur at any age, but always needs investigation when encountered in female...
suspected of being a serious condition - Past history of breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and no evidence of current disease for 5 years - Active liver diseaseLiver diseaseLiver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
: (acute viral hepatitisViral hepatitisViral hepatitis is liver inflammation due to a viral infection. It may present in acute or chronic forms. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E...
, severe decompensated cirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, benign or malignantHepatocellular carcinomaHepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
liver tumours) - Conditions of concern for hypo-estrogenic effects and reduced HDLHigh density lipoproteinHigh-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
levels theoretically increasing cardiovascular risk:- HypertensionHypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
with vascular diseaseVascular diseaseVascular disease is a form of cardiovascular disease primarily affecting the blood vessels.Some conditions, such as angina and myocardial ischemia, can be considered both vascular diseases and heart diseases .Cigarette smoking is the major risk factor.... - Current and history of ischemic heart disease
- History of strokeStrokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
- Diabetes for over 20 years or with nephropathyDiabetic nephropathyDiabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
/retinopathyDiabetic retinopathyDiabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
/neuropathyDiabetic neuropathyDiabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus. These conditions are thought to result from diabetic microvascular injury involving small blood vessels that supply nerves in addition to macrovascular conditions that can culminate in diabetic neuropathy...
or vascular diseaseVascular diseaseVascular disease is a form of cardiovascular disease primarily affecting the blood vessels.Some conditions, such as angina and myocardial ischemia, can be considered both vascular diseases and heart diseases .Cigarette smoking is the major risk factor....
- Hypertension
Conditions which represent an unacceptable health risk if Depo-Provera is used:
- Current or recent breast cancerBreast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
(a hormonally sensitive tumour)
Conditions where use of Depo-Provera is not indicated and should not be initiated:
- PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
Warnings and precautions
- Takes one week to take effect if given after the first five days of the period cycle. Effective immediately if given during the first five days of the period cycle.
- Offers no protection against Sexually transmitted diseases (STDs)Sexually transmitted diseaseSexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...
. - Depo-Provera can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhoeaAmenorrhoeaAmenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
; 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. - Delayed return of fertilityFertilityFertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
. 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 - 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.
- 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.
Black box warning
While it has long been known that Depo-Provera causes bone lossOsteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, 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 these reasons, on November 17, 2004 the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
and Pfizer agreed to put a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
on Depo-Provera's label.
However, the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(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. 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. Use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density. 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. However, a 2008 Committee Opinion from the American Congress of Obstetricians and Gynecologists
American Congress of Obstetricians and Gynecologists
The American Congress of Obstetricians and Gynecologists , formerly the American College of Obstetricians and Gynecologists, is a professional association of medical doctors specializing in obstetrics and gynecology in the United States. It has a membership of over 55,000 and represents 90 percent...
(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.
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), depression, hair loss and nervousness. Other, less frequently reported adverse reactions are listed in the patient and physician label information for Depo-Provera.Related studies
- A study of 819 women in one city found an association between using Depo-Provera and higher incidence of chlamydia and gonorrheaGonorrheaGonorrhea is a common sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. The usual symptoms in men are burning with urination and penile discharge. Women, on the other hand, are asymptomatic half the time or have vaginal discharge and pelvic pain...
. 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 trichomoniasisTrichomoniasisTrichomoniasis, sometimes referred to as "trich", is a common cause of vaginitis. It is a sexually transmitted disease, and is caused by the single-celled protozoan parasite Trichomonas vaginalis producing mechanical stress on host cells and then ingesting cell fragments after cell death...
and pelvic inflammatory diseasePelvic inflammatory diseasePelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
, when compared to women using no contraception. - Primate studies of medroxyprogesterone have suggested that it may increase the risk of transmission of simian immunodeficiency virusSimian immunodeficiency virusSimian immunodeficiency virus , also known as African Green Monkey virus and also as Monkey AIDS is a retrovirus able to infect at least 33 species of African primates...
(SIV), an animal model of HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
. At least one study in humans has suggested an increased rate of HIV infection in Depo-Provera users, while a number of other studies have found no such association. A large prospective clinical trial addressing the issue of Depo-Provera and HIV susceptibility is currently ongoing.
Other uses
Depo-Provera is also used with male sex offenders as a form of chemical castrationChemical castration
Chemical castration is the administration of medication designed to reduce libido and sexual activity, usually in the hope of preventing rapists, child molesters and other sex offenders from repeating their crimes...
as it has the effect of drastically reducing sex drive in males.
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 AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
. The original manufacturer, Upjohn
Upjohn
The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Kalamazoo, Michigan by Dr. William E. Upjohn, an 1875 graduate of the University of Michigan medical school. The company was originally formed to make friable pills, which were specifically designed to be easily digested...
, 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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
, Thailand
Thailand
Thailand , officially the Kingdom of Thailand , formerly known as Siam , is a country located at the centre of the Indochina peninsula and Southeast Asia. It is bordered to the north by Burma and Laos, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the...
, New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...
and Indonesia
Indonesia
Indonesia , officially the Republic of Indonesia , is a country in Southeast Asia and Oceania. Indonesia is an archipelago comprising approximately 13,000 islands. It has 33 provinces with over 238 million people, and is the world's fourth most populous country. Indonesia is a republic, with an...
. 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 phaseLuteal phaseThe luteal phase is the latter phase of the menstrual cycle or the estrous cycle . It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis...
progesterone level for dogs. (Which is lower than the pregnancy level of progesterone for dogs, and is species-specific.)http://www.inchem.org/documents/iarc/suppl7/progestins.html
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." - 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 InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
. 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 in the US, raising serious questions about coercion and lack of informed consent, particularly for the illiterate 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.
- 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 NetworkNational Women's Health NetworkThe National Women's Health Network is a non-profit women's health advocacy organization located in Washington, D.C.. It was founded in 1975 by Barbara Seaman, Alice Wolfson, Belita Cowan, Mary Howell, M.D., and Phyllis Chesler, Ph.D. The stated mission of the organization is to give women a...
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.http://db.jhuccp.org/ics-wpd/exec/icswppro.dll?AC=GET_RECORD&XC=/ics-wpd/exec/icswppro.dll&BU=http%3A%2F%2Fdb.jhuccp.org%2Fics-wpd%2Fpopweb%2Fexpert.html&TN=popline&SN=AUTO11821&SE=190&RN=0&MR=50&TR=0&TX=0&ES=0&CS=1&XP=&RF=ShortRecordDisplay&EF=&DF=LongRecordDisplay&RL=1&EL=0&DL=1&NP=0&ID=&MF=&MQ=&TI=0&DT=&ST=0&IR=128257&NR=0&NB=0&SV=0&BG=&FG=&QS=&OEX=ISO-8859-1&OEH=ISO-8859-1The Alan Guttmacher Institute has speculated that US approval of Depo may increase its availability and acceptability in developing countries.http://www.monitor.net/monitor/controlled/bc-depohearing.html
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.
- One in five black teenagers using birth control in the US uses Depo-Provera, a far higher rate of use than for white teenagers. One activist, Dorothy RobertsDorothy RobertsDorothy E. Roberts is the Kirkland & Ellis Professor at Northwestern University School of Law in Chicago, Illinois.Roberts received her Bachelor of Arts from Yale University and her Doctor of Jurisprudence from Harvard Law School. She is an author, lecturer, and lawyer...
, claims this is because black teenagers are disproportionately targeted for the least safe contraceptives.
Controversy outside of the United States
- 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.
- 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 osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of Depo-Provera with the Canadian medical community.
- Clinical trials for this drug regarding women in ZimbabweZimbabweZimbabwe is a landlocked country located in the southern part of the African continent, between the Zambezi and Limpopo rivers. It is bordered by South Africa to the south, Botswana to the southwest, Zambia and a tip of Namibia to the northwest and Mozambique to the east. Zimbabwe has three...
were controversial with regards to human rights abuses and Medical Experimentation in AfricaMedical experimentation in AfricaAfrican countries have been sites for clinical trials by large pharmaceutical companies. There have been reports of unethical experimentation and unethical clinical trials in Africa and improper informed consent methods...
.
External links
- Pfizer official site
- Research on Injectable contraceptives - Family Health International's fact sheet on injectables, including Depo-Provera.