|Trade names||Provera, Depo-Provera, Depo-SubQ Provera 104, Curretab, Cycrin, Farlutal, Gestapuran, Perlutex, Veramix, others|
|by mouth, intramuscular, subcutaneous|
|Protein binding||88% (to albumin)|
|Biological half-life||By mouth: 12–33 hours
I.M.: ~50 days
S.C.: ~40 days
|Chemical and physical data|
|Molar mass||386.52 g/mol|
|3D model (Jmol)|
Medroxyprogesterone acetate (MPA), sold under the brand name Depo-Provera among others, is a manufactured hormone of the progestin type. It is used as birth control and as part of hormone replacement therapy for menopausal symptoms. It is also used to treat endometriosis, abnormal uterine bleeding, abnormal sexuality in males, and certain types of cancer. It is used by mouth or injection into a muscle or under the skin
Common side effects include no periods, abdominal pain, headaches, and anxiety. Other serious side effects include bone loss, blood clots, allergic reactions, depression, and liver problems. Use is not recommended during pregnancy as it may harm the baby. It works by decreasing the body's release of gonadotropins.
Medroxyprogesterone acetate was patented and came into medical use in 1958. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 0.59 to 1.57 USD per vial. In the United Kingdom this dose costs the NHS about 6.01 pounds. In the United States it costs less than 25 USD a dose as of 2015.
- 1 Medical uses
- 2 Contraindications
- 3 Side effects
- 4 Breastfeeding
- 5 Mechanism of action
- 6 Interactions
- 7 Pharmacodynamics
- 7.1 Steroid hormone receptor agonist
- 7.2 Steroidogenesis inhibitor
- 7.3 GABAA receptor allosteric modulator
- 7.4 Appetite stimulant
- 8 Pharmacokinetics
- 9 Chemistry
- 10 History
- 11 Society and culture
- 12 See also
- 13 References
In females, the most common use of MPA is as an oral or depot-injected contraceptive and also as the progestin component of menopausal hormone replacement therapy to prevent endometrial hyperplasia and cancer. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea. MPA, along with other progestins were developed to allow the hormones to be taken orally, as progesterone (the hormone made by the human body) could not be taken orally before the process of micronization was developed.
MPA is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. It has also been used to treat benign prostatic hyperplasia, as a palliative appetite stimulant for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancers of primarily the breast, but also other types.
Though not used as a treatment for epilepsy, MPA has been found to reduce the frequency of seizures and does not interact with anti-epileptic medications. MPA does not interfere with blood clotting and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis and chronic active hepatitis. Women taking MPA may experience spotting shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhoea can occur as can irregular menstruation which is a major source of dissatisfaction, though both can result in improvements with iron deficiency and risk of pelvic inflammatory disease and often do not result in discontinuing the medication. MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia in post-menopausal women who are undergoing hormone replacement therapy.[needs update]
|Medroxyprogesterone acetate by injection|
|Failure rates (first year)|
|Duration effect||3 months
|User reminders||Maximum interval is just under 3 months|
|Advantages and disadvantages|
|Period disadvantages||Especially in first 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|
|For those intending to start family, suggest switch 6 months prior to alternative method (e.g. POP) allowing more reliable return fertility.|
Estimates of first-year failure rates are about 0.3%.
Trussell's estimated perfect use first-year failure rate for medroxyprogesterone acetate by injection as the average of failure rates in seven clinical trials at 0.3%. It was considered perfect use because the clinical trials measured efficacy during actual use of medroxyprogesterone acetate 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).
Prior to 2004, Trussell's typical use failure rate for medroxyprogesterone acetate by injection was the same as his perfect use failure rate: 0.3%.
- medroxyprogesterone acetate by injection estimated typical use first-year failure rate = 0.3% in:
- Depo-Provera estimated typical use first-year failure rate = 3% in:
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 medroxyprogesterone acetate by injection) 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.
- 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.
- Minimal drug interactions (compared to other hormonal contraceptives).
- Decreased risk of endometrial cancer. 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 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.
- Decreased incidence and severity of sickle cell crises in women with sickle-cell disease.
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.
Comparison with progesterone
Proponents of bioidentical hormone replacement therapy believe that progesterone offers fewer side effects and improved quality of life compared to MPA. The evidence for this view has been questioned; MPA is better absorbed when taken by mouth, with a much longer terminal half-life leading to more stable blood levels though it may lead to greater breast tenderness and more sporadic vaginal bleeding. The two compounds do not differentiate in their ability to suppress endometrial hyperplasia, nor does either increase the risk of pulmonary embolism. The two drugs have not been adequately compared in direct tests to clear conclusions about safety and superiority.
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
- A history of breast cancer and no evidence of current disease for five 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:
Conditions which represent an unacceptable health risk if Depo-Provera is used:
- Current or recent breast cancer (a hormonally sensitive tumour)
Conditions where use is not indicated and should not be initiated:
In females, the most common adverse effects are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.
The Women's Health Initiative investigated the use of MPA and conjugated equine estrogens compared to placebo. The study was prematurely terminated when previously unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of the hormone replacement therapy (reduced risk of hip fracture, colorectal and endometrial cancer and all other causes of death) were offset by increased risk of coronary heart disease, breast cancer, strokes and pulmonary embolism. However, the study focused on MPA only and extrapolated the benefits versus risks to all synthetic progesterones—a conclusion that has been challenged by several researchers as unjustified and leading to unnecessary avoidance of HRT for many women as synthetic progesterones are not alike.
At high doses for the treatment of breast cancer, MPA can cause weight gain, worsen diabetes mellitus and edema (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis (though it is not clear if this is truly a risk, it cannot be ruled out), painful urination, anxiety, headache, nausea and vomiting. When used to treat benign prostatic hyperplasia, more frequent complaints include reduced libido, impotence, reduced ejaculate volume, and within three days, chemical castration. MPA may cause reduced bone density though this appears to be reversible to a normal level even after years of use. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression and interfere with carbohydrate metabolism but does not cause diabetes.
Fetuses exposed to progesterones have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic pregnancy particularly when MPA is used as an injected form of long-term birth control. When used as a form of injected birth control, MPA can reduce fertility for as long as 10 months, taking longer for overweight or obese women. When combined with conjugated equine estrogens (Premarin), MPA has been associated with an increased risk of breast cancer, dementia and thrombus in the eye. In combination with estrogens in general, MPA may increase the risk of cardiovascular disease, with a stronger association when used by post-menopausal women also taking CEE. MPA is not recommended for use prior to menarche or before or during recovery from surgery. It was because of these unexpected interactions that the Women's Health Initiative study was ended early due the extra risks of hormone replacement therapy, producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.
- 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).
- Depo-Provera can affect menstrual bleeding. After a year of use, 55% of women experience amenorrhoea (missed periods); 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 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
- 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
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. 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. 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. Other studies have suggested that the effect of medroxyprogesterone acetate by injection 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.
The FDA recommends that medroxyprogesterone acetate by injection 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 medroxyprogesterone acetate by injection beyond 2 years of use.
There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk, others do not. 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.
Two meta-analyses of observational studies in sub-Saharan Africa were published in January 2015. They found a 1.4 to 1.5 fold increase risk of HIV acquisition for DMPA users relative to no hormonal contraceptive use. 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.
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 has been controversial.
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.
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. 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.
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.
MPA increases the risk of breast cancer, dementia and thrombus when used in combination with conjugated equine estrogens to treat the symptoms of menopause. When used as a contraceptive, MPA does not generally interact with other drugs. When combined with aminoglutethimide to treat metastases from breast cancer, MPA is associated with an increase in depression. St John's wort may decrease its effectiveness as a contraceptive.
Steroid hormone receptor agonist
MPA acts as an agonist of the progesterone, androgen, and glucocorticoid receptors (PR, AR, and GR, respectively), activating these receptors with EC50 values of approximately 0.01 nM, 1 nM, and 10 nM, respectively. It has negligible affinity for the estrogen receptor. The drug has relatively high affinity for the mineralocorticoid receptor, but in spite of this, it has no mineralocorticoid or antimineralocorticoid activity. The intrinsic activities of MPA in activating the PR and the AR have been reported to be at least equivalent to those of progesterone and dihydrotestosterone (DHT), respectively, indicating that it is a full agonist of these receptors.
||PR (%)||AR (%)||ER (%)||GR (%)||MR (%)|
|PR (promegestone = 100%), AR (metribolone = 100%), ER (E2 = 100%), GR (DEXA = 100%), MR (aldosterone = 100%)|
MPA is a potent agonist of the progesterone receptor with similar affinity and efficacy relative to progesterone. While both MPA and its deacetylated analogue medroxyprogesterone bind to and agonize the PR, MPA has approximately 100-fold higher binding affinity and transactivation potency in comparison. As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in veterinary medicine.
|Ligand||PR Ki||Coactivator recruitment EC50||Reporter cell line EC50|
|Progesterone||4.3 ± 1.0 nM||0.9 ± 0.2 nM||25 ± 11 nM|
|Medroxyprogesterone||241 ± 96 nM||47 ± 14 nM||32 ± 1 nM|
|Medroxyprogesterone acetate||1.2 ± 0.3 nM||0.6 ± 0.08 nM||0.15 ± 0.03 nM|
The oral dosage of MPA required to inhibit ovulation (i.e., the effective contraceptive dosage) is 10 mg/day, whereas 5 mg/day was not sufficient to inhibit ovulation in all women. In accordance, the dosage of MPA used in oral contraceptives in the past was 10 mg per tablet. For comparison to MPA, the dosage of progesterone required to inhibit ovulation is 300 mg/day, whereas that of the 19-nortestosterone derivatives norethisterone and norethisterone acetate is only 0.4–0.5 mg/day.
|OID = ovulation-inhibiting dosage (without additional estrogen); TFD = endometrial transformation dosage;
ODP = oral dosage in commercial contraceptive preparations; ECD = estimated comparable dosage
In addition to its direct effects on steroid receptors, MPA, at sufficient doses, inhibits the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes, resulting in a marked suppression of gonadotropin, androgen, estrogen, adrenocorticotropic hormone (ACTH), and cortisol levels as well as concentrations of sex hormone-binding globulin (SHBG). There is evidence that the downregulatory effects of MPA on the HPG axis are mediated by activation of both PRs and ARs in the pituitary gland. Due to its effects on androgen levels, MPA has strong functional antiandrogen properties, and it is used in androgen-sensitive conditions such as precocious puberty in prepubescent boys and hypersexuality in men. In addition, since it affects estrogen levels similarly, unlike many other antiandrogens such as spironolactone and cyproterone acetate which have a high propensity for causing gynecomastia via indirect stimulation of estrogen, MPA is not thought to possess any estrogenic effects. Indeed, due to its inhibitory effects on estrogen levels, it has potent antiestrogenic effects, and has been used to treat precocious puberty in prepubescent girls. Accordingly, MPA should not be used in high doses without an estrogen in women due to the risk of osteoporosis and other symptoms associated with hypoestrogenism.
MPA is a potent full agonist of the AR. Its activation of the AR has been shown to play an important and major role in its antigonadotropic effects and in its beneficial effects against breast cancer. However, although MPA does have the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women), it seldom actually does so, and when it does, the effects tend to be only mild, regardless of the dosage used. In fact, likely due to its suppressive actions on androgen levels, it has been reported that MPA is generally highly effective in improving pre-existing symptoms of hirsutism in women with the condition. Moreover, MPA rarely causes any androgenic effects in children with precocious puberty, even at very high doses. The reason for the general lack of virilizing effects with MPA, despite it binding to and activating the AR with a high affinity and this action playing an important role in many of its physiological and therapeutic effects, is not entirely clear. However, MPA has been found to interact with the AR in a fundamentally different way than other agonists of the receptor such as dihydrotestosterone (DHT). The result of this difference appears to be that MPA binds to the AR with a similar affinity and intrinsic activity to that of DHT, but requires about 100-fold higher concentrations for a comparable induction of gene transcription, while at the same time not antagonizing the transcriptional activity of normal androgens like DHT at any concentration. Thus, this may explain the low propensity of MPA for producing androgenic side effects.
MPA has been found to act as a competitive inhibitor of rat 3α-hydroxysteroid dehydrogenase (3α-HSD). This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol, respectively. MPA is described as extremely potent in its inhibition of rat 3α-HSD, with an IC50 of 0.2 μM and a Ki (in rat testicular homogenates) of 0.42 μM. Inhibitory neurosteroids have antidepressant and anxiolytic effects, and the blockade of their production could be causative of the symptoms of depression, anxiety, and irritability that have been associated with MPA treatment. Indeed, other drugs that are known to block the synthesis of these neurosteroids, such as 5α-reductase inhibitors like finasteride and dutasteride, have also been associated with symptoms of depression and anxiety. However, it should be noted that inhibition of 3α-HSD by MPA does not appear to have been confirmed yet using human proteins, and the concentrations required with rat proteins are far above typical human therapeutic concentrations.
MPA has been identified as a competitive inhibitor of human 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase II (3β-HSDII). This enzyme is essential for the biosynthesis of sex steroids and corticosteroids. The Ki of MPA for inhibition of 3β-HSDII is 3.0 μM, and this concentration is reportedly near the circulating levels of the drug that are achieved by very high therapeutic dosages of MPA of 5 to 20 mg/kg/day (dosages of 300 to 1,200 mg/day for a 60 kg (132 lb) person). Aside from 3β-HSDII, other human steroidogenic enzymes, including cholesterol side-chain cleavage enzyme (P450scc/CYP11A1) and 17α-hydroxylase/17,20-lyase (CYP17A1), were not found to be inhibited by MPA. MPA has been found to be effective in the treatment of gonadotropin-independent precocious puberty and in breast cancer in postmenopausal women at high dosages, and inhibition of 3β-HSDII could be responsible for its effectiveness in these conditions.
GABAA receptor allosteric modulator
Progesterone, via transformation into neurosteroids such as 5α-dihydroprogesterone, 5β-dihydroprogesterone, allopregnanolone, and pregnanolone (catalyzed by the enzymes 5α- and 5β-reductase and 3α- and 3β-HSD), is a positive allosteric modulator of the GABAA receptor, and is associated with a variety of effects mediated by this property including dizziness, sedation, hypnotic states, mood changes, anxiolysis, and cognitive/memory impairment, as well as effectiveness as an anticonvulsant in the treatment of catamenial epilepsy. It has also been found to produce anesthesia via this action in animals when administered at sufficiently high dosages. MPA was found to significantly reduce seizure incidence when added to existing anticonvulsant regimens in 11 of 14 women with uncontrolled epilepsy, and has also been reported to induce anesthesia in animals, raising the possibility that it may modulate the GABAA receptor similarly to progesterone.
MPA shares some of the same metabolic routes of progesterone and, analogously, can be transformed into metabolites such as 5α-dihydro-MPA (DHMPA) and 3α,5α-tetrahydro-MPA (THMPA). However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor. Conversely, unlike progesterone, MPA itself actually modulates the GABAA receptor, although notably not at the neurosteroid binding site, but rather than act as a potentiator of the receptor, MPA appears to act as a negative allosteric modulator. Whereas the reduced metabolites of progesterone enhance binding of the benzodiazepine flunitrazepam to the GABAA receptor in vitro, MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 μM. However, the concentrations of MPA required for inhibition are high relative to therapeutic concentrations, and hence, this action is probably of little or no clinical relevance. The lack of potentiation of the GABAA receptor by MPA or its metabolites is surprising in consideration of the apparent anticonvulsant and anesthetic effects of MPA described above, and they remain unexplained.
Clinical studies using massive dosages of up to 5,000 mg/day oral MPA and 2,000 mg/day intramuscular MPA for 30 days in women with advanced breast cancer have reported "no relevant side effects", which suggests that MPA has no meaningful direct action on the GABAA receptor in humans even at extremely high dosages.
Although MPA and the closely related drug megestrol acetate are effective appetite stimulants at very high dosages, the mechanism of action of their beneficial effects on appetite is not entirely clear. However, glucocorticoid, cytokine, and possibly anabolic-related mechanisms are all thought to possibly be involved, and a number of downstream changes have been implicated, including stimulation of the release of neuropeptide Y in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus, and inhibition of the secretion of proinflammatory cytokines including IL-1α, IL-1β, IL-6, and TNF-α, actions that have all been linked to an increase in appetite.
The oral bioavailability of MPA is 100%. Treatment of postmenopausal women with 2.5 or 5 mg/day MPA in combination with estradiol valerate for two weeks has been found to rapidly increase circulating MPA levels, with steady-state concentrations achieved after three days and peak concentrations occurring 1.5 to 2 hours after ingestion. With 2.5 mg/day MPA, levels of the drug were 0.3 ng/mL (0.8 nmol/L) in women under 60 years of age and 0.45 ng/mL (1.2 nmol/L) in women 60 years of age or over, and with 5 mg/day MPA, levels were 0.6 ng/mL (1.6 nmol/L) and 0.9 ng/mL (2.3 nmol/L), respectively. With intramuscular administration of a 150 mg dose of MPA, the drug is detectable in the circulation within 30 minutes, serum concentrations vary but generally plateau at 1.0 ng/mL (2.6 nmol/L) for 3 months. Following this, there is a gradual decline in MPA levels, and the drug can be detected in the circulation for as long as nine months post-injection.
The terminal half-life of MPA via oral administration has been reported as both 11.6–16.6 hours and 33 hours, whereas the terminal half-lives with intramuscular and subcutaneous injection are 50 and 40 days, respectively. The metabolism of MPA is mainly via hydroxylation, such as of positions C6β and C21, but 3- and 5-dihydro and 3,5-tetrahydro metabolites of MPA are also formed. Deacetylation of MPA and its metabolites (into, e.g., medroxyprogesterone) has been observed to occur in non-human primate research to a substantial extent as well (30 to 70%). MPA and/or its metabolites are also metabolized via conjugation.
Relation to clinical effects
With intramuscular administration, the high levels of MPA in the blood inhibit luteinizing hormone and ovulation for several months, with an accompanying decrease in serum progesterone to below 0.4 ng/mL. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/mL. Serum estradiol remains at approximately 50 pg/mL for approximately four months post-injection (with a range of 10–92 pg/mL after several years of use), rising once MPA levels fall below 0.5 ng/mL.
Hot flashes are rare while MPA is found at significant blood levels in the body, and the vaginal lining remains moist and creased. The endometrium undergoes atrophy, with small, straight glands and a stroma that is decidualized. Cervical mucus remains viscous. Because of its steady blood levels over the long term and multiple effects that prevent fertilisation, MPA is a very effective means of birth control.
MPA is a pregnane (C21) steroid and a derivative of 17α-hydroxyprogesterone. Specifically, it is the 17α-acetate ester of medroxyprogesterone or the 6α-methylated analogue of hydroxyprogesterone acetate. MPA is known chemically as 6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-en-3,20-dione, and its generic name is a contraction of 6α-methyl-17α-hydroxyprogesterone acetate. MPA is closely related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, cyproterone acetate, and megestrol acetate, as well as to medrogestone and nomegestrol acetate.
MPA was independently discovered in 1956 by Syntex and the Upjohn Company. It was first introduced on 18 June 1959 by Upjohn in the United States under the brand name Provera (2.5, 5, and 10 mg tablets) for the treatment of amenorrhea, metrorrhagia, and recurrent miscarriage. An intramuscular formulation, Depo-Provera (400 mg/mL MPA), was also introduced in 1960 in the U.S. for the treatment of endometrial and renal cancer. MPA in combination with ethinylestradiol was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinylestradiol tablets) as an oral contraceptive, but this formulation was discontinued in 1970. This formulation was marketed by Upjohn outside of the U.S. under the brand names Provestral and Provestrol, while Cyclo-Farlutal (or Ciclofarlutal) and Nogest-S were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets). Upjohn also sought FDA approval of intramuscular MPA as a long-acting contraceptive under the brand name Depo-Provera (150 mg/mL MPA) but the applications were rejected in 1967, 1978, and yet again in 1983. However, in 1992, the drug was finally approved by the FDA for this indication. A subcutaneous formulation was introduced in the U.S. under the brand name Depo-SubQ Provera 104 (104 mg/0.65 mL MPA) in December 2004 as a contraceptive, and subsequently was also approved for the treatment of endometriosis-related pelvic pain. MPA has also been marketed widely throughout the rest of the world as Provera and Depo-Provera as well as Farlutal, Perlutex, and Gestapuran, among many other brand names.
Society and culture
- Oral pills: Amen, Curretab, Cycrin, Provera – 2.5 mg, 5 mg, 10 mg
- Aqueous suspension for intramuscular injection: Depo-Provera – 150 mg/mL (for contraception), 400 mg/mL (for cancer)
- Aqueous suspension for subcutaneous injection: Depo-SubQ Provera 104 – 104 mg/0.65 mL
It is also available in combination with estrogen in the following formulations:
- Oral pills: conjugated estrogens and MPA (Premphase (Premarin, Cycrin 14/14), Premphase 14/14, Prempro, Prempro (Premarin, Cycrin), Prempro/Premphase) – 0.3 mg / 1.5 mg; 0.45 mg / 1.5 mg; 0.625 mg / 2.5 mg; 0.625 mg / 5 mg
- Oral pills: ethinylestradiol and MPA (Provest) – 50 μg / 10 mg
- Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) – 5 mg / 25 mg
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. It was approved in the United States by the FDA for contraceptive use on 29 October 1992, 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.
Outside 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 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.
- Clinical trials for this drug regarding women in Zimbabwe were controversial with regard to human rights abuses and Medical Experimentation in Africa.
- A controversy erupted in Israel when the government was accused of giving Depo-Provera to Ethiopian immigrants without their consent. Some women claimed they were told it was a vaccination. The Israeli government denied the accusations but instructed the four health maintenance organizations to stop administering Depo-Provera injections to women "if there is the slightest doubt that they have not understood the implications of the treatment".
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. 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. This 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 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 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 or 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", although 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.
- In 1995, several women's health groups asked the FDA to put a moratorium on Depo-Provera, and to institute standardized informed consent forms.
- Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 638–. ISBN 978-3-88763-075-1.
- Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (2008). "Classification and pharmacology of progestins". Maturitas. 61 (1–2): 171–80. doi:10.1016/j.maturitas.2008.11.013. PMID 19434889.
- "Provera" (PDF). FDA. 2007. Retrieved 23 December 2016.
- Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration". Climacteric. 8 Suppl 1: 3–63. doi:10.1080/13697130500148875. PMID 16112947.
- "Depo_Provera" (PDF). FDA. 2002. Retrieved 23 December 2016.
- "depo-subQ Provera" (PDF). FDA. 2009. Retrieved 23 December 2016.
- Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. p. 657. ISBN 978-1-4757-2085-3.
- "Medroxyprogesterone Acetate". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
- Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 478. ISBN 978-3-527-60749-5.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
- "Medroxyprogesterone Acetate". International Drug Price Indicator Guide. Retrieved 8 December 2016.
- British National Formulary : BNF 69 (69th ed.). British Medical Association. 2015. p. 555. ISBN 978-0-85711-156-2.
- Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 363. ISBN 9781284057560.
- "Medroxyprogesterone". MedlinePlus. 2008-01-09. Retrieved 2010-07-02.
- Panay N, Fenton A (February 2010). "Bioidentical hormones: what is all the hype about?". Climacteric. 13 (1): 1–3. doi:10.3109/13697130903550250. PMID 20067429.
- Light SA, Holroyd S (March 2006). "The use of medroxyprogesterone acetate for the treatment of sexually inappropriate behaviour in patients with dementia" (PDF). Journal of Psychiatry & Neuroscience. 31 (2): 132–4. PMC . PMID 16575429.
- Meyler L (2009). Meyler's side effects of endocrine and metabolic drugs. Amsterdam: Elsevier Science. pp. 281–284]. ISBN 0-444-53271-4.
- Furness S, Roberts H, Marjoribanks J, Lethaby A, Hickey M, Farquhar C (April 2009). "Hormone therapy in postmenopausal women and risk of endometrial hyperplasia". The Cochrane Database of Systematic Reviews (2): CD000402. doi:10.1002/14651858.CD000402.pub3. PMID 19370558.
- Trussell J (2011). "Contraceptive efficacy". In Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar MS. Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 779–863. ISBN 978-1-59708-004-0. OCLC 781956734. Table 26–1 =
- Trussell J (2004). "Contraceptive Efficacy". In Hatcher RA, Trussell J, Stewart FH, Nelson AL, Cates Jr W, Guest F, Kowal D. Contraceptive Technology (18th rev. ed.). New York: Ardent Media. pp. 773–845. ISBN 0-9664902-5-8.
- Trussell J (August 2004). "Contraceptive failure in the United States". Contraception. 70 (2): 89–96. doi:10.1016/j.contraception.2004.03.009. PMID 15288211.
- Trussell J, Hatcher RA, Cates W, Stewart FH, Kost K (September 1990). "A guide to interpreting contraceptive efficacy studies". Obstetrics and Gynecology. 76 (3 Pt 2): 558–67. PMID 2199875.
- Trussell J (1994). "Contraceptive Failure Rates". In Hatcher RA, Trussell J, Stewart F, Stewart GK, Kowal D, Guest F, Cates W, Policar MS. Contraceptive Technology (16th rev. ed.). New York: Irvington Publishers. pp. 637–688. ISBN 0-8290-3171-5.
- Trussell J (1998). "Contraceptive Efficacy". In Hatcher RA, Trussell J, Stewart F, Cates W, Stewart GK, Guest F, Kowal D. Contraceptive Technology (17th rev. ed.). New York: Ardent Media. pp. 779–844. ISBN 0-9664902-0-7.
- FDA (1998). "Guidance for Industry - Uniform Contraceptive Labeling" (PDF). Archived from the original (PDF) on February 25, 2007. Retrieved 2007-06-21.
- Trussell J (2007). "Contraceptive Efficacy". In Hatcher RA, Trussell J, Nelson AL, Cates W, Stewart FH, Kowal D. Contraceptive Technology (19th rev. ed.). New York: Ardent Media. Retrieved 2007-06-21.
- Trussell J, Vaughan B (1999). "Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth" (PDF). Family Planning Perspectives. 31 (2): 64–72, 93. doi:10.2307/2991641. JSTOR 2991641. PMID 10224544.
- Hatcher RA (2004). "Depo-Provera Injections, Implants, and Progestin-Only Pills (Minipills)". In Hatcher RA, Trussell J, Stewart FH, Nelson AL, Cates Jr W, Guest F, Kowal D. Contraceptive Technology (18th rev. ed.). New York: Ardent Media. pp. 461–494. ISBN 0-9664902-5-8.
- Speroff L, Darney PD (2005). "Injectable Contraception". A Clinical Guide for Contraception (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 201–220. ISBN 0-7817-6488-2.
- Westhoff C (August 2003). "Depot-medroxyprogesterone acetate injection (Depo-Provera): a highly effective contraceptive option with proven long-term safety". Contraception. 68 (2): 75–87. doi:10.1016/S0010-7824(03)00136-7. PMID 12954518.
- Mishell DR (2004). "Contraception". In Strauss JF, Barbieri RL. Yen and Jaffe's Reproductive Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp. 899–938. ISBN 0-7216-9546-9.
- Kaunitz AM (December 2001). "Current options for injectable contraception in the United States". Seminars in Reproductive Medicine. 19 (4): 331–7. doi:10.1055/s-2001-18641. PMID 11727175.
- Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M (July 1999). "Depo Provera. Position paper on clinical use, effectiveness and side effects". The British Journal of Family Planning. 25 (2): 69–76. PMID 10454658.
- "Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives". International Journal of Cancer. 49 (2): 186–90. September 1991. doi:10.1002/ijc.2910490207. PMID 1831802.
- Santen RJ (2004). "Endocrinology of Breast and Endometrial Cancer". In Strauss JF, Barbieri RL. Yen and Jaffe's Reproductive Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp. 787–809. ISBN 0-7216-9546-9.
- Bartz D, Goldberg AB (2011). "Injectable contraceptives". In Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Kowal D, Policar MS. Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 212–213. ISBN 978-1-59708-004-0. OCLC 781956734.
Advantages of DMPA Injectables. 5. Reduced risk of ectopic pregnancy. Compared with women who use no contraceptive at all, women who use DMPA have a reduced risk for having an ectopic pregnancy. Although the overall risk of pregnancy and thus ectopic pregnancy is lowered by DMPA, the possibility of an ectopic pregnancy should be excluded if a woman using DMPA becomes pregnant. One study showed that 1.5% of women who got pregnant on DMPA had an ectopic pregnancy, the same ectopic rate as women who conceived while not using contraception.27
- Borgatta L, Murthy A, Chuang C, Beardsley L, Burnhill MS (September 2002). "Pregnancies diagnosed during Depo-Provera use". Contraception. 66 (3): 169–72. doi:10.1016/S0010-7824(02)00340-2. PMID 12384205.
- O'Brien MD, Guillebaud J (September 2006). "Contraception for women with epilepsy". Epilepsia. 47 (9): 1419–22. doi:10.1111/j.1528-1167.2006.00671.x. PMID 16981856.
- "Increasing use of long-acting reversible contraception". Nursing Times.net. 21 October 2008. Retrieved 2009-06-19.
- "CG30 Long-acting reversible contraception: quick reference guide" (PDF). National Institute for Health and Clinical Excellence. Retrieved 2009-06-19.
- "Sexual Health Ruleset" (PDF). New GMS Contract Quality and Outcome Framework - Implementation Dataset and Business Rules. Primary Care Commissioning. 1 May 2009. Retrieved 2009-06-19.
* "Contraception - Management QOF indicators". NHS Clinical Knowledge Summaries. NHS Institute for Innovation and Improvement. Retrieved 2009-06-19.
- "The chemical knife". Retrieved 2009-01-22.
- Holtorf K (January 2009). "The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?" (PDF). Postgraduate Medicine. 121 (1): 73–85. doi:10.3810/pgm.2009.01.1949. PMID 19179815.
- Cirigliano M (June 2007). "Bioidentical hormone therapy: a review of the evidence" (PDF). Journal of Women's Health. 16 (5): 600–31. doi:10.1089/jwh.2006.0311. PMID 17627398.
- Boothby LA, Doering PL (August 2008). "Bioidentical hormone therapy: a panacea that lacks supportive evidence". Current Opinion in Obstetrics & Gynecology. 20 (4): 400–7. doi:10.1097/GCO.0b013e3283081ae9. PMID 18660693.
- WHO (2004). "Progestogen-only contraceptives". Medical Eligibility Criteria for Contraceptive Use (3rd ed.). Geneva: Reproductive Health and Research, WHO. ISBN 92-4-156266-8.
- FFPRHC (2006). "The UK Medical Eligibility Criteria for Contraceptive Use (2005/2006)" (PDF). Archived from the original (PDF) on June 19, 2007. Retrieved 2007-01-11.
- Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (July 2002). "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial". JAMA. 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397.
- Bethea CL (February 2011). "MPA: medroxy-progesterone acetate contributes to much poor advice for women". Endocrinology. 152 (2): 343–5. doi:10.1210/en.2010-1376. PMC . PMID 21252179.
- "MedroxyPROGESTERone: Drug Information Provided by Lexi-Comp". Merck Manual. 2009-12-01. Retrieved 2010-07-08.
- Prentice RL, Anderson GL (2008). "The women's health initiative: lessons learned". Annual Review of Public Health. 29: 131–50. doi:10.1146/annurev.publhealth.29.020907.090947. PMID 18348708.
- Buist DS, Newton KM, Miglioretti DL, Beverly K, Connelly MT, Andrade S, Hartsfield CL, Wei F, Chan KA, Kessler L (November 2004). "Hormone therapy prescribing patterns in the United States". Obstetrics and Gynecology. 104 (5 Pt 1): 1042–50. doi:10.1097/01.AOG.0000143826.38439.af. PMID 15516400.
- Pazol K, Wilson ME, Wallen K (June 2004). "Medroxyprogesterone acetate antagonizes the effects of estrogen treatment on social and sexual behavior in female macaques". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 2998–3006. doi:10.1210/jc.2003-032086. PMC . PMID 15181090.
- King SR (9 November 2012). Neurosteroids and the Nervous System. Springer Science & Business Media. pp. 45–. ISBN 978-1-4614-5559-2.
- Trüeb RM (26 February 2013). Female Alopecia: Guide to Successful Management. Springer Science & Business Media. pp. 46–. ISBN 978-3-642-35503-5.
- Diamanti-Kandarakis E (1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–23. PMID 10495361.
- Amatayakul K, Sivasomboon B, Thanangkul O (September 1978). "Vitamin and trace mineral metabolism in medroxyprogesterone acetate users". Contraception. 18 (3): 253–69. doi:10.1016/s0010-7824(78)80019-5. PMID 720068.
- Pfizer (October 2004). "Depo-Provera Contraceptive Injection, US patient labeling" (PDF). Retrieved 2007-02-21.
- "Exposure to DMPA in pregnancy may cause low birth weight". Progress in Human Reproduction Research (23): 2–3. 1992. PMID 12286194.
- "Depot medroxyprogesterone acetate and bone effects. Committee Opinion #602". June 2014. Retrieved 2015-05-03.
- FDA (November 17, 2004). "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Archived from the original on 2005-12-21. Retrieved 2006-05-12.
- World Health Organization (September 2005). "Hormonal contraception and bone health". Family Planning. Retrieved 2006-05-12.
- Curtis KM, Martins SL (May 2006). "Progestogen-only contraception and bone mineral density: a systematic review". Contraception. 73 (5): 470–87. doi:10.1016/j.contraception.2005.12.010. PMID 16627031.
- Cundy T, Cornish J, Evans MC, Roberts H, Reid IR (January 1994). "Recovery of bone density in women who stop using medroxyprogesterone acetate". BMJ. 308 (6923): 247–8. doi:10.1136/bmj.308.6923.247. PMC . PMID 8111260.
- Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (September 2002). "Injectable hormone contraception and bone density: results from a prospective study". Epidemiology. 13 (5): 581–7. doi:10.1097/00001648-200209000-00015. PMID 12192229.
- Scholes D, LaCroix AZ, Ichikawa LE, Barlow WE, Ott SM (February 2005). "Change in bone mineral density among adolescent women using and discontinuing depot medroxyprogesterone acetate contraception". Archives of Pediatrics & Adolescent Medicine. 159 (2): 139–44. doi:10.1001/archpedi.159.2.139. PMID 15699307.
- Orr-Walker BJ, Evans MC, Ames RW, Clearwater JM, Cundy T, Reid IR (November 1998). "The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women". Clinical Endocrinology. 49 (5): 615–8. doi:10.1046/j.1365-2265.1998.00582.x. PMID 10197077.
- Cundy T, Cornish J, Roberts H, Reid IR (May 2002). "Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception". American Journal of Obstetrics and Gynecology. 186 (5): 978–83. doi:10.1067/mob.2002.122420. PMID 12015524.
- Walsh JS, Eastell R, Peel NF (February 2010). "Depot medroxyprogesterone acetate use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density". Fertility and Sterility. 93 (3): 697–701. doi:10.1016/j.fertnstert.2008.10.004. PMID 19013564.
- "ACOG Committee Opinion No. 415: Depot medroxyprogesterone acetate and bone effects". Obstetrics and Gynecology. 112 (3): 727–30. September 2008. doi:10.1097/AOG.0b013e318188d1ec. PMID 18757687.
- Polis CB, Phillips SJ, Curtis KM, Westreich DJ, Steyn PS, Raymond E, Hannaford P, Turner AN (October 2014). "Hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence". Contraception. 90 (4): 360–90. doi:10.1016/j.contraception.2014.07.009. PMID 25183264.
- WHO Department of Reproductive Health and Research (February 16, 2012). "Technical Statement: Hormonal contraception and HIV". Geneva: World Health Organization.
- WHO Department of Reproductive Health and Research (July 23, 2014). "2014 Guidance Statement: Hormonal contraceptive methods for women at high risk of HIV and living with HIV" (PDF). Geneva: World Health Organization.
- AVAC (January 27, 2015). "News from the HC-HIV front: it's raining meta (analyses)!". New York: AIDS Vaccine Advocacy Coalition.
- Ralph LJ, McCoy SI, Shiu K, Padian NS (February 2015). "Hormonal contraceptive use and women's risk of HIV acquisition: a meta-analysis of observational studies". The Lancet. Infectious Diseases. 15 (2): 181–9. doi:10.1016/S1473-3099(14)71052-7. PMC . PMID 25578825.
- Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, Van Damme L, Delany-Moretlwe S, Francis SC, Friedland BA, Hayes RJ, Heffron R, Kapiga S, Karim QA, Karpoff S, Kaul R, McClelland RS, McCormack S, McGrath N, Myer L, Rees H, van der Straten A, Watson-Jones D, van de Wijgert JH, Stalter R, Low N (January 2015). "Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis". PLoS Medicine. 12 (1): e1001778. doi:10.1371/journal.pmed.1001778. PMC . PMID 25612136.
- Faculty of Sexual; Reproductive Healthcare (January 2015). "CEU Statement: Depot medroxyprogesterone acetate (DMPA, Depo-Provera) and risk of HIV acquisition" (PDF). London: Royal College of Obstetricians and Gynaecologists.
- FHI 360 (July 2014). "Research on hormonal contraception and HIV acquisition" (PDF). Durham, N.C.: FHI 360.
- Westhoff CL, Winikoff B (October 2014). "DMPA and HIV: do we need a trial?". Contraception. 90 (4): 353. doi:10.1016/j.contraception.2014.08.008. PMID 25183262.
- "DMPA and HIV: why we need a trial". Contraception. 90 (4): 354–6. October 2014. doi:10.1016/j.contraception.2014.08.007. PMID 25183263.
- Jones HE (October 2014). "Time to focus on improving the contraceptive method mix in high HIV prevalence settings and let go of unanswerable questions". Contraception. 90 (4): 357–9. doi:10.1016/j.contraception.2014.05.014. PMID 24993486.
- Lancet Infectious Diseases (January 8, 2015). "End of the debate on hormonal contraception and HIV risk? (editorial)". Lancet Infectious Diseases. 15 (2): 131. doi:10.1016/S1473-3099(15)70011-3.
- Colvin CJ, Harrison A (February 2015). "Broadening the debate over HIV and hormonal contraception". The Lancet. Infectious Diseases. 15 (2): 135–6. doi:10.1016/S1473-3099(14)71076-X. PMC . PMID 25578824.
- Dahlberg K (February 1982). "Some effects of depo-medroxyprogesterone acetate (DMPA): observations in the nursing infant and in the long-term user". International Journal of Gynaecology and Obstetrics. 20 (1): 43–8. doi:10.1016/0020-7292(82)90044-3. PMID 6126406.
- Pardthaisong T, Yenchit C, Gray R (April 1992). "The long-term growth and development of children exposed to Depo-Provera during pregnancy or lactation". Contraception. 45 (4): 313–24. doi:10.1016/0010-7824(92)90053-V. PMID 1387602.
- Glasier A (2006). "Contraception". In DeGroot LJ, Jameson JL. Endocrinology (5th ed.). Philadelphia: Elsevier Saunders. pp. 2993–3003. ISBN 978-0-7216-0376-6.
- Loose DS, Stancel GM (2006). "Estrogens and Progestins". In Brunton LL, Lazo JS, Parker KL. Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 1541–1571. ISBN 0-07-142280-3.
- Rivera R, Yacobson I, Grimes D (November 1999). "The mechanism of action of hormonal contraceptives and intrauterine contraceptive devices". American Journal of Obstetrics and Gynecology. 181 (5 Pt 1): 1263–9. doi:10.1016/S0002-9378(99)70120-1. PMID 10561657.
- World Health Organization (2004). Residues of Some Veterinary Drugs in Animals and Food: Monographs Prepared by the Sixty-second Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Rome, 4-12 February 2004. Food & Agriculture Org. p. 49. ISBN 978-92-5-105195-5.
- Kemppainen JA, Langley E, Wong CI, Bobseine K, Kelce WR, Wilson EM (March 1999). "Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone". Molecular Endocrinology. 13 (3): 440–54. doi:10.1210/mend.13.3.0255. PMID 10077001.
- Bentel JM, Birrell SN, Pickering MA, Holds DJ, Horsfall DJ, Tilley WD (August 1999). "Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells". Molecular and Cellular Endocrinology. 154 (1–2): 11–20. doi:10.1016/S0303-7207(99)00109-4. PMID 10509795.
- Pullen MA, Laping N, Edwards R, Bray J (September 2006). "Determination of conformational changes in the progesterone receptor using ELISA-like assays". Steroids. 71 (9): 792–8. doi:10.1016/j.steroids.2006.05.009. PMID 16784762.
- Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 638. ISBN 978-3-88763-075-1.
- Wikström A, Green B, Johansson ED (1984). "The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses". Acta Obstetricia Et Gynecologica Scandinavica. 63 (2): 163–8. doi:10.3109/00016348409154654. PMID 6233840.
- Blum RW (22 October 2013). Adolescent Health Care: Clinical Issues. Elsevier Science. pp. 216–. ISBN 978-1-4832-7738-7.
- Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JH (December 2003). "Classification and pharmacology of progestins". Maturitas. 46 Suppl 1: S7–S16. doi:10.1016/j.maturitas.2003.09.014. PMID 14670641.
- Kuhl H (2011). "Pharmacology of Progestogens" (PDF). J Reproduktionsmed Endokrinol. 8 (1): 157–177.
- Fritz MA, Speroff L (28 March 2012). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. pp. 761–. ISBN 978-1-4511-4847-3.
- Genazzani AR (15 January 1993). Frontiers in Gynecologic and Obstetric Investigation. Taylor & Francis. p. 320. ISBN 978-1-85070-486-7.
- Poulin R, Baker D, Poirier D, Labrie F (March 1989). "Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells". Breast Cancer Research and Treatment. 13 (2): 161–72. doi:10.1007/bf01806528. PMID 2525057.
- Brady BM, Anderson RA, Kinniburgh D, Baird DT (April 2003). "Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male". Clinical Endocrinology. 58 (4): 506–12. doi:10.1046/j.1365-2265.2003.01751.x. PMID 12641635.
- Saleh FM, Grudzinskas AJ, Bradford JM (11 February 2009). Sex Offenders: Identification, Risk Assessment, Treatment, and Legal Issues. Oxford University Press. p. 44. ISBN 978-0-19-517704-6.
- Stuart MC, Kouimtzi M, Hill SR (2009). Who Model Formulary 2008. World Health Organization. p. 368. ISBN 978-92-4-154765-9.
- Birrell SN, Hall RE, Tilley WD (January 1998). "Role of the androgen receptor in human breast cancer". Journal of Mammary Gland Biology and Neoplasia. 3 (1): 95–103. doi:10.1023/A:1018730519839. PMID 10819508.
- Buchanan G, Birrell SN, Peters AA, Bianco-Miotto T, Ramsay K, Cops EJ, Yang M, Harris JM, Simila HA, Moore NL, Bentel JM, Ricciardelli C, Horsfall DJ, Butler LM, Tilley WD (September 2005). "Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate". Cancer Research. 65 (18): 8487–96. doi:10.1158/0008-5472.CAN-04-3077. PMID 16166329.
- Rees MC, Hope S, Ravnikar V (12 August 2005). The Abnormal Menstrual Cycle. Taylor & Francis. p. 213. ISBN 978-1-84214-212-7.
- Aronson JK (20 January 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. p. 283. ISBN 978-0-444-53271-8.
- Ettinger B, Golditch IM (December 1977). "Medroxyprogesterone acetate for the evaluation of hypertestosteronism in hirsute women". Fertility and Sterility. 28 (12): 1285–8. PMID 590535.
- Correa de Oliveira RF, Novaes LP, Lima MB, Rodrigues J, Franco S, Khenaifes AI, Francalanci CP (December 1975). "A new treatment for hirsutism". Annals of Internal Medicine. 83 (6): 817–9. doi:10.7326/0003-4819-83-6-817. PMID 1200527.
- Richman RA, Underwood LE, French FS, Van Wyk JJ (December 1971). "Adverse effects of large doses of medroxyprogesterone (MPA) in idiopathic isosexual precocity". The Journal of Pediatrics. 79 (6): 963–71. doi:10.1016/s0022-3476(71)80191-9. PMID 4332067.
- Merrin PK, Alexander WD (August 1990). "Cushing's syndrome induced by medroxyprogesterone". BMJ. 301 (6747): 345. doi:10.1136/bmj.301.6747.345-a. PMC . PMID 2144198.
- Systemic Effects of Oral Glucocorticoids
- Sunde A, Rosness PA, Eik-Nes KB (August 1982). "Effects in vitro of medroxyprogesterone acetate on steroid metabolizing enzymes in the rat: selective inhibition of 3 alpha-hydroxysteroid oxidoreductase activity". Journal of Steroid Biochemistry. 17 (2): 197–203. doi:10.1016/0022-4731(82)90122-4. PMID 6213817.
- Penning TM, Sharp RB, Krieger NR (December 1985). "Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins". The Journal of Biological Chemistry. 260 (28): 15266–72. PMID 2933398.
- Meyer L, Venard C, Schaeffer V, Patte-Mensah C, Mensah-Nyagan AG (April 2008). "The biological activity of 3alpha-hydroxysteroid oxido-reductase in the spinal cord regulates thermal and mechanical pain thresholds after sciatic nerve injury". Neurobiology of Disease. 30 (1): 30–41. doi:10.1016/j.nbd.2007.12.001. PMID 18291663.
- Mellon SH, Griffin LD (2002). "Neurosteroids: biochemistry and clinical significance". Trends in Endocrinology and Metabolism. 13 (1): 35–43. doi:10.1016/s1043-2760(01)00503-3. PMID 11750861.
- Civic D, Scholes D, Ichikawa L, LaCroix AZ, Yoshida CK, Ott SM, Barlow WE (June 2000). "Depressive symptoms in users and non-users of depot medroxyprogesterone acetate". Contraception. 61 (6): 385–90. doi:10.1016/s0010-7824(00)00122-0. PMID 10958882.
- Traish AM, Mulgaonkar A, Giordano N (June 2014). "The dark side of 5α-reductase inhibitors' therapy: sexual dysfunction, high Gleason grade prostate cancer and depression". Korean Journal of Urology. 55 (6): 367–79. doi:10.4111/kju.2014.55.6.367. PMC . PMID 24955220.
- Lee TC, Miller WL, Auchus RJ (June 1999). "Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes". The Journal of Clinical Endocrinology and Metabolism. 84 (6): 2104–10. doi:10.1210/jcem.84.6.5646. PMID 10372718.
- Söderpalm AH, Lindsey S, Purdy RH, Hauger R, Wit de H (April 2004). "Administration of progesterone produces mild sedative-like effects in men and women". Psychoneuroendocrinology. 29 (3): 339–54. doi:10.1016/s0306-4530(03)00033-7. PMID 14644065.
- McAuley JW, Kroboth PD, Stiff DD, Reynolds IJ (May 1993). "Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents". Pharmacology, Biochemistry, and Behavior. 45 (1): 77–83. doi:10.1016/0091-3057(93)90089-c. PMID 8516376.
- Weizman A (1 February 2008). Neuroactive Steroids in Brain Function, Behavior and Neuropsychiatric Disorders: Novel Strategies for Research and Treatment. Springer Science & Business Media. pp. 104, 107, 112. ISBN 978-1-4020-6854-6.
- Muss HB, Cruz JM (August 1992). "High-dose progestin therapy for metastatic breast cancer". Annals of Oncology. 3 Suppl 3: 15–20. PMID 1390312.
- Hofbauer KG, Anker SD, Inui A, Nicholson JR (22 December 2005). Pharmacotherapy of Cachexia. CRC Press. pp. 292–. ISBN 978-1-4200-4895-7.
Medroxyprogesterone [acetate] has similarly been shown to increase appetite and food intake with stabilization of body weight at a dose of 1000 mg (500 mg twice daily).13 Although the drug may be used at 500 to 4000 mg daily, side effects increase above oral doses of 1000 mg daily.16
- Doyle D, Hanks G, Cherny NI (3 February 2005). Oxford Textbook Of Palliative Medicine. Oxford University Press. p. 553. ISBN 978-0-19-856698-4.
- Mishell DR (May 1996). "Pharmacokinetics of depot medroxyprogesterone acetate contraception". The Journal of Reproductive Medicine. 41 (5 Suppl): 381–90. PMID 8725700.
- Ishihara M, Kirdani Y, Osawa Y, Sandberg AA (January 1976). "The metabolic fate of medroxyprogesterone acetate in the baboon". Journal of Steroid Biochemistry. 7 (1): 65–70. doi:10.1016/0022-4731(76)90167-9. PMID 1271819.
- Sneader W (2005). "Chapter 18: Hormone analogs". Drug discovery: a history. New York: Wiley. p. 204. ISBN 0-471-89980-1.
- FR 1295307, "Procédé de préparation de dérivés cyclopentano-phénanthréniques", published 1962-06-08, assigned to Syntex SA
- US granted 3377364, Spero G, "6-methyl-17alpha-hydroxyprogesterone, the lower fatty acid 17-acylates and methods for producing the same", published 1968-04-09, assigned to Upjohn Company
- William Green (1987). "Odyssey of Depo-Provera: Contraceptives, Carcinogenic Drugs, and Risk-Management Analyses". The. Food Drug Cosm. LJ. Chicago (42): 567–587.
Depo-Provera is a drug, manufactured by The Upjohn Co., whose active ingredient is medroxyprogesterone acetate (MPA). FDA first approved the drug in 1959 to treat amenorrhea,5 irregular uterine bleeding, and threatened and habitual abortion.
- Hartmann KE, Jerome RN, Lindegren ML, Potter SA, Shields TC, Surawicz TS, Andrews JC (2013). Primary Care Management of Abnormal Uterine Bleeding. PMID 23617013.
- Depo-Provera. fda.gov
- Gelijns A (1991). Innovation in Clinical Practice: The Dynamics of Medical Technology Development. National Academies. pp. 167–. NAP:13513.
- William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia. Elsevier. pp. 1501–. ISBN 978-0-8155-1856-3.
- Kolbe HK (1976). Population/fertility control thesaurus (PDF). Population Information Program, Science Communication Division, Dept. of Medical and Public Affairs, George Washington University.
- Bolivar De Lee J (1966). The ... Year Book of Obstetrics and Gynecology. Year Book Publishers. p. 339.
One of these is medroxyprogesterone acetate, which is sold in the United States by Upjohn as Provest, and is obtainable abroad as Provestral, Provestrol, Cyclo-Farlutal, and the more frankly suggestive Nogest.
- Fínkelstein M (1966). Research on Steroids. Pergamon. pp. 469, 542.
- Levitt JI (30 April 2015). Black Women and International Law: Deliberate Interactions, Movements and Actions. Cambridge University Press. pp. 230–231. ISBN 978-1-316-29840-4.
- name="Women1998"Documentation on Women's Concerns. Library and Documentation Centre, All India Association for Christian Higher Education. January 1998.
Upjohn meanwhile, had been repeatedly seeking FDA approval for use of DMPA as a contraceptive, but applications were rejected in 1967, 1978 and yet again in 1983, [...]
- Shoupe D, Mishell DR (28 September 2015). The Handbook of Contraception: A Guide for Practical Management. Humana Press. pp. 126–. ISBN 978-3-319-20185-6.
- "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Retrieved 29 November 2016.
- Stacey, Dawn. Depo Provera: The Birth Control Shot Accessed October 13, 2009
- Leary WE (October 1992). "U.S. approves injectable drug as birth control". The New York Times on the Web: A1, A14. PMID 11646958.
- "Contraceptives. Case for public enquiry". Economic and Political Weekly. 29 (15): 825–6. 1994. Popline database document number 096527.
- Sorojini, NB (January–March 2005). "Why women's groups oppose injectable contraceptives". Indian Journal of Medical Ethics. 13 (1). Archived from the original (– Scholar search) on May 6, 2006.
- Madeline Boscoe (December 6, 1991). "Canadian Coalition on Depo-Provera letter to The Honorable Benoit Bouchard, National Minister of Health and Welfare". Canadian Women's Health Network. Archived from the original on 5 Feb 2007. Retrieved 2006-08-22.
- "Class action suit filed over birth control drug". CTV.ca. December 19, 2005. Retrieved 2006-08-22.
- "Progestins (IARC Summary & Evaluation, Supplement7, 1987)". Retrieved 15 October 2016.
- Amy Goodman (February–March 1985). "The Case Against Depo-Provera - Problems in the U.S". Multinational Monitor. 6 (2 & 3).
- "Controversy over Depo-Provera". Washington Drug & Device Letter. 9 (1): 2. January 1977. PMID 12335988.
- Thomas DB, Ye Z, Ray RM (January 1995). "Cervical carcinoma in situ and use of depot-medroxyprogesterone acetate (DMPA). WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 51 (1): 25–31. doi:10.1016/0010-7824(94)00007-J. PMID 7750280.
- "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive squamous cell cervical cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 45 (4): 299–312. April 1992. doi:10.1016/0010-7824(92)90052-U. PMID 1387601.
- Thomas DB, Ray RM (November 1995). "Depot-medroxyprogesterone acetate (DMPA) and risk of invasive adenocarcinomas and adenosquamous carcinomas of the uterine cervix. WHO Collaborative Study of Neoplasia and Steroid Contraceptives". Contraception. 52 (5): 307–12. doi:10.1016/0010-7824(95)00215-V. PMID 8585888.
- Shapiro S, Rosenberg L, Hoffman M, Kelly JP, Cooper DD, Carrara H, Denny LE, du Toit G, Allan BR, Stander IA, Williamson AL (June 2003). "Risk of invasive cancer of the cervix in relation to the use of injectable progestogen contraceptives and combined estrogen/progestogen oral contraceptives (South Africa)". Cancer Causes & Control. 14 (5): 485–95. doi:10.1023/A:1024910808307. PMID 12946044.
- Kaunitz AM (May 1996). "Depot medroxyprogesterone acetate contraception and the risk of breast and gynecologic cancer". The Journal of Reproductive Medicine. 41 (5 Suppl): 419–27. PMID 8725705.
- Hawkins K, Elliott J (5 May 1996). "Seeking Approval". Albion Monitor. Archived from the original on 21 November 2015. Retrieved 20 November 2006.
- "Sterilization of minors leads to controversy". Family Planning/Population Reporter; A Review of State Laws and Policies. 2 (4): 77–8. August 1973. PMID 12257656.
- Egan TM, Siegert RJ, Fairley NA (August 1993). "Use of hormonal contraceptives in an institutional setting: reasons for use, consent and safety in women with psychiatric and intellectual disabilities". The New Zealand Medical Journal. 106 (961): 338–41. PMID 8341476.
- Singh S (May 1995). "Adolescent knowledge and use of injectable contraceptives in developing countries". The Journal of Adolescent Health. 16 (5): 396–404. doi:10.1016/S1054-139X(94)00060-R. PMID 7662691.
- "Clinicians clash with consumer groups over possible Depo ban". Contraceptive Technology Update. 16 (1): 11–4. January 1995. PMID 12319319.