Medroxyprogesterone acetate

src: www.cheap-generic.co

Medroxyprogesterone acetate (MPA), sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of birth control and as a part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, abnormal sexuality in males, and certain types of cancer, among other indications. The medication is available both alone and in combination with an estrogen. It is taken by mouth or by injection into a muscle or under the skin.

Common side effects include menstrual disturbances such as absence of periods, abdominal pain, anxiety, and headaches. More serious side effects include bone loss, blood clots, allergic reactions, and liver problems. Use is not recommended during pregnancy as it may harm the baby. MPA is an artificial progestogen, and as such activates the progesterone receptor, the biological target of progesterone. It also has weak androgenic and glucocorticoid activity but no other important hormonal activity. Due to its progestogenic activity, MPA decreases the body's release of gonadotropins. It works as a form of birth control by preventing ovulation.

MPA was discovered in 1956 and was introduced for medical use in the United States in 1959. 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.

Video Medroxyprogesterone acetate

Medical uses

In women, the most common use of MPA is as a depot-injected contraceptive in premenopausal women and also as the progestin component of menopausal hormone therapy in postmenopausal women in combination with an estrogen to prevent endometrial hyperplasia and cancer. It is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea. Along with other progestins, MPA was 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.

Injected MPA reduces sex drive in men and has been used as a form of chemical castration to control inappropriate or unwanted sexual behavior in those with paraphilias or hypersexuality, including in convicted sex offenders. MPA 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. MPA has also been prescribed in feminizing hormone therapy for transgender women due to its progestogenic and antigonadotropic effects.

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 amenorrhea 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.

Birth control

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

Perfect use

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).

Typical use

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:
- Contraceptive Technology, 16th revised edition (1994)
- Contraceptive Technology, 17th revised edition (1998)
  - adopted in 1998 by the FDA for its current Uniform Contraceptive Labeling guidance

In 2004, using the 1995 NSFG failure rate, Trussell increased (by 10 times) his typical use failure rate for medroxyprogesterone acetate by injection 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 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.

Benefits

Medroxyprogesterone acetate by injection 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 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

Proponents of bioidentical hormone 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 medications have not been adequately compared in direct tests to clear conclusions about safety and superiority.

Available forms

MPA is available alone in the form of 2.5, 5, and 10 mg oral tablets, as a 150 mg/mL (1 mL) or 400 mg/mL (2.5 mL) aqueous suspension for intramuscular injection, and as a 104 mg (0.65 mL of 160 mg/mL) aqueous suspension for subcutaneous injection. It has also been reported to be marketed in the form of 100, 200, 250, and 500 mg oral tablets and as a 50 mg/mL aqueous suspension for intramuscular injection. A 100 mg/mL aqueous suspension for intramuscular injection was previously available. In addition to single-drug formulations, MPA is available in the form of oral tablets in combination with conjugated estrogens or estradiol for use in menopausal hormone therapy, and has been available in combination with estradiol cypionate as a combined injectable contraceptive.

Maps Medroxyprogesterone acetate

Contraindications

It is not usually recommended because of unacceptable health risk or because it is not indicated in the following cases:

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:
- Hypertension with vascular disease
- Current and history of ischemic heart disease
- History of stroke
- Diabetes for over 20 years or with nephropathy/retinopathy/neuropathy or vascular disease

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

Current or recent breast cancer (a hormonally sensitive tumour)

Conditions where use is not indicated and should not be initiated:

Pregnancy

src: buy-pharma.com

Side effects

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 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 menopausal hormone 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 progestogens -- a conclusion that has been challenged by several researchers as unjustified and leading to unnecessary avoidance of HRT for many women as progestogens 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, 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 progestogens 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 estrogens, 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 postmenopausal 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 menopausal hormone therapy, producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.

Lowered libido has been reported as a side effect of MPA in women.

Unlike the related medication cyproterone acetate, MPA does not appear to be associated with vitamin B12 deficiency.

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 amenorrhea (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.

Depression

There have been concerns about a possible risk of depression with MPA, and this has led to reluctance of some clinicians and women to use the medication. However, a 2018 systematic review of the relationship between progestin-based contraception and depression included three studies of DMPA and reported no association between DMPA and depression. According to a 2003 review of DMPA, the majority of published clinical studies indicate that DMPA is not associated with depression, and the overall data support the notion that the medication does not significantly affect mood.

In the largest study to have assessed the relationship between MPA and depression to date, in which over 3,900 women were treated with DMPA for up to 7 years, the incidence of depression was infrequent at 1.5% and the discontinuation rate due to depression was 0.5%. This study did not include baseline data on depression, and as a result of the incidence of depression and associated discontinuation observed in the study, the FDA required package labeling for DMPA stating that women with depression should be observed carefully and that DMPA should be discontinued if depression recurs. A subsequent study of 495 women treated with DMPA over the course of 1 year found that the mean depression score slightly decreased in the whole group of continuing users from 7.4 to 6.7 (by 9.5%) and decreased in the quintile of that group with the highest depression scores at baseline from 15.4 to 9.5 (by 38%). Based on the results of this study and others, it has been said that a consensus appears to be emerging that DMPA does not in fact increase the risk of depression nor worsen the severity of pre-existing depression.

Similarly to the case of DMPA for hormonal contraception, the Heart and Estrogen/Progestin Replacement Study (HERS), a study of 2,763 postmenopausal women treated with 0.625 mg/day conjugated estrogens plus 2.5 mg/day oral MPA or placebo for 36 months as a method of menopausal hormone therapy, found no change in depressive symptoms. However, a small study of 48 women has reported that MPA might counteract the positive effects of estrogens on depression.

Bone density

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 postmenopausal 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.

HIV risk

There is uncertainty regarding the risk of HIV acquisition among depot MPA (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 systematic review and meta-analysis of risk of HIV infection in DMPA users published in fall of 2015 stated that "the epidemiological and biological evidence now make a compelling case that DMPA adds significantly to the risk of male-to-female HIV transmission."

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.

src: www.buy-pharma.md

Breastfeeding

MPA may be used by breastfeeding 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.

src: previews.123rf.com

Overdose

MPA has been studied at "massive" dosages of up to 5,000 mg per day orally and 2,000 mg per day via intramuscular injection, without major tolerability or safety issues described. Overdose is not described in the Food and Drug Administration (FDA) product labels for injected MPA (Depo-Provera or Depo-SubQ Provera 104). In the FDA product label for oral MPA (Provera), it is stated that overdose of an estrogen and progestin may cause nausea and vomiting, breast tenderness, dizziness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care.

src: www.allgenericpharmacy.com

Interactions

MPA increases the risk of breast cancer, dementia, and thrombus when used in combination with conjugated estrogens to treat menopausal symptoms. When used as a contraceptive, MPA does not generally interact with other medications. The combination of MPA with aminoglutethimide to treat metastases from breast cancer has been associated with an increase in depression. St John's wort may decrease the effectiveness of MPA as a contraceptive due to acceleration of its metabolism.

src: www.buy-pharma.md

Pharmacology

Pharmacodynamics

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 medication 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.

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.

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.

Progestogenic activity

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.

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.

Antigonadotropic and anticorticotropic effects

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.

Androgenic activity

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 shows weak androgenic effects on liver protein synthesis, similarly to other weakly androgenic progestins like megestrol acetate and 19-nortestosterone derivatives. While it does not antagonize estrogen-induced increases in levels of triglycerides and HDL cholesterol, depot MPA every other week may decrease levels of HDL cholesterol. In addition, MPA has been found to suppress hepatic sex hormone-binding globulin (SHBG) production; at a dosage of 10 mg/day oral MPA, it has been found to decrease circulating SHBG levels by 14 to 18% in women taking 4 mg/day oral estradiol valerate.

Glucocorticoid activity

As an agonist of the GR, MPA has glucocorticoid activity, and as a result can cause symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency at sufficiently high doses. It has been suggested that MPA may cause bone loss via its glucocorticoid activity.

Steroidogenesis inhibition

MPA has been found to act as a competitive inhibitor of rat 3?-hydroxysteroid dehydrogenase (3?-HSD). This enzyme is essential for the transformation of progesterone, deoxycorticosterone, and DHT into inhibitory neurosteroids such as allopregnanolone, THDOC, and 3?-androstanediol, respectively. MPA has been described as very potent in its inhibition of rat 3?-HSD, with an IC₅₀ of 0.2 ?M and a K_i (in rat testicular homogenates) of 0.42 ?M. However, it should be noted that inhibition of 3?-HSD by MPA does not appear to have been confirmed using human proteins yet, and the concentrations required with rat proteins are far above typical human therapeutic concentrations.

MPA has been identified as a competitive inhibitor of human 3?-hydroxysteroid dehydrogenase/?^5-4 isomerase II (3?-HSD II). This enzyme is essential for the biosynthesis of sex steroids and corticosteroids. The K_i of MPA for inhibition of 3?-HSD II is 3.0 ?M, and this concentration is reportedly near the circulating levels of the medication 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 3?-HSD II, other human steroidogenic enzymes, including cholesterol side-chain cleavage enzyme (P450scc/CYP11A1) and 17?-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 3?-HSD II could be responsible for its effectiveness in these conditions.

GABA_A receptor allosteric modulation

Progesterone, via transformation into neurosteroids such as 5?-dihydroprogesterone, 5?-dihydroprogesterone, allopregnanolone, and pregnanolone (catalyzed by the enzymes 5?- and 5?-reductase and 3?- and 3?-HSD), is a positive allosteric modulator of the GABA_A 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 might modulate the GABA_A receptor similarly to progesterone.

MPA shares some of the same metabolic routes of progesterone and, analogously, can be transformed into metabolites such as 5?-dihydro-MPA (DHMPA) and 3?,5?-tetrahydro-MPA (THMPA). However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABA_A receptor. Conversely, unlike progesterone, MPA itself actually modulates the GABA_A receptor, although notably not at the neurosteroid binding site. However, 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 GABA_A receptor in vitro, MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 ?M. 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 GABA_A 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 GABA_A receptor in humans even at extremely high dosages.

Appetite stimulation

Although MPA and the closely related medication 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-1?, IL-1?, IL-6, and TNF-?, actions that have all been linked to an increase in appetite.

Pharmacokinetics

Absorption

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 medication 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 65 years of age or over, and with 5 mg/day MPA, levels were 0.6 ng/mL (1.6 nmol/L) in women under 60 years of age and in women 65 years of age or over. Hence, area-under-curve levels of the medication were 1.6 to 1.8 times higher in those who were 65 years of age or older relative to those who were 60 years of age or younger. As such, levels of MPA have been found to vary with age, and MPA may have an increased risk of side effects in elderly postmenopausal women.

With intramuscular administration of a 150 mg dose of MPA, the medication 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 medication can be detected in the circulation for as long as nine months post-injection.

Distribution

In the circulation, 88% of MPA is weakly bound to albumin, with no binding to sex hormone-binding globulin or corticosteroid-binding globulin.

Metabolism

The terminal half-life of MPA via oral administration has been reported as both 11.6 to 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, including at positions C6?, C21, C2?, and C1?, mediated primarily via CYP3A4, 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. The C6? methyl and C17? acetoxy groups of MPA make it more resistant to metabolism and allow for higher bioavailability than oral progesterone.

Elimination

MPA is eliminated 20 to 50% in urine and 5 to 10% in feces following intravenous administration. Less than 3% of a dose is excreted in unconjugated form.

Relationship between concentrations and 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.

src: c8.alamy.com

Chemistry

MPA is a synthetic pregnane steroid and a derivative of progesterone and 17?-hydroxyprogesterone. Specifically, it is the 17?-acetate ester of medroxyprogesterone or the 6?-methylated analogue of hydroxyprogesterone acetate. MPA is known chemically as 6?-methyl-17?-acetoxyprogesterone or as 6?-methyl-17?-acetoxypregn-4-ene-3,20-dione, and its generic name is a contraction of 6?-methyl-17?-hydroxyprogesterone acetate. MPA is closely related to other 17?-hydroxyprogesterone derivatives such as chlormadinone acetate, cyproterone acetate, and megestrol acetate, as well as to medrogestone and nomegestrol acetate.

src: dmd.aspetjournals.org

History

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 ?g 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 ?g 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 medication 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.

src: sc02.alicdn.com

Society and culture

Generic names

Medroxyprogesterone acetate is the generic name of the drug and its INN, USAN, BAN, and JAN, while medrossiprogesterone is the DCIT and médroxyprogestérone the DCF of its free alcohol form. It is also known as 6?-methyl-17?-acetoxyprogesterone (MAP) or 6?-methyl-17?-hydroxyprogesterone acetate.

Brand names

MPA is marketed under a large number of brand names throughout the world. Its most major brand names are Provera as oral tablets and Depo-Provera as an aqueous suspension for intramuscular injection. A formulation of MPA as an aqueous suspension for subcutaneous injection is also available in the United States under the brand name Depo-SubQ Provera 104. Other brand names of MPA formulated alone include Farlutal and Sayana for clinical use and Depo-Promone, Perlutex, Promone-E, and Veramix for veterinary use. In addition to single-drug formulations, MPA is marketed in combination with estrogens, most commonly conjugated estrogens, but also estradiol. Brand names of MPA in combination with conjugated estrogens as oral tablets in different countries include Prempro, Premphase, Premique, Premia, and Premelle. Brand names of MPA in combination with estradiol as oral tablets include Indivina and Tridestra.

Availability

United States

As of November 2016, MPA is available in the United States in the following formulations:

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 (for contraception)

It is also available in combination with an 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

While the following formulations have been discontinued:

Oral pills: ethinylestradiol and MPA (Provest) - 50 ?g / 10 mg
Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) - 5 mg / 25 mg (for contraception)

Formulations

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.

Controversy

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 medication 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".

United States

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

src: www.onlinejacc.org

References

Source of the article : Wikipedia

Jumat, 15 Juni 2018