Medroxyprogesterone acetate

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Medroxyprogesterone acetate ( MPA ), sold under the trademark of Depo-Provera , among others, is a progestin-type hormonal drug. It is used as a method of birth control and as part of menopausal hormone therapy. It is also used to treat endometriosis, abnormal uterine bleeding, abnormal sexuality in men, and certain types of cancer, among other indications. The drug is available on its own and combined with estrogen. Taken by mouth or by injection into muscle or under skin.

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

The MPA was discovered in 1956 and was introduced for medical use in the United States in 1959. It is a List of Essential Medicines of the World Health Organization, the most effective and safe medication needed in the health system. Wholesale costs in developing countries are around 0.59 to 1.57 USD per bottle. In the United Kingdom, this dose weighed on the NHS about 6.01 pounds. In the United States it costs less than 25 USD per dose by 2015.

Video Medroxyprogesterone acetate

Medical use

In women, the most common use of MPA is as contraceptive depot in premenopausal women and also as a component of progestin of menopausal hormone therapy in postmenopausal women combined with estrogen to prevent endometrial hyperplasia and cancer. This is a very effective contraceptive when used with a relatively high dose to prevent ovulation. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea. Along with other progestin, MPA was developed to allow hormones to be taken orally, because progesterone (a hormone made by the human body) can not be taken orally before micronization is developed.

Injectable MPA reduces men's sexual urges and has been used as a form of chemical castration to control inappropriate or unwanted sexual behavior in those with paraphilias or hypersexuality, including convicted sex offenders. MPA has also been used to treat benign prostate hyperplasia, as a stimulant of palliative appetite for cancer patients, and at high doses (800 mg per day) to treat cancer-dependent hormones especially breast, but also other types. MPA has also been prescribed in feminization hormone therapy for transgender women due to its progestogenic and antigonadotropic effects.

Although not used as a treatment for epilepsy, MPA has been found to reduce seizure frequency and not interact with anti-epileptic drugs. The MPA does not interfere with blood clots and appears to increase blood parameters for women with sickle cell anemia. Similarly, MPA does not seem to affect liver metabolism, and may increase primary biliary cirrhosis and chronic active hepatitis. Women taking MPA may experience spotting immediately after starting treatment but are usually not serious enough to require medical intervention. With the use of longer amenorrhea can occur such as irregular menstruation which is a major source of dissatisfaction, although both can result in improvements with iron deficiency and pelvic inflammatory disease risk and often do not result in discontinuation of the drug.

Birth control

The estimated first-year failure rate is about 0.3%.

Perfect use

It is estimated Trussell estimates the perfect use rate of first-year failure rate for medroxyprogesterone acetate with injection as the mean failure rate in seven clinical trials of 0.3%. This is considered perfect use because clinical trials measure efficacy during the actual use of medroxyprogesterone acetate are defined as no more than 14 or 15 weeks after injection (ie, no more than 1 or 2 weeks late for subsequent injections).

Common uses

Prior to 2004, the typical failure rate for Trussell use for medroxyprogesterone acetate with injection was similar to the failure rate of perfect use : 0.3%.

• medroxyprogesterone acetate by injection estimated typical use first-year failure rate = 0.3% at:
  • Contraception Technology, 16th revised edition (1994)
  • Contraception technology, revised 17th edition (1998)
    • was adopted in 1998 by the FDA for current Contemporary Countermeasures contraceptive guidance >

In 2004, using the 1995 NSFG failure rate, Trussell increased (10 times) typical levels of use for medroxyprogesterone acetate with injection from 0.3% to 3%.

• Depo-Provera estimates typical usage first year failure rate = 3% in:
  • Contraception Technology, 18th revised edition (2004)
  • Contraception Technology, 19th revised edition (2007)

Trussell did not use the 1995 NSFG failure rate as a typical failure rate for the other two who then used long-acting contraceptives, Norplant implants (2.3%) and ParaGard T 380A IUD copper (3.7% ), which (as with medroxyprogesterone acetate by injection) is of a higher magnitude than in clinical trials. Because Norplant and ParaGard do not allow scope for user error, the higher 1995 NSFG failure rate is caused by Trussell on excessive contraception at the time of conception that leads to live births.

Benefits

Medroxyprogesterone acetate by injection has several advantages:

• Very effectively prevent pregnancy.
• Injected every 12 weeks. The only ongoing action is to order subsequent follow-up shots every twelve weeks, and to monitor for side effects to ensure that they do not require medical attention.
• Without estrogen. There is no increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction.
• Minimum drug interactions (compared with other hormonal contraceptives).
• Decreases the risk of endometrial cancer. Depo-Provera reduces the risk of endometrial cancer by up to 80%. The decreased risk of endometrial cancer in Depo-Provera users is thought to be due to the direct anti-proliferative effects of progestogens on the endometrium and the indirect decrease in estrogen levels by suppressing the development of ovarian follicles.
• Decreases the risk of iron deficiency anemia, pelvic inflammatory disease (PID), ectopic pregnancy, and uterine fibroids.
• Decreased symptoms of endometriosis.
• Decreased incidence of primary dysmenorrhea, ovulatory pain, and functional ovarian cysts.
• Decreased incidence of seizures in women with epilepsy. Moreover, unlike most other hormonal contraceptives, the effectiveness of Depo-Provera contraception is not influenced by antiepileptic drugs that stimulate the enzyme.
• Decreased incidence and sickle cell crisis severity in women with sickle cell disease.

The United Kingdom Department of Health has been actively promoting the use of Reversible contraceptives since 2008, especially for young people; following from the National Institutes for Health and Clinical Excellence guidelines in October 2005. Providing advice on these methods of contraception has been included in the 2009 "Good Practice" Quality and Results Framework for "good practice" for primary care.

Comparison

Proponents of bioidentic hormone therapy believe that progesterone offers fewer side effects and improves quality of life compared to MPA. The evidence for this view has been questioned; MPA is better absorbed when taken, with longer half-life of the terminal leading to a more stable blood level although it may cause greater breast pain and more sporadic vaginal bleeding. Both of these compounds do not distinguish their ability to suppress endometrial hyperplasia, or increase the risk of pulmonary embolism. Both drugs have not been adequately compared in direct tests to clear the conclusions about safety and excellence.

Available form

MPA is available alone in the form of 2.5, 5, and 10 mg oral tablets, as 150 mg/mL (1 mL) or 400 mg/mL (2.5 mL) of water suspension for intramuscular injection, and as 104 mg (0, 65Ã, mL of 160Ã, mg/mL) aqueous suspension for subcutaneous injection. It has also been reported to be marketed in oral tablets of 100, 200, 250, and 500 mg and as a 50 mg/mL water suspension for intramuscular injection. A 100 mg/mL water suspension for prior intramuscular injection is available. In addition to a single drug formulation, MPA is available in oral tablet form 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 usually not recommended because of unacceptable health risks or because it is not indicated in the following cases:

Conditions in which theoretical or proven risks are usually greater than the advantages of using Depo-Provera:

• Several risk factors for arterial cardiovascular disease
• deep venous thrombosis (DVT) or pulmonary embolism (PE)
• Migraine headaches with aura while using Depo-Provera
• Before evaluation of unexplained vaginal bleeding suspected as serious condition
• 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 tumor)
• The condition of concern for hypo-estrogenic effects and reducing HDL levels theoretically increases cardiovascular risk:
  • Hypertension with vascular disease
  • Current and history of ischemic heart disease
  • Stroke history
  • Diabetes for more than 20 years or with nephropathy/retinopathy/neuropathy or vascular disease

Conditions representing unacceptable health risks if Depo-Provera is used:

• Current or recent breast cancer (hormone-sensitive tumor)

Conditions in which use is not indicated and should not start:

• Pregnancy

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Side effects

In women, the most common side effects are acne, menstrual flow changes, drowsiness, and can cause birth defects if taken by a pregnant woman. Other common side effects include breast tenderness, increased facial hair, diminished head hair, difficulty falling or falling asleep, abdominal pain, and decreased or weight gain.

The Women's Health Initiative investigated the use of MPA and conjugate estrogens compared with placebo. This study was prematurely discontinued when previously unexpected risks were found, in particular the finding that although all the causes of death were not affected by hormone therapy, the benefits of menopausal hormone therapy (reduced risk of hip fractures, colorectal cancer and endometrium and all other causes of death) were offset by an increase risk of coronary heart disease, breast cancer, stroke and pulmonary embolism. However, this study focuses on MPA alone and extrapolates the benefit versus risk for all progestogens - a conclusion that has been challenged by some researchers as unjustifiable and leads to unnecessary HRT avoidance for many women because the progestogen is not the same.

At high doses for the treatment of breast cancer, MPA can cause weight gain, aggravate diabetes mellitus and edema (especially on the face). Side effects peaked at five weeks, and reduced by a lower dose. Rare effects may include thrombosis (although it is unclear whether this is a true risk, can not be excluded), painful urination, headache, nausea, and vomiting. When used to treat benign prostate hyperplasia, more frequent complaints include decreased libido, impotence, reduced ejaculation volume, and within three days, chemical castration. MPA can lead to reduced bone density even though this appears to be reversible to normal levels even after years of use. At very high doses (used to treat cancer, not for contraception) MPA can cause adrenal suppression and disrupt carbohydrate metabolism but not cause diabetes.

Fetuses exposed to progestogens have shown higher rates of genital abnormality, low birth weight, and increased ectopic pregnancy especially when MPA is used as a form of long-term birth control injections. When used as a form of birth control injected, the MPA can reduce fertility for 10 months, taking longer for women who are overweight or obese. 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 estrogen in general, MPA may increase the risk of cardiovascular disease, with a stronger relationship when used by postmenopausal women also using CEE. MPA is not recommended for use before menarche or before or during recovery from surgery. It is because of these unexpected interactions that the Women's Health Initiative study ends early because of the additional risk of menopausal hormone therapy, resulting in dramatic declines in new recipes and renewal for hormone therapy.

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

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

• It takes a 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.
• Does not offer protection against sexually transmitted diseases (STDs).
• Depo-Provera can affect menstrual bleeding. After one year of use, 55% of women had amenorrhea (missed period); after 2 years, the rate rose to 68%. In the first months of the use of "irregular or unpredictable bleeding or spotting, or, rarely, heavy or sustained bleeding" is reported.
• The return of fertility is delayed. The return of the average fertility is 9 to 10 months after the last injection. At 18 months after the last injection, fertility is the same as for other former users of the contraceptive method
• Long-term study of Depo-Provera users has found little or no increased risk of breast cancer overall. However, the study population did show a slightly increased risk of breast cancer in recent users (use of Depo in the last four years) under age 35, similar to that seen with combined oral contraceptive pill use.
• A study of unintentional pregnancies among poor women in Thailand found that infants who had been exposed to Depo-Provera during pregnancy had a higher risk for low birth weight and an 80% greater than usual chance to die in the year first. life.

Depression

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

In the largest study to assess the association between MPA and depression to date, in which more than 3,900 women were treated with DMPA for up to 7 years, the incidence of depression was rare at 1.5% and the rate of depression depression was 0.5% baseline data on depression, and as a result of the associated depression and discontinuation events observed in the study, the FDA requires package labels for DMPA stating that women with depression should be carefully observed and that DMPA should be stopped if depression recurs. A subsequent study of 495 women treated with DMPA for 1 year found that the average depression score slightly decreased in all the continuing user groups from 7.4 to 6.7 (9.5%) and decreased in the quintile of the group to the highest. depression scores at baseline from 15.4 to 9.5 (with 38%). Based on the results of this study and others, it has been said that consensus appears to be that DMPA does in fact not increase the risk of depression or worsen the severity of pre-existing depression.

Similarly, the case of DMPA for hormonal contraceptives, Cardiac Substitute and Estrogen/Progestin (HERS) Studies, a study of 2,763 postmenopausal women treated with 0.625 mg/day conjugated estrogen plus 2.5 mg/day oral MPA or placebo for 36 months as a method Menopausal hormone therapy, did not find any change in symptoms of depression. However, a small study of 48 women has reported that MPA may neutralize the positive effects of estrogen on depression.

Bone density

On November 17, 2004, the United States Food and Drug Administration alerted the black box on the label, indicating that there was a potential adverse effect 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 use is not restricted. The American College of Obstetricians and Gynecologists note that potential side-effects on BMD are offset by known negative effects of unwanted pregnancies using other birth control methods or no method, especially among teenagers.

Three studies have shown that bone loss is reversible after discontinuation of Depo-Provera. Other studies have shown that the medroxyprogesterone acetate effect by injection use in postmenopausal bone density is minimal, probably because Depo users experience less bone loss during menopause. Use after peak bone mass was associated with increased bone turnover but no decrease in bone mineral density.

The FDA recommends that medroxyprogesterone acetate with injections not be used for more than 2 years, unless there is no viable alternative contraceptive method, due to concerns over bone loss. However, the 2008 Committee of the American Congress of Obstetricians and Gynecologists (ACOG) recommends that healthcare providers who are concerned about bone mineral density loss should not prevent prescription or continue medroxyprogesterone acetate with injection beyond 2 years of use.

HIV risk

There is uncertainty about the risk of HIV transmission among users of MPA depots (DMPA); some observational studies show an increased risk, others do not. The World Health Organization issued a statement in February 2012 and July 2014 that said the data did not guarantee a change in their recommendations about no restrictions - Medical Eligibility for Contraception (MEC) category 1 - on the use of DMPA in women at high risk for HIV.

Two meta-analyzes of observational studies in sub-Saharan Africa were published in January 2015. They found an increase of 1.4 to 1.5 times the risk of HIV transmission for DMPA users compared with no use of hormonal contraceptives. In January 2015, Faculty of Letters & amp; Reproductive Health Care of the Royal College of Obstetricians and Gynecologists issued a statement confirming that there is no reason to suggest the use of DMPA in the UK even for 'high-risk' women infected with HIV. A systematic review and meta-analysis of the risk of HIV infection in DMPA users published in the fall of 2015 suggests that "epidemiological and biological evidence now makes an interesting case that DMPA significantly increases the risk of men-female HIV transmission."

A four-year, large-scale controlled trial of hormonal contraceptives and HIV in sub-Saharan Africa (to provide better evidence than the observational studies available today) planned to begin in 2015 has been controversial.

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Breastfeeding

MPA can be used by nursing mothers. Severe bleeding is possible if given in immediate postpartum time and should be delayed up to six weeks after birth. It can be used within five days if not breastfeeding. While a study showed "no significant difference in birth weight or incidence of birth defects" and "no significant immune change against infectious diseases caused by breastfeeding containing DMPA", a subgroup of infants whose mothers started Depo-Provera on 2 days postpartum had an incidence 75% higher than doctor's visit for infectious diseases during the first year of their life.

A larger study with longer follow-up concluded that "the use of DMPA during pregnancy or breastfeeding does not adversely affect long-term growth and development of children". The study also notes that "children with exposure to DMPA during pregnancy and breastfeeding have an increased risk of high growth that is not optimal," but that "after adjustment for socioeconomic factors with multiple logistic regression, there is no increased risk of growth disorders among DMPA - exposed children. "The study also notes that the effect of DMPA exposure on puberty requires further study, as so few children over the age of 10 are observed.

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Overdose

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

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Interactions

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

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Pharmacology

Pharmacodynamics

MPA acts as a progesterone, androgen and glucocorticoid receptor agonist (PR, AR, and GR, respectively), activating this receptor with an EC ₅₀ value of about 0.01 nM, 1 nM, and 10 nM , each. It has a negligible affinity for estrogen receptors. This drug has a relatively high affinity for mineralocorticoid receptors, but regardless, it has no mineralocorticoid activity or antimineralocorticoid activity. MPA intrinsic activity in activating PR and AR has been reported to be at least equivalent to progesterone and dihydrotestosterone (DHT), respectively, indicating that it is a full agonist of these receptors.

Action mechanism

The mechanism of action of progestogen contraceptives depends only on progestogen activity and dosage. High-dose progestogen contraceptives, such as DMPA injections, inhibit follicle development and prevent ovulation as the main mechanism of their action. Progestogens decrease the frequency of release of the gonadotropin-releasing hormone (GnRH) by the hypothalamus, which decreases the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary. A decrease in FSH levels inhibits follicle development, preventing elevated levels of estradiol. The progestogen negative feedback and lack of estrogen positive feedback on LH release prevent LH spikes. Inhibition of follicular development and the absence of LH waves prevent ovulation.

The secondary mechanism of action of all contraceptives containing progestogens is inhibition of sperm penetration by changes in cervical mucus.

Inhibition of ovarian function during DMPA use causes the endometrium to become thin and atrophy. These endometrial changes can, theoretically, prevent implantation. However, since DMPA is highly effective in inhibiting ovulation and sperm penetration, the chances of conception are negligible. There is no data supporting the prevention of implantation as a DMPA mechanism of action.

Progestogenic activity

MPA is a strong agonist of progesterone receptors with affinity and similar efficacy relative to progesterone. While both MPA and deacetylated analogue medroxyprogesterone bind and exclude PR, MPA has about 100 times higher affinity binding and potential transactivation in comparison. Thus, unlike MPA, medroxyprogesterone is not used clinically, although it has been used in veterinary medicine.

The oral dose of MPA required to inhibit ovulation (ie, effective dose of contraception) is 10 mg/day, whereas 5 mg/day is not sufficient to inhibit ovulation in all women. Accordingly, the dose of MPA used in oral contraceptives in the past was 10 mg per tablet. For comparison with MPA, the progesterone dose required to inhibit ovulation was 300 mg/day, whereas those from 19-nortestosterone norethisterone and norethisterone acetate derivatives were 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 hypothalamus-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonad (HPG) axes, results in suppression of gonadotropin, androgen, estrogen, adrenocorticotropic hormone (ACTH), and levels of cortisol and concentration of sex hormone binding globulin (SHBG). There is evidence that the downregulatory effects of MPA on the HPG axis are mediated by activation of PR and AR in the pituitary gland. Due to its effect on androgen levels, MPA has strong functional antiandrogen properties, and is used in androgen-sensitive conditions such as premature puberty in preteen and hypersexual men. In addition, because it affects the same level of estrogen, unlike many other antiandrogens such as spironolactone and cyproterone acetate which have a high tendency to cause gynecomastia through indirect estrogen stimulation, MPA is not considered to have an estrogenic effect. Indeed, because of its inhibitory effect on estrogen levels, it has a strong antiestrogenic effect, and has been used to treat premature puberty in preteen women. Thus, MPA should not be used in high doses without estrogen in women because of the risk of osteoporosis and other symptoms associated with hypoestrogenism.

Androgenic Activity

MPA is a powerful AR agonist. Its activation of AR has been shown to play an important and major role in its antigonadotropic effects and beneficial effects on breast cancer. However, although the MPA has the capacity to cause androgenic side effects such as acne and hirsutism in some patients (especially women), it is rare, and when it does, the effect tends to be mild, regardless of the dose used.. In fact, possibly due to its emphasis on androgen levels, it has been reported that MPA is generally very effective in improving the symptoms of hirsutism already present in women with the condition. In addition, MPA rarely causes androgenic effects in children with puberty prematurely, even at very high doses. The reason for the lack of virilizing effects with MPA, although binding and activating AR with high affinity and this act plays an important role in many of its physiological and therapeutic effects, is not entirely clear. However, MPA has been found to interact with AR in a way that is fundamentally different from other receptor agonists such as dihydrotestosterone (DHT). The result of this difference seems to be that the MPA binds to AR with the same intrinsic affinity and activity as DHT, but requires about 100 times higher concentrations for comparable gene transcription inductions while at the same time not in conflict with normal androgen transcription activities such as DHT at any concentration. Thus, this may explain the low propensity of MPA to produce androgenic side effects.

The MPA exhibits a weak androgenic effect on the synthesis of liver proteins, just like other weak androgenic progestin such as megestrol acetate and 19-nortestosterone derivatives. Although it does not conflict with elevated levels of triglycerides and estrogen-induced HDL cholesterol, MPA depots each week can lower HDL cholesterol levels. In addition, MPA has been found to suppress the production of sex hormone-binding globulin (SHBG) hepatic; at a dose of 10 mg/day of oral MPA, has been found to decrease SHBG levels in circulation by 14 to 18% in women taking oral estradiol valerate 4 mg/day.

Glucocorticoid activity

As a GR agonist, MPA has glucocorticoid activity, and as a result can cause symptoms of Cushing syndrome, steroidal diabetes, and adrenal insufficiency at high doses. It has been suggested that MPA can cause bone loss through its glucocorticoid activity.

Steroidogenesis inhibition

MPA has been found to act as a competitive inhibitor of rat 3-hydroxisteroid dehydrogenase (3? -HSD). This enzyme is important for the transformation of progesterone, deoxycorticosterone, and DHT into neurosteroid inhibitors such as allopregnanolone, THDOC , and 3? -androstanediol, respectively. MPA has been described as very potent in its inhibition in rat 3? -HSD, with IC ₅₀ 0.2Ã,? M and K _i (in testicular homogenate mice) 0.42Ã,? M. However, it should be noted that the 3 inhibition? -HSD by MPA appears to be unconfirmed using human proteins, and the concentration required with rat proteins is well above typical human therapeutic concentrations.

MPA has been identified as a competitive human inhibitor of 3-hydroxysteroid dehydrogenase/? ^5-4 isomerase II (3? -HSD II). This enzyme is essential for the biosynthesis of sex steroids and corticosteroids. K _i MPA for inhibition 3? -HSD II is 3.0Ã,? M, and this concentration is reported to be near the level of drug circulation achieved with very high MPA 5 therapy doses. up to 20 mg/kg/day (dose 300 to 1,200 mg/day for 60 kg (132 pounds)). Apart from 3? -HSD II, other steroidogenic human enzymes, including cholesterol side cleavage enzymes (P450scc/CYP11A1) and 17? -hydroxylase/17,20-lyase (CYP17A1), not found to be inhibited by MPA. MPA has been found to be effective in the treatment of early gonadotropin-independent puberty and in breast cancer in postmenopausal women with high doses, and inhibition of 3? -HSD II may be responsible for its effectiveness under these conditions.

GABA _A allosteric modulation receptor

Progesterone, through transformation into a neurosteroid like 5? -dihydroprogesterone, 5? -dihydroprogesterone, allopregnanolone, and pregnanolone (catalyzed by the enzymes 5 "- and 5" -reductase and 3? - and 3? -HSD), are all positive alpha receptor modulators GABA _A , and are associated with various effects mediated by this property including dizziness, sedation, hypnotic state, mood swings, ansiolysis, and cognitive/memory impairment, as well as effectiveness as anticonvulsants in the treatment of catamenial epilepsy. It has also been found to produce anesthesia through this action in animals when given at a fairly high dose. MPA was found to significantly reduce the incidence of seizures when added to existing anticonvulsant regimens in 11 of 14 women with uncontrolled epilepsy, and has also been reported to induce anesthesia in animals, increasing the likelihood that it may modulate GABA _A receptor is the same as progesterone.

MPA shares some of the same progesterone metabolic route and, analogously, can be converted into metabolites such as 5? -dihydro-MPA (DHMPA) and 3?, 5? -tetrahydro-MPA (THMPA). However, unlike decreased progesterone metabolites, DHMPA and THMPA have been found to not modulate GABA receptors _A . Conversely, unlike progesterone, the MPA itself actually modulates the GABA receptor _A , although not in the neurosteroid binding site. However, instead of acting as a receptor potential, the MPA seems to act as a negative allosteric modulator. While reducing the progesterone metabolite increases the binding of flunitrazepam benzodiazepine to an in vitro recipe GABA _{A in vitro , MPA may inhibit some of the binding of flunitrazepam by up to 40% by half-inhibition to a maximum of 1 °, M. However, the MPA concentrations required for inhibition are relatively high against therapeutic concentrations, and therefore, these measures may have little or no clinical relevance. The lack of potential GABA receptor A by MPA or its metabolites is staggering by considering the obvious anticonvulsant and anesthetic effects of the MPA described above, and they remain unexplained.}

Clinical studies using large doses of up to 5,000 mg/day of oral MPA and 2,000 mg/day of intramuscular MPA for 30 days in women with advanced breast cancer have reported "no relevant side effects", indicating that the MPA has no significant immediate action. on the recipe GABA _A in humans even at very high doses.

Appetite Stimulation

Although MPA and the closely related megestrol acetate drug is an effective appetite stimulant at very high doses, the mechanism of action of its beneficial effects on appetite is not entirely clear. However, glucocorticoids, cytokines and possibly anabolic-related mechanisms are all considered to be involved, and a number of downstream changes have been involved, including stimulation of neuropeptide Y release in the hypothalamus, calcium channel modulation in the ventromedial hypothalamus, and inhibition of proinflammatory cytokine secretion including IL-1? , IL-1 ?, IL-6, and TNF-?, Actions that have all been associated with increased appetite.

Pharmacokinetics

Absorption

The oral bioavailability of the 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 MPA circulation rates, with steady-state concentrations reached after three days and peak concentrations occurring 1.5 to 2 hours after consumption. With 2.5 mg/day MPA, the drug level was 0.3 ng/mL (0.8 nmol/L) in women under 60 years and 0.45 ng/mL (1.2 nmol/L) in women 65 years of age or older, and with 5 mg/day MPA, a level of 0.6 ng/mL (1.6 nmol/L) in women under 60 years and in women aged 65 years or older. Therefore, the area under the treatment rate curve is 1.6 to 1.8 times higher in those aged 65 years or older than those aged 60 years or younger. Thus, MPA levels have been found to vary with age, and MPA may have an increased risk of adverse events in postmenopausal elderly women.

With intramuscular administration of MPA doses of 150 mg, this drug can be detected in circulation within 30 minutes, serum concentrations vary but generally reach 1.0 ng/mL (2.6 nmol/L) for 3 months. After this, there is a gradual decrease in MPA levels, and drugs can be detected in circulation for nine months after injection.

Distribution

In circulation, 88% of MPA is weakly bound to albumin, without binding sex hormone binding globulin or corticosteroid binding globulin.

Metabolism

The half-life of the MPA terminal through oral administration has been reported to be either 11.6 to 16.6 hours and 33 hours, while the half-life of the terminal with intramuscular and subcutaneous injections is 50 and 40 days respectively. MPA metabolism primarily through hydroxylation, including the positions C6 ?, C21, C2 ?, and C1 ?, is mediated primarily through CYP3A4, but 3 and 5-dihydro and 3,5-tetrahydro metabolites of MPA are also formed. Deacetylation of MPA and its metabolites (into, for example, medroxyprogesterone) has been observed in non-human primate studies up to substantial levels as well (30 to 70%). MPA and/or metabolites are also metabolized through conjugation. C6? methyl and C17? the MPA acetoxy group makes it more resistant to metabolism and allows for higher bioavailability than oral progesterone.

Elimination

MPA is removed from 20 to 50% in urine and 5 to 10% in stool after intravenous administration. Less than 3% of doses are excreted in unconjugated form.

The relationship between concentration and effects

With intramuscular administration, high levels of MPA in the blood inhibit luteinizing hormone and ovulation for several months, with a decrease in serum progesterone to below 0.4 ng/mL. Ovulation is continued when once the blood MPA level falls below 0.1 ng/mL. The serum estradiol remained at about 50 pg/mL for about four months after injection (with a range of 10-92 pg/mL after several years of use), increasing as MPA levels fell 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 wrinkled. The endometrium develops atrophy, with a small straight gland and a decadimized stroma. Cervical mucus remains thick. Because of its long-term stable blood levels and various effects that prevent conception, the MPA is a very effective birth control tool.

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Chemistry

MPA is a synthetic pregnancy steroid and a progesterone derivative and 17? -hydroxyprogesterone. Specifically, it is a 17-estet ester of medroxyprogesterone or 6? -metal 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 contraction 6? -metil-17? -hydroxyprogesterone acetate. MPA is closely related to other 17-hydroxyprogesterone derivatives such as chlormadinone acetate, cyproterone acetate, and megestrol acetate, as well as medrogestone and nomegestrol acetate.

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History

The MPA was found independently in 1956 by Syntex and Upjohn Company. It was first introduced on June 18, 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. The intramuscular formulation, Depo-Provera (400 mg/mL MPA), was also introduced in 1960 in the US for the treatment of endometrial and kidney cancers. MPA in combination with ethinylestradiol was introduced in 1964 by Upjohn in the United States under the brand name Provest (10 mg MPA and 50g ethinylestradiol tablets) as an oral contraceptive, but the formulation was discontinued in 1970. This formulation was marketed by Upjohn outside of the US under the name Provestral and Provestrol brands, while Cyclo-Farlutal (or Ciclofarlutal) and Nogest-S are formulations available outside the US at different doses (tablets 5 mg MPA and 50 or 75Ã, ethinylestradiol).

Upjohn also sought the approval of the intramuscular MPA as a long-term contraceptive under the brand name Depo-Provera (150mg/mL MPA) but the application was rejected in 1967. 1978 , and again in 1983. However, in 1992, the drug was finally approved by the FDA for this indication. Subcutaneous formulations were introduced in the US under the brand name Depo-SubQ Provera 104 (104Ã, mg/0.65Ã, mL MPA) in December 2004 as contraceptives, and then also approved for treatment of pelvic pain associated with endometriosis. MPA has also been widely marketed worldwide as Provera and Depo-Provera as well as Farlutal, Perlutex, and Gestapuran, among many other brand names.

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Society and culture

Common names

Medroxyprogesterone acetate is the generic name of the drug and INN , USAN , < abbr title = "English Name Approved"> BAN , and JAN , while medrossiprogesterone is DCF of its free alcohol form. It is also known as 6? -methyl-17? -acetoxyprogesterone ( MAP ) or 6? -methyl-17? -hydroxyprogesterone acetate .

Brand name

MPA is marketed under a large number of worldwide brand names. Its most prominent brand name is Provera as an oral tablet and Depo-Provera as an aqueous suspension for intramuscular injection. The MPA formulation as an aqueous suspension for subcutaneous injection is also available in the United States under the brand name Depo-SubQ Provera 104. Other proprietary MPA brand names include Farlutal and Sayana for clinical use and Depo-Promone, Perlutex, Promone -E and Veramix for animal use. In addition to a single drug formulation, MPA is marketed in combination with estrogen, the most commonly conjugated estrogen, but also estradiol. The brand names of MPA in combination with conjugated estrogens as oral tablets in various countries include Prempro, Premphase, Premique, Premia, and Premelle. The brand names of MPA in combination with estradiol as oral tablets include Indivina and Tridestra.

Availability

United States

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

• Oral Pills: Amine, Curretab, Cycrin, Provera - 2.5 mg, 5 mg, 10 mg
• Aqueous suspension for intramuscular injection: Depo-Provera - 150Ã, mg/mL (for contraception), 400Ã, mg/mL (for cancer)
• Aqueous suspension for subcutaneous injection: Depo-SubQ Provera 104 - 104Ã, mg/0.65Ã, mL (for contraception)

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

While the following formulation has been discontinued:

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

Formulation

Depo-Provera is the brand name for injection 150A mg DMPA depot medroxyprogesterone acetate . This is applied in the form of intramuscular injection. Shots should be injected into the thighs or buttocks or deltoids four times a year (every 11 to 13 weeks) and provide immediate pregnancy protection after the first injection. It was approved in the United States by the FDA for contraceptive use on October 29, 1992, and for the management of endometriosis-associated pain on March 25, 2005. Depo-subQ Provera 104 , also produced by Pfizer, is a variation of the original Depot Shot which is a subcutaneous injection of 104 mg. It contains 69 percent of the progestin found in the original Depo-Provera shot. It can be injected using a smaller hypodermic needle inserting the hormones just under the skin, not to the muscles, either in the stomach or thighs. This subcutaneous injection claims to reduce the side effects of progestin while retaining all the same benefits from the original Depo shot.

Controversy

Outside the United States

In 1994, when the Depo was approved in India, India's Weekly Economy and Politics reported that "the FDA eventually licensed the drug in 1990 in response to concerns about population explosions in the world's third and the reluctance third-world governments to license unlicensed drugs in their home countries. "Some scientists and women's groups in India continue to oppose Depo-Provera. In 2002, Depo was excluded from the family planning protocol in India.

The Canadian coalition in Depo-Provera, a coalition of professional groups and women's health advocates, opposes Depo's approval in Canada. Since the approval of the Depo in Canada in 1997, a $ 700 million class action suit has been filed against Pfizer by Depo users who developed osteoporosis. In response, Pfizer believes that it has fulfilled its obligation to disclose and discuss the risks of Depo-Provera with the Canadian medical community.

Clinical trials for this drug about women in Zimbabwe are controversial with regard to human rights abuses and Medical Experiments in Africa.

A controversy erupted in Israel when the government was accused of granting Depo-Provera to Ethiopian immigrants without their consent. Some women claim to be told that it is a vaccination. The Israeli government denied the allegations but instructed four health care organizations to stop giving Depo-Provera injections to women "if there is little doubt that they have not understood the implications of treatment".

United States

Source of the article : Wikipedia