Depot Medroxyprogesterone Acetate
   HOME

TheInfoList



OR:

Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the
progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...
type. It is used as a method of
birth control Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...
and as a part of
menopausal hormone therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...
. It is also used to treat
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
,
abnormal uterine bleeding Abnormal uterine bleeding is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term "dysfunctional uterine bleeding" was used when no underlying cause was presen ...
,
paraphilia A paraphilia is an experience of recurring or intense sexual arousal to atypical objects, places, situations, fantasies, behaviors, or individuals. It has also been defined as a sexual interest in anything other than a legally consenting human ...
, and certain types of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. The medication is available both alone and in combination with an
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
. It is taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
, used under the tongue, or by injection into a muscle or
fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers specif ...
. Common
side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...
s include
menstrual disturbance A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, ...
s such as absence of periods,
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
, and
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s. More serious side effects include bone loss,
blood clot A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
s,
allergic reaction Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...
s, and
liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
. Use is not recommended during
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
as it may harm the baby. MPA is an
artificial Artificiality (the state of being artificial, anthropogenic, or man-made) is the state of being the product of intentional human manufacture, rather than occurring naturally through processes not involving or requiring human activity. Connotati ...
progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...
, and as such activates the
progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...
, the
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
of
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
. It also has
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
ic activity and weak
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
activity. Due to its progestogenic activity, MPA decreases the body's release of
gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...
s and can suppress
sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
levels. It works as a form of birth control by preventing
ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...
. 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 WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. MPA is the most widely used progestin in menopausal hormone therapy and in progestogen-only birth control. DMPA is approved for use as a form of long-acting birth control in more than 100 countries. In 2022, it was the 276th most commonly prescribed medication in the United States, with more than 800,000 prescriptions.


Medical uses

The most common use of MPA is in the form of DMPA as a long-acting progestogen-only injectable contraceptive to prevent pregnancy in women. It is an extremely effective
contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...
when used with relatively high doses to prevent
ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...
. MPA is also used in combination with an estrogen in
menopausal hormone therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...
in
postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women to treat and prevent
menopausal symptoms Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
such as
hot flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...
es, vaginal atrophy, and
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. It is used in menopausal hormone therapy specifically to prevent
endometrial hyperplasia Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus. Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of th ...
and
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
that would otherwise be induced by prolonged unopposed estrogen therapy in women with intact
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
es. In addition to contraception and menopausal hormone therapy, MPA is used in the treatment of gynecological and
menstrual disorder A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, ...
s such as
dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in th ...
,
amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
, and
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
. Along with other progestins, MPA was developed to allow for oral progestogen therapy, as
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
(the progestogen hormone made by the human body) could not be taken orally for many decades before the process of
micronization Micronization is the process of reducing the average diameter of a solid material's particles. Traditional techniques for micronization focus on mechanical means, such as milling and grinding. Modern techniques make use of the properties of superc ...
was developed and became feasible in terms of
pharmaceutical manufacturing Pharmaceutical manufacturing is the process of industrial-scale synthesis of pharmaceutical drugs as part of the pharmaceutical industry. The process of drug manufacturing can be broken down into a series of unit operations, such as milling, gr ...
. DMPA reduces
sex drive In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...
in men and is used as a form of
chemical castration Chemical castration is castration via anaphrodisiac drugs, whether to reduce libido and sexual activity, management of cancer, to treat cancer, or otherwise. Unlike orchiectomy, surgical castration, where the gonads are removed through an incision ...
to control inappropriate or unwanted sexual behavior in those with
paraphilia A paraphilia is an experience of recurring or intense sexual arousal to atypical objects, places, situations, fantasies, behaviors, or individuals. It has also been defined as a sexual interest in anything other than a legally consenting human ...
s or
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
, including in convicted
sex offender A sex offender (sexual offender, sex abuser, or sexual abuser) is a person who has committed a Sex and the law, sex crime. What constitutes a sex crime differs by culture and legal jurisdiction. The majority of convicted sex offenders have convi ...
s. DMPA has also been used to treat
benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, urinary retention, inability t ...
, as a
palliative Palliative care (from Latin root "to cloak") is an interdisciplinary medical care-giving approach aimed at optimizing quality of life and mitigating or reducing suffering among people with serious, complex, and often terminal illnesses. Man ...
appetite stimulant An orexigenic, or appetite stimulant, is a drug, hormone, or chemical compound, compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropep ...
for
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
patients, and at high doses (800 mg per day) to treat certain hormone-dependent cancers including
endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...
, renal cancer, and
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
. MPA has also been prescribed in
feminizing hormone therapy Feminizing hormone therapy, also known as transfeminine hormone therapy, is a form of Transgender_health_care#Gender-affirming_care , gender-affirming care and a gender-affirming hormone therapy , gender-affirming hormone therapy to change t ...
for
transgender women A trans woman or transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity and may experience gender dysphoria (distress brought upon by the discrepancy between a person's gender identity and their ...
due to its
progestogen Progestogens, also sometimes written progestins, progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestoge ...
ic and functional
antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...
ic effects. It has been used to delay puberty in children with
precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. There is early developm ...
but is not satisfactory for this purpose as it is not able to completely suppress puberty (specifically, it does not fully halt skeletal maturation and hence does not sufficiently resolve the reduced height at adulthood). DMPA at high doses has been reported to be definitively effective in the treatment of
hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...
as well. Though not used as a treatment for
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, MPA has been found to reduce the frequency of
seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
and does not interact with
antiepileptic Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatmen ...
medications. MPA does not interfere with
blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
and appears to improve blood parameters for women with
sickle cell anemia Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying ...
. Similarly, MPA does not appear to affect
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
, and may improve
primary biliary cirrhosis Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to buil ...
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 Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
(absence of
menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...
) can occur as can
irregular menstruation Irregular menstruation is a menstrual disorder whose manifestations include irregular cycle lengths as well as metrorrhagia ( vaginal bleeding between expected periods). The possible causes of irregular menstruation may vary. The common factors ...
which is a major source of dissatisfaction, though both can result in improvements with
iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...
and risk of
pelvic inflammatory disease Pelvic inflammatory disease (PID), also known as pelvic inflammatory disorder, is an infection of the upper part of the female reproductive system, mainly the uterus, fallopian tubes, and ovaries, and inside of the pelvis. Often, there may be no ...
and often do not result in discontinuation of the medication.


Birth control

DMPA, under brand names such as Depo-Provera and Depo-SubQ Provera 104, is used in
hormonal birth control Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...
as a long-lasting progestogen-only injectable contraceptive to prevent pregnancy in women. It is given by
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
or
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
and forms a long-lasting depot, from which it is slowly released over a period of several months. It takes one week to take effect if given after the first five days of the period cycle, and is effective immediately if given during the first five days of the period cycle. Estimates of first-year failure rates are about 0.3%.


Effectiveness

Trussell's estimated ''perfect use'' first-year failure rate for DMPA 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 DMPA defined as being no longer than 14 or 15 weeks after an injection (i.e., no more than 1 or 2 weeks late for a next injection). Prior to 2004, Trussell's ''typical use'' failure rate for DMPA was the same as his ''perfect use'' failure rate: 0.3%. * DMPA 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 The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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 DMPA from 0.3% to 3%. * DMPA 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 DMPA) 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.


Advantages

DMPA has a number of advantages and benefits: * 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 Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
. No increased risk of
deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...
,
pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...
,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
, or
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
. * Minimal
drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...
s (compared to other hormonal contraceptives). * Decreased risk of
endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...
. DMPA reduces the risk of endometrial cancer by 80%. The reduced risk of endometrial cancer in DMPA 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 Iron-deficiency anemia is anemia caused by a lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as feeling tired, weak, sh ...
, pelvic inflammatory disease (PID) and
ectopic pregnancy Ectopic pregnancy is a complication of pregnancy in which the embryo attaches outside the uterus. Signs and symptoms classically include abdominal pain and vaginal bleeding, but fewer than 50 percent of affected women have both of these sympto ...
. * Decreased symptoms of
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
. * Decreased incidence of primary dysmenorrhea, ovulation pain, and functional ovarian cysts. * Decreased incidence of
seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
in women with
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
. Additionally, unlike most other hormonal contraceptives, DMPA'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 Long-acting reversible contraceptives (LARC) are methods of birth control that provide effective contraception for an extended period without requiring user action. They include hormonal and non-hormonal intrauterine devices (IUDs) and subdermal ...
use since 2008, particularly for young people; following on from the October 2005
National Institute for Health and Clinical Excellence The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care. As the national health technology assessment body of England, it is responsible for j ...
guidelines. Giving advice on these methods of contraception has been included in the 2009
Quality and Outcomes Framework The Quality and Outcomes Framework (QOF) is a system for the performance management and payment of general practitioners (GPs) in the National Health Service (NHS) in England, Wales, Scotland and Northern Ireland. It was introduced as part of a n ...
"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
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
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 Endometrial hyperplasia is a condition of excessive proliferation of the cells of the endometrium, or inner lining of the uterus. Most cases of endometrial hyperplasia result from high levels of estrogens, combined with insufficient levels of th ...
, nor does either increase the risk of
pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...
. 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 The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...
tablets, as a 150 mg/mL (1 mL) or 400 mg/mL (2.5 mL)
microcrystalline A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination. There is little agreement on the range of crystal sizes that should be regarded as microcrystalline, but ...
aqueous suspension for
intramuscular injection Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...
, and as a 104 mg (0.65 mL of 160 mg/mL) microcrystalline aqueous suspension for
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
. It has also been marketed in the form of 100, 200, 250, 400, and 500 mg oral tablets; 500 and 1,000 mg oral suspensions; and as a 50 mg/mL microcrystalline aqueous suspension for intramuscular injection. A 100 mg/mL microcrystalline aqueous suspension for intramuscular injection was previously available as well. In addition to single-drug formulations, MPA is available in the form of oral tablets in combination with
conjugated estrogens Conjugated estrogens (CEs), or conjugated equine estrogens (CEEs), sold under the brand name Premarin among others, is an estrogen medication which is used in menopausal hormone therapy and for various other indications. It is a mixture of th ...
(CEEs),
estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
, and
estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...
for use in menopausal hormone therapy, and is available in combination with estradiol cypionate in a microcrystalline aqueous suspension as a combined injectable contraceptive. Depo-Provera is the brand name for a 150 mg microcrystalline aqueous suspension of DMPA that is administered by intramuscular injection. The shot must be injected into thigh, buttock, or deltoid muscle four times a year (every 11 to 13 weeks), and provides pregnancy protection instantaneously after the first injection. Accessed 13 October 2009. Depo-subQ Provera 104 is a variation of the original intramuscular DMPA that is instead a 104 mg microcrystalline dose in aqueous suspension administered by subcutaneous injection. It contains 69% of the MPA found in the original intramuscular DMPA formulation. It can be injected using a smaller injection needle inserting the medication 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 DMPA while still maintaining all the same benefits of the original intramuscular DMPA.


Contraindications

MPA 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 DMPA: * Multiple risk factors for
arterial An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
* Current
deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...
or
pulmonary embolus Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
*
Migraine headache Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...
with aura while using DMPA * Before evaluation of unexplained vaginal bleeding suspected of being a serious condition * A history of
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
and no evidence of current disease for five years * Active
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
: (acute viral hepatitis, severe decompensated
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
,
benign Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
or
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
liver tumours) * Conditions of concern for estrogen deficiency and reduced HDL levels theoretically increasing cardiovascular risk: **
Hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
with
vascular disease Vascular disease is a class of diseases of the vessels of the circulatory system in the human body, body, including blood vessels – the arteries and veins, and the lymphatic vessels. Vascular disease is a subgroup of cardiovascular disease. Diso ...
** Current and history of
ischemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the ...
** History of
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
**
Diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
for over 20 years or with
nephropathy Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipap ...
/
retinopathy Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically in ...
/
neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
or
vascular disease Vascular disease is a class of diseases of the vessels of the circulatory system in the human body, body, including blood vessels – the arteries and veins, and the lymphatic vessels. Vascular disease is a subgroup of cardiovascular disease. Diso ...
Conditions which represent an unacceptable health risk if DMPA is used: * Current or recent
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
(a hormonally sensitive tumour) Conditions where use is not indicated and should not be initiated: *
Pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
MPA is not recommended for use prior to
menarche Menarche ( ; ) is the first menstrual cycle, or first menstruation, menstrual bleeding, in female humans. From both social and medical perspectives, it is often considered the central event of female puberty, as it signals the possibility of fe ...
or before or during recovery from
surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...
.


Side effects

In women, the most common
adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s of MPA are acne, changes in menstrual flow, drowsiness, and can cause
birth defect A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...
s if taken by pregnant women. Other common side effects include
breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a ...
, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain. Lowered
libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...
has been reported as a side effect of MPA in women. DMPA can affect menstrual bleeding. After a year of use, 55% of women experience
amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
(missed periods); after two 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. MPA does not appear to be associated with
vitamin B12 deficiency Vitamins are organic molecules (or a set of closely related molecules called vitamers) that are essential to an organism in small quantities for proper metabolic function. Essential nutrients cannot be synthesized in the organism in suff ...
. Data on weight gain with DMPA likewise are inconsistent. At high doses for the treatment of breast cancer, MPA can cause weight gain and can worsen
diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...
and
edema Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
(particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include
thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...
(though it is not clear if this is truly a risk, it cannot be ruled out), painful urination,
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, and
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
. When used as a form of
androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen, androgen hormones, ...
in men, more frequent complaints include reduced
libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...
,
impotence Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
, reduced
ejaculate Ejaculation is the discharge of semen (the ''ejaculate''; normally containing sperm) from the penis through the urethra. It is the final stage and natural objective of male sexual stimulation, and an essential component of natural concepti ...
volume, and within three days,
chemical castration Chemical castration is castration via anaphrodisiac drugs, whether to reduce libido and sexual activity, management of cancer, to treat cancer, or otherwise. Unlike orchiectomy, surgical castration, where the gonads are removed through an incision ...
. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression and may interfere with carbohydrate metabolism, but does not cause
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
. When used as a form of injected birth control, there is a delayed return of
fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...
. The average return to fertility is 9 to 10 months after the last injection, taking longer for overweight or obese women. By 18 months after the last injection, fertility is the same as that in former users of other contraceptive methods.
Fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...
es exposed to progestogens have demonstrated higher rates of genital abnormalities, low birth weight, and increased
ectopic pregnancy Ectopic pregnancy is a complication of pregnancy in which the embryo attaches outside the uterus. Signs and symptoms classically include abdominal pain and vaginal bleeding, but fewer than 50 percent of affected women have both of these sympto ...
particularly when MPA is used as an injected form of long-term birth control. A study of accidental pregnancies among poor women in Thailand found that infants who had been exposed to DMPA 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. There were noticeable adverse effects to the cardiovascular system of those who took the treatment. It was also found that after the user had stopped taking the treatment, bone density changes were observed The formation of meningiomas due to the treatment have been the subject of lawsuits. Blood pressure changes were observed in addition to bone density changes.


Mood changes

There have been concerns about a possible risk of depression and mood changes with progestins like MPA, and this has led to reluctance of some clinicians and women to use them. However, contrary to widely-held beliefs, most research suggests that progestins do not cause adverse psychological effects such as depression or
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
. A 2018 systematic review of the relationship between progestin-based contraception and depression included three large 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 due to the incidence of depression 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, a consensus began 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 oral CEEs plus 2.5 mg/day oral MPA or placebo for 36 months as a method of
menopausal hormone therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...
, found no change in depressive symptoms. However, some small studies have reported that progestins like MPA might counteract beneficial effects of estrogens against depression.


Long-term effects

The
Women's Health Initiative The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three ...
investigated the use of a combination of oral CEEs and MPA 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 A hip fracture is a break that occurs in the upper part of the femur (thigh bone), at the femoral neck or (rarely) the femoral head. Symptoms may include pain around the hip, particularly with movement, and shortening of the leg. Usually ...
, colorectal and
endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the epithelium, lining of the uterus or womb). It is the result of the abnormal growth of cells (biology), cells that can invade or spread to other parts of the body. The first s ...
and all other causes of death) were offset by increased risk of
coronary heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
,
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
s and
pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...
. When combined with CEEs, MPA has been associated with an increased risk of breast cancer,
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, and
thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
in the eye. In combination with estrogens in general, MPA may increase the risk of
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
, with a stronger association when used by
postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women also taking CEEs. It was because of these unexpected interactions that the
Women's Health Initiative The Women's Health Initiative (WHI) was a series of clinical studies initiated by the U.S. National Institutes of Health (NIH) in 1991, to address major health issues causing morbidity and mortality in postmenopausal women. It consisted of three ...
study was ended early due to the extra risks of
menopausal hormone therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. Effects of menopause can include symptoms such ...
, resulting in a dramatic decrease in both new and renewal prescriptions for hormone therapy. Long-term studies of users of DMPA 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 (DMPA use in the last four years) under age 35, similar to that seen with the use of
combined oral contraceptive pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be Oral administration, taken orally by women. It is the oral form of combi ...
s.


Blood clots

DMPA has been associated in multiple studies with a higher risk of
venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...
(VTE) when used as a form of progestogen-only birth control in premenopausal women. The increase in incidence of VTE ranges from 2.2-fold to 3.6-fold. Elevated risk of VTE with DMPA is unexpected, as DMPA has little or no effect on
coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
and
fibrinolytic factor Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...
s, and progestogens by themselves normally do not increase the risk of thrombosis. It has been argued that the higher incidence with DMPA has reflected preferential prescription of DMPA to women considered to be at an increased risk of VTE. Alternatively, it is possible that MPA may be an exception among progestins in terms of VTE risk. A 2018
meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
reported that MPA was associated with a 2.8-fold higher risk of VTE than other progestins. It is possible that the
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
activity of MPA may increase the risk of VTE.


Bone density

DMPA may cause reduced
bone density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although medicine#Clinical practice, clinically it is measured by ...
in premenopausal women and in men when used without an estrogen, particularly at high doses, though this appears to be reversible to a normal level even after years of use. On 17 November 2004, the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
put a
black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...
on the label, indicating that there were potential adverse effects of loss of bone mineral density. While it causes temporary bone loss, most women fully regain their bone density after discontinuing use. The
World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(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 DMPA. Other studies have suggested that the effect of DMPA use on postmenopausal bone density is minimal, perhaps because DMPA 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 DMPA not be used for longer than two 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 DMPA beyond two years of use.


HIV risk

There is uncertainty regarding the risk of HIV acquisition among DMPA users; some observational studies suggest an increased risk of HIV acquisition among women using DMPA, while 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." In 2019, a randomized controlled trial found no significant association between DMPA use and HIV.


Breastfeeding

MPA may be used by
breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
mothers. Heavy bleeding is possible if given in the immediate
postpartum The postpartum (or postnatal) period begins after childbirth and is typically considered to last for six to eight weeks. There are three distinct phases of the postnatal period; the acute phase, lasting for six to twelve hours after birth; the ...
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 DMPA at two 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.


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 Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...
issues described. Overdose is not described in the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(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 Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
and
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
,
drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
,
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
, and withdrawal bleeding. According to the label, treatment of overdose should consist of discontinuation of MPA therapy and symptomatic care.


Interactions

MPA increases the risk of
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
,
dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, and
thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
when used in combination with CEEs to treat
menopausal symptoms Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
. When used as a contraceptive, MPA does not generally interact with other medications. The combination of MPA with
aminoglutethimide Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. ...
to treat
metastases Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
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 Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
.


Pharmacology


Pharmacodynamics

MPA acts as an
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
,
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
, and
glucocorticoid receptor The glucocorticoid receptor (GR or GCR) also known by its gene name ''NR3C1'' ( nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol. The GR is expressed in almost every cell in the bod ...
s (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 Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
for the
estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...
. The medication has relatively high affinity for the
mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...
, but in spite of this, it has no
mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary ...
or
antimineralocorticoid A mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which receptor antagonist, antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive t ...
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 Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...
(DHT), respectively, indicating that it is a
full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...
of these receptors.


Progestogenic activity

MPA is a potent
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
of the
progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...
with similar
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
and
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...
relative to
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
. While both MPA and its deacetylated analogue
medroxyprogesterone Medroxyprogesterone (MP), is a progestin which is not used medically. A derivative, medroxyprogesterone acetate (MPA), is used as a medication in humans, and is far more widely known in comparison. ''Medroxyprogesterone'' is sometimes used as a ...
bind to and agonize the PR, MPA has approximately 100-fold higher
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
and transactivation potency in comparison. As such, unlike MPA, medroxyprogesterone is not used clinically, though it has seen some use in
veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...
. The oral dosage of MPA required to inhibit
ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...
(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 Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
required to inhibit ovulation is 300 mg/day, whereas that of the
19-nortestosterone Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionat ...
derivatives
norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...
and norethisterone acetate is only 0.4 to 0.5 mg/day. The mechanism of action of progestogen-only contraceptives like DMPA depends on the progestogen activity and dose. High-dose progestogen-only contraceptives, such as DMPA, inhibit follicular development and prevent
ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...
as their primary mechanism of action. The progestogen decreases the pulse frequency of
gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...
(GnRH) release by the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, which decreases the release of
follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, puberty, pubertal maturat ...
(FSH) and
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...
(LH) by the
anterior pituitary The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
. Decreased levels of FSH inhibit follicular development, preventing an increase in
estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
levels. Progestogen
negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...
and the lack of
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
positive feedback Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop where the outcome of a process reinforces the inciting process to build momentum. As such, these forces can exacerbate the effects ...
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 Sperm (: sperm or sperms) is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm ...
penetration by changes in the
cervical mucus The cervix (: cervices) or cervix uteri is a dynamic fibromuscular sexual organ of the female reproductive system that connects the vagina with the uterine cavity. The human female cervix has been documented anatomically since at least the tim ...
. Inhibition of ovarian function during DMPA use causes the
endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...
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 Fertilisation or fertilization (see American and British English spelling differences#-ise, -ize (-isation, -ization), spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give ...
is negligible. No available data support prevention of implantation as a mechanism of action of DMPA.


Antigonadotropic and anticorticotropic effects

MPA suppresses the hypothalamic–pituitary–adrenal (HPA) and hypothalamic–pituitary–gonadal (HPG)
axes Axes, plural of ''axe'' and of ''axis'', may refer to * ''Axes'' (album), a 2005 rock album by the British band Electrelane * a possibly still empty plot (graphics) See also * Axis (disambiguation) An axis (: axes) may refer to: Mathematics ...
at sufficient dosages, resulting decreased levels of
gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. They are central to the complex endocrine system that regulates normal growth, sexual development, and reproductive function. T ...
s,
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s,
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
s,
adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...
(ACTH), and
cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...
, as well as levels of
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
(SHBG). There is evidence that the suppressive effects of MPA on the HPG axis are mediated by activation of both the PR and the AR in the
pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...
. Due to its effects on androgen levels, MPA can produce strong functional
antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...
ic effects, and is used in the treatment of
androgen-dependent condition An androgen-dependent condition, disease, disorder, or syndrome, is a medical condition that is, in part or full, dependent on, or is sensitive to, the presence of androgenic activity in the body. Known androgen-dependent conditions include acne ...
s such as
precocious puberty In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. There is early developm ...
in boys and
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
in men. In addition, since the medication suppresses estrogen levels as well, MPA can produce strong functional antiestrogenic effects similarly, and has been used to treat estrogen-dependent conditions such as precocious puberty in girls and
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
in women. Due to low estrogen levels, the use of MPA without an estrogen poses a risk of decreased
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to opti ...
and other symptoms of estrogen deficiency. Oral MPA has been found to suppress testosterone levels in men by about 30% (from 831 ng/dL to 585 ng/dL) at a dosage of 20 mg/day, by about 45–75% (average 60%; to 150–400 ng/dL) at a dosage of 60 mg/day, and by about 70–75% (from 832 to 862 ng/dL to 214 to 251 ng/dL) at a dosage of 100 mg/day. Dosages of oral MPA of 2.5 to 30 mg/day in combination with estrogens have been used to help suppress testosterone levels in transgender women. One study of injectable MPA in men with
benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, urinary retention, inability t ...
reported that a single 150 mg dose suppressed testosterone levels into the defined male castrate range (<58 ng/dL) within 7 days and that castration levels of testosterone were maintained for 3 months. Very high doses of intramuscular MPA of 150 to 500 mg per week (but up to 900 mg per week) have similarly been reported to suppress testosterone levels to less than 100 ng/dL. The typical initial dose of intramuscular MPA for testosterone suppression in men with paraphilias is 400 or 500 mg per week.


Androgenic activity

MPA is a potent full agonist of the AR. Its activation of the AR may play an important and major role in its antigonadotropic effects and in its beneficial effects against
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
. However, although MPA may produce androgenic side effects such as
acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...
and
hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a male pattern of hair growth in a female that ma ...
in some women,. 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. However, MPA has been seen to cause androgenic effects in children with precocious puberty. The reason for the general lack of virilizing effects with MPA, despite it binding to and activating the AR with high affinity and this action potentially 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 differently compared to other agonists of the receptor such as
dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...
(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 Transcription is the process of copying a segment of DNA into RNA for the purpose of gene expression. Some segments of DNA are transcribed into RNA molecules that can encode proteins, called messenger RNA (mRNA). Other segments of DNA are transc ...
, 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 Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionat ...
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
s. While it does not antagonize estrogen-induced increases in levels of
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
s and HDL cholesterol, DMPA every other week may decrease levels of HDL cholesterol. In addition, MPA has been found to suppress
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
(SHBG) production by the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
. At a dosage of 10 mg/day oral MPA, it has been found to decrease circulating SHBG levels by 14–18% in women taking 4 mg/day oral
estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...
. Conversely, in a study that combined 2.5 mg/day oral MPA with various oral estrogens, no influence of MPA on estrogen-induced increases in SHBG levels was discerned. In another, higher-dose study, SHBG levels were lower by 59% in a group of women treated with 50 mg/day oral MPA alone relative to an untreated control group of women. In massive-dose studies of oral or injectable MPA (e.g., 500–1,000 mg/day), the medication decreased SHBG levels by about 80%. Unlike the related steroids megestrol acetate and
cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...
, MPA is not an
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...
ic activity. As such, although MPA is sometimes described as an
antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...
, it is not a "true" antiandrogen (i.e., AR antagonist).


Glucocorticoid activity

As an agonist of the GR, MPA has
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
activity, and as a result can cause symptoms of
Cushing's syndrome Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. Signs and symptoms may include high blood pressure, abdominal obesity but with thin arms and legs, reddish stretch marks, ...
, steroid diabetes, and
adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...
at sufficiently high doses. It has been suggested that the glucocorticoid activity of MPA may contribute to bone loss. The glucocorticoid activity of MPA may also result in an
upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...
of the thrombin receptor in
blood vessel Blood vessels are the tubular structures of a circulatory system that transport blood throughout many Animal, animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the Tissue (biology), tissues of a Body (bi ...
walls, which may contribute to procoagulant effects of MPA and risk of
venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...
and
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. The relative glucocorticoid activity of MPA is among the highest of the clinically used progestins.


Steroidogenesis inhibition

MPA has been found to act as a
competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indi ...
inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...
of rat 3α-hydroxysteroid dehydrogenase (3α-HSD). This
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
is essential for the transformation of
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, deoxycorticosterone, and DHT into inhibitory
neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...
s such as
allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...
, , and 3α-androstanediol, respectively. MPA has been described as very potent in its inhibition of rat 3α-HSD, with an IC50 of 0.2 μM and a Ki (in rat testicular
homogenate Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
s) of 0.42 μM. However, inhibition of 3α-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 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase II (3β-HSD II). This enzyme is essential for the
biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
of
sex steroid Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
s and
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s. The Ki of MPA for inhibition of 3β-HSD II is 3.0 μM, 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 3β-HSD II, other human steroidogenic enzymes, including cholesterol side-chain cleavage enzyme (P450scc/CYP11A1) and 17α-hydroxylase/17,20-lyase (CYP17A1), were not found to be inhibited by MPA. MPA has been found to be effective in the treatment of gonadotropin-independent precocious puberty and in
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
in
postmenopausal Menopause, also known as the climacteric, is the time when menstrual periods permanently stop, marking the end of the reproductive stage for the female human. It typically occurs between the ages of 45 and 55, although the exact timing can ...
women at high dosages, and inhibition of 3β-HSD II could be responsible for its effectiveness in these conditions.


GABAA receptor allosteric modulation

Progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, via transformation into
neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coi ...
s such as 5α-dihydroprogesterone, 5β-dihydroprogesterone,
allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...
, and
pregnanolone Pregnanolone, also known as eltanolone, is an endogenous inhibitory neurosteroid which is produced in the body from progesterone. It is closely related to allopregnanolone, which has similar properties. Biological activity Pregnanolone is a pos ...
(catalyzed by the enzymes 5α- and 5β-reductase and 3α- and 3β-HSD), is a
positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...
of the GABAA receptor, and is associated with a variety of effects mediated by this property including
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
,
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
state State most commonly refers to: * State (polity), a centralized political organization that regulates law and society within a territory **Sovereign state, a sovereign polity in international law, commonly referred to as a country **Nation state, a ...
s,
mood changes A mood swing is an extreme or sudden change of mood. Such changes can play a positive or a disruptive part in promoting problem solving and in producing flexible forward planning. When mood swings are severe, they may be categorized as part ...
,
anxiolysis An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
, and cognitive/memory impairment, as well as effectiveness as an
anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...
in the treatment of catamenial epilepsy. It has also been found to produce
anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
via this action in animals when administered at sufficiently high dosages. MPA was found to significantly reduce
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
incidence when added to existing anticonvulsant regimens in 11 of 14 women with uncontrolled
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, and has also been reported to induce anesthesia in animals, raising the possibility that it might modulate the GABAA receptor similarly to progesterone. MPA shares some of the same metabolic routes of progesterone and, analogously, can be transformed into metabolites such as 5α-dihydro-MPA (DHMPA) and 3α,5α-tetrahydro-MPA (THMPA). However, unlike the reduced metabolites of progesterone, DHMPA and THMPA have been found not to modulate the GABAA receptor. Conversely, unlike progesterone, MPA itself actually modulates the GABAA receptor, although notably not at the neurosteroid binding site. However, rather than act as a potentiator of the receptor, MPA appears to act as a
negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...
. Whereas the reduced metabolites of progesterone enhance binding of the
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
flunitrazepam to the GABAA receptor ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'', MPA can partially inhibit the binding of flunitrazepam by up to 40% with half-maximal inhibition at 1 μM. However, the concentrations of MPA required for inhibition are high relative to therapeutic concentrations, and hence, this action is probably of little or no clinical relevance. The lack of potentiation of the GABAA receptor by MPA or its metabolites is surprising in consideration of the apparent anticonvulsant and anesthetic effects of MPA described above, and they remain unexplained. Clinical studies using massive dosages of up to 5,000 mg/day oral MPA and 2,000 mg/day intramuscular MPA for 30 days in women with advanced breast cancer have reported "no relevant side effects", which suggests that MPA has no meaningful direct action on the GABAA receptor in humans even at extremely high dosages.


Appetite stimulation

Although MPA and the closely related medication megestrol acetate are effective
appetite stimulant An orexigenic, or appetite stimulant, is a drug, hormone, or chemical compound, compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropep ...
s at very high dosages, the
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
of their beneficial effects on
appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...
is not entirely clear. However,
glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
,
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
, and possibly
anabolic Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...
-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 Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that is involved in various physiological and homeostatic processes in both the central and peripheral nervous systems. It is secreted alongside other neurotransmitters such as GABA and glu ...
in the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
, modulation of
calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, which are a type of calcium channel regulated by changes in membrane potential. Some calcium chan ...
s in the ventromedial hypothalamus, and inhibition of the secretion of
proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...
s including IL-1α,
IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...
, IL-6, and
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
, actions that have all been linked to an increase in appetite.


Other activity

MPA weakly stimulates the proliferation of
MCF-7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers ...
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
cells ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'', an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins are also active in this assay, whereas
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and
norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...
in
clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
.


Pharmacokinetics


Absorption

Surprisingly few studies have been conducted on the
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
of MPA at postmenopausal replacement dosages. The
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
of MPA with
oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
is approximately 100%. A single oral dose of 10 mg MPA has been found to result in peak MPA levels of 1.2 to 5.2 ng/mL within 2 hours of administration using
radioimmunoassay A radioimmunoassay (RIA) is an immunoassay that uses radioactive tracer, radiolabeled molecules in a stepwise formation of immune complexes. A RIA is a very sensitive in vitro assay technique used to measure concentrations of substances, usually m ...
. Following this, levels of MPA decreased to 0.09 to 0.35 ng/mL 12 hours post-administration. In another study, peak levels of MPA were 3.4 to 4.4 ng/mL within 1 to 4 hours of administration of 10 mg oral MPA using radioimmunoassay. Subsequently, MPA levels fell to 0.3 to 0.6 ng/mL 24 hours after administration. In a third study, MPA levels were 4.2 to 4.4 ng/mL after an oral dose of 5 mg MPA and 6.0 ng/mL after an oral dose of 10 mg MPA, both using radioimmunoassay as well. 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 In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties ''p'' ...
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. This study assessed MPA levels using liquid-chromatography–tandem mass spectrometry (LC–MS/MS), a more accurate method of blood determinations. Oral MPA tablets can be administered sublingually instead of orally.
Rectal administration Rectal administration (colloquially known as boofing or plugging) uses the rectum as a route of administration for medication and other fluids, which are absorbed by the rectum's blood vessels,The rectum has numerous blood vessels available to a ...
of MPA has also been studied. With intramuscular administration of 150 mg
microcrystalline A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination. There is little agreement on the range of crystal sizes that should be regarded as microcrystalline, but ...
MPA in aqueous suspension, 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 6 to 9 months post-injection. The
particle size Particle size is a notion introduced for comparing dimensions of solid particles ('' flecks''), liquid particles ('' droplets''), or gaseous particles ('' bubbles''). The notion of particle size applies to particles in colloids, in ecology, in ...
of MPA crystals significantly influences its rate of absorption into the body from the local tissue depot when used as a microcrystalline aqueous suspension via intramuscular injection. Smaller crystals dissolve faster and are absorbed more rapidly, resulting in a shorter duration of action. Particle sizes can differ between different formulations of MPA, potentially influencing clinical efficacy and tolerability.


Distribution

The
plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...
of MPA is 88%. It is weakly bound to
albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...
and is not bound to
sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
or
corticosteroid-binding globulin Transcortin, also known as corticosteroid-binding globulin (CBG) or serpin A6, is a protein produced in the liver in animals. In humans it is encoded by the SERPINA6 gene. It is an alpha-globulin. Function This gene encodes an alpha-globulin ...
.


Metabolism

The
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
of MPA via oral administration has been reported as both 11.6 to 16.6 hours and 33 hours, whereas the elimination half-lives with
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
and
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
of microcrystalline MPA in aqueous suspension are 50 and 40 days, respectively. The
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
of MPA is mainly via
hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
, including at positions C6β, C21, C2β, and C1β, mediated primarily via
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, but 3- and 5-dihydro and 3,5-tetrahydro
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s of MPA are also formed. Deacetylation of MPA and its metabolites (into, e.g.,
medroxyprogesterone Medroxyprogesterone (MP), is a progestin which is not used medically. A derivative, medroxyprogesterone acetate (MPA), is used as a medication in humans, and is far more widely known in comparison. ''Medroxyprogesterone'' is sometimes used as a ...
) 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 Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form *Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change o ...
. The C6α
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
and C17α acetoxy
group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic iden ...
s of MPA make it more resistant to metabolism and allow for greater bioavailability than oral
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
.


Elimination

MPA is eliminated 20 to 50% in
urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...
and 5 to 10% in
feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...
following
intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
. Less than 3% of a dose is excreted in unconjugated form.


Level–effect relationships

With intramuscular administration, the high levels of MPA in the blood inhibit
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...
and
ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...
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 flash Hot flushes are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, and may typically last from t ...
es are rare while MPA is found at significant blood levels in the body, and the
vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...
l lining remains moist and creased. The
endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...
undergoes
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
, with small, straight glands and a stroma that is decidualized.
Cervical mucus The cervix (: cervices) or cervix uteri is a dynamic fibromuscular sexual organ of the female reproductive system that connects the vagina with the uterine cavity. The human female cervix has been documented anatomically since at least the tim ...
remains
viscous Viscosity is a measure of a fluid's rate-dependent resistance to a change in shape or to movement of its neighboring portions relative to one another. For liquids, it corresponds to the informal concept of ''thickness''; for example, syrup h ...
. Because of its steady blood levels over the long term and multiple effects that prevent
fertilization Fertilisation or fertilization (see American and British English spelling differences#-ise, -ize (-isation, -ization), spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give ...
, MPA is a very effective means of
birth control Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...
.


Time–concentration curves


Chemistry

MPA is a
synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...
pregnane Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...
steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...
and a
derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...
of
progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
and 17α-hydroxyprogesterone. Specifically, it is the 17α-
acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic, or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...
ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...
of
medroxyprogesterone Medroxyprogesterone (MP), is a progestin which is not used medically. A derivative, medroxyprogesterone acetate (MPA), is used as a medication in humans, and is far more widely known in comparison. ''Medroxyprogesterone'' is sometimes used as a ...
or the 6α-
methylated Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...
analogue of hydroxyprogesterone acetate. MPA is known chemically as 6α-methyl-17α-acetoxyprogesterone or as 6α-methyl-17α-acetoxypregn-4-ene-3,20-dione, and its generic name is a contraction of 6α-methyl-17α-hydroxyprogesterone acetate. MPA is closely related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate,
cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...
, and megestrol acetate, as well as to medrogestone and nomegestrol acetate. 9α-fluoromedroxyprogesterone acetate (FMPA), the C9α fluoro analogue of MPA and an angiogenesis inhibitor with two orders of magnitude greater potency in comparison to MPA, was investigated for the potential treatment of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s but was never marketed.


History

MPA was independently discovered in 1956 by
Syntex Laboratorios Syntex SA (later Syntex Laboratories, Inc.) was a pharmaceutical company formed in Mexico City in January 1944 by Russell Marker, Emeric Somlo, and Federico Lehmann to manufacture therapeutic steroids from the Mexican yams called ''c ...
and the Upjohn Company. It was first introduced on 18 June 1959 by Upjohn in the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
under the brand name Provera (2.5, 5, and 10 mg tablets) for the treatment of
amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...
,
metrorrhagia Intermenstrual bleeding (IMB), or metrorrhagia, is vaginal bleeding at irregular intervals between expected menstrual periods. It may be associated with bleeding with sexual intercourse. The term metrorrhagia, in which metro means measure and ...
, and
recurrent miscarriage Recurrent miscarriage or recurrent pregnancy loss (RPL) is the spontaneous loss of 2-3 pregnancies that is estimated to affect up to 5% of women. The exact number of pregnancy losses and gestational weeks used to define RPL differs among medic ...
. An intramuscular formulation of MPA, now known as DMPA (400 mg/mL MPA), was also introduced, under the brand name brand name Depo-Provera, in 1960 in the U.S. for the treatment of
endometrial The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...
and renal cancer. MPA in combination with
ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol was widely used for various indications such as the treatment of menopausal symptoms, gynecological ...
was introduced in 1964 by Upjohn in the U.S. under the brand name Provest (10 mg MPA and 50 μg ethinylestradiol tablets) as an
oral contraceptive Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. The introduction of the birth control pill ("the Pill") in 1960 revolutionized the options for contraception, ...
, but this formulation was discontinued in 1970. This formulation was marketed by Upjohn outside of the U.S. under the brand names Provestral and Provestrol, while Cyclo-Farlutal (or Ciclofarlutal) and Nogest-S were formulations available outside of the U.S. with a different dosage (5 mg MPA and 50 or 75 μg ethinylestradiol tablets). Following its development in the late 1950s, DMPA was first assessed in clinical trials for use as an injectable contraceptive in 1963. Upjohn sought approval of intramuscular DMPA as a long-acting contraceptive under the brand name Depo-Provera (150 mg/mL MPA) in 1967, but the application was rejected. However, this formulation was successfully introduced in countries outside of the United States for the first time in 1969, and was available in over 90 countries worldwide by 1992. Upjohn attempted to gain FDA approval of DMPA as a contraceptive again in 1978, and yet again in 1983, but both applications failed similarly to the 1967 application. However, in 1992, the medication was finally approved by the FDA, under the brand name Depo-Provera, for use in contraception. A subcutaneous formulation of DMPA was introduced in the United States as a contraceptive under the brand name Depo-SubQ Provera 104 (104 mg/0.65 mL MPA) in December 2004, and subsequently was also approved for the treatment of
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
-related pelvic pain. MPA has also been marketed widely throughout the world under numerous other brand names such as Farlutal, Perlutex, and Gestapuran, among others.


Society and culture


Generic names

''Medroxyprogesterone acetate'' is the generic name of the drug and its , , , and , while ''medrossiprogesterone'' is the and ''médroxyprogestérone'' the of its free alcohol form. It is also known as ''6α-methyl-17α-acetoxyprogesterone'' (''MAP'') or ''6α-methyl-17α-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 The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
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 the estrogens CEEs, estradiol, and estradiol valerate. Brand names of MPA in combination with CEEs 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

Oral MPA and DMPA are widely available throughout the world. Oral MPA is available both alone and in combination with the estrogens CEEs, estradiol, and estradiol valerate. DMPA is registered for use as a form of birth control in more than 100 countries worldwide. The combination of injected MPA and estradiol cypionate is approved for use as a form of birth control in 18 countries.


United States

, MPA is available in the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
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: CEEs and MPA (Prempro, Prempro (Premarin, Cycrin), Premphase (Premarin, Cycrin 14/14), Premphase 14/14, 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 μg / 10 mg * Aqueous suspension for intramuscular injection: estradiol cypionate and MPA (Lunelle) – 5 mg / 25 mg (for contraception) The state of
Louisiana Louisiana ( ; ; ) is a state in the Deep South and South Central regions of the United States. It borders Texas to the west, Arkansas to the north, and Mississippi to the east. Of the 50 U.S. states, it ranks 31st in area and 25 ...
permits
sex offender A sex offender (sexual offender, sex abuser, or sexual abuser) is a person who has committed a Sex and the law, sex crime. What constitutes a sex crime differs by culture and legal jurisdiction. The majority of convicted sex offenders have convi ...
s to be given MPA.


Generation

Progestins in birth control pills are sometimes grouped by generation. While the
19-nortestosterone Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionat ...
progestins are consistently grouped into generations, the
pregnane Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...
progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes". In any case, based on its date of introduction in such formulations of 1964, MPA could be considered a "first-generation" progestin.


Controversy


Outside the United States

* In 1994, when DMPA 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 DMPA. In 2016, India introduced DMPA depo-medroxyprogesterone IM preparation in the public health system. * The Canadian Coalition on Depo-Provera, a coalition of women's health professional and advocacy groups, opposed the approval of DMPA in Canada. Since the approval of DMPA in Canada in 1997, a $700 million
class-action lawsuit A class action is a form of lawsuit. Class Action may also refer to: * ''Class Action'' (film), 1991, starring Gene Hackman and Mary Elizabeth Mastrantonio * Class Action (band), a garage house band * "Class Action" (''Teenage Robot''), a 2002 e ...
has been filed against Pfizer by users of DMPA who developed
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
. In response, Pfizer argued that it had met its obligation to disclose and discuss the risks of DMPA with the Canadian medical community. * Clinical trials for this medication regarding women in
Zimbabwe file:Zimbabwe, relief map.jpg, upright=1.22, Zimbabwe, relief map Zimbabwe, officially the Republic of Zimbabwe, is a landlocked country in Southeast Africa, between the Zambezi and Limpopo Rivers, bordered by South Africa to the south, Bots ...
were controversial with regard to human rights abuses and Medical Experimentation in Africa. * A controversy erupted in
Israel Israel, officially the State of Israel, is a country in West Asia. It Borders of Israel, shares borders with Lebanon to the north, Syria to the north-east, Jordan to the east, Egypt to the south-west, and the Mediterranean Sea to the west. Isr ...
when the government was accused of giving DMPA 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 DMPA 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 DMPA by the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
. 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 29 October 1992, the FDA approved DMPA for birth control, 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 The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...
,
France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...
,
Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...
,
Sweden Sweden, formally the Kingdom of Sweden, is a Nordic countries, Nordic country located on the Scandinavian Peninsula in Northern Europe. It borders Norway to the west and north, and Finland to the east. At , Sweden is the largest Nordic count ...
,
Thailand Thailand, officially the Kingdom of Thailand and historically known as Siam (the official name until 1939), is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. With a population of almost 66 million, it spa ...
,
New Zealand New Zealand () is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and List of islands of New Zealand, over 600 smaller islands. It is the List of isla ...
and
Indonesia Indonesia, officially the Republic of Indonesia, is a country in Southeast Asia and Oceania, between the Indian Ocean, Indian and Pacific Ocean, Pacific oceans. Comprising over List of islands of Indonesia, 17,000 islands, including Sumatra, ...
. Points in the controversy included: * Animal testing for
carcinogenicity A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...
– DMPA 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 DMPA which caused malignant mammary tumors in dogs were equivalent to 25 times the amount of the normal
luteal phase The menstrual cycle is on average 28 days in length. It begins with Menstruation, menses (day 1–7) during the follicular phase (day 1–14), followed by ovulation (day 14) and ending with the luteal phase (day 14–28). While historically, medi ...
progesterone level for dogs. This is lower than the pregnancy level of progesterone for dogs, and is species-specific.
DMPA 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, DMPA ''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 DMPA 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 The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
. However, numerous larger subsequent studies have shown that DMPA use does not increase the risk of cervical cancer. * Coercion and lack of informed consent. Testing or use of DMPA was focused almost exclusively on women in
developing countries A developing country is a sovereign state with a less-developed Secondary sector of the economy, industrial base and a lower Human Development Index (HDI) relative to developed countries. However, this definition is not universally agreed upon. ...
and poor women in the United States, raising serious questions about coercion and lack of informed consent, particularly for the illiterate and for mentally disabled people, who in some reported cases were given DMPA long-term for reasons of "menstrual hygiene", although they were not sexually active. * Atlanta/Grady Study – Upjohn studied the effect of DMPA 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 DMPA 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 DMPA 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 DMPA in developing countries. DMPA was approved for use in United States 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 United States approval of DMPA may increase its availability and acceptability in developing countries. * In 1995, several women's health groups asked the FDA to put a moratorium on DMPA, and to institute standardized informed consent forms.


Research

DMPA was studied by Upjohn for use as a progestogen-only injectable contraceptive in women at a dose of 50 mg once a month but produced poor cycle control and was not marketed for this use at this dosage. A combination of DMPA and polyestradiol phosphate, an
estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
and long-lasting
prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...
of
estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...
, was studied in women as a combined injectable contraceptive for use by
intramuscular injection Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...
once every three months. High-dose oral and intramuscular MPA monotherapy has been studied in the treatment of prostate cancer but was found to be inferior to monotherapy with
cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...
or
diethylstilbestrol Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with ...
. High-dose oral MPA has been studied in combination with diethylstilbestrol and CEEs as an addition to high-dose estrogen therapy for the treatment of
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
in men, but was not found to provide better effectiveness than diethylstilbestrol alone. DMPA has been studied for use as a potential male hormonal contraceptive in combination with the
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s/
anabolic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
s
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
and
nandrolone Nandrolone, also known as 19-nortestosterone, is an endogenous androgen. It is also an anabolic steroid (AAS) which is medically used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate ...
(19-nortestosterone) in men. However, it was never approved for this indication. MPA was investigated by InKine Pharmaceutical, Salix Pharmaceuticals, and the
University of Pennsylvania The University of Pennsylvania (Penn or UPenn) is a Private university, private Ivy League research university in Philadelphia, Pennsylvania, United States. One of nine colonial colleges, it was chartered in 1755 through the efforts of f ...
as a potential
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
medication for the treatment of
autoimmune hemolytic anemia Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
,
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
,
idiopathic thrombocytopenic purpura Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an Autoimmunity, autoimmune primary disorder of hemostasis characterized by a low platelet count in the absence of other cause ...
, and
ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
, but did not complete clinical development and was never approved for these indications. It was formulated as an oral medication at very high dosages, and was thought to inhibit the signaling of
proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...
s such as
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
and tumor necrosis factor alpha, with a
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
that was said to be similar to that of
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
s. The formulation of MPA had the tentative brand names Colirest and Hematrol for these indications. MPA has been found to be effective in the treatment of manic symptoms in women with
bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...
.


Veterinary use

MPA has been used to reduce
aggression Aggression is behavior aimed at opposing or attacking something or someone. Though often done with the intent to cause harm, some might channel it into creative and practical outlets. It may occur either reactively or without provocation. In h ...
and spraying in male cats. It may be particularly useful for controlling such behaviors in
neutered Neutering, from the Latin ('of neither sex'), is the removal of a non-human animal's reproductive organ, either all of it or a considerably large part. The male-specific term is castration, while spaying is usually reserved for female animals. C ...
male cats. The medication can be administered in cats as an injection once per month.


See also

* Conjugated estrogens/medroxyprogesterone acetate * Estradiol/medroxyprogesterone acetate * Estradiol cypionate/medroxyprogesterone acetate * Polyestradiol phosphate/medroxyprogesterone acetate


References

{{Portal bar, Medicine 3α-Hydroxysteroid dehydrogenase inhibitors 3β-Hydroxysteroid dehydrogenase inhibitors Acetate esters Anabolic–androgenic steroids Antigonadotropins Appetite stimulants Diketones Drugs with unknown mechanisms of action Hormonal antineoplastic drugs GABAA receptor negative allosteric modulators Glucocorticoids Pregnanes Progestogen esters Progestogens Feminizing hormone therapy World Health Organization essential medicines Wikipedia medicine articles ready to translate Hormonal contraception