Medroxyprogesterone 17-acetate
Encyclopedia
Medroxyprogesterone 17-acetate (also known as medroxyprogesterone acetate or MPA) is a progestin
, a synthetic variant of the human hormone progesterone
. It is used as a contraceptive
, in hormone replacement therapy
and for the treatment of endometriosis
as well as several other indications
.
MPA is a more potent derivative of its parent alcohol medroxyprogesterone
. While medroxyprogesterone is sometimes used as a synonym for medroxyprogesterone 17-acetate, what is normally being administered is medroxyprogesterone 17-acetate and not medroxyprogesterone.
and the Upjohn Company
.
(MP) and its acylated derivative medroxyprogesterone acetate (MPA) bind to the progesterone receptor
(PR) and both act as agonist
s, MPA has approximately 100 fold higher binding affinity
and transactivation
potency compared to MP:
to prevent endometrial hyperplasia
and cancer
. MPA is also used as a treatment for endometriosis
, dysmenorrhea
, and amenorrhea. MPA, along with other progestin
s were developed to allow the hormones to be taken orally, as progesterone
(the hormone made by the human body) could not be taken orally before the process of micronization was developed.
In males, MPA has been used to control inappropriate sexual behavior to chemically castrate
convicted sex offender
s.
MPA is an extremely effective contraceptive
when used with relatively high doses to prevent ovulation
. It has also been used to treat benign prostatic hyperplasia
, as a palliative
appetite stimulant
for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancer
s of primarily the breast
, but also other types.
Though not used as a treatment for epilepsy
, MPA reduces the frequency of seizures and does not interact with anti-epileptic medications. MPA does not interfere with blood clotting
and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis
and chronic active hepatitis
. Women taking MPA may experience spotting
shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhoea
can occur as can irregular menstruation
which is a major source of dissatisfaction, though both can result in improvements with iron deficiency
and risk of pelvic inflammatory disease
and often do not result in discontinuing the medication. MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia
in post-menopausal women who are undergoing hormone replacement therapy
.
s are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.
The Women's Health Initiative
investigated the use of medroxyprogesterone 17-acetate and conjugated equine estrogens compared to placebo. The study was prematurely terminated when previously-unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of the hormone replacement therapy (reduced risk of hip fracture
, colorectal
and endometrial cancer
and all other causes of death) were offset by increased risk of coronary heart disease
, breast cancer
, stroke
s and pulmonary embolism
.
At high doses for the treatment of breast cancer, MPA can cause weight gain, worsen diabetes mellitus
and edema
(particularly of the face). Adverse effect
s peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis
(though it is not clear if this is truly a risk, it can not be ruled out), painful urination
, anxiety, headache
, nausea
and vomiting
. When used to treat benign prostatic hyperplasia, more frequent complaints include reduced libido
, impotence, reduced ejaculate
volume, and within three days, chemical castration
. MPA may cause reduced bone density
though this appears to be reversible to a normal level even after years of use. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression
and interfere with carbohydrate metabolism but does not cause diabetes
.
Fetuses exposed to progesterones have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic pregnancy
particularly when MPA is used as an injected form of long-term birth control. When used as a form of injected birth control, MPA can reduce fertility for as long as 10 months, taking longer for overweight or obese women. When combined with conjugated equine estrogens
(Premarin), MPA has been associated with an increased risk of breast cancer
, dementia
and thrombus
in the eye. In combination with estrogen
s in general, MPA may increase the risk of cardiovascular disease
, with a stronger association when used by post-menopausal
women also taking CEE. MPA is not recommended for use prior to menarche
or before or during recovery from surgery
. It was because of these unexpected interactions that the Women's Health Initiative
study was ended early due the extra risks of hormone replacement therapy
, producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.
in the blood, and is metabolized
primarily through the liver
via hydroxylation
and conjugation. Intramuscular MPA is released slowly; a 150 mg dose is first detectable in the blood 30 minutes after injection, plateauing at 1.0 ng/mL for three months, followed by a gradual, tapering decline that lasts up to nine months in some women. The high levels of MPA in the blood inhibits luteinizing hormone
and ovulation
for several months, with an accompanying decrease in serum progesterone
to below 0.4 ng/mL. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/ml. Serum estradiol
remains at approximately 50 pg/nl for approximately four months post-injection (with a range of 10-92 pg/nL after several years of use), rising once MPA levels fall below 0.5 ng/ml.
secretion from the pituitary which in turn prevents ovarian follicle
maturation and ovulation
, as well as thining the endometrium
.
In males, MPA represses spermatogenesis
and increases the basal levels of growth hormone
but reduces the release of growth hormone
stimulated by insulin
or arginine
.
In both males and females, at low doses it may slightly reduce the levels of high-density lipoprotein and increases low-density lipoprotein in a dose-response manner, though there is considerable difference across people.
Hot flashes are rare while MPA is found at significant blood levels in the body, and the vagina
l lining
remains moist and creased. The endometrium
undergoes atrophy
, with small, straight glands and a stroma
that is decidualized
. Cervical mucus remains viscous
. Because of its steady blood levels over the long term and multiple effects that prevent fertilisation
, MPA is a very effective means of birth control
.
with other drug
s. When combined with aminoglutethimide
to treat metastases
from breast cancer, MPA is associated with an increase in depression
. St John's wort
may decrease its effectiveness as a contraceptive.
believe progesterone
offers fewer side effects and improved quality of life compared to medroxyprogesterone acetate. The evidence for this view has been questioned; medroxyprogesterone is better absorbed when taken orally, with a much longer half life leading to more stable blood levels though it may lead to greater breast tenderness and more sporadic vaginal bleeding
. The two compounds do not differentiate in their ability to suppress endometrial hyperplasia
, nor does either increase the risk of pulmonary embolism
. The two compounds have not been adequately compared in direct tests to clear conclusions about safety and superiority.
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
, a synthetic variant of the human hormone progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
. It is used as a contraceptive
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
, in hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
and for the treatment of endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
as well as several other indications
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
.
MPA is a more potent derivative of its parent alcohol medroxyprogesterone
Medroxyprogesterone
Medroxyprogesterone is a pregnane that acts as a progestin. An acylated derivative, medroxyprogesterone 17-acetate is clinically used as a drug. Compared to MPA, MP is approximately 100 fold less potent as a progestin...
. While medroxyprogesterone is sometimes used as a synonym for medroxyprogesterone 17-acetate, what is normally being administered is medroxyprogesterone 17-acetate and not medroxyprogesterone.
History
Medroxyprogesterone 17-acetate was independently discovered in 1956 by SyntexSyntex
Laboratorios Syntex SA was a pharmaceutical company formed in Mexico City in 1944 by Russell Marker to manufacture therapeutic steroids from the Mexican yam....
and the Upjohn Company
Upjohn
The Upjohn Company was a pharmaceutical manufacturing firm founded in 1886 in Kalamazoo, Michigan by Dr. William E. Upjohn, an 1875 graduate of the University of Michigan medical school. The company was originally formed to make friable pills, which were specifically designed to be easily digested...
.
Preclinical pharmacology
While both the parent medroxyprogesteroneMedroxyprogesterone
Medroxyprogesterone is a pregnane that acts as a progestin. An acylated derivative, medroxyprogesterone 17-acetate is clinically used as a drug. Compared to MPA, MP is approximately 100 fold less potent as a progestin...
(MP) and its acylated derivative medroxyprogesterone acetate (MPA) bind to the progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
(PR) and both act as agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
s, MPA has approximately 100 fold higher binding affinity
Dissociation constant
In chemistry, biochemistry, and pharmacology, a dissociation constant is a specific type of equilibrium constant that measures the propensity of a larger object to separate reversibly into smaller components, as when a complex falls apart into its component molecules, or when a salt splits up into...
and transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
potency compared to MP:
| Ligand | PR Progesterone receptor The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone... Ki (nM) | Coactivator Coactivator (genetics) A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself.... recruitment EC50 (nM) | Reporter cell line EC50 (nM) |
|---|---|---|---|
| Progesterone | 4.3±1.0 | 0.9±0.2 | 25±11 |
| Medroxyprogesterone acetate | 1.2±0.3 | 0.6±0.08 | 0.15±0.03 |
| Medroxyprogesterone | 241±96 | 47±14 | 32±1 |
Indications
In females, the most common use of MPA is as an oral or depot-injected contraceptive and also as the progestin component of menopausal hormone replacement therapyHormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
to prevent endometrial hyperplasia
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 the progesterone-like hormones which ordinarily...
and cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
. MPA is also used as a treatment for endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...
, dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...
, and amenorrhea. MPA, along with other progestin
Progestin
A progestin is a synthetic progestogen that has progestinic effects similar to progesterone. The two most common uses of progestins are for hormonal contraception , and to prevent endometrial hyperplasia from unopposed estrogen in hormone replacement therapy...
s were developed to allow the hormones to be taken orally, as progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
(the hormone made by the human body) could not be taken orally before the process of micronization was developed.
In males, MPA has been used to control inappropriate sexual behavior to chemically castrate
Chemical castration
Chemical castration is the administration of medication designed to reduce libido and sexual activity, usually in the hope of preventing rapists, child molesters and other sex offenders from repeating their crimes...
convicted sex offender
Sex offender
A sex offender is a person who has committed a sex crime. What constitutes a sex crime differs by culture and by legal jurisdiction. Most jurisdictions compile their laws into sections such as traffic, assault, sexual, etc. The majority of convicted sex offenders have convictions for crimes of a...
s.
MPA is an extremely effective contraceptive
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
when used with relatively high doses to prevent ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
. It has also been used to treat benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
, as a palliative
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...
appetite stimulant
Orexigenic
An orexigenic is a drug or hormone that increases appetite. This can be a naturally occurring neuropeptide hormone such as ghrelin, orexin or neuropeptide Y, or a medication which increases hunger and therefore enhances food consumption...
for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s of primarily the breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, but also other types.
Though not used as a treatment for epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, MPA reduces the frequency of seizures and does not interact with anti-epileptic medications. MPA does not interfere with blood clotting
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
and appears to improve blood parameters for women with sickle cell anemia. Similarly, MPA does not appear to affect liver metabolism, and may improve primary biliary cirrhosis
Primary biliary cirrhosis
Primary biliary cirrhosis, often abbreviated PBC, is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts within the liver. When these ducts are damaged, bile builds up in the liver and over time damages the tissue. This can lead to scarring,...
and chronic active hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. Women taking MPA may experience spotting
Metrorrhagia
Metrorrhagia, also known as breakthrough bleeding or spotting, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods.In some women, menstrual spotting between periods occurs as a normal and harmless part of ovulation...
shortly after starting the medication but is not usually serious enough to require medical intervention. With longer use amenorrhoea
Amenorrhoea
Amenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
can occur as can irregular menstruation
Irregular menstruation
Irregular menstruation is an abnormal variation in length of menstrual cycles in a woman. Normally, it is actually unusual for a woman to experience cycle length variations of less than four days between the shortest and longest cycle lengths. However, length variation between eight and 20 days is...
which is a major source of dissatisfaction, though both can result in improvements with iron deficiency
Iron deficiency (medicine)
Iron deficiency is one of the most common of the nutritional deficiencies. Iron is present in all cells in the human body, and has several vital functions...
and risk of pelvic inflammatory disease
Pelvic inflammatory disease
Pelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
and often do not result in discontinuing the medication. MPA is also prescribed in combination with an estrogen to prevent endometrial hyperplasia
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 the progesterone-like hormones which ordinarily...
in post-menopausal women who are undergoing hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
.
Adverse effects
In females, the most common adverse effectAdverse effect
In medicine, an adverse effect is a harmful and undesired 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. If it results from an unsuitable or incorrect dosage or...
s are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain.
The Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
investigated the use of medroxyprogesterone 17-acetate and conjugated equine estrogens compared to placebo. The study was prematurely terminated when previously-unexpected risks were discovered, specifically the finding that though the all-cause mortality was not affected by the hormone therapy, the benefits of the hormone replacement therapy (reduced risk of hip fracture
Hip fracture
A hip fracture is a femoral fracture that occurs in the proximal end of the femur , near the hip.The term "hip fracture" is commonly used to refer to four different fracture patterns and is often due to osteoporosis; in the vast majority of cases, a hip fracture is a fragility fracture due to a...
, colorectal
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
and endometrial cancer
Endometrial cancer
Endometrial cancer refers to several types of malignancies that arise from the endometrium, or lining, of the uterus. Endometrial cancers are the most common gynecologic cancers in the United States, with over 35,000 women diagnosed each year. The incidence is on a slow rise secondary to the...
and all other causes of death) were offset by increased risk of coronary heart disease
Coronary disease
Coronary disease refers to the failure of coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. It is already the most common form of disease affecting the heart and an important cause of premature death in Europe, the Baltic states, Russia, North and South...
, breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s and pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
.
At high doses for the treatment of breast cancer, MPA can cause weight gain, worsen diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
and edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(particularly of the face). Adverse effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired 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. If it results from an unsuitable or incorrect dosage or...
s peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
(though it is not clear if this is truly a risk, it can not be ruled out), painful urination
Dysuria
In medicine, specifically urology, dysuria refers to painful urination.Difficult urination is also sometimes described as dysuria.It is one of a constellation of irritative bladder symptoms, which includes urinary frequency and haematuria....
, anxiety, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
. When used to treat benign prostatic hyperplasia, more frequent complaints include reduced libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, impotence, reduced ejaculate
Ejaculation
Ejaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...
volume, and within three days, chemical castration
Chemical castration
Chemical castration is the administration of medication designed to reduce libido and sexual activity, usually in the hope of preventing rapists, child molesters and other sex offenders from repeating their crimes...
. MPA may cause reduced bone density
Bone density
Bone density is a medical term normally referring to the amount of mineral matter per square centimeter of bones. Bone density is used in clinical medicine as an indirect indicator of osteoporosis and fracture risk.This medical bone density is not the true physical "density" of the bone, which...
though this appears to be reversible to a normal level even after years of use. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
and interfere with carbohydrate metabolism but does not cause diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
Fetuses exposed to progesterones have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic pregnancy
Ectopic pregnancy
An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...
particularly when MPA is used as an injected form of long-term birth control. When used as a form of injected birth control, MPA can reduce fertility for as long as 10 months, taking longer for overweight or obese women. When combined with conjugated equine estrogens
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
(Premarin), MPA has been associated with an increased risk of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
and thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
in the eye. In combination with estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s in general, MPA may increase the risk of cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, with a stronger association when used by post-menopausal
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
women also taking CEE. MPA is not recommended for use prior to menarche
Menarche
Menarche is the first menstrual cycle, or first menstrual bleeding, in female human beings. From both social and medical perspectives it is often considered the central event of female puberty, as it signals the possibility of fertility....
or before or during recovery from surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
. It was because of these unexpected interactions that the Women's Health Initiative
Women's Health Initiative
The Women's Health Initiative was initiated by the U.S. National Institutes of Health in 1991. The objective of this women's health research initiative was to conduct medical research into some of the major health problems of older women...
study was ended early due the extra risks of hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.
Pharmacokinetics
MPA is well-absorbed orally and through intramuscular injection, peaking at 2–4 hours for the former. The half life is 12 to 17 hours for an oral dose, and 50 days for an intramuscular injection. MPA binds to albuminAlbumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
in the blood, and is metabolized
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
primarily through the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
via hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
and conjugation. Intramuscular MPA is released slowly; a 150 mg dose is first detectable in the blood 30 minutes after injection, plateauing at 1.0 ng/mL for three months, followed by a gradual, tapering decline that lasts up to nine months in some women. The high levels of MPA in the blood inhibits luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
and ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
for several months, with an accompanying decrease in serum progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
to below 0.4 ng/mL. Ovulation resumes when once blood levels of MPA fall below 0.1 ng/ml. Serum estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
remains at approximately 50 pg/nl for approximately four months post-injection (with a range of 10-92 pg/nL after several years of use), rising once MPA levels fall below 0.5 ng/ml.
Pharmacodynamics
In females, MPA inhibits gonadotropinGonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
secretion from the pituitary which in turn prevents ovarian follicle
Ovarian follicle
Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single...
maturation and ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
, as well as thining the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
.
In males, MPA represses spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
and increases the basal levels of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
but reduces the release of growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
stimulated by insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
or arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
.
In both males and females, at low doses it may slightly reduce the levels of high-density lipoprotein and increases low-density lipoprotein in a dose-response manner, though there is considerable difference across people.
Hot flashes are rare while MPA is found at significant blood levels in the body, and the vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
l lining
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
remains moist and creased. The endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
undergoes atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
, with small, straight glands and a stroma
Stroma (animal tissue)
In animal tissue, stroma refers to the connective, supportive framework of a biological cell, tissue, or organ.The stroma in animal tissue is contrasted with the parenchyma.Examples include:* Stroma of iris...
that is decidualized
Decidualization
Decidualization is a characteristic of the endometrium of the pregnant uterus. It is a response of maternal cells to progesterone. Decidualization may be used to describe any change due to progesterone...
. Cervical mucus remains viscous
Viscosity
Viscosity is a measure of the resistance of a fluid which is being deformed by either shear or tensile stress. In everyday terms , viscosity is "thickness" or "internal friction". Thus, water is "thin", having a lower viscosity, while honey is "thick", having a higher viscosity...
. Because of its steady blood levels over the long term and multiple effects that prevent fertilisation
Fertilisation
Fertilisation is the fusion of gametes to produce a new organism. In animals, the process involves the fusion of an ovum with a sperm, which eventually leads to the development of an embryo...
, MPA is a very effective means of birth control
Birth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
.
Interactions
MPA increases the risk of breast cancer, dementia and thrombus when used in combination with conjugated equine estrogens to treat the symptoms of menopause. When used as a contraceptive, MPA does not generally interactDrug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with other drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s. When combined with aminoglutethimide
Aminoglutethimide
Aminoglutethimide is an anti-steroid drug marketed under the tradename Cytadren by Novartis around the world. It blocks the production of steroids derived from cholesterol and is clinically used in the treatment of Cushing's syndrome and metastatic breast cancer...
to treat metastases
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
from breast cancer, MPA is associated with an increase in depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
. St John's wort
St John's wort
St John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
may decrease its effectiveness as a contraceptive.
Comparison with progesterone
Proponents of bioidentical hormone replacement therapyBioidentical hormone replacement therapy
Bioidentical hormone replacement therapy , also known as bioidentical hormone therapy or natural hormone therapy, is a poorly-defined term referring to the use of hormones that are identical, on a molecular level, with endogenous hormones in hormone replacement therapy...
believe progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
offers fewer side effects and improved quality of life compared to medroxyprogesterone acetate. The evidence for this view has been questioned; medroxyprogesterone is better absorbed when taken orally, with a much longer half life leading to more stable blood levels though it may lead to greater breast tenderness and more sporadic vaginal bleeding
Metrorrhagia
Metrorrhagia, also known as breakthrough bleeding or spotting, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods.In some women, menstrual spotting between periods occurs as a normal and harmless part of ovulation...
. The two compounds do not differentiate in their ability to suppress endometrial hyperplasia
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 the progesterone-like hormones which ordinarily...
, nor does either increase the risk of pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
. The two compounds have not been adequately compared in direct tests to clear conclusions about safety and superiority.