A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...
which produces effects similar to those of the
natural
Nature, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans ar ...
female
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 effect ...
progesterone in the body.
A progestin is a ''
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic ...
'' progestogen.
Progestogens are used most commonly in
hormonal birth control and
menopausal hormone therapy.
They can also be used in the treatment of
gynecological condition
Gynaecology or gynecology (see spelling differences) is the area of medicine that involves the treatment of women's diseases, especially those of the reproductive organs. It is often paired with the field of obstetrics, forming the combined area ...
s, to support
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...
and
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
, to lower
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 effect ...
levels for various purposes, and for other indications.
Progestogens are used alone or in combination with
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s.
They are available in a wide variety of
formulations and for use by many different
routes of administration.
Examples of progestogens include natural or
bioidentical progesterone as well as progestins such as
medroxyprogesterone acetate and
norethisterone.
Side effects of progestogens include
menstrual irregularities,
headaches,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
,
breast tenderness,
mood changes,
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
increased hair growth, and changes in
liver protein production among others.
Other side effects of progestogens may include an increased risk of
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
,
cardiovascular disease, and
blood clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
s.
At high doses, progestogens can cause
low sex hormone levels and associated side effects like
sexual dysfunction and an
increased risk of bone fractures.
Progestogens are
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 ag ...
s of the
progesterone receptors (PRs) and produce progestogenic or progestational effects.
They have important effects in the
female reproductive system (
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
,
cervix
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
, and
vagina
In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...
), the
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
s, and the
brain
A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
.
In addition, many progestogens also have other hormonal activities, such as
androgenic,
antiandrogenic,
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
ic,
glucocorticoid, or
antimineralocorticoid activity.
They also have
antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
effects and at high doses can strongly 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 effect ...
production.
Progestogens mediate their contraceptive effects both by inhibiting
ovulation and by thickening
cervical mucus
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
, thereby preventing
fertilization
Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Pro ...
.
They have functional
antiestrogenic effects in certain tissues like the
endometrium, and this underlies their use in menopausal hormone therapy.
Progesterone was first introduced for medical use in 1934 and the first progestin,
ethisterone, was introduced for medical use in 1939.
More
potent progestins, such as
norethisterone, were developed and started to be used in birth control in the 1950s.
Around 60 progestins have been marketed for clinical use in humans or use in
veterinary medicine
Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...
.
These progestins can be grouped into different classes and generations.
Progestogens are available widely throughout the world and are used in all forms of hormonal birth control and in most menopausal hormone therapy regimens.
Medical uses
Available forms
Progestogens are available in many different
form
Form is the shape, visual appearance, or configuration of an object. In a wider sense, the form is the way something happens.
Form also refers to:
*Form (document), a document (printed or electronic) with spaces in which to write or enter data
* ...
s for use by many different
routes of administration. These include
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 or ...
tablet
Tablet may refer to:
Medicine
* Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill"
Computing
* Tablet computer, a mobile computer that is primarily operated by touching the ...
s and
capsules,
oil and
aqueous solutions and
suspensions for
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 ha ...
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 into the subcutis, the layer of skin directly below the dermis and epidermis, c ...
, and various others (e.g.,
transdermal patches,
vaginal rings,
intrauterine devices,
subcutaneous implants).
Dozens of different progestogens have been marketed for
clinical and/or
veterinary use.
Birth control
Progestogens are used in a variety of different forms of
hormonal birth control for females, including
combined estrogen and progestogen forms like
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 taken orally by women. The pill contains two important hormones: proges ...
s,
combined contraceptive patches,
combined contraceptive vaginal rings, and
combined injectable contraceptive
Combined injectable contraceptives (CICs) are a form of hormonal birth control for women. They consist of monthly injections of combined formulations containing an estrogen and a progestin to prevent pregnancy.
CICs are different from progestoge ...
s; and
progestogen-only forms like
progestogen-only contraceptive pills ("mini-pills"),
progestogen-only emergency contraceptive pills ("day-after pills"),
progestogen-only contraceptive implants,
progestogen-only intrauterine devices,
progestogen-only contraceptive vaginal rings, and
progestogen-only injectable contraceptives.
Progestogens mediate their contraceptive effects by multiple mechanisms, including prevention of
ovulation via their
antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
effects; thickening of
cervical mucus
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
, making the
cervix
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
largely impenetrable to
sperm
Sperm is the male reproductive 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 with a tail known as a flagellum, ...
; preventing
capacitation
Capacitation is the penultimate step in the maturation of mammalian spermatozoa and is required to render them competent to fertilize an oocyte. This step is a biochemical event; the sperm move normally and look mature prior to capacitation.
''In ...
of
sperm
Sperm is the male reproductive 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 with a tail known as a flagellum, ...
due to changes in cervical fluid, thereby making sperm unable to penetrate the
ovum
The egg cell, or ovum (plural ova), is the female reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the female gamete i ...
; and
atrophic changes in the
endometrium, making the endometrium unsuitable for
implantation.
They may also decrease
tubal
Tubal ( he, תֻבָל, ''Ṯuḇāl'', ), in Genesis 10 (the "Table of Nations"), was the name of a son of Japheth, son of Noah. He is known to be the father of the Caucasian Iberians (ancestors of the Georgians) according to primary sources. ...
motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
and
cilia
The cilium, plural cilia (), is a membrane-bound organelle found on most types of eukaryotic cell, and certain microorganisms known as ciliates. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike proje ...
ry action.
Hormone therapy
Menopause and hypogonadism
Progestogens are used in combination with
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s in
menopausal hormone therapy in women. They are also used in combination with estrogens in hormone therapy for
hypogonadism and
delayed puberty in girls and women. They are used mainly to prevent
endometrial hyperplasia and increased risk of
endometrial cancer from unopposed estrogen therapy.
Transgender hormone therapy
Progestogens are used as a component of
hormone therapy for
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
and
transgender men
A trans man is a man who was assigned female at birth. The label of transgender man is not always interchangeable with that of transsexual man, although the two labels are often used in this way. ''Transgender'' is an umbrella term that incl ...
. They are used in transgender women in combination with estrogens to help suppress and block
testosterone. Progestogens might also have other beneficial effects in transgender women, but these are controversial and unsupported at present. Examples of progestogens used in hormone therapy for transgender women include
cyproterone acetate,
medroxyprogesterone acetate, and
progesterone. Progestogens, such as medroxyprogesterone and
lynestrenol
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination w ...
, are used in transgender men to help suppress
menses. Progestogens have also been used to delay
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...
in
transgender boys and girls.
Other uses
Certain progestogens, including
megestrol acetate, medroxyprogesterone acetate, cyproterone acetate, and
chlormadinone acetate, have been used at high doses to reduce
hot flash
Hot flashes (also known as 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, an ...
es in men undergoing
androgen deprivation therapy
Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT red ...
, for instance to treat
prostate cancer.
Gynecological disorders
Menstrual disorders
Progestogens are used to treat
menstrual disorders such as
secondary amenorrhea
Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...
and
dysfunctional uterine bleeding.
In a normal
menstrual cycle, declining levels of progesterone trigger
menstruation. Progestogens such as
norethisterone acetate and
medroxyprogesterone acetate may be used to artificially induce progesterone-associated
breakthrough bleeding
Intermenstrual bleeding, previously known as metrorrhagia, is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. It is a cause of vaginal bleeding.
In some women, menstrual spotting between periods occur ...
.
The
progestogen challenge test or progestogen withdrawal test is used to diagnose
amenorrhea. Due to the availability of assays to measure estrogen levels, it is now rarely used.
Uterine disorders
Progestogens are used in the prevention and treatment of
uterine disorders such as
endometrial hyperplasia,
endometriosis
Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...
,
uterine fibroids, and
uterine hypoplasia.
Breast disorders
Progestogens are used to treat
benign breast disorders.
They are associated not only with a reduction in
breast pain
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 br ...
, but also a decrease in
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
cell proliferation
Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation r ...
, a decrease in
breast gland size, and a disappearance of breast
nodularity
In medicine, nodules are small firm lumps, usually greater than 1 cm in diameter. If filled with fluid they are referred to as cysts. Smaller (less than 0.5 cm) raised soft tissue bumps may be termed papules.
The evaluation of a skin nodule inc ...
.
Progestogens that have been used for such purposes include
topical progesterone,
dydrogesterone,
promegestone,
lynestrenol
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination w ...
,
medroxyprogesterone acetate,
dienogest, and
medrogestone.
Progestogens are used in the treatment of
breast hypoplasia and
lactation insufficiency. This is because they induce
lobuloalveolar
A mammary alveolus (plural: alveoli, from Latin ''alveolus'', "little cavity") is a small cavity or sac found in the mammary gland. Mammary alveoli are the site of milk production and storage in the mammary gland. Mammary alveoli cluster into g ...
development of the
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
s, which is required for
lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
and
breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
.
Enlarged prostate
Progestogens have been used at high doses to treat
benign prostatic hyperplasia (BPH). They act by suppressing
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...
al
testosterone production and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of the
prostate gland
The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and physi ...
.
Hormone-sensitive cancers
Endometrial cancer
Progestogens were first found to be effective at high doses in the treatment of
endometrial hyperplasia and
endometrial cancer in 1959.
Subsequently, high-dose
gestonorone caproate,
hydroxyprogesterone caproate,
medroxyprogesterone acetate, and
megestrol acetate were approved for the treatment of endometrial cancer.
Breast cancer
Progestogens, such as megestrol acetate and medroxyprogesterone acetate, are effective at high doses in the treatment of
advanced postmenopausal breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
.
They have been extensively evaluated as a second-line therapy for this indication.
However, they produce various
side effects, such as
dyspnea,
weight gain,
vaginal bleeding,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
,
fluid retention,
hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
,
thrombophlebitis
Thrombophlebitis is a phlebitis (inflammation of a vein) related to a thrombus (blood clot). When it occurs repeatedly in different locations, it is known as thrombophlebitis migrans (migratory thrombophlebitis).
Signs and symptoms
The following s ...
, and
thromboembolic complications.
In addition, megestrol acetate has been found to be significantly inferior to
aromatase inhibitors in the treatment of breast cancer, and in relation to this, progestogens have been moved down in the sequential therapy of the disease.
Megestrol acetate is the only
Food and Drug Administration
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 ...
-approved progestogen for breast cancer.
The
mechanism of action of progestogens in the treatment of breast cancer is unknown, but may be related to their functional
antiestrogenic and/or
antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
effects.
Prostate cancer
Certain progestogens, particularly those with antiandrogenic properties, have been used at high doses in the treatment of
prostate cancer.
These include
cyproterone acetate,
chlormadinone acetate, and
megestrol acetate.
Other progestogens such as
medroxyprogesterone acetate,
hydroxyprogesterone caproate, and
gestonorone caproate have also been studied, but have inadequate effectiveness. They act by suppressing
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...
al
testosterone production and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of prostate
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s.
Fertility and pregnancy
Progestogens are used in
fertility medicine
Reproductive endocrinology and infertility (REI) is a surgical subspecialty of obstetrics and gynecology that trains physicians in reproductive medicine addressing hormonal functioning as it pertains to reproduction as well as the issue of infert ...
for women. For example, progesterone (or sometimes
dydrogesterone or
hydroxyprogesterone caproate) is used for
luteal support Luteal support is the administration of medication, generally progesterone, progestins, hCG or GnRH agonists, to increase the success rate of implantation and early embryogenesis, thereby complementing and/or supporting the function of the corpus ...
in
''in-vitro'' fertilization protocols.
Certain progestogens are used to support
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
, including
progesterone,
hydroxyprogesterone caproate,
dydrogesterone, and
allylestrenol. They are used questionably for treatment of
recurrent pregnancy loss and for prevention of
preterm birth
Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...
in pregnant women with a history of at least one spontaneous preterm birth.
Puberty suppression
Progestogens have been used to treat
precocious puberty in both boys and girls. They have also been used to delay puberty in
transgender youth
Transgender youth are children or adolescents who do not identify with the sex they were assigned at birth. Because transgender youth are usually dependent on their parents for care, shelter, financial support, and other needs, transgender y ...
.
Sexual deviance
Certain progestogens, such as
cyproterone acetate and
medroxyprogesterone acetate, are used as a form of
chemical castration
Chemical castration is castration via anaphrodisiac drugs, whether to reduce libido and sexual activity, to treat cancer, or otherwise. Unlike surgical castration, where the gonads are removed through an incision in the body, to treat
sexual deviance in men, particularly
sex offenders. They are specifically used to treat
paraphilias and
hypersexuality. They work by suppressing
gonad
A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...
al
testosterone production and hence circulating testosterone levels. This results in decreased
libido and interference with
erectile function and ability to attain
orgasm
Orgasm (from Greek , ; "excitement, swelling") or sexual climax is the sudden discharge of accumulated sexual excitement during the sexual response cycle, resulting in rhythmic, involuntary muscular contractions in the pelvic region chara ...
.
Skin and hair conditions
Progestogens are used to treat
androgen-dependent skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
and
hair conditions in women. These include
oily skin
The human skin is the outer covering of the body and is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue guarding muscles, bones, ligaments and internal organs. Human skin is similar to most ...
,
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
seborrhea,
hirsutism,
scalp hair loss, and
hidradenitis suppurativa
Hidradenitis suppurativa (HS), sometimes known as acne inversa or Verneuil's disease, is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lumps. These are typically painful and break open, releasin ...
. They act by suppressing testosterone levels and, in the case of antiandrogenic progestogens, by directly blocking the actions of androgens.
Androgen excess
Progestogens are used to treat
hyperandrogenism, such as due to
polycystic ovary syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
and
congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex ...
, in women. Examples include
cyproterone acetate and
chlormadinone acetate.
Appetite stimulation
Certain progestins can be used at very high doses to
increase appetite in conditions like
cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart fa ...
,
anorexia, and
wasting syndrome
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart fa ...
s. In general, they are used in combination with certain other steroid medications such as
dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those 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 inv ...
s. Furthermore, they are recognized as being the only medications to increase
lean body mass.
Megestrol acetate is the lead drug of this class for the management of cachexia, and
medroxyprogesterone acetate is also used.
The
mechanism of action of the appetite-related effects of these two medications is unknown and may not be related to their progestogenic activity. Very high doses of other progestogens, like
cyproterone acetate, have minimal or no influence on appetite and weight.
Contraindications
Contraindications of progestogens may include
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
and a history of
venous thromboembolism
Venous thrombosis is 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 lungs to ...
among others.
Side effects
Progestogens have relatively few
side effects at typical dosages.
Side effects of progestogens may include
tiredness
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
dysphoria,
depression,
mood changes,
menstrual irregularities,
hypomenorrhea Hypomenorrhea or hypomenorrhoea, also known as short or scanty periods, is extremely light menstrual blood flow. It is the opposite of heavy periods or hypermenorrhea which is more properly called menorrhagia.
Overview
In some women it may be no ...
,
edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
,
vaginal dryness
Vaginal lubrication is a naturally produced fluid that lubricates a
vagina. Vaginal lubrication is always present, but production increases significantly near ovulation and during sexual arousal in anticipation of sexual intercourse. Vaginal dr ...
,
vaginal atrophy,
headaches,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
,
breast tenderness, decreased
libido.
Progestins with androgenic activity, namely 19-nortestosterone derivatives, can also cause
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
hirsutism,
seborrhea,
voice deepening
A hoarse voice, also known as dysphonia or hoarseness, is when the voice involuntarily sounds breathy, raspy, or strained, or is softer in volume or lower in pitch. A hoarse voice, can be associated with a feeling of unease or scratchiness in the ...
, changes in
liver protein production (e.g., decreased
HDL cholesterol,
sex hormone-binding globulin), increased
appetite, and
weight gain, among others.
Other side effects of progestogens may include an increased risk of
breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
,
cardiovascular disease, and
blood clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
s, among others.
Some of the side effects of progestogens are due not to their progestogenic activity but rather due to
off-target activities (e.g.,
androgenic activity,
glucocorticoid activity,
antimineralocorticoid activity).
At high doses, due to their
antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
effects, progestogens can cause
low sex hormone levels and associated side effects like diminished
secondary sexual characteristics
Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a ...
,
sexual dysfunction (e.g., reduced
sex drive and
erectile dysfunction), reversible
infertility, reduced
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 optical ...
, and an increased risk of
bone fracture
A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...
s, both in men and in
premenopausal women.
Mood changes
Birth control
The available evidence on the risk of
mood changes and
depression with progestogens in
hormonal birth control is limited.
As of 2019, there is no consistent evidence for adverse effects on mood of hormonal birth control, including
progestogen-only birth control
Progestogen-only contraception (or progestin-only contraception) relies on progestogens alone to achieve contraception. It is one of the two major types of hormonal contraception, with the other major type being combined hormonal contraceptive me ...
and
combined birth control
Combined hormonal contraception (CHC), or combined birth control, is a form of hormonal contraception which combines both an estrogen (medication), estrogen and a progestogen in varying formulations.
The different types available include combined ...
, in the general population.
Most women taking
combined birth control
Combined hormonal contraception (CHC), or combined birth control, is a form of hormonal contraception which combines both an estrogen (medication), estrogen and a progestogen in varying formulations.
The different types available include combined ...
experience no influence or a beneficial effect on mood.
Adverse effects on mood appear to be infrequent, occurring only in a small percentage of women.
About 5 to 10% of women experience negative mood changes with combined birth control pills, and about 5% of women discontinue birth control pills due to such changes.
A study of about 4,000 women found that progestogen-only birth control with
depot medroxyprogesterone acetate had an incidence of depression of 1.5% and discontinuation due to depression of 0.5%.
Beneficial effects of hormonal birth control such as decreased
menstrual pain and
bleeding may positively influence mood.
A 2018
systematic review
A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...
of 26 studies, including 5
randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical t ...
s and 21
observational studies, found that the overall evidence showed no association between
progestogen-only birth control
Progestogen-only contraception (or progestin-only contraception) relies on progestogens alone to achieve contraception. It is one of the two major types of hormonal contraception, with the other major type being combined hormonal contraceptive me ...
and depression.
The progestins assessed included depot
medroxyprogesterone acetate,
levonorgestrel-containing
contraceptive implants and
intrauterine devices, and
progestogen-only birth control pills.
Findings of large observational studies are mixed due to prominent
confounding factors, but overall show no association of hormonal birth control with depression.
Randomized controlled trials typically do not find clinically significant influences of hormonal birth control on mood.
Reviews from before 1980 reported a high incidence of adverse mood effects with combined birth control pills.
However, doses of estrogens and progestogens in birth control pills before 1980 were considerably higher than those used today, and these doses frequently caused unpleasant side effects that may have unfavorably influenced mood.
Mood with birth control pills may be better with monophasic and continuous formulations than with triphasic and cyclic formulations.
Limited and inconsistent evidence supports differences in mood with hormonal birth control using different doses of ethinylestradiol or different
routes of administration, such as birth control pills versus
contraceptive vaginal rings and
contraceptive patch
A contraceptive patch, also known as "the patch", is a transdermal patch applied to the skin that releases synthetic oestrogen and progestogen hormones to prevent pregnancy. They have been shown to be as effective as the combined oral contr ...
es.
Combined birth control with less
androgenic or
antiandrogenic progestins like
desogestrel,
gestodene, and
drospirenone may have a more favorable influence on mood than birth control with more androgenic progestins like
levonorgestrel.
However,
androgen supplementation with hormonal birth control has also been reported to improve mood.
Hormonal birth control that suppresses
ovulation is effective in the treatment of
premenstrual dysphoric disorder
Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptom ...
(PMDD).
Combined birth control pills containing
drospirenone are approved for the treatment of PMDD and may be particularly beneficial due to the
antimineralocorticoid activity of drospirenone.
Studies on the influence of hormonal birth control on mood in women with existing
mood disorder
A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where a disturbance in the person's mood is the main underlying feature. The classification is in the '' Diagnostic and St ...
s or
polycystic ovary syndrome
Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
are limited and mixed.
Women with underlying mood disorders may be more likely to experience mood changes with hormonal birth control.
A 2016 systematic review found based on limited evidence from 6 studies that hormonal birth control, including combined birth control pills, depot medroxyprogesterone acetate, and levonorgestrel-containing intrauterine devices, was not associated with worse outcomes compared to non-use in women with
depressive or
bipolar disorder
Bipolar disorder, 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 last from days to weeks each. If the elevat ...
s.
A 2008
Cochrane Cochrane may refer to:
Places Australia
*Cochrane railway station, Sydney, a railway station on the closed Ropes Creek railway line
Canada
* Cochrane, Alberta
* Cochrane Lake, Alberta
* Cochrane District, Ontario
** Cochrane, Ontario, a town wit ...
review found a greater likelihood of
postpartum depression in women given
norethisterone enanthate as a form of
progestogen-only injectable birth control
Progestogen-only injectable contraceptives (POICs) are a form of hormonal contraception and progestogen-only contraception that are administered by injection and providing long-lasting birth control. As opposed to combined injectable contracept ...
, and recommended caution on the use of progestogen-only birth control in the
postpartum period.
Studies suggest a
negativity bias in
emotion recognition and
reactivity with hormonal birth control.
Some data suggests blunted
reward responses and potential dysregulation of the
stress response with hormonal birth control in some women.
Hormone therapy
Estrogen therapy appears to have a beneficial influence on mood in
depressed and
euthymic perimenopausal women.
Conversely, research on combined estrogen and progestogen therapy for depressive symptoms in menopausal women is scarce and inconclusive.
Some researchers contend that progestogens have an adverse influence on mood and reduce the benefits of estrogens on mood,
whereas other researchers maintain that progestogens have no adverse influence on mood.
Progesterone differs from progestins in terms of effects in the
brain
A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
and might have different effects on mood in comparison.
The available evidence, although limited, suggests no adverse influence of progesterone on mood when used in menopausal hormone therapy.
Sexual function
In most women,
sexual desire is unchanged or increased with combined birth control pills.
This is despite an increase in
sex hormone-binding globulin (SHBG) levels and a decrease in total and free
testosterone levels.
However, findings are conflicting, and more research is needed.
Blood clots
Venous thromboembolism
Venous thrombosis is 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 lungs to ...
(VTE) consists of
deep vein thrombosis (DVT) and
pulmonary embolism (PE).
DVT is a
blood clot
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
in a
deep vein
A deep vein is a vein that is deep in the body. This contrasts with superficial veins that are close to the body's surface.
Deep veins are almost always beside an artery with the same name (e.g. the femoral vein is beside the femoral artery). ...
, most commonly in the
legs, while PE occurs when a clot breaks free and blocks an
artery
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
in the
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of ...
s.
VTE is a rare but potentially fatal
cardiovascular event
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, he ...
.
Estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
s and progestogens can increase
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
by modulating
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
* Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
**Organic synthesis, the chemical synthesis of organ ...
of
coagulation factors.
As a result, they increase the risk of VTE, especially during
pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
when estrogen and progesterone levels are very high as well as during the
postpartum period.
Physiological
Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemica ...
levels of estrogen and/or progesterone may also influence risk of VTE—with late
menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
(≥55 years) being associated with greater risk than early menopause (≤45 years).
Progestogen monotherapy
Progestogens when used by themselves at typical clinical dosages, for instance in
progestogen-only birth control
Progestogen-only contraception (or progestin-only contraception) relies on progestogens alone to achieve contraception. It is one of the two major types of hormonal contraception, with the other major type being combined hormonal contraceptive me ...
, do not affect coagulation
and are not generally associated with a higher risk of
venous thromboembolism
Venous thrombosis is 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 lungs to ...
(VTE).
An exception is medroxyprogesterone acetate as a
progestogen-only injectable contraceptive, which has been associated with a 2- to 4-fold increase in risk of VTE relative to other progestogens and non-use.
The reasons for this are unknown, but the observations might be a
statistical artifact of preferential prescription of depot medroxyprogesterone acetate to women at risk for VTE.
Alternatively, medroxyprogesterone acetate may be an exception among progestogens in terms of influence on VTE risk,
possibly due to its
partial
Partial may refer to:
Mathematics
*Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant
** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial d ...
glucocorticoid activity.
In contrast to depot medroxyprogesterone acetate, no increase in VTE risk has been observed with moderately high doses of the related progestin
chlormadinone acetate (10 mg/day for 18–20 days/cycle), though based on limited data.
Very-high-dose progestogen therapy, including with medroxyprogesterone acetate,
megestrol acetate, and
cyproterone acetate, has been associated with activation of coagulation and a dose-dependent increased risk of VTE.
In studies with high-dose cyproterone acetate specifically, the increase in VTE risk has ranged from 3- to 5-fold.
The incidence of VTE in studies with very-high-dose progestogen therapy has been found to range from 2 to 8%.
However, the relevant patient populations, namely aged individuals with
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, are already predisposed to VTE, and this greatly amplifies the risk.
Estrogen plus progestogen therapy
In contrast to progestogen-only birth control, the addition of progestins to
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 or ...
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
therapy, including in
combined birth control 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 taken orally by women. The pill contains two important hormones: progesti ...
s and
menopausal hormone therapy, is associated with a higher risk of VTE than with oral estrogen therapy alone.
The risk of VTE is increased by about 2-fold or less with such regimens in menopausal hormone therapy and by 2- to 4-fold with combined birth control pills containing
ethinylestradiol, both relative to non-use.
In contrast to oral estrogen therapy,
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
estradiol, such as with
transdermal estradiol, is not associated with a higher risk of VTE.
This is likely due to its lack of
first-pass effect in the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
.
Research is mixed on whether addition of progestins to transdermal estradiol is associated with a greater risk of VTE, with some studies finding no increase in risk and others finding higher risk.
Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containing
contraceptive vaginal rings and
contraceptive patch
A contraceptive patch, also known as "the patch", is a transdermal patch applied to the skin that releases synthetic oestrogen and progestogen hormones to prevent pregnancy. They have been shown to be as effective as the combined oral contr ...
es compared to combined birth control pills with ethinylestradiol.
This is thought to be due to the resistance of ethinylestradiol to
hepatic metabolism
Metabolism (, from el, μεταβολή ''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 ...
.
The type of progestin in combined birth control may modulate the risk of VTE.
Studies have found that combined birth control pills containing
newer-generation progestins such as
desogestrel,
gestodene,
norgestimate,
drospirenone, and
cyproterone acetate are associated with a 1.5- to 3-fold higher risk of VTE than birth control pills containing
first-generation progestins such as
levonorgestrel and
norethisterone.
However, although this has been apparent in
retrospective cohort and
nested case–control studies, no greater risk of VTE has been observed in
prospective cohort and
case–control studies.
These kinds of
observational studies have certain advantages over the aforementioned types of studies, such as better ability to control for
confounding factors like new-user bias.
As such, it is unclear whether the higher risk of VTE with newer-generation birth control pills is a real finding or a statistical artifact.
Androgenic progestins have been found to
antagonize to some degree the effect of estrogens on coagulation.
First-generation progestins are more androgenic, while newer-generation progestins are weakly androgenic or antiandrogenic, and this might explain the observed differences in risk of VTE.
The type of estrogen also influences VTE risk.
Birth control pills containing
estradiol valerate are associated with about half the VTE risk of birth control pills with ethinylestradiol.
The type of progestogen in combined menopausal hormone therapy may also modulate VTE risk.
Oral estrogens plus
dydrogesterone appears to have lower VTE risk relative to inclusion of other progestins.
Norpregnane derivatives such as
nomegestrol acetate and
promegestone have been associated with a significantly greater risk of VTE than
pregnane derivatives such as
medroxyprogesterone acetate and dydrogesterone and
nortestosterone
Nandrolone, also known as 19-nortestosterone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate (brand name Durabolin). Nandrolon ...
derivatives such as
norethisterone and
levonorgestrel.
However, these findings may just be statistical artifacts.
In contrast to progestins, the addition of oral
progesterone to either oral or transdermal estrogen therapy is not associated with a higher risk of VTE.
However, oral progesterone achieves very low progesterone levels and has relatively weak progestogenic effects, which might be responsible for the absence of increase in VTE risk.
Parenteral progesterone, such as
vaginal
In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen. ...
or
injectable progesterone, which can achieve
luteal-phase levels of progesterone and associated progestogenic effects, has not been characterized in terms of VTE risk.
A 2012
meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
estimated that the
absolute risk of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for ethinylestradiol and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing ethinylestradiol and a newer-generation progestin.
For comparison, the absolute risk of VTE is generally estimated as 1 to 5 per 10,000 woman-years for non-use, 5 to 20 per 10,000 woman-years for pregnancy, and 40 to 65 per 10,000 woman-years for the postpartum period.
Risk of VTE with estrogen and progestogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time.
Older
age, higher
body weight
Human body weight is a person's mass or weight.
Strictly speaking, body weight is the measurement of weight without items located on the person. Practically though, body weight may be measured with clothes on, but without shoes or heavy accessor ...
, lower
physical activity
Physical activity is defined as any voluntary bodily movement produced by skeletal muscles that requires energy expenditure.Global Recommendations on Physical Activity for Health, 2009. World Health Organization. Geneva, Switzerland. Accessed 13/ ...
, and
smoking
Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Most commonly, the substance used is the dried leaves of the tobacco plant, which have b ...
are all associated with a higher risk of VTE with oral estrogen and progestogen therapy.
Women with
thrombophilia have a dramatically higher risk of VTE with estrogen and progestogen therapy than women without thrombophilia.
Depending on the condition, risk of VTE can be increased as much as 50-fold in such women relative to non-use.
Estrogens induce the production of
sex hormone-binding globulin (SHBG) in the liver.
As such, SHBG levels indicate hepatic estrogenic exposure and may be a reliable
surrogate marker In clinical trials, a surrogate endpoint (or surrogate marker) is a measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of He ...
for coagulation and VTE risk with estrogen therapy.
Combined birth control pills containing different progestins result in SHBG levels that are increased 1.5- to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and
dienogest, and 4- to 5-fold with cyproterone acetate.
SHBG levels differ depending on the progestin because androgenic progestins oppose the effect of ethinylestradiol on hepatic SHBG production as with its procoagulatory effects.
Contraceptive vaginal rings and
contraceptive patch
A contraceptive patch, also known as "the patch", is a transdermal patch applied to the skin that releases synthetic oestrogen and progestogen hormones to prevent pregnancy. They have been shown to be as effective as the combined oral contr ...
es likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively.
Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy.
Conversely, increases in SHBG levels are much lower with estradiol, especially when it is used parenterally.
Estradiol-containing combined birth control pills, like
estradiol valerate/dienogest and
estradiol/nomegestrol acetate
Nomegestrol acetate/estradiol (NOMAC-E2), sold under the brand names Naemis and Zoely among others, is a fixed-dose combination medication of nomegestrol acetate, a progestogen, and estradiol, an estrogen, which is used in menopausal hormone th ...
, and high-dose parenteral
polyestradiol phosphate
Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy ...
therapy have both been found to increase SHBG levels by about 1.5-fold.
Hormone therapy with high-dose ethinylestradiol and cyproterone acetate in
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
has been associated with a 20- to 45-fold higher risk of VTE relative to non-use.
The absolute incidence was about 6%.
Conversely, the risk of VTE in transgender women is much lower with oral or transdermal estradiol plus high-dose cyproterone acetate.
Ethinylestradiol is thought to have been primarily responsible for the VTE risk, but cyproterone acetate may have contributed as well.
Ethinylestradiol is no longer used in transgender hormone therapy,
and doses of cyproterone acetate have been reduced.
Cardiovascular health
Progestogens may influence the risk of
cardiovascular disease in women.
In the
women's Health Initiative (WHI), the risk of
coronary heart disease was greater with the combination of estrogen plus a progestin (specifically
medroxyprogesterone acetate) than with estrogen alone.
However, progestogens have varying activities and may differ in terms of cardiovascular risk.
A 2015 Cochrane review provided strong evidence that the treatment of post-menopausal women with hormone therapy for cardiovascular disease had little if any effect and increased the risk of
stroke
A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
and
venous thromboembolic events.
It is thought that
androgenic progestins like
medroxyprogesterone acetate and
norethisterone may antagonize the beneficial effects of estrogens on
biomarkers of cardiovascular health (e.g., favorable
lipid profile changes).
However, these findings are mixed and controversial.
Differences of progestogens on cardiovascular health and risk have been reviewed and summarized:
:"Unfortunately, there are few long-term clinical studies comparing different progestogens used in
ormone therapywith respect to cardiovascular outcomes. However, some aspects of potential cardiovascular risk have been examined, namely effects on lipids, vascular function/blood pressure, inflammation, thrombosis, and carbohydrate metabolism.
..Although progestins have differing effects on aspects of cardiovascular risk, in general, those more similar to progesterone have been associated with a lower impact than the more androgenic progestins on the beneficial effects of concomitant estrogen therapy. However, the limited number of long-term clinical studies makes it difficult to extrapolate the short-term effects on various markers of cardiovascular risk to long-term cardiovascular morbidity."
Route of administration might also influence the cardiovascular health effects of progestogens, but more research is needed similarly.
Breast cancer
Estrogen alone, progestogen alone, and combined estrogen and progestogen therapy are all associated with increased risks of breast cancer when used in
menopausal hormone therapy for
peri- and
postmenopausal women relative to non-use.
These risks are higher for combined estrogen and progestogen therapy than with estrogen alone or progestogen alone.
In addition to breast cancer risk, estrogen alone and estrogen plus progestogen therapy are associated with higher breast cancer
mortality.
With 20 years of use, breast cancer incidence is about 1.5-fold higher with estrogen alone and about 2.5-fold higher with estrogen plus progestogen therapy relative to non-use.
The increase in breast cancer risk with estrogen and progestogen therapy was shown to be causal with
conjugated estrogens plus
medroxyprogesterone acetate in the
Women's Health Initiative randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical t ...
s.
Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used.
Progestins including
chlormadinone acetate,
cyproterone acetate,
medrogestone,
medroxyprogesterone acetate,
nomegestrol acetate,
norethisterone acetate,
promegestone, and
tibolone have all been associated with similarly increased risk of breast cancer.
Some research has found that
oral progesterone and
dydrogesterone with short-term use (<5 years) may be associated with lower risk of breast cancer relative to other progestins.
In the long-term however (>5 years), oral progesterone and dydrogesterone have been associated with significantly increased breast cancer risk similarly to other progestogens.
The lower risk of breast cancer with oral progesterone than with other progestogens may be related to the very low progesterone levels and relatively weak progestogenic effects it produces.
The risk of breast cancer with estrogen and progestogen therapy in peri- and postmenopausal women is dependent on the duration of treatment, with more than 5 years of use being associated with significantly greater risk than less than five years of use.
In addition, continuous estrogen and progestogen therapy is associated with a higher risk of breast cancer than cyclic use.
A nationwide
observational study found that
transfeminine hormone therapy with estrogen plus high-dose
cyproterone acetate was associated with a 46-fold increased risk of breast cancer in
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
relative to the expected incidence for
cisgender men.
However, the risk of breast cancer was still lower than that in
cisgender women.
The extent to which the increase in breast cancer risk was related to estrogen versus cyproterone acetate is unknown.
Overdose
Progestogens are relatively safe in acute
overdose.
Interactions
Inhibitor
Inhibitor or inhibition may refer to:
In 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 neurotra ...
s and
inducers of
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s and other enzymes such as
5α-reductase
5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes o ...
may
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with progestogens.
Pharmacology
Pharmacodynamics
Progestogens act by binding to and activating the
progesterone receptors (PRs), including the
PR-A,
PR-B, and
PR-C.
Major
tissues affected by progestogens include the
uterus
The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...
,
cervix
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
,
vagina
In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...
,
breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
s, and
brain
A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
.
By activating PRs in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
and
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...
, progestogens suppress the secretion of
gonadotropins and thereby function as
antigonadotropins at sufficiently high doses.
Progesterone interacts with
membrane progesterone receptors, but interaction of progestins with these receptors is less clear.
In addition to their progestogenic activity, many progestogens have
off-target activities such as
androgenic,
antiandrogenic,
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
ic,
glucocorticoid, and
antimineralocorticoid activity.
Progestogens mediate their contraceptive effects in women both by inhibiting
ovulation (via their antigonadotropic effects) and by thickening
cervical mucus
The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...
, thereby preventing the possibility of
fertilization
Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the fusion of gametes to give rise to a new individual organism or offspring and initiate its development. Pro ...
of the
ovum
The egg cell, or ovum (plural ova), is the female reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the female gamete i ...
by
sperm
Sperm is the male reproductive 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 with a tail known as a flagellum, ...
.
Progestogens have functional
antiestrogenic effects in various tissues like the
endometrium via activation of the PR, and this underlies their use in menopausal hormone therapy (to prevent unopposed
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
-induced
endometrial hyperplasia and
endometrial cancer).
The PRs are induced in the breasts by estrogens, and for this reason, it is assumed that progestogens cannot mediate breast changes in the absence of estrogens.
The off-target activities of progestogens can contribute both to their beneficial effects and to their adverse effects.
Antigonadotropic effects
Progestogens, similarly to the androgens and estrogens through their own respective
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
s, inhibit the secretion of the
gonadotropins
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, pubertal maturation, ...
(FSH) and
luteinizing hormone (LH) via activation of the PR in the
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...
. This effect is a form of
negative feedback on the
hypothalamic–pituitary–gonadal axis (HPG axis) and takes advantage of the mechanism that the body uses to prevent
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 effect ...
levels from becoming too high.
Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have
antigonadotropic
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...
effects,
and progestogens in sufficiently high amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens as well as inhibit
fertility
Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...
(
ovulation in women and
spermatogenesis
Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubu ...
in men).
Progestogens have been found to maximally suppress circulating testosterone levels in men by up to 70 to 80% at sufficiently high doses.
This is notably less than that achieved by
GnRH analogues, which can effectively abolish gonadal production of testosterone and suppress circulating testosterone levels by as much as 95%.
It is also less than that achieved by
high-dose estrogen
High-dose estrogen (HDE) is a type of hormone therapy in which high doses of estrogens are given. When given in combination with a high dose of a progestogen, it has been referred to as pseudopregnancy. It is called this because the estrogen and p ...
therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues.
The
retroprogesterone derivative
In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
s
dydrogesterone and
trengestone are atypical progestogens and unlike all other clinically used progestogens do not have antigonadotropic effects nor inhibit ovulation even at very high doses.
In fact, trengestone may have
progonadotropic
A progonadotropin, or hypergonadotropin, also known as a gonad stimulant, is a type of drug which increases the secretion of one or both of the major gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This, in turn, re ...
effects, and is actually able to
''induce'' ovulation, with about a 50% success rate on average.
These progestins also show other atypical properties relative to other progestogens, such as a lack of a
hyperthermic effect.
Androgenic activity
Some progestins have
androgenic activity and can produce androgenic
side effects such as increased
sebum
A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest nu ...
production (
oilier skin),
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
, and
hirsutism (excessive facial/body hair growth), as well as changes in
liver protein production.
Only certain progestins are androgenic however, these being the
testosterone derivatives and, to a lesser extent, the
17α-hydroxyprogesterone derivatives
medroxyprogesterone acetate and
megestrol acetate.
No other progestins have such activity (though some, conversely, possess antiandrogenic activity).
Moreover, the androgenic activity of progestins within the testosterone derivatives also varies, and while some may have high or moderate androgenic activity, others have only low or no such activity.
The androgenic activity of androgenic progestins is mediated by two mechanisms: 1) direct binding to and activation of the
androgen receptor; and 2) displacement of
testosterone from
sex hormone-binding globulin (SHBG), thereby increasing free (and thus bioactive) testosterone levels.
The androgenic activity of many androgenic progestins is offset by combination with
ethinylestradiol, which robustly increases SHBG levels, and most oral contraceptives in fact markedly reduce free testosterone levels and can treat or improve acne and hirsutism.
An exception is progestin-only contraceptives, which do not also contain an estrogen.
The relative androgenic activity of testosterone-derivative progestins and other progestins that have androgenic activity can be roughly ranked as follows:
* Very high:
danazol,
ethisterone,
gestrinone,
normethandrone,
norvinisterone
Norvinisterone, sold under the brand names Neoprogestin and Nor-Progestelea, is a progestin and androgen/anabolic steroid (AAS) medication which was used in Europe but is now no longer marketed. It is taken by mouth.
Norvinisterone is a proges ...
* High:
levonorgestrel,
norgestrel,
norgestrienone,
tibolone
* Moderate:
norethisterone and its
prodrugs (
norethisterone acetate,
norethisterone enanthate,
etynodiol diacetate,
lynestrenol
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination w ...
,
quingestanol acetate
Quingestanol acetate, sold under the brand names Demovis and Pilomin among others, is a progestin medication which was used in birth control pills but is no longer marketed. It is taken by mouth.
Quingestanol acetate is a progestin, or a synthe ...
)
* Low:
desogestrel,
etonogestrel,
gestodene,
norgestimate
* Very low or negligible:
allylestrenol,
dimethisterone
Dimethisterone, formerly sold under the brand names Lutagan and Secrosteron among others, is a progestin medication which was used in birth control pills and in the treatment of gynecological disorders but is now no longer available. It was used ...
,
medroxyprogesterone acetate,
megestrol acetate,
norelgestromin,
noretynodrel,
norgesterone
Norgesterone, also known as norvinodrel or vinylestrenolone and sold under the brand name Vestalin, is a progestin medication which was formerly used in birth control pills for women but is now no longer marketed. It was used in combination with ...
* Antiandrogenic:
dienogest,
oxendolone
The clinical androgenic and
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breakin ...
activity of the androgenic progestins listed above is still far lower than that of conventional
androgens and
anabolic steroid
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone as well as synthetic androgens that are structurally related and have similar effects ...
s like
testosterone and
nandrolone ester
This is a list of androgen esters, including esters (as well as ethers) of natural androgens like testosterone and dihydrotestosterone (DHT) and synthetic anabolic–androgenic steroids (AAS) like nandrolone (19-nortestosterone).
Esters of n ...
s. As such, they are only generally associated with such effects in women and often only at high doses. In men, due to their concomitant progestogenic activity and by extension antigonadotropic effects, these progestins can have potent functional antiandrogenic effects via suppression of testosterone production and levels.
Antiandrogenic activity
Some progestogens have
antiandrogenic activity in addition to their progestogenic activity.
These progestogens, with varying degrees of potency as antiandrogens, include
chlormadinone acetate,
cyproterone acetate,
dienogest,
drospirenone,
medrogestone,
megestrol acetate,
nomegestrol acetate,
osaterone acetate (veterinary), and
oxendolone.
The relative antiandrogenic activity in animals of some of these progestogens has been ranked as follows: cyproterone acetate (100%) > nomegestrol acetate (90%) > dienogest (30–40%) ≥ chlormadinone acetate (30%) = drospirenone (30%).
Antiandrogenic activity in certain progestogens may help to improve symptoms of
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
seborrhea,
hirsutism, and other
androgen-dependent conditions in women.
Estrogenic activity
A few progestins have weak
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
ic activity.
These include the 19-nortestosterone derivatives
norethisterone,
noretynodrel, and
tibolone, as well as the norethisterone
prodrugs
norethisterone acetate,
norethisterone enanthate,
lynestrenol
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination w ...
, and
etynodiol diacetate.
The estrogenic activity of norethisterone and its prodrugs are due to
metabolism
Metabolism (, from el, μεταβολή ''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 ...
into
ethinylestradiol.
High doses of norethisterone and noretynodrel have been associated with estrogenic side effects such as
breast enlargement in women and
gynecomastia in men, but also with alleviation of
menopausal symptoms in postmenopausal women.
In contrast, non-estrogenic progestins were not found to be associated with such effects.
Glucocorticoid activity
Some progestogens, mainly certain
17α-hydroxyprogesterone derivatives, have weak
glucocorticoid activity.
This can result, at sufficiently high doses, in side effects such as symptoms of
Cushing's syndrome,
steroid diabetes
Steroid diabetes is a medical term referring to prolonged hyperglycemia due to glucocorticoid therapy for another medical condition. It is usually, but not always, a transient condition.
Cause
The most common glucocorticoids which cause steroi ...
,
adrenal suppression and insufficiency, and
neuropsychiatric symptoms like
depression,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
,
irritability, and
cognitive impairment.
Progestogens with the potential for clinically relevant glucocorticoid effects include the 17α-hydroxyprogesterone derivatives
chlormadinone acetate,
cyproterone acetate,
medroxyprogesterone acetate,
megestrol acetate,
promegestone, and
segesterone acetate and the testosterone derivatives
desogestrel,
etonogestrel, and
gestodene.
Conversely,
hydroxyprogesterone caproate possesses no such activity, while
progesterone itself has very weak glucocorticoid activity.
Antimineralocorticoid activity
Certain progestogens, including
progesterone,
drospirenone, and
gestodene, as well as to a lesser extent
dydrogesterone and
trimegestone, have varying degrees of
antimineralocorticoid activity.
Other progestins might also have significant antimineralocorticoid activity.
Progesterone itself has potent antimineralocorticoid activity.
No clinically used progestogens are known to have
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 ...
activity.
Progestins with potent antimineralocorticoid activity like drospirenone may have properties more similar to those of natural progesterone, such as counteraction of cyclical estrogen-induced
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable ...
and
fluid retention,
edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
, and associated
weight gain; lowered
blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure ...
; and possibly improved
cardiovascular health.
Neurosteroid activity
Progesterone has
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 co ...
activity via metabolism into
allopregnanolone and
pregnanolone, potent
positive allosteric modulators of the
GABAA receptor.
As a result, it has associated effects such as
sedation,
somnolence
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 ...
, and
cognitive impairment.
No progestin is known to have similar such neurosteroid activity or effects.
However,
promegestone has been found to act as a
non-competitive antagonist of the
nicotinic acetylcholine receptor similarly to progesterone.
Other activities
Certain progestins have been found to stimulate the
proliferation of
MCF-7 breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...
cells ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'', an action that is independent of the classical PRs and is instead mediated via the
progesterone receptor membrane component-1 (PGRMC1).
Norethisterone,
desogestrel,
levonorgestrel, and
drospirenone strongly stimulate proliferation and
medroxyprogesterone acetate,
dienogest, and
dydrogesterone weakly stimulate proliferation, whereas
progesterone,
nomegestrol acetate, and
chlormadinone acetate act neutrally in the assay and do not stimulate proliferation.
It is unclear whether these findings may explain the different risks of breast cancer observed with progesterone, dydrogesterone, and other progestins such as medroxyprogesterone acetate and norethisterone 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, diet ...
.
Pharmacokinetics
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 or ...
progesterone has very low
bioavailability and
potency
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
.
Micronization and dissolution in
oil-filled
capsules, a formulation known as oral micronized progesterone (OMP), increases the bioavailability of progesterone by several-fold.
However, the bioavailability of oral micronized progesterone nonetheless remains very low at less than 2.4%.
Progesterone also has a very short
elimination half-life
Biological half-life (also known as elimination half-life, pharmacologic 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 b ...
in the
circulation of no more than 1.5 hours.
Due to the poor oral activity of oral micronized progesterone, it has relatively weak progestogenic effects.
Administration of progesterone in
oil solution by
intramuscular injection
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 ...
has a duration of about 2 or 3 days, necessitating frequent injections.
Transdermal administration of progesterone in the form of
cream
Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this process ...
s or
gel
A gel is a semi-solid that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state, although the liquid phase may still di ...
s achieves only very low levels of progesterone and weak progestogenic effects.
Due to the poor oral activity of progesterone and its short duration with intramuscular injection, progestins were developed in its place both for oral use and for parenteral administration.
[ ] Orally active progestins have high oral bioavailability in comparison to oral micronized progesterone.
Their bioavailability is generally in the range of 60 to 100%.
Their elimination half-lives are also much longer than that of progesterone, in the range of 8 to 80 hours.
Due mainly to their
pharmacokinetic improvements, progestins have oral potency that is up to several orders of magnitude greater than that of oral micronized progesterone.
For example, the oral potency of medroxyprogesterone acetate is at least 30-fold that of oral micronized progesterone, while the oral potency of
gestodene is at least 10,000-fold that of oral micronized progesterone.
Parenterally administered progestins, such as
hydroxyprogesterone caproate in oil solution,
norethisterone enanthate in oil solution, and medroxyprogesterone acetate in
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 the ...
aqueous suspension, have durations in the range of weeks to months.
Chemistry
All currently available progestogens are
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
al in terms of
chemical structure
A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...
.
Progestogens include the
naturally occurring progesterone and the
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic ...
progestogens (otherwise known as progestins).
Progestins can be broadly grouped into two structural classes—
chemical derivatives of
progesterone and chemical derivatives of
testosterone.
Progesterone derivatives can be classified into subgroups including
pregnanes,
retropregnanes,
norpregnanes, and
spirolactones.
Examples of progestins of each of these subgroups include
medroxyprogesterone acetate,
dydrogesterone,
nomegestrol acetate, and
drospirenone, respectively.
Testosterone derivatives can be classified into subgroups including
androstanes,
estrane
Estrane is a C18 steroid derivative, with a gonane core.
''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...
s (19-norandrostanes), and
gonane
Gonane is a chemical compound with formula , whose molecule can be described as three molecules or entities of cyclohexane and one of cyclopentane, fused in a particular way. More specifically, the molecule can be described as that of cycloh ...
s (18-methylestranes).
Examples of progestins of each of these subgroups include
ethisterone,
norethisterone, and
levonorgestrel, respectively.
Many progestins have
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...
and/or
ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again ...
substitution
Substitution may refer to:
Arts and media
*Chord substitution, in music, swapping one chord for a related one within a chord progression
*Substitution (poetry), a variation in poetic scansion
* "Substitution" (song), a 2009 song by Silversun Pic ...
s (see
progestogen ester) which result in greater
lipophilicity and in some cases cause the progestins in question to act as
prodrugs in the body.
History
The recognition of progesterone's ability to suppress
ovulation during pregnancy spawned a search for a similar hormone that could bypass the problems associated with administering progesterone (e.g. low
bioavailability when administered orally and local irritation and pain when continually administered
parenteral
A route of administration in pharmacology and toxicology is the way by which a drug, fluid, poison, or other substance is taken into the body.
Routes of administration are generally classified by the location at which the substance is applied. ...
ly) and, at the same time, serve the purpose of controlling ovulation. The many synthetic hormones that resulted are known as progestins.
The first orally active progestin,
ethisterone (pregneninolone, 17α-ethynyltestosterone), the C17α
ethynyl analogue of
testosterone, was
synthesized in 1938 from
dehydroandrosterone by
ethynylation, either before or after
oxidation of the C3 hydroxyl group, followed by
rearrangement of the C5(6) double bond to the C4(5) position. The synthesis was designed by chemists Hans Herloff Inhoffen, Willy Logemann, Walter Hohlweg and Arthur Serini at
Schering AG in
Berlin
Berlin ( , ) is the capital and largest city of Germany by both area and population. Its 3.7 million inhabitants make it the European Union's most populous city, according to population within city limits. One of Germany's sixteen constitu ...
and was marketed in
Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwee ...
in 1939 as ''Proluton C'' and by
Schering in the
U.S. in 1945 as ''Pranone''.
A more potent orally active progestin,
norethisterone (norethindrone, 19-nor-17α-ethynyltestosterone), the C19
nor analogue of ethisterone, synthesized in 1951 by
Carl Djerassi
Carl Djerassi (October 29, 1923 – January 30, 2015) was an Austrian-born Bulgarian-American pharmaceutical chemist, novelist, playwright and co-founder of Djerassi Resident Artists Program with Diane Wood Middlebrook. He is best known for his ...
,
Luis Miramontes, and
George Rosenkranz at
Syntex in
Mexico City
Mexico City ( es, link=no, Ciudad de México, ; abbr.: CDMX; Nahuatl: ''Altepetl Mexico'') is the capital and largest city of Mexico, and the most populous city in North America. One of the world's alpha cities, it is located in the Valley o ...
, was marketed by
Parke-Davis
Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although Parke, Davis & Co. is no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history. In 19 ...
in the U.S. in 1957 as ''Norlutin'', and was used as the progestin in some of the
first oral contraceptives (''Ortho-Novum'', ''Norinyl'', etc.) in the early 1960s.
Noretynodrel, an
isomer of norethisterone, was synthesized in 1952 by
Frank B. Colton at
Searle in
Skokie, Illinois
Skokie (; formerly Niles Center) is a village in Cook County, Illinois, United States, neighboring the City of Chicago's northern border. Its population, according to the 2020 census, was 67,824. Skokie lies approximately north of Chicago's d ...
and used as the progestin in ''Enovid'', marketed in the U.S. in 1957 and approved as the first oral contraceptive in 1960.
Society and culture
Generations
Progestins used in birth control are sometimes grouped, somewhat arbitrarily and inconsistently, into ''generations''. One categorization of these generations is as follows:
* First generation: Approved for marketing before 1973. Examples:
noretynodrel,
norethisterone (norethindrone),
lynestrenol
Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination w ...
,
levonorgestrel.
* Second generation: Approved for marketing between 1973 and 1989. Examples:
desogestrel,
nomegestrol acetate,
norgestimate.
* Third generation: Approved for marketing between 1990 and 2000. Examples:
dienogest,
etonogestrel.
* Fourth generation: Approved for marketing after 2000. Examples:
drospirenone,
norelgestromin,
segesterone acetate.
Alternatively,
estrane
Estrane is a C18 steroid derivative, with a gonane core.
''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...
s such as
noretynodrel and
norethisterone are classified as first-generation while
gonane
Gonane is a chemical compound with formula , whose molecule can be described as three molecules or entities of cyclohexane and one of cyclopentane, fused in a particular way. More specifically, the molecule can be described as that of cycloh ...
s such as
norgestrel and
levonorgestrel are classified as second-generation, with less androgenic gonanes such as
desogestrel,
norgestimate, and
gestodene classified as third-generation and newer progestins like
drospirenone classified as fourth-generation.
Yet another classification system considers there to be only first- and second-generation progestins.
Availability
Progestogens are available widely throughout the world in many different forms. They are present in all birth control pills.
Etymology
''Progestogens'', also termed ''progestagens'', ''progestogens'', or ''gestagens'', are compounds which act as
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 ag ...
s of the
progesterone receptors.
Progestogens include ''
progesterone''—which is the main natural and endogenous progestogen—and ''progestins'', which are
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to:
Science
* Synthetic chemical or compound, produced by the process of chemical synthesis
* Synthetic ...
progestogens.
Progestins include the
17α-hydroxyprogesterone derivative
In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...
medroxyprogesterone acetate and the
19-nortestosterone
Nandrolone, also known as 19-nortestosterone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate (brand name Durabolin). Nandrolon ...
derivative
norethisterone, among many other synthetic progestogens.
As progesterone is a single compound and has no plural form, the term "progesterones" does not exist and is grammatically incorrect.
The terms describing progestogens are often confused.
However, progestogens have differing
activities and effects and it is inappropriate to interchange them.
Research
A variety of progestins have been studied for use as potential
male hormonal contraceptives in combination with
androgens in men.
These include the
pregnanes
medroxyprogesterone acetate,
megestrol acetate, and
cyproterone acetate, the
norpregnane segesterone acetate, and the
estrane
Estrane is a C18 steroid derivative, with a gonane core.
''Estrenes'' are estrane derivatives that contain a double bond, with an example being nandrolone. ''Estratrienes'' (estrins) are estrane derivatives that contain three double bonds, for i ...
s
norethisterone acetate,
norethisterone enanthate,
levonorgestrel,
levonorgestrel butanoate,
desogestrel, and
etonogestrel.
The androgens that have been used in combination with these progestins include
testosterone,
testosterone esters,
androstanolone
Androstanolone, or stanolone, also known as dihydrotestosterone (DHT) and sold under the brand name Andractim among others, is an androgen and anabolic steroid (AAS) medication and hormone which is used mainly in the treatment of low testostero ...
(dihydrotestosterone), and
nandrolone ester
This is a list of androgen esters, including esters (as well as ethers) of natural androgens like testosterone and dihydrotestosterone (DHT) and synthetic anabolic–androgenic steroids (AAS) like nandrolone (19-nortestosterone).
Esters of n ...
s.
Dual androgens and progestogens such as
trestolone
Trestolone, also known as 7α-methyl-19-nortestosterone (MENT), is an experimental androgen/anabolic steroid (AAS) and progestogen medication which has been under development for potential use as a form of hormonal birth control for men and in ...
and
dimethandrolone undecanoate
Dimethandrolone undecanoate (DMAU), also known by its developmental code name CDB-4521, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under development as a potential birth control pill for men. It is tak ...
have also been developed and studied as male contraceptives.
Doses of progestins used in male hormonal contraception have been noted to be in the range of 5 to 12times the doses used in female hormonal contraception.
See also
*
Phytoprogestogen
*
Antiprogestogen
*
Selective progesterone receptor modulator
References
Further reading
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{{Portal bar, Medicine
Contraception for males
Galactagogues
IARC Group 2B carcinogens
Progestogens