Combined injectable contraceptives (CICs) are a form of

hormonal birth control Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...

for women. They consist of monthly

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

s of combined formulations containing an

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

and a

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a '' synthetic'' progestogen. ...

to prevent

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. CICs are different from progestogen-only injectable contraceptives (POICs), such as depot

medroxyprogesterone acetate Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of ...

(DMPA; brand names Depo-Provera, Depo-SubQ Provera 104) and norethisterone enantate (NETE; brand name Noristerat), which are not combined with an estrogen and are given once every two to three months instead of once a month. Hormonal contraception works primarily by preventing ovulation, but it may also thicken the cervical mucus inhibiting sperm penetration. Hormonal contraceptives also have effects on the endometrium, that theoretically could affect implantation.

Medical uses

CICs are administered by intramuscular injection into the

deltoid Deltoid (delta-shaped) can refer to: * The deltoid muscle, a muscle in the shoulder * Kite (geometry), also known as a deltoid, a type of quadrilateral * A deltoid curve, a three-cusped hypocycloid * A leaf shape * The deltoid tuberosity, a part o ...

gluteus maximus The gluteus maximus is the main extensor muscle of the hip in humans. It is the largest and outermost of the three gluteal muscles and makes up a large part of the shape and appearance of each side of the hips. It is the single largest muscle in ...

, or anterior thigh. They are ideally administered every 28 to 30 days, though they have been demonstrated to be effective up to 33 days. Some CICs have been said to be used by

transgender women A trans woman or transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity and may experience gender dysphoria (distress brought upon by the discrepancy between a person's gender identity and their ...

as a means of

feminizing hormone therapy Feminizing hormone therapy, also known as transfeminine hormone therapy, is a form of Transgender_health_care#Gender-affirming_care , gender-affirming care and a gender-affirming hormone therapy , gender-affirming hormone therapy to change t ...

as well.

Available forms

A variety of different CICs, generally containing a short-acting natural

estradiol ester This is a list of estrogen esters, or ester prodrugs of estrogens. It includes esters, as well as ethers, of steroidal estrogens like estradiol, estrone, and estriol and of nonsteroidal estrogens like the stilbestrols diethylstilbestrol an ...

and a long-acting progestin ester, are available for clinical use. Estrogens that are used include

estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...

, estradiol cypionate, estradiol enantate, estradiol benzoate butyrate, and

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

, while progestins that are used include norethisterone enantate,

, algestone acetophenide (dihydroxyprogesterone acetophenide),

hydroxyprogesterone caproate Hydroxyprogesterone caproate, sold under the brand name Delalutin among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manuf ...

, and megestrol acetate. Estradiol benzoate has a duration that is too short for once-monthly CICs, and is not used in them. Conversely, estradiol enantate is said to have a duration that is too long for once-monthly CICs, but is nonetheless used in them.

Side effects

Side effects of CICs, besides menstrual bleeding changes, are minimal. The most prominent side effects of CICs are menstrual irregularities during the first 3 to 6 months of use.

Dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in th ...

has been reported in 30 to 65% of women. Other side effects include breast tenderness/pain,

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, and

libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

changes. Some fluid retention can occur, but

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

is minimal. Local

injection site reaction Injection site reactions (ISRs) are reactions that occur at the site of injection of a drug. They may be mild or severe and may or may not require medical intervention. Some reactions may appear immediately after injection, and some may be delayed ...

s have also been reported in 15 to 35% of women. Effects of CICs on

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...

and

fibrinolysis Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other c ...

are minimal and are not thought to be clinically relevant. Conversely,

combined oral contraceptive pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be Oral administration, taken orally by women. It is the oral form of combi ...

s containing

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol was widely used for various indications such as the treatment of menopausal symptoms, gynecological ...

have considerable effects on coagulation and fibrinolysis. The differences can be attributed to the lack of the first-pass effect with

parenteral administration In pharmacology and toxicology, a route of administration 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. ...

as well as

structural A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

and

pharmacological Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

differences between estradiol and ethinylestradiol.

Pharmacology

Idealized curves of estradiol levels after injection of different estradiol esters in women

CICs contain an

and a

. The estrogen is generally a short-acting

, which acts as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

. Esters of estradiol are

natural Nature is an inherent character or constitution, particularly of the ecosphere or the universe as a whole. In this general sense nature refers to the laws, elements and phenomena of the physical world, including life. Although humans are part ...

and bioidentical estrogens, and are believed to have more favorable effects on

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

health, and

hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. Hemostasis involves three ...

than

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

estrogens such as

. The progestin is a long-acting progestogen ester, which may or may not act as a prodrug.

Progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

s including

, algestone acetophenide (dihydroxyprogesterone acetophenide),

, and megestrol acetate are active themselves and are not prodrugs, whereas the

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

derivative norethisterone enantate is a prodrug of

norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...

. Regardless of whether they are prodrugs or not, steroid esters form a depot and have an extended

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

due to a

depot effect A depot injection, also known as a long-acting injectable (LAI), is a term for an Injection (medicine), injection formulation of a medication which Extended release, releases slowly over time to permit less frequent administration of a medication ...

when administered by

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...

. Because CICs are administered

parenteral In pharmacology and toxicology, a route of administration 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, they bypass the first-pass effect in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

s that occurs with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

of estrogens. However, is estimated that about 20% of an administered dose does still eventually pass through the liver. Hence, these preparations are not completely liver-neutral. Nonetheless, they have dramatically reduced hepatic effects relative to oral ethinylestradiol. In addition, parenteral

in general has about 4- or 5-fold reduced potency in the liver than oral estradiol. Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil

Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil

CICs have antigonadotropic effects via their estrogenic and progestogenic activity and inhibit

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

and suppress

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...

levels. A single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) has been found to strongly suppress testosterone levels in men. Testosterone levels decreased from a baseline of ~503 ng/dL to a trough of ~30 ng/dL (a 94% decrease) which occurred at day 7 post-injection.

History

The first CIC to be studied was estradiol valerate/hydroxyprogesterone caproate (EV/OHPC) in 1963, and the second CIC to be studied was estradiol enantate/algestone acetophenide (E2-EN/DHPA) in 1964. In 1967, E2-EN/DHPA was in the late stages of clinical development.Hecht-Lucari, G. (1967). Recientes Progresos de la Terapia Hormonal en Ginecología. Revista Colombiana de Obstetricia y Ginecología, 18(5), 307-319. 10.18597/rcog.2584 https://revista.fecolsog.org/index.php/rcog/article/view/2584 By 1969, the medication was available for medical use under the brand name Perlutal. Within a few years, it was marketed under other brand names such as Topasel and Ova-Repos as well.Botella-Llusia, J. (1970). Les ovaires au cours de l'administration des sterpides anticonceptionnels. he ovaries during administration of contraceptive steroids.In: Netter, A. L'Inhibition de l'ovulation; Colloque de la Societe Nationale pour l'Etude de la Sterilite et de la Fecondite. (Inhibition of ovulation: Proceedings of the National Society for the Study of Sterility and Fertility.) Paris, Masson, 1970. p. 141-156Liria, R. H. (1972). Anticoncepcionismo (Un problema de hoy, de ayer y de siempre). In Anales de medicina y cirugía (Vol. 52, No. 230, pp. 329-348). https://www.raco.cat/index.php/AnalesMedicina/article/download/99455/152590 In addition, several other CICs had been introduced for medical use by 1972. By 1976, two major CICs were in use: E2-EN/DHPA (brand names Perlutan, Topasel) in

Spain Spain, or the Kingdom of Spain, is a country in Southern Europe, Southern and Western Europe with territories in North Africa. Featuring the Punta de Tarifa, southernmost point of continental Europe, it is the largest country in Southern Eur ...

and

Latin America Latin America is the cultural region of the Americas where Romance languages are predominantly spoken, primarily Spanish language, Spanish and Portuguese language, Portuguese. Latin America is defined according to cultural identity, not geogr ...

, and EV/OHPC (brand name Injectable No. 1) in

China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...

. These CICs have been described as first-generation CICs. Two second-generation CICs, estradiol cypionate/medroxyprogesterone acetate (EC/MPA; brand names Cyclofem and later Lunelle) and estradiol valerate/norethisterone enantate (EV/NETE; brand name Mesigyna), were introduced for clinical use in 1993. On 5 October 2000,

Pharmacia Pharmacia was a pharmaceutical and biotechnological company in Sweden that merged with the American pharmaceutical company Upjohn in 1995. History Pharmacia company was founded in 1911 in Stockholm, Sweden by pharmacist Gustav Felix Grönfel ...

received FDA approval for Lunelle Monthly Contraceptive Injection. In April 2003, Pharmacia was acquired by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

(makers of depot medroxyprogesterone acetate). In October 2003, Lunelle was discontinued in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

Society and culture

Availability

CICs are available in many countries throughout the world, including widely throughout Central and

South America South America is a continent entirely in the Western Hemisphere and mostly in the Southern Hemisphere, with a considerably smaller portion in the Northern Hemisphere. It can also be described as the southern Subregion#Americas, subregion o ...

, in

Mexico Mexico, officially the United Mexican States, is a country in North America. It is the northernmost country in Latin America, and borders the United States to the north, and Guatemala and Belize to the southeast; while having maritime boundar ...

and the

Caribbean The Caribbean ( , ; ; ; ) is a region in the middle of the Americas centered around the Caribbean Sea in the Atlantic Ocean, North Atlantic Ocean, mostly overlapping with the West Indies. Bordered by North America to the north, Central America ...

, in

, in several

Southeast Asia Southeast Asia is the geographical United Nations geoscheme for Asia#South-eastern Asia, southeastern region of Asia, consisting of the regions that are situated south of China, east of the Indian subcontinent, and northwest of the Mainland Au ...

n and

Africa Africa is the world's second-largest and second-most populous continent after Asia. At about 30.3 million km2 (11.7 million square miles) including adjacent islands, it covers 20% of Earth's land area and 6% of its total surfac ...

n countries, and in

Turkey Turkey, officially the Republic of Türkiye, is a country mainly located in Anatolia in West Asia, with a relatively small part called East Thrace in Southeast Europe. It borders the Black Sea to the north; Georgia (country), Georgia, Armen ...

. They were also previously available in the

Portugal Portugal, officially the Portuguese Republic, is a country on the Iberian Peninsula in Southwestern Europe. Featuring Cabo da Roca, the westernmost point in continental Europe, Portugal borders Spain to its north and east, with which it share ...

, and

, but have been discontinued in these countries.

Research

Many other CICs have been studied but have not been approved or marketed for clinical use. The following are marketed CICs at different doses than those that are approved: *

Estradiol valerate Estradiol valerate (EV), sold for use oral administration, by mouth under the brand name Progynova and for use by injection (medicine), injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen (medication), es ...

2.5 to 5 mg + norethisterone enantate 50 to 80 mg in an

oil solution An oil is any nonpolar chemical substance that is composed primarily of hydrocarbons and is hydrophobic (does not mix with water) and lipophilic (mixes with other oils). Oils are usually flammable and surface active. Most oils are unsaturat ...

10 mg +

500 mg in an oil solution * Estradiol cypionate 2.5 to 10 mg +

12.5 to 50 mg in a

microcrystalline A microcrystalline material is a crystallized substance or rock that contains small crystals visible only through microscopic examination. There is little agreement on the range of crystal sizes that should be regarded as microcrystalline, but ...

aqueous suspension * Estradiol enantate 5 to 50 mg + algestone acetophenide 75 to 200 mg in an oil solution The half-progestin-dose formulation of estradiol valerate/norethisterone enantate (5 mg / 25 mg) is also known as HRP-103 and the half-progestin-dose formulation of estradiol cypionate/medroxyprogesterone acetate (5 mg / 12.5 mg) is also known as HRP-113. The following are CICs that have never been marketed: *

20 mg +

100 mg in a microcrystalline aqueous suspension * Estradiol undecylate 5 to 10 mg + norethisterone enantate 50 to 70 mg in an oil solution * Estradiol cypionate + norethisterone enantate *

10 mg +

methenmadinone caproate Methenmadinone caproate (MMC, also known as superlutin caproate) is a progestin medication which was developed in Czechoslovakia in the 1960s and was studied for potential use in combined injectable contraceptives in the 1970s but was never mark ...

60 mg (Lutofollin) * Estradiol hexahydrobenzoate 5 mg (oil solution) + norgestrel 25 mg (aqueous suspension) * Estradiol cypionate 3.5 to 5 mg + megestrol acetate 25 mg in a microcrystalline aqueous suspension (marketed in China?) *

3 to 5 mg + chlormadinone caproate 80 mg in an oil solution *

5 mg + megestrol acetate 15 mg in an aqueous suspension of

gelatin Gelatin or gelatine () is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also be referred to as hydrolyzed collagen, coll ...

microspheres (50–80 μm) *

Estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

5 mg +

levonorgestrel Levonorgestrel is a hormonal medication used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand names Plan B One-Step and Julie, ...

7 mg in an aqueous suspension of

monolithic A monolith is a monument or natural feature consisting of a single massive stone or rock. Monolith or monolithic may also refer to: Architecture * Monolithic architecture, a style of construction in which a building is carved, cast or excavated f ...

microspheres (80 μm) or in a macrocrystalline suspension (15 μm) * Estradiol cypionate 5 mg + levonorgestrel butanoate 7 mg in an aqueous suspension * Estradiol benzoate 5 to 10 mg +

norethisterone enanthate Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined inje ...

50 to 100 mg * Mestranol 1.0–1.2 mg +

10–12 mg in a

aqueous suspension of defined

particle size Particle size is a notion introduced for comparing dimensions of solid particles ('' flecks''), liquid particles ('' droplets''), or gaseous particles ('' bubbles''). The notion of particle size applies to particles in colloids, in ecology, in ...

s (125–177 μm) *

Ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol was widely used for various indications such as the treatment of menopausal symptoms, gynecological ...

5 mg and

progesterone Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...

100 to 300 mg in an aqueous suspension of

microspheres or in a macrocrystalline suspension * Polyestradiol phosphate 40 mg +

150 mg