Progestogen (medication)

Available forms Progestogens are available in many different forms for use by many different routes of administration. These include oral tablets and capsules, oil and aqueous solutions and suspensions for intramuscular or subcutaneous injection, 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 pills, combined contraceptive patches, combined contraceptive vaginal rings, and combined injectable contraceptives; 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 effects; thickening of cervical mucus, making the cervix largely impenetrable to sperm; preventing capacitation of sperm due to changes in cervical fluid, thereby making sperm unable to penetrate the ovum; and atrophic changes in the endometrium, making the endometrium unsuitable for implantation. They may also decrease tubal motility and ciliary action. Gynecological disorders Menstrual disorders Progestogens are used to treat menstrual disorders such as secondary amenorrhea and dysfunctional uterine bleeding. 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, 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, but also a decrease in breast cell proliferation, a decrease in breast gland size, and a disappearance of breast nodularity. Progestogens are used in the treatment of breast hypoplasia and lactation insufficiency. This is because they induce lobuloalveolar development of the breasts, which is required for lactation and breastfeeding. Enlarged prostate Progestogens have been used at high doses to treat benign prostatic hyperplasia (BPH). They act by suppressing gonadal testosterone production and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of the prostate gland. 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. They have been extensively evaluated as a second-line therapy for this indication. These include cyproterone acetate, chlormadinone acetate, and megestrol acetate. Certain progestogens are used to support pregnancy, including progesterone, hydroxyprogesterone caproate, dydrogesterone, and allylestrenol. They are used questionably for treatment of recurrent pregnancy loss and for prevention of preterm birth in pregnant women with a history of at least one spontaneous preterm birth. 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 and a history of venous thromboembolism among others. ==Side effects==

Progestogens have relatively few side effects at typical dosages. Side effects of progestogens may include tiredness, dysphoria, depression, mood changes, menstrual irregularities, hypomenorrhea, edema, vaginal dryness, vaginal atrophy, headaches, nausea, breast tenderness, decreased libido. As of 2019, there is no consistent evidence for adverse effects on mood of hormonal birth control, including progestogen-only birth control and combined birth control, in the general population. Beneficial effects of hormonal birth control such as decreased menstrual pain and bleeding may positively influence mood. The progestins assessed included depot medroxyprogesterone acetate, levonorgestrel-containing contraceptive implants and intrauterine devices, and progestogen-only birth control pills. Mood with birth control pills may be better with monophasic and continuous formulations than with triphasic and cyclic formulations. 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 disorders or polycystic ovary syndrome are limited and mixed. 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 disorders. A 2008 Cochrane review found a greater likelihood of postpartum depression in women given norethisterone enanthate as a form of progestogen-only injectable birth control, 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. Conversely, research on combined estrogen and progestogen therapy for depressive symptoms in menopausal women is scarce and inconclusive. whereas other researchers maintain that progestogens have no adverse influence on mood. Progesterone differs from progestins in terms of effects in the brain and might have different effects on mood in comparison. 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 (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a blood clot in a deep vein, most commonly in the legs, while PE occurs when a clot breaks free and blocks an artery in the lungs. As a result, they increase the risk of VTE, especially during pregnancy when estrogen and progesterone levels are very high as well as during the postpartum period. Physiological levels of estrogen and/or progesterone may also influence risk of VTE—with late menopause (≥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, do not affect coagulation 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. 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. However, the relevant patient populations, namely aged individuals with cancer, 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 estrogen therapy, including in combined birth control pills 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. Unlike the case of transdermal estradiol, VTE risk is not lower with ethinylestradiol-containing contraceptive vaginal rings and contraceptive patches compared to combined birth control pills with ethinylestradiol. 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. 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. Older age, higher body weight, lower physical activity, and smoking 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. 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. 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, and high-dose parenteral polyestradiol phosphate therapy have both been found to increase SHBG levels by about 1.5-fold. and doses of cyproterone acetate have been reduced. Cardiovascular health Progestogens may influence the risk of cardiovascular disease in women. 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 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. 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. 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. Breast cancer risk with combined estrogen and progestogen therapy may differ depending on the progestogen used. 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. 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==

Inhibitors and inducers of cytochrome P450 enzymes and other enzymes such as 5α-reductase may interact 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, cervix, vagina, breasts, and brain. In addition to their progestogenic activity, many progestogens have off-target activities such as androgenic, antiandrogenic, estrogenic, glucocorticoid, and antimineralocorticoid activity. Progestogens mediate their contraceptive effects in women both by inhibiting ovulation (via their antigonadotropic effects) and by thickening cervical mucus, thereby preventing the possibility of fertilization of the ovum by sperm. The off-target activities of progestogens can contribute both to their beneficial effects and to their adverse effects. Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic 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 (ovulation in women and spermatogenesis in men). 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 therapy, which can suppress testosterone levels into the castrate range similarly to GnRH analogues. The retroprogesterone derivatives 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 effects, and is actually able to induce ovulation, with about a 50% success rate on average. 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). 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. • High: levonorgestrel, norgestrel, norgestrienone, tibolone • Low: desogestrel, etonogestrel, gestodene, norgestimate • Very low or negligible: allylestrenol, dimethisterone, medroxyprogesterone acetate, megestrol acetate, norelgestromin, noretynodrel, norgesterone • Antiandrogenic: dienogest, oxendolone 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, seborrhea, hirsutism, and other androgen-dependent conditions in women. norethisterone acetate, norethisterone enanthate, lynestrenol, and etynodiol diacetate. In contrast, non-estrogenic progestins were not found to be associated with such effects. This can result, at sufficiently high doses, in side effects such as symptoms of Cushing's syndrome, steroid diabetes, adrenal suppression and insufficiency, and neuropsychiatric symptoms like depression, anxiety, 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. Progesterone itself has potent antimineralocorticoid activity. Neurosteroid activity Progesterone has neurosteroid activity via metabolism into allopregnanolone and pregnanolone, potent positive allosteric modulators of the GABAA receptor. Other activities Certain progestins have been found to stimulate the proliferation of MCF-7 breast cancer cells in vitro, 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. Pharmacokinetics Oral progesterone has very low bioavailability and potency. 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 in the circulation of no more than 1.5 hours. 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. ==Chemistry==

All currently available progestogens are steroidal in terms of chemical structure. Examples of progestins of each of these subgroups include ethisterone, norethisterone, and levonorgestrel, respectively. Many progestins have ester and/or ether substitutions (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 parenterally) 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 and was marketed in Germany 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, Luis Miramontes, and George Rosenkranz at Syntex in Mexico City, was marketed by Parke-Davis 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 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, 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, estranes such as noretynodrel and norethisterone are classified as first-generation while gonanes 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. Classification of progestins by generation has been criticized and it has been argued that the classification scheme should be abandoned. 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 agonists of the progesterone receptors. Progestogens include progesterone—which is the main natural and endogenous progestogen—and progestins, which are synthetic progestogens. Progestins include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate and the 19-nortestosterone 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 estranes 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 (dihydrotestosterone), and nandrolone esters. 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==