A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the biological female sex hormone progesterone in the body. A progestin is a 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 conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. 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, breast tenderness, mood changes, acne, increased hair growth, and changes in liver protein production among others. Other side effects of progestogens may include an increased risk of breast cancer, cardiovascular disease, and blood clots. 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 agonists of the progesterone receptors (PRs) and produce progestogenic, or progestational, effects. They have important effects in the female reproductive system (uterus, cervix, and vagina), the breasts, and the brain. In addition, many progestogens also have other hormonal activities, such as androgenic, antiandrogenic, estrogenic, glucocorticoid, or antimineralocorticoid activity. They also have antigonadotropic effects and at high doses can strongly suppress sex hormone production. Progestogens mediate their contraceptive effects both by inhibiting ovulation and by thickening cervical mucus, thereby preventing fertilization. They have functional antiestrogenic effects in certain tissues like the endometrium, and this underlies their use in menopausal hormone therapy.
Progesterone was first isolated 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. 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 marketed for clinical or veterinary use Generic name Class Brand name Route Acetomepregenol P Diamol 1981 Algestone acetophenide P Deladroxate 1964 Allylestrenol T Gestanin PO 1961 Altrenogest T Regumate PO 1980s Chlormadinone acetate P Belara PO 1965 Cyproterone acetate P Androcur PO, IM 1973 Danazol T Danocrine PO 1971 Delmadinone acetate P Tardak PO 1972 Desogestrel T Cerazette PO 1981 Dienogest T Natazia PO 1995 Drospirenone S Angeliq PO 2000 Dydrogesterone Duphaston PO 1961 Etonogestrel T Implanon (SC), NuvaRing (V) , 1998 Etynodiol diacetate T Demulen PO 1965 Flugestone acetate P Chronogest PO 1960s Gestodene T Femodene PO 1987 Gestonorone caproate P Depostat IM 1968 Gestrinone T Dimetriose PO 1986 Hydroxyprogesterone caproate P Makena IM 1954 Levonorgestrel T Plan B PO, ,, SC 1970 Lynestrenol T Exluton PO 1961 Medrogestone P Colprone PO 1966 Medroxyprogesterone acetate P Provera PO, IM, SC 1958 Megestrol acetate P Megace PO, IM 1963 Melengestrol acetate P Heifermax IM 1960s Nomegestrol acetate P Lutenyl PO 1986 Norelgestromin T Evra TD patch 2002 Norethisterone T Aygestin PO 1957 Norethisterone acetate T Primolut-Nor PO, TD patch 1964 Norethisterone enanthate T Noristerat IM 1957 Norgestimate T Ortho-Cyclen PO 1986 Norgestomet P Syncro-Mate B PO 1970s Norgestrel T Ovral PO 1966 Normethandrone T Metalutin PO 1957 Osaterone acetate P Ypozane PO 2007 Oxendolone T Prostetin IM 1981 Progesterone Prometrium PO, V, IM 1934 Proligestone P Corvinan PO 1975 Promegestone P Surgestone PO 1983 Segesterone acetate P Elcometrine SC, V 2000 Tibolone T Livial PO 1988 Trimegestone P Lovelle PO 2001
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.
Hormone therapy
Menopause and hypogonadism Progestogens are used in combination with estrogens 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 and transgender men. 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, such as improved breast growth, but there is insufficient research to prove or disprove these claims. Examples of progestogens used in hormone therapy for transgender women include cyproterone acetate, medroxyprogesterone acetate, and progesterone. Progestogens, such as medroxyprogesterone and lynestrenol, are used in transgender men to help suppress menses. Progestogens have also been used to delay puberty 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 flashes in men undergoing androgen deprivation therapy, for instance to treat prostate cancer.
Gynecological disorders
Menstrual disorders Progestogens are used to treat menstrual disorders such as secondary amenorrhea 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.
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 that have been used for such purposes include topical progesterone, dydrogesterone, promegestone, lynestrenol, medroxyprogesterone acetate, dienogest, and medrogestone.
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. However, they produce various side effects, such as dyspnea, weight gain, vaginal bleeding, nausea, fluid retention, hypertension, thrombophlebitis, 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-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 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 gonadal testosterone production and hence circulating testosterone levels. Androgens like testosterone stimulate the growth of prostate tumors.
Fertility and pregnancy Progestogens are used in fertility medicine for women. For example, progesterone (or sometimes dydrogesterone or hydroxyprogesterone caproate) is used for luteal support in in-vitro fertilization protocols.
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.
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.
Sexual deviance