Progestogen

Progestogens are a class of steroid hormones—either naturally occurring or synthetic—that work by binding to and activating progesterone receptors. Their name comes from their key role in supporting pregnancy (the term "progestational" refers to this function), but they are also active during other stages of the menstrual and estrous cycles. The body’s primary and most significant progestogen is progesterone.

These hormones are one of three types of sex hormones, alongside estrogens (like estradiol) and androgens/anabolic steroids (like testosterone). They also belong to the five major classes of steroid hormones, which include androgens, estrogens, glucocorticoids, mineralocorticoids, and neurosteroids. All natural progestogens share a basic 21-carbon structure known as a pregnane skeleton (C21). For comparison, estrogens have an estrane skeleton (C18), and androgens have an androstane skeleton (C19).

The terms progesterone, progestogen, and progestin are often used interchangeably in scientific writing and clinical settings, but this is incorrect. Progestins are synthetic progestogens used in medicine. Common examples include medroxyprogesterone acetate (derived from 17α-hydroxyprogesterone) and norethisterone (derived from 19-nortestosterone). These progestins are structural analogs of progesterone and have similar progestogenic activity, but they differ from progesterone in various pharmacological ways.

Beyond their natural hormonal roles, progestogens are used as medications—for instance, in menopausal hormone therapy and in transgender hormone therapy for transgender women. For more on their medical applications, see the articles on progesterone (medication) and progestogen (medication).

**Types and examples** The most important progestogen in the body is progesterone (P4). Other endogenous progestogens, with varying levels of activity, include 16α-hydroxyprogesterone, 17α-hydroxyprogesterone (very weak), 20α-dihydroprogesterone, 20β-dihydroprogesterone, 5α-dihydroprogesterone, 5β-dihydroprogesterone (very weak), 3β-dihydroprogesterone, 11-deoxycorticosterone, and 5α-dihydrodeoxycorticosterone. All of these are metabolites of progesterone, meaning they are produced downstream in the biosynthesis pathway.

**Biological function** Progestogens mainly affect the uterus, vagina, cervix, breasts, testes, and brain. Their primary biological role is in the female reproductive system, where they help regulate the menstrual cycle, maintain pregnancy, and prepare the mammary glands for lactation and breastfeeding after childbirth. In males, progestogens influence spermiogenesis, sperm capacitation, and testosterone synthesis. They also have effects elsewhere in the body. Unlike estrogens, progestogens play little to no role in feminization.

**Biochemistry** *Biosynthesis* Progesterone is made from cholesterol, with pregnenolone as an intermediate. The first step in the steroidogenic pathway converts cholesterol into pregnenolone, which then becomes progesterone and 17α-hydroxyprogesterone. These progestogens, along with 17α-hydroxypregnenolone, serve as precursors for all other endogenous steroids, including androgens, estrogens, glucocorticoids, mineralocorticoids, and neurosteroids. As a result, many steroid-producing tissues—such as the adrenal glands, testes, and ovaries—produce progestogens.

In some tissues, the enzymes needed for the final product are not all in one cell. For example, in ovarian follicles, cholesterol is converted to androstenedione (an androgen) in theca cells, which is then turned into estrogen in granulosa cells. In some species, fetal adrenal glands produce pregnenolone, which the placenta then converts into progesterone and estrogens. In humans, fetal adrenals produce dehydroepiandrosterone (DHEA) via the pregnenolone pathway.

*Ovarian production* In all mammals, the corpus luteum of the ovary is the main source of progesterone. Luteal cells have the enzymes needed to convert cholesterol into pregnenolone, which is then turned into progesterone. Progesterone levels are highest during the diestrus phase of the estrous cycle.

*Placental production* How the placenta contributes to progestogen production varies by species. In sheep, horses, and humans, the placenta takes over most progestogen production, while in other species the corpus luteum remains the primary source. In sheep and humans, progesterone is the main placental progestogen.

In horses, the placenta produces a variety of progestogens, mainly 5α-dihydroprogesterone and 5α,20α-tetrahydroprogesterone, starting around day 60. A complete shift from the corpus luteum to the placenta occurs by day 120–150.

**Chemistry** Natural progestogens are pregnane steroids that have ketone and/or hydroxyl groups at the C3 and C20 positions.

**Medical use** Progestogens—both progesterone and progestins—are used in medicine for hormonal birth control, hormone therapy, treating gynecological disorders, suppressing sex hormone levels for various purposes, and other indications.