Progestogen

Progestogens are a class of steroid hormones, either natural 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 also appear 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 (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 incorrectly as synonyms in both research and clinical settings. Progestins are synthetic progestogens used in medicine. Common examples include medroxyprogesterone acetate (a derivative of 17α-hydroxyprogesterone) and norethisterone (a derivative of 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. They appear in menopausal hormone therapy and in transgender hormone therapy for transgender women. For more on their medical use, see the articles on progesterone (medication) and progestogen (medication).

**Types and examples**

The most important progestogen in the body is progesterone (P4). Other natural progestogens, with varying levels of progestogenic 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 from progesterone 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 and male reproductive systems. In women, they help regulate the menstrual cycle, maintain pregnancy, and prepare the mammary glands for lactation and breastfeeding after childbirth. In men, progesterone influences spermiogenesis, sperm capacitation, and testosterone synthesis. Progestogens also have effects elsewhere in the body. Unlike estrogens, they play little to no role in feminization.

**Biochemistry**

**Biosynthesis**

Progesterone is made from cholesterol, with pregnenolone as an intermediate. In the first step of the steroidogenic pathway, cholesterol is converted into pregnenolone, which then becomes the precursor for the progestogens progesterone and 17α-hydroxyprogesterone. These progestogens, along with 17α-hydroxypregnenolone, are the precursors for all other natural 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 instance, in ovarian follicles, cholesterol is turned into androstenedione (an androgen) in the theca cells, which is then converted into estrogen in the granulosa cells. In some species, fetal adrenal glands produce pregnenolone, which the placenta then converts into progesterone and estrogens. In humans, the fetal adrenals produce dehydroepiandrosterone (DHEA) via the pregnenolone pathway.

**Ovarian production**

In all mammals, the corpus luteum of the ovary produces progesterone as the major progestogen. 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 main source. In sheep and humans, progesterone is the major 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 days 120–150.

**Chemistry**

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

**Medical use**

Progestogens, including 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.