Progestogen

Steroidogenesis, with progestogens and their precursors inside the yellow box.

Progestogens (also sometimes spelled progestagens or gestagens)[1] are a class of steroid hormones that bind to and activate the progesterone receptor (PR).[2][3] The most important progestogen in the body is progesterone (P4). Other endogenous progestogens include 17α-hydroxyprogesterone, 20α-dihydroprogesterone, 5α-dihydroprogesterone, 11-deoxycorticosterone, and 5α-dihydrodeoxycorticosterone. Synthetic progestogens are generally referred to as progestins.[2] However, the terms progesterone, progestogen, and progestin are frequently used interchangeably both in the scientific literature and in clinical settings.[1][4]

The progestogens are one of the five major classes of steroid hormones, in addition to the androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as the neurosteroids. All progestogens are characterized by their basic 21-carbon skeleton, called a pregnane skeleton (C21). In similar manner, the estrogens possess an estrane skeleton (C18), and androgens, an andrane skeleton (C19).

The progestogens are named for their function in maintaining pregnancy (i.e., progestational), although they are also present at other phases of the estrous and menstrual cycles.[2][3]

Functions

In the first step in the steroidogenic pathway, cholesterol is converted into pregnenolone (P5), which serves as the precursor to the progestogens progesterone and 17-hydroxyprogesterone. These progestogens, along with another steroid, 17-hydroxypregnenolone, are the precursors of all other endogenous steroids, including the androgens, estrogens, glucocorticoids, mineralocorticoids, and neurosteroids. Thus, many tissues producing steroids, including the adrenal glands, testes, and ovaries, produce progestogens.

In some tissues, the enzymes required for the final product are not all located in a single cell. For example, in ovarian follicles, cholesterol is converted to androstenedione, an androgen, in the theca cells, which is then further converted into estrogen in the granulosa cells. Fetal adrenal glands also produce pregnenolone in some species, which is converted into progesterone and estrogens by the placenta (see below). In the human, the fetal adrenals produce dehydroepiandrosterone (DHEA) via the pregnenolone pathway.

Production by the ovary

Progesterone is the major progestogen produced by the corpus luteum of the ovary in all mammalian species. Luteal cells possess the necessary enzymes to convert cholesterol to pregnenolone, which is subsequently converted into progesterone. Progesterone is highest in the diestrus phase of the estrous cycle.

Production by the placenta

The role of the placenta in progestogen production varies by species. In the sheep, horse, and human, the placenta takes over the majority of progestogen production, whereas in other species the corpus luteum remains the primary source of progestogens. In the sheep and human, progesterone is the major placental progestogen.

The equine placenta produces a variety of progestogens, primarily 5α-dihydroprogesterone and 5α,20α-tetrahydroprogesterone, beginning on day 60. A complete luteo-placental shift occurs by day 120–150.

Uses

Female indications

Progestins are used in a variety of different forms of hormonal contraception, including birth control pills, implants, and the intrauterine devices.[2][3]

In women, progestogens are commonly used to prevent endometrial hyperplasia from unopposed estrogen during hormone replacement therapy. They also used to treat secondary amenorrhea, dysfunctional uterine bleeding and endometriosis.[2][3]

In a normal menstrual cycle, declining levels of progesterone triggers menstruation. Norethisterone acetate and medroxyprogesterone acetate may be used to artificially induce progestogen-associated breakthrough bleeding.[5]

As antiandrogens

Main article: Antiandrogen

In addition to their progestogen properties, some progestins are antagonists of the androgen receptor, and can be used clinically as antiandrogens. Examples include chlormadinone acetate, cyproterone acetate, dienogest, drospirenone, megestrol acetate, nomegestrol acetate,[6] and norgestimate.[7] Care must be taken as to which progestin is used however, as various others, such as levonorgestrel,[8] norgestrel,[9] norethisterone,[8] norethisterone acetate,[8] and medroxyprogesterone acetate,[10] conversely have androgenic properties.

Desogestrel, norgestimate, gestodene, dienogest, and etynodiol diacetate have little or no androgenic effects.[9][11][12] Moreover, dydrogesterone[13] and nestorone[14] lack any androgenic effects.

As antigonadotropins

Progestogens, similarly to the androgens and estrogens through their own respective receptors, inhibit the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) via activation of the progesterone receptor. This effect is a form of negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis that the body uses to prevent sex hormone levels from becoming too elevated.[15][16][17] Accordingly, progestogens, both endogenous and exogenous (i.e., progestins), have antigonadotropic effects,[18] and progestins in sufficient amounts can markedly suppress the body's normal production of progestogens, androgens, and estrogens, as well as, in theory, neurosteroids.[17] As such, some of the more potent progestins, including chlormadinone acetate,[16] cyproterone acetate, medroxyprogesterone acetate,[19] and megestrol acetate[18] are sometimes used to suppress sex hormone levels in a variety of androgen and estrogen-associated conditions. Examples of indications include treating sex hormone-sensitive cancers (e.g., breast cancer), suppressing precocious puberty and puberty in transgender youth, and reducing sex drive in sex offenders and individuals with paraphilias or hypersexuality.

Cachexia

Further information: Cachexia

In many people suffering from solid malignancy, especially gastric and pancreatic cancer, high doses of certain progestins can be employed to improve appetite and reduce wasting. In general, they are used in combination with certain other steroids such as dexamethasone. Their effects take several weeks to become apparent, but are relatively long-lived when compared to those of corticosteroids. Furthermore, they are recognized as being the only drugs to increase lean body mass. Megestrol acetate is the lead drug of this class for the management of cachexia, and medroxyprogesterone acetate is also used.[20][21]

See also

References

  1. 1 2 Tekoa L. King; Mary C. Brucker (25 October 2010). Pharmacology for Women's Health. Jones & Bartlett Publishers. p. 373. ISBN 978-1-4496-5800-7.
  2. 1 2 3 4 5 Michelle A. Clark; Richard A. Harvey; Richard Finkel; Jose A. Rey; Karen Whalen (15 December 2011). Pharmacology. Lippincott Williams & Wilkins. p. 322. ISBN 978-1-4511-1314-3.
  3. 1 2 3 4 Bhattacharya (1 January 2003). Pharmacology, 2/e. Elsevier India. p. 378. ISBN 978-81-8147-009-6.
  4. ↑ Tara Parker-Pope (25 March 2008). The Hormone Decision. Simon and Schuster. p. 228. ISBN 978-1-4165-6201-6.
  5. ↑ Hickey M, Fraser IS (August 2000). "A functional model for progestogen-induced breakthrough bleeding". Hum. Reprod. 15 Suppl 3: 1–6. doi:10.1093/humrep/15.suppl_3.1. PMID 11041215.
  6. ↑ Botella, J.; Paris, J.; Lahlou, B. (1987). "The cellular mechanism of the antiandrogenic action of nomegestrol acetate, a new 19-nor progestagen, on the rat prostate". European Journal of Endocrinology 115 (4): 544–550. doi:10.1530/acta.0.1150544. ISSN 0804-4643.
  7. ↑ Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
  8. 1 2 3 Georg Wick; Cecilia Grundtman (3 December 2011). Inflammation and Atherosclerosis. Springer Science & Business Media. pp. 560–. ISBN 978-3-7091-0338-8.
  9. 1 2 Armen H. Tashjian; Ehrin J. Armstrong (21 July 2011). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 523–. ISBN 978-1-4511-1805-6.
  10. ↑ Kenneth Hugdahl; René Westerhausen (2010). The Two Halves of the Brain: Information Processing in the Cerebral Hemispheres. MIT Press. pp. 272–. ISBN 978-0-262-01413-7.
  11. ↑ Kuhl H (1996). "Comparative pharmacology of newer progestogens". Drugs 51 (2): 188–215. doi:10.2165/00003495-199651020-00002. PMID 8808163.
  12. ↑ Chaudhuri (1 January 2007). Practice Of Fertility Control: A Comprehensive Manual (7Th Edition). Elsevier India. pp. 122–. ISBN 978-81-312-1150-2.
  13. ↑ Volodymyr Dvornyk (22 January 2013). Current Topics in Menopause. Bentham Science Publishers. pp. 357–. ISBN 978-1-60805-453-4.
  14. ↑ A.R. Genazzani (15 May 2001). Hormone Replacement Therapy and Cardiovascular Disease: The Current Status of Research and Practice. CRC Press. pp. 94–. ISBN 978-1-84214-038-3.
  15. ↑ de Lignières B, Silberstein S (April 2000). "Pharmacodynamics of oestrogens and progestogens". Cephalalgia : an International Journal of Headache 20 (3): 200–7. doi:10.1046/j.1468-2982.2000.00042.x. PMID 10997774.
  16. 1 2 Chassard D, Schatz B (2005). "[The antigonadrotropic activity of chlormadinone acetate in reproductive women]". Gynécologie, Obstétrique & Fertilité (in French) 33 (1-2): 29–34. doi:10.1016/j.gyobfe.2004.12.002. PMID 15752663.
  17. 1 2 Brady BM, Anderson RA, Kinniburgh D, Baird DT (April 2003). "Demonstration of progesterone receptor-mediated gonadotrophin suppression in the human male". Clinical Endocrinology 58 (4): 506–12. doi:10.1046/j.1365-2265.2003.01751.x. PMID 12641635.
  18. 1 2 Neumann F (1978). "The physiological action of progesterone and the pharmacological effects of progestogens--a short review". Postgraduate Medical Journal. 54 Suppl 2: 11–24. PMID 368741.
  19. ↑ Andrea R. Genazzani (15 January 1993). Frontiers in Gynecologic and Obstetric Investigation. Taylor & Francis. p. 320. ISBN 978-1-85070-486-7. Retrieved 29 May 2012.
  20. ↑ Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D (March 2001). "High-dose progestins for the treatment of cancer anorexia-cachexia syndrome: a systematic review of randomised clinical trials". Ann. Oncol. 12 (3): 289–300. PMID 11332139.
  21. ↑ Lelli G, Montanari M, Gilli G, Scapoli D, Antonietti C, Scapoli D (June 2003). "Treatment of the cancer anorexia-cachexia syndrome: a critical reappraisal". J Chemother 15 (3): 220–5. doi:10.1179/joc.2003.15.3.220. PMID 12868546.

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