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Progesterone

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Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen.

Progesterone should not be confused with progestins, which are synthetically produced progestogens.


Natural Sources in the Human Body

Progesterone is produced in the adrenal glands, the gonads (specifically after ovulation in the corpus luteum), the brain, and, during pregnancy, in the placenta.

Levels

In women, progesterone levels are relatively low during the preovulatory phase of the menstrual cycle, rise after ovulation, and are elevated during the luteal phase. Progesterone levels tend to be < 2 ng/ml prior to ovulation, and > 5 ng/ml after ovulation. If pregnancy occurs, progesterone levels are initially maintained at luteal levels. With the onset of the luteal-placental shift in progesterone support of the pregnancy, levels start to rise further and may reach 100-200 ng/ml at term. Whether a decrease in progesterone levels is critical for the initiation of labor has been argued and may be species-specific. After delivery of the placenta and during lactation, progesterone levels are very low.

Progesterone levels are relatively low in children and postmenopausal women.[1] Adult males have levels similar to those in women during the follicular phase of the menstrual cycle.

Effects

Progesterone exerts its action primarily through the intracellular progesterone receptor although a distinct, membrane bound progesterone receptor has also been postulated.[2][3] Progesterone has a number of physiological effects which are amplified in the presence of estrogen. Estrogen through estrogen receptors upregulates the expression of progesterone receptors. [4]

Reproductive system

Progesterone is sometimes called the "hormone of pregnancy",[5] and it has many roles relating to the development of the fetus:

  • Progesterone converts the uterine lining to its secretory stage to prepare the uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical mucus, making the mucus thick and impermeable to sperm. If pregnancy does not occur, progesterone levels will decrease, leading, in the human, to menstruation. Normal menstrual bleeding is progesterone withdrawal bleeding.
  • During implantation and gestation, progesterone appears to decrease the maternal immune response to allow for the acceptance of the pregnancy.
  • Progesterone decreases contractility of the uterine smooth muscle.
  • In addition progesterone inhibits lactation during pregnancy. The fall in progesterone levels following delivery is one of the triggers for milk production.
  • A drop in progesterone levels is possibly one step that facilitates the onset of labor.
  • Progesterone receptor antagonists, or selective progesterone receptor modulators (SPRM)s, such as RU-486 (Mifepristone), can be used to prevent conception or induce medical abortions.

The fetus metabolizes placental progesterone in the production of adrenal mineralo- and glucosteroids.

Other effects

  • It raises epidermal growth factor-1 levels, a factor often used to induce proliferation, and used to sustain cultures, of stem cells.
  • It increases core temperature (thermogenic function) during ovulation.
  • It reduces spasm and relaxes smooth muscle. Bronchi are widened and mucus regulated. (Progesterone receptors are widely present in submucosal tissue.)
  • It acts as an anti-inflammatory agent and regulates the immune response.
  • It reduces gall-bladder activity.[6]
  • It normalizes blood clotting and vascular tone, zinc and copper levels, cell oxygen levels, and use of fat stores for energy.
  • It assists in thyroid function, in bone building by osteoblasts, in bone, teeth, gums, joint, tendon, ligament and skin resilience and in some cases healing by regulating various types of collagen, and in nerve function and healing by regulating myelin.
  • It appears to prevent endometrial cancer (involving the uterine lining) by regulating the effects of estrogen.

Medical applications

The use of progesterone and its analogues have many medical applications -- both to address acute situations, and to address the long-term decline of natural progesterone levels. Because of the poor bio-availability of progesterone when taken orally, many synthetic progestins have been designed. However, the roles of progesterone may not be fulfilled by the synthetic progestins which in some cases were designed solely to mimic progesterone's uterine effects.

Progesterone is used in hormone replacement therapy for trans women, and some women with intersex conditions - especially when synthetic progestins have been ineffective or caused side-effects - since normal breast tissue cannot develop except in the presence of both progestogen and estrogen. Mammary glandular tissue is otherwise fibrotic, the breast shape conical and the areola immature. Progesterone can correct those even after years of inadequate hormonal treatment. Research usually cited against such value was conducted using Provera, a synthetic progestin. Progesterone also has a role in skin elasticity and bone strength, in respiration, in nerve tissue and in female sexuality, and the presence of progesterone receptors in certain muscle and fat tissue may hint at a role in sexually-dimorphic proportions of those.

Bioavailability

Progesterone is poorly absorbed by oral ingestion unless micronised and in oil, or with fatty foods; it does not dissolve in water. Products such as Prometrium, Utrogestan, Minagest and Microgest are therefore capsules containing micronised progesterone in oil - in all three mentioned the oil is peanut oil, which may cause serious allergic reactions in some people, but compounding pharmacies, which have the facilities and licenses to make their own products, can use alternatives. Vaginal and rectal application is also effective, with products such as CRINONE and PROCHIEVE bioadhesive progesterone vaginal gels (the only progesterone products FDA-approved for use in infertility and during pregnancy) and Cyclogest, which is progesterone in cocoa butter in the form of pessaries. Progesterone can be given by injection, but because it has a short half-life they need to be daily. Implants, for a longer period, are also available. Marketing of progesterone phamaceutical products, country to country, varies considerably, with many countries having no oral progesterone products marketed, but they can usually be specially imported by pharmacies through international wholesalers.

"Natural progesterone" products derived from yams, do not require a prescription. Wild yams contain a plant steroid called diosgenin, however there is no evidence that the human body can metabolize diosgenin into progesterone.[7][8] Diosgenin can however be chemically converted into progesterone in the lab.[9]

Aging

Since most progesterone in males is created during testicular production of testosterone, and most in females by the ovaries, the shutting down (whether by natural or chemical means), or removal, of those inevitably causes a considerable reduction in progesterone levels. Previous concentration upon the role of progestagens (progesterone and molecules with similar effects) in female reproduction, when progesterone was simply considered a "female hormone", obscured the significance of progesterone elsewhere in both sexes.

The tendency for progesterone to have a regulatory effect, the presence of progesterone receptors in many types of body tissue, and the pattern of deterioration (or tumor formation) in many of those increasing in later years when progesterone levels have dropped, is prompting research into the potential value of maintaining progesterone levels in both males and females.

Synthesis

Progesterone consists of four interconnected cyclic hydrocarbons. It contains ketone and oxygenated functional groups, as well as two methyl branches. Like all steroid hormones, it is hydrophobic.

It is synthesized from pregnenolone, a derivative of cholesterol. This conversion takes place in two steps. The 3-hydroxyl group is converted to a keto group and the double bond is moved to C-4, from C-5.

Progesterone is the precursor of the mineralocorticoid aldosterone, and after conversion to 17-hydroxyprogesterone (another natural progestogen) of cortisol and androstenedione. Androstenedione can be converted to testosterone, estrone and estradiol.

References

  1. ↑ NIH Clinical Center (2004-08-16). Progesterone Historical Reference Ranges. United States National Institutes of Health. Retrieved on 2008-03-12.
  2. ↑ Luconi M, Bonaccorsi L, Maggi M, Pecchioli P, Krausz C, Forti G, Baldi E (1998). "Identification and characterization of functional nongenomic progesterone receptors on human sperm membrane". J. Clin. Endocrinol. Metab. 83 (3): 877–85. doi:10.1210/jc.83.3.877. PMID 9506743. 
  3. ↑ Jang S, Yi LS (2005). "Identification of a 71 kDa protein as a putative non-genomic membrane progesterone receptor in boar spermatozoa". J. Endocrinol. 184 (2): 417–25. doi:10.1677/joe.1.05607. PMID 15684349. 
  4. ↑ Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemeyer H, Chambon P (1990). "Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B". EMBO J. 9 (5): 1603–14. PMID 2328727. 
  5. ↑ Bowen R (2000-08-06). Placental Hormones. Retrieved on 2008-03-12.
  6. ↑ Hould FS, Fried GM, Fazekas AG, Tremblay S, Mersereau WA (1988). "Progesterone receptors regulate gallbladder motility". J. Surg. Res. 45 (6): 505–12. doi:10.1016/0022-4804(88)90137-0. PMID 3184927. 
  7. ↑ Zava DT, Dollbaum CM, Blen M (1998). "Estrogen and progestin bioactivity of foods, herbs, and spices". Proc. Soc. Exp. Biol. Med. 217 (3): 369–78. PMID 9492350. 
  8. ↑ Komesaroff PA, Black CV, Cable V, Sudhir K (2001). "Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women". Climacteric 4 (2): 144–50. doi:10.1080/713605087. PMID 11428178. 
  9. ↑ Marker RE, Krueger J (1940). "Sterols. CXII. Sapogenins. XLI. The Preparation of Trillin and its Conversion to Progesterone". J. Am. Chem. Soc. 62 (12): 3349–3350. doi:10.1021/ja01869a023. 


External links

  • Kimball JW (2007-05-27). Progesterone. Kimball's Biology Pages. Retrieved on 2008-06-18.

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