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Progesterone 101

Progesterone is the hormone that prepares the uterus and endometrial lining to support an early pregnancy (Progesterone = "Pro-gestation hormone"). Produced in the ovary between ovulation and the following menstrual period, and by the placenta in the early embryo, progesterone stimulates cells in the endometrial lining to become receptive to the early embryo and, after implantation, to support growth of the embryo. Without progesterone, implantation could not occur; if progesterone were to be removed in early pregnancy, miscarriage would be certain to follow.

Hormones are produced in the ovary by the developing follicle, or egg sac. In the first two weeks of the menstrual cycle, as the egg sac matures, stimulated by Follicle Simulating Hormone (FSH) and Luteinizing Hormone (LH) from the pituitary, the follicle increases its production of estrogen to a peak just before ovulation. At the mid-cycle surge of LH, the follicle abruptly shuts down its estrogen production pathway, converting over to producing large amounts of progesterone. The follicle becomes the corpus luteum, a richly vascularized progesterone production factory.

As the pregnancy is established, the placenta produces chorionic gonadotropin, hCG, a hormone that stimulates the corpus luteum to produce additional progesterone. hCG is very similar to LH, binds to the same receptors, and stimulates the ovary much like LH. Rising hCG stimulates rising progesterone, which strengthens the pregnancy and allows it to produce more hCG, again increasing progesterone; this feedback loop is essential to enabling a strong pregnancy.

Progesterone is essential to the development of the early embryo. Progesterone from the corpus luteum circulates through the bloodstream to the uterus, where the endometrium that has been prepared by estrogen starts to change to support the early pregnancy. This change in the endometrial lining, luteinization, is essential for the embryo. The role of the corpus luteum was demonstrated years ago in experiments where the ovary containing the corpus luteum was removed; miscarriage immediately followed. More recently, progesterone antagonists, such as RU-486, which block the progesterone receptor, have been used in animal studies to induce miscarriage when given in early pregnancy.

Progesterone also has effects on the immune system, stimulating protective proteins, such as HLA-G, in the early pregnancy (Yie, Xiao et al. 2006). Without HLA-G the maternal immune system would reject the embryo, therefore, production of HLA-G antigens are critical to protecting the early pregnancy. Progesterone plays an important role in stimulating HLA-G and preventing rejection of the embryo.

Progesterone also acts as a chemoattractant for sperm (Albano, Smitz et al. 1999; Teves, Barbano et al. 2006). Progesterone in tiny amounts will draw sperm, and may attract sperm to the egg after ovulation. Uterine contractions, which play a role in sperm movement, are also controlled by progesterone.

Because it aids in creating a receptive environment for the embryo, insufficient progesterone can be a source of infertility and miscarriage. Low progesterone levels will result in luteal phase defect, a condition in which there is insufficient hormonal support for the early pregnancy. Failure of implantation of an otherwise healthy embryo, or loss of an early pregnancy, may occur with luteal phase defect. Some women do not produce any progesterone at all, for example, after menopause, or when a menopausal state is temporarily induced using medications to prevent ovulation. Without progesterone, pregnancy cannot occur.

The progesterone receptor mediates the action of the hormone and is critically important to pregnancy; some cases of infertility may be related to abnormalities in the progesterone receptor (Spandorfer, Normand et al. 2006). A simple alteration in the genetic code for the progesterone receptor is common in patients with infertility, and appears to be associated with poorer pregnancy outcomes.

The method of In Vitro Fertilization (IVF) is associated with luteal phase defects and low progesterone levels (Albano, Smitz et al. 1999). With IVF treatment, many of the cells that produce progesterone are removed from the ovary in the course of oocyte retrieval. In addition, the use of GnRH agonists and antagonists (leuprolide, ganirelix, cetrorelix) prevent the release of LH and FSH from the pituitary, removing the primary stimulus for progesterone production from the ovary. Progesterone levels may not be adequate to support the pregnancy, resulting in a luteal phase defect, implantation failure, and early miscarriage.

For treatment, progesterone usage falls into two broad groups, progesterone supplementation, where progesterone is produced in the ovary and supplemented with medication, and progesterone replacement, where there is no natural progesterone production. Progesterone replacement would be used in an oocyte donation recipient. Since ovulation occurs in the donor, and there is no natural progesterone in the recipient, all progesterone must be administered. Progesterone replacement is also common for cryopreserved embryo transfers, though natural cycles can also be used in many women with regular menstrual cycles. Medical supplementation might be used in a variety of conditions associated with luteal phase defect or to reduce the risk of early miscarriage associated with low progesterone levels.

Progesterone is supplemented medically to reduce the risk of pregnancy problems arising from low progesterone levels. Progesterone may be given orally, by vaginal supplement, by injection, or its production enhanced by injection of hCG, which stimulates the corpus luteum to produce additional progesterone(Pouly, Bassil et al. 1996).

Oral progesterone is relatively weak in its effect. Absorbed through the upper intestine, progesterone taken orally is metabolized in the liver. This is known as "first pass effect", because the hormone passes through the liver first before traveling to its site of action. These metabolites are not effective in inducing luteinization and can induce effects on the central nervous system such as sedation. Very little active progesterone is available after oral use (Friedler, Raziel et al. 1999).

Vaginal progesterone, in the form of creams, gels, and suppositories, is highly effective in supplementing or replacing natural progesterone, and has been the most popular form of progesterone supplementation. Progesterone is absorbed through the vaginal wall and moves through local circulation directly to the endometrium. Levels are sufficient to induce the normal changes in endometrial lining to support the early pregnancy (Pritts and Atwood 2002). The primary clinical concern with vaginal progesterone is the variability in absorption. While most women absorb progesterone vaginally without difficulty, some may not; as an indirect mode of administration, one cannot be certain of the amount that is absorbed.

Progesterone by intramuscular injection is well absorbed, and in some ways closest to natural ovarian secretion (Lightman, Kol et al. 1999). High serum levels of progesterone are achieved with effective preparation of the endometrium. Traditional intramuscular injections, in an oil base, require a relatively large needle; local reactions to the oil base at the site of injection are common. Newer preparations of intramuscular progesterone, such as progesterone ethyl oleate, are considerably easier to inject, but still require daily administration. Injectable progesterone remains the primary progesterone for those patients that produce no natural progesterone, such as for a donated oocyte recipient, or for a frozen embryo transfer in a medicated cycle.

hCG, by acting directly on the ovary, is a good stimulant to progesterone production (Herman, Raziel et al. 1996). Its use requires that an active corpus luteum be present, so it can only be used in a natural or stimulated ovulation cycle. It produces good progesterone levels and reduces the risk of luteal phase defect (Mochtar, Hogerzeil et al. 1996). hCG requires periodic injections and may increase the risk of ovarian hyperstimulation syndrome in patients that have been on fertility drugs. As the hormone that is measured in a pregnancy test, hCG causes a false positive pregnancy test, potentially confusing the diagnosis of early pregnancy. hCG is used occasionally to supplement progesterone production in women with an active corpus luteum.

Vaginal and injectable progesterone appear to be similar in actions on the endometrial lining (Khan, Richter et al. 2007); while the amount of progesterone absorbed can be dramatically different, the clinical effects are similar. Progesterone receptors appear to be saturated at fairly low levels of progesterone in the blood, and additional progesterone does not seem to increase pregnancy rates or reduce miscarriage rates. The specific route or agent for progesterone supplementation is probably not as important as assuring that at least some progesterone is present. Equivalent pregnancy rates have been shown using vaginal gels, progesterone vaginal capsules, and progesterone in a dissolving effervescent vaginal tablet (Schoolcraft, Miller et al. 2007). Vaginal and injected progesterone, in general, show higher bioavailability than oral progesterone.

In patients with no ovarian function, recipients of egg donors, or those patients utilizing cryopreserved embryos in medicated (estrogen/progesterone replaced) cycles, all progesterone must be supplied medically. These patients require a reliable source of progesterone, and injectable progesterone has been established as the best standard (Prapas, Prapas et al. 1998). Vaginal progesterone has also been used successfully, though less commonly. In these patients, progesterone replacement must be continued for an extended period. Because there is no corpus luteum in the ovary, the rising hCG from the placenta cannot stimulate progesterone production, as it would in a conventional pregnancy.

In those patients with an active corpus luteum, such as after in vitro fertilization, external progesterone is required for only a limited time period. In the first two weeks after ovulation, the pregnancy is critically dependent on ovarian progesterone. After a positive pregnancy test, progesterone administration can be stopped entirely (Proctor, Hurst et al. 2006), relying on the embryo to stimulate the corpus luteum through the placental hCG effect on the ovary.

Leuprolide, a GnRH agonist, seems to supplement progesterone and its actions. A single injection of a GnRH agonist releases LH from the pituitary, stimulating progesterone production in the ovary, and may act directly on the endometrium and the embryo, enhancing implantation (Pirard, Donnez et al. 2006). With more study, this may prove to be a useful adjunct to use of progesterone.

Philip Chenette, MD

References
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Spandorfer, Normand, et al. (2006). "O-7 A G->A POLYMORPHISM AT POSITION +331 IN THE PROGESTERONE RECEPTOR GENE IS STRONGLY ASSOCIATED WITH IVF OUTCOME." Fertility and Sterility 86(3): S3-S4.

Teves, Barbano, et al. (2006). "Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa." Fertility and Sterility 86(3): 745-749.

Yie, S.-m., R. Xiao, et al. (2006). "Progesterone regulates HLA-G gene expression through a novel progesterone response element." Hum. Reprod. 21(10): 2538-2544.

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