Why progesterone in the prevention of preterm birth?

30 10 2012

The miracle of birth and why it occurs the way it does, especially in humans is still quite a mystery.  The inquisitive scientist in me was quite intrigued by the article “Limits of Progesterone in Curbing Early Birth,” by Nicholas Bakalar in the Oct. 23 edition of the New York Times, which explains the latest developments in research for prevention of premature labor/birth.  While the recently published study, which was the peg behind the story, was well explained, I felt the need to dig a little deeper and answer a few more of my own questions.

My research typically focuses on one end of the hypothalamic-pituitary-gonadal (HPG) axis, particularly the hypothalamus, I have had some exposure to the gonadal and pituitary end, via a reproductive physiology class.  As the scientific research machine continues to chug onward, I was surprised to find that much of the material that was taught in my class, less than a year ago was now out of date.  There have been significant advancements and new theories hashed out to explain why/how labor is naturally induced in humans and what doctors can do to delay it.

The HPG axis is the interaction between three critical endocrine organs of the body, each providing variable amounts of different hormones and interacting with each other via positive or negative feedback loops, to regulate bodily balance, homeostasis.  This is a really complex, nuanced system, but those are the basic nuts and bolts of it all.

One of the hormones that interacts within the HPG system is progesterone and it is the focus of the NYT’s piece.  Where they explain, how in a new study, progesterone injections were given to women to see if it could dramatically reduce the number of preterm births in women that have a cervix shorter than 30 millimeters.  Previously, it was found that progesterone vaginally reduced the number of preterm births among women with a cervix shorter than 20 millimeters.  As the success of the vaginal form of progesterone was found in 2% of the population, the number of women with a cervix length of less than 20 millimeters, the authors of the current study desired to expand the market, attempting to help women with cervix lengths 10 millimeters longer.  However, an injection of progesterone was used rather than vaginal administration, the injectable was found to be effective previously in women who had had previous preterm births.  No significant effects were found.  Now this could be attributable to several factors, the route of administration could be less effective, or that the women that were focused on need some other treatment to prevent preterm birth.

While the story nicely highlights the current study and several different studies that lead up to it, the information required to understand the underlying theories and research responsible for the medicinal advancement was probably outside the scope of the word limit provided.  Therefore I’ll attempt to expand on some of my own questions and the results of some digging into recent publications.

Why progesterone?

From the beginning of a pregnancy, progesterone is critical to pregnancy retention, it is produced until the placenta is developed about two months into the pregnancy, where it takes over the task of maintaining the developing embryo.  This role in maintaining a pregnancy is where progesterone got its name, “progestational steroid ketone” (Norwitz, Phaneuf, Caughey). 

Later into the pregnancy, progesterone’s role is not quite as clear, though there are several theories that progesterone acts to inhibit the action of a multitude of other signals and molecules that are developing to initiate the start of labor, including the action of prostaglandins and the activation of oxytocin receptors (which are responsible for uterine contractions).  Note: uterine tissue when placed in a dish, without progesterone signaling, can begin to contract spontaneously.

This theory behind progesterone acting to suppress all the other signaling mechanisms that tell the body to initiate labor is why it was initially tested as a drug to prevent preterm labor.  The thought was that if during a normal pregnancy it is naturally used to prevent labor, then it may also be effective when medically administered.

How recent is the approval of this treatment?

Several clinical trials were completed using different dosages, administration methods, and women in different risk categories for preterm birth.  Positive results were found in a few of these trials, leading the FDA to approve the use of progesterone during pregnancy to prevent preterm birth in February of 2011.  The approval indicates that injections of progesterone can be used effectively in cases of prior spontaneous preterm birth.

More recent studies have indicated that in cases of extreme cervical shortening, vaginal suppositories can be effective in reducing preterm labor, leading to the focus of the study in the NYT article.

Why is preterm birth/labor so prevalent? Why is it an issue?

Premature birth, or giving birth before 37 weeks of gestation (full term), accounts for 85% of perinatal death and complications in the US.  1 in 8 births can be affected.  Based on data from 2008, the rate of preterm birth has increased by 35% in the last 25 years, thus there has been increased interest in prevention over the past decade.  The reasons for this increase in premature birth are rather elusive to scientists, though there is a prominent theory that it is associated with an increase in maternal age.

Why would increased maternal age result in increased numbers of preterm births?

Well, the researchers behind a recently released study, “Metabolic hypothesis for human altriciality,” in the August 29th edition of PNAS, by Dunsworth et al, would probably lead you to believe that it may be associated with decreased metabolic capacity of the mom.

Their theory is that the induction of labor is initiated when the mom’s metabolic ability to support the growing fetus reaches a certain threshold.  When the mom cannot burn enough calories a day to create energy enough to support both herself and the fetus, then signals are released to initiate labor and birth.  Because an older mom would have a decreased metabolic rate, her capacity to produce energy would be reduced, thus birth would be initiated earlier than in a younger mom with a faster metabolism.  This lifting of suppressive signals (including progesterone) results in labor.  Thus, providing progesterone to an older mom at a high risk of preterm birth would/could synthetically keep providing the inhibitory signal, which may already be lifted in the body, that is needed to maintain pregnancy.

Do we know for sure?

The mechanism by which a fetus, when fully developed, stimulates the release of labor inducing hormones in mom is well defined in species such as cows, however humans lack the enzyme that seems to work as the trigger in bovines.  Thus, researchers are still puzzled as to how labor is induced, is it because of metabolic limits, signals from fetus that says “I’m developed,” or another mechanism? We still don’t know.  We only have theories to work with for now, though potential hypothesized mechanisms, which are being tested currently, are plentiful.

Norwitz ER, Phaneuf LE, Caughey AB. Progesterone supplementation and the prevention of preterm birth. Rev Obstet Gynecol. 2011 Summer, 4(2):60-72.

Norwitz ER, Robinson JN, Challis JRG. The control of labor. N Engl J Med. 1999;341:660–666.

Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000;21:514–550.

Dunsworth HM, Warrener AG, Deacon T, Ellison P, Pontzer H. Metabolic hypothesis for human altriciality. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15212-6. Epub 2012 Aug 29.
doi: 10.1073/pnas.1205282109