Progesterone therapy: Is it beneficial to my pregnancy?

Posted By Braverman IVF & Reproductive Immunology || 17-Dec-2015

A recent study published in The New England Journal of Medicine discredited the beneficial role of Progesterone therapy for women experiencing recurrent pregnancy losses (RPL).
The article presented recent findings from a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether progesterone therapy could benefit women with RPL when administrated during the first trimester (PROMISE trial, Coomarasamy).

The results showed that supplemental progesterone did not increase the rate of live births in progesterone-treated patients when compared to patients receiving a placebo.

  1. Study’s methodology could explain the lack of effects with progesterone treatment

a. Patient’s selection may have excluded those with euploid losses

Patients with identifiable causes of RPL, related to immune alterations (Anti Phospholipid Syndrome, Systemic Lupus Erythematosus, Diabetes) have been excluded from the study.

The exclusion criteria may have biased this study toward idiopathic losses (1-2), which have been shown to be mostly aneuploid (3-4).
Treating patients with recurrent aneuploid losses should offer no benefit, as aneuploid loss is not predictive of further miscarriages (5).
These selection criteria are the same than the one found in the Brigham study (discussed in a previous blog, Patients with 5 or more miscarriages have an outstanding 80% chance of having a successful pregnancy with our treatment protocols (all pregnancies delivered or currently past 20 weeks). A review of 30 cases at Braverman Reproductive Immunology) that is still a reference to date (6).
Patients were enrolled anywhere from a positive βhCG to 6 weeks of pregnancy, which could have eliminate a fair number of chemical pregnancies, possibly explaining the unexpectedly high success rate in their control population.

Ploidy analysis on the products of conception would have allowed assessment on a euploid population, the only group that could potentially benefit from any treatment protocol.

b. Wrong timing in progesterone administration

The timing of progesterone administration was not consistent as the pregnant patients were enrolled anywhere between the positive pregnancy urine test and up to 6 weeks gestation. It should have been given, at least, before the implantation period to fully provide its immunological effects (7).

  1. How could Progesterone support my pregnancy?

Progesterone is the key hormone of pregnancy, first secreted by the corpus luteum during the luteal phase (post ovulation) of your menstrual cycle, this continues once the pregnancy is established until about 5 weeks of gestation. The placenta is then taking the relay to support and maintain the pregnancy.

a. Endometrial lining

Progesterone induces secretory changes in endometrial lining that are essential for implantation and maintenance of normal pregnancy (8). Indeed, a recent study showed that the use of luteal phase progesterone supplementation improved endometrial receptivity in women undergoing treatment with clomiphene citrate and led to increased rate of clinical pregnancies that was 2 times higher compared to the non-treated group (9).

b. Immunological regulation

Progesterone have several immunological benefits that promotes and maintain pregnancy (4).

- Progesterone is a key suppressor of inflammatory T cells

Some T cells can trigger an inflammatory response to fetal antigens leading to miscarriages or pregnancy complications. Progesterone suppresses the generation of T cell producing IFNΥ (10) or T cells (Th17) producing the inflammatory IL-17 (11).

- Progesterone induces regulatory T cells (Treg cells)

Treg cells are essential for maternal immune tolerance towards the embryo. Progesterone was shown to promote the generation of Treg cells (12-13) that are then recruited to the placenta to support the development of the embryo (14).

There are strong evidences showing the crucial role of progesterone during pregnancy.

A biased study population as well as improper timing of progesterone administration may have led to incorrect conclusions about the potential benefits of progesterone in recurrent pregnancy loss as seen in the latter study.
Large trial with proper patient selection, enrollment and timing in therapy administration should bring more clarity on progesterone beneficial effects in RPL patients.


  1. Christiansen OB, Nielsen HS, Kolte A, Pedersen AT. Research methodology and epidemiology of relevance in recurrent pregnancy loss. Semin Reprod Med. 2006 Feb;24(1):5-16. Review.
  2. Christiansen OB. Research methodology in recurrent pregnancy loss. Obstet Gynecol Clin North Am. 2014 Mar;41(1):19-39. Review.
  3. Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M, Munné S. Idiopathic recurrent miscarriage is caused mostly by aneuploid embryos. Fertil Steril. 2012 Sep;98(3):675-80.
  4. Sugiura-Ogasawara M, Ozaki Y, Suzumori N. Management of recurrent miscarriage. J Obstet Gynaecol Res. 2014 May;40(5):1174-9.
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  6. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999 Nov; 14(11):2868-71 Stirrat GM. Recurrent miscarriage. Lancet 1990; 336:673–5.
  7. Lissauer D, Eldershaw SA, Inman CF, Coomarasamy A, Moss PA, Kilby MD. Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell poly functionality and inducing a specific cytokine profile. Eur J Immunol. 2015 Oct;45(10):2858-72.
  8. Gonen Y, Casper RF, Jacobson W, Blankier J: Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization. Fertil Steril 1989, 52:446–450.
  9. Elguero S, Wyman A, Hurd WW, Barker N, Patel B, Liu JH. Does progesterone supplementation improve pregnancy rates in clomiphene citrate and intrauterine insemination treatment cycles? Gynecol Endocrinol. 2015 Mar;31(3):229-32.
  10. Miyaura, H., and Iwata, M. (2002). Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 168, 1087–1094.
  11. Lee, J.H., Ulrich, B., Cho, J., Park, J., and Kim, C.H. (2011). Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol 187, 1778–1787.
  12. Lee, J.H., Lydon, J.P., and Kim, C.H. (2012). Progesterone suppresses the mTOR pathway and promotes generation of induced regulatory T cells with increased stability. Eur J Immunol 42, 2683–2696.
  13. Areia A, Vale-Pereira S, Alves V, Rodrigues-Santos P, Moura P, Mota-Pinto A. Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy. BJOG. 2015 Oct; 122(11):1544-50.
  14. Ramhorst R, Fraccaroli L, Aldo P, Alvero AB, Cardenas I, Leirós CP, Mor G. Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. Am J Reprod Immunol. 2012 Jan;67(1):17-27
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