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.
- 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).
- 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.
References
- 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.
- Christiansen OB. Research methodology in recurrent pregnancy loss. Obstet
Gynecol Clin North Am. 2014 Mar;41(1):19-39. Review.
- 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.
- Sugiura-Ogasawara M, Ozaki Y, Suzumori N. Management of recurrent miscarriage.
J Obstet Gynaecol Res. 2014 May;40(5):1174-9.
- Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses
in relation to the number of previous miscarriages. Fertil Steril 2000;
73:300–304.
- 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.
- 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.
- 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.
- 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.
- Miyaura, H., and Iwata, M. (2002). Direct and indirect inhibition of Th1
development by progesterone and glucocorticoids. J Immunol 168, 1087–1094.
- 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.
- 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.
- 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.
- 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