Prospective, Clinical Cohort Study on the Endocrinology and Vaginal/Endometrial Microbiome of the Luteal Phase and Pregnancy After Embryo Transfer in Assisted Reproduction

Introduction and rationale Progesterone is a steroid hormone with different functions. In the luteal phase of the menstrual cycle elevated progesterone levels maintain the endometrium. Amongst others it stimulates glandular secretion and adjusts pattern of secreted proteins of the endometrium to provide a supportive environment for of embryo implantation. A sudden decline in progesterone levels leads to endometrial shedding and thereby menstrual bleeding. Thus, elevated progesterone levels are vital to maintain a pregnancy after successful embryo implantation. Progesterone is produced by the Corpus luteum (CL), a relict of the Graaf follicle, after ovulation in the luteal phase of the menstrual cycle and in the first weeks of pregnancy. The lifespan of the CL is assumed to be several weeks.

Before luteolysis of the CL, the production of progesterone shifts from the CL to the placenta which ensures maintenance of the pregnancy. This process is termed luteoplacental shift. Adequate placental progesterone increase is vital for the maintenance of the pregnancy and low progesterone levels can indicate inadequate development of early pregnancies. However, laboratory measurement of progesterone by conventional ELISA techniques cannot distinguish between placental progesterone and progesterone produced by the CL.

This is one reason why still little is known about the exact time point of the luteoplacental shift. In 1972 a decline of progesterone and subsequent loss of pregnancy for n=12 patients after ovariectomy or luteectomy in the 8th week of gestation but not for operations taking place in the 9th week of gestation (n= 5 patients) was reported. This is in line with in-vitro measurements from 1985 in a placental organ culture which shows the capability for progesterone production between 6th and 8th week of gestation. In 1990 it was observed in women (n=17) with absent of ovaries and constant exogenous progesterone administration achieving pregnancy by an egg donation program a significant progesterone increase in the 9th gestational week. This is in contrast to a study in a similar setting from 1991 in n=9 women who reported onset of endogenous progesterone production around the 5th week of gestation. Additionally, even the existence of the luteoplacental shift itself was questioned because of a wide range of progesterone levels observed in women achieving successful pregnancies by assisted reproduction technique (ART).

Moreover, 17-OH progesterone (17-OHP) was suspected to be produced solely by the CL in early pregnancy. This is supported by a study who found 17-OHP blood levels and vascularity of the CL decreasing from 5th till 11th week of gestation suggesting the luteoplacental shift to take place.

In summary, little is known about the exact time point of the luteoplacental shift.