w: week of pregnancy

Conversion from ng/mL to nmol/L for progesterone *3.18

 A prospective cohort study published by Ku et al. investigated the serum progesterone distribution in normal pregnancies compared to pregnancies complicated by threatened miscarriage, in women from 5 to 13 weeks of gestation. The sample of the study consisted of 929 patients from Singapore, and the pregnancy outcome was decided at 16 weeks of gestation. The median serum progesterone concentration was characterized by a linearly increasing trend from 57.5 nmol/L to 80.8 nmol/L from 5 to 13 weeks gestation in the normal pregnancy cohort, while, in the threatened miscarriage cohort, median serum progesterone concentration increased from 41.7 nmol/L to 78.1 nmol/L. The median progesterone levels, in the threatened miscarriage group were uniformly lower by approximately 10 nmol/L at each gestational week, compared to the normal pregnancy ones. At the same time, the median serum progesterone concentration at 16 weeks of gestation showed a linearly increasing trend from 5 to 13 weeks of gestation in both cohorts, while women with spontaneous miscarriage demonstrated a marginal and non-significant increase in their serum progesterone levels. The aforementioned data emphasize on the significant role of progesterone during early gestation, as lower serum progesterone levels are linked to threatened miscarriage and a subsequent complete miscarriage at 16 weeks of gestation [20].

In March 2020, Deng et al. investigated the baseline levels of serum progesterone in women with threatened miscarriage, during first trimester. Seven hundred twenty-six women with threatened miscarriage were included in the study. The levels of progesterone were statistically associated with the women’s basic demographic data, obstetric history, and clinical information. The results showed that there is a negative correlation between the maternal serum progesterone levels and the first trimester pregnancy outcome. Specifically, when progesterone levels were lower than 90.62 nmol/L, increase in the serum progesterone by 1 nmol/L was associated with a 3% decrease of the risk of miscarriage (OR: 0.97, 95% CI: 0.95-0.98) concluding that there is a higher risk of miscarriage when serum progesterone levels are less than 90.62 nmol/L. Those results do not clearly depict the difference in progesterone levels during the first trimester, however they still reflect the anticipating serum progesterone levels during the first trimester and the potential screening value of maternal serum progesterone levels in the prognosis of the pregnancy outcome [21].

Ku et al. published in February 2021, another interesting primary, cross-sectional study that focused on the normal fluctuations of progesterone blood levels in 590 healthy pregnant women between 5 and 12weeks. The progesterone blood levels were statistically correlated with the women’s age, body mass index (BMI), parity, gestational age, and pregnancy outcomes at 16 weeks. The results proven that, during the first trimester of healthy pregnancy, serum progesterone starts to decline after 5 weeks, reaching their nadir two weeks later, at 7 weeks of gestation. The mean serum progesterone in week 5 was 75.0 nmol/L, compared to 66.9 nmol/L in week 6 (p = 0.057), and 63.4 nmol/L in week 7 (p = 0.029)]. Followed by , an increasing trajectory from 7 to 9 weeks with the mean serum progesterone levels being equal to63.4 nmol/L at 7 weeks, 67.7 nmol/L at 8 weeks (p = 0.374) and 78.9 nmol/L at 9 weeks (p < 0.001) [22].

In January 2022, the secondary analysis of prospective multicentre study data of consecutive women with a pregnancy of unknown location, from Bobdiwala et al., evaluated the predictive value of progesterone, β human chorionic gonadotropin, and β human chorionic gonadotropin ratio cut-off levels to exclude a viable intrauterine pregnancy in women with a pregnancy of unknown location between 11-14 weeks of gestation. Focusing on maternal progesterone levels, with data deriving from 2248 women, the study concluded that the likelihood of viability decreased in correlation with the serum progesterone levels. Analytically, the median progesterone levels associated with viability were 59 nmol/L, and the viable intrauterine pregnancy was identified with levels as low as 5 nmol/L. Again, as with the data of Deng et al. that was mentioned above, these results do not clearly depict the fluctuations of progesterone levels. Nevertheless, they still reflect the anticipated serum progesterone levels during the first trimester of intrauterine pregnancies and can be a useful tool in the prognosis of the pregnancy outcome. [21,23]

A longitudinal study by Schock et al., published in 2016, aimed to investigate the levels of maternal hormone concentrations during 71 uncomplicated pregnancies. Focusing on estradiol levels, the researchers concluded that they were highly correlated with the other hormones of placental origin (estrone and progesterone) (r > 0.72, p < 0.0001), while gestational age was found to be highly correlated with the levels of estradiol (r = 0.89; p < 0.0001). The median estradiol levels during the first, second and third

Trimester were 2.18(1.16- 3.59) ng/mL, 9.71 (5.33- 15.1) ng/mL and 20.4 (12.8- 32.9) ng/mL, respectively. Regarding progesterone levels, the initial median value was 25.6 (16.6- 40.7) ng/mL during the first trimester, increasing to 48.1 (31.6- 78.5) ng/mL in the second half of pregnancy and further raising to 130 (72.6- 200) in the third trimester. Another significant finding was that estradiol concentrations were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g. estradiol, rT1 vs. T2 = 0.51 and rT2 vs. T3 = 0.60, p  <  0.01; rT1 vs. T3 = 0.32, p  <  0.05) [12].

In April 2022, Hu et al. gave to publication another primary study which suggested that high circulating estradiol levels during the first trimester in women with multiple pregnancies, seem to significantly contribute to small for gestational age fetuses, and more specifically, that this contribution is accomplished via DNA methyltransferase 1 (DNMT1)-mediated cyclin dependent kinase inhibitor 1C (CDKN1C) upregulation [24]. The researchers found that at 8 weeks of gestation the maternal serum estradiol tend to rise with the number of fetuses and seem to be negatively correlated with the newborns’ birth weight [25].

Few months later, Pappa et al, analyzed the maternal serum progesterone and estradiol levels in 304 nulliparous women during the first trimester between 10 and 12 weeks, at the time of admission before childbirth and intrapartum during the 2nd stage of labour. Women were divided in three different groups according to the way of delivery. There was a significant increase in the progesterone and oestradiol levels during pregnancy among all the three groups. Analytically, progesterone levels increased by a mean value of 109.77 ± 85.39 ng/mL in the natural delivery group, 84.89 ± 71.71 ng/mL in the instrumental delivery group and 63.20 ± 41.42 ng/mL in the caesarean section after failure to progress (FTP) group. Estradiol levels were also found to increase by a mean value of 15,031 ± 5,959 pg/mL, 12,063 ± 5,695 pg/mL and 12,970 ± 6,899 pg/mL in the normal delivery, instrumental delivery and Caesarean section (FTP) cohort, respectively [26].

Progesterone and Oestradiol Levels during Parturition

Research focusing exclusively on maternal serum progesterone and estradiol levels during parturition dates to several decades.

Since June 1978, Boroditsky et al. measured the maternal serum estrone (E1), oestradiol (E2), estriol (E3) and progesterone concentrations during the last 3-10 weeks of healthy pregnancy. The results analysis showed that all estrogens and progesterone levels showed a small diurnal variation during gestation, did not change during labor and significantly declined after delivery [27].

In 1997, Löfgren et al, shown that progesterone concentrations in maternal and umbilical serum were higher following normal labour than after dystocia (p < 0.005) and elective Caesarean section (p < 0.005). The maternal progesterone levels in dystocia and elective Caesarean section accounted between 77-43% of those in normal labour, concluding that high progesterone concentrations during parturition appear to be related to effective labour [28].

A primary study coming from Tan et al. in 2012, explained how two different progesterone receptors on myometrial cells; progesterone receptor-A (PR-A) and -B (PR-B), have opposite effects on pro-inflammatory gene expression, subsequently affecting the initiation of the parturition in healthy women. The researchers analyze the main pre-labour signals, including intra-uterine infection, uterine distention, the increase in fetal prostaglandins, the rupture of membranes and severe haemorrhage. Moreover, they suggest that the different expression of PR-A and PR-B genes, ensure that the responsiveness of the myometrial cells to pre-inflammatory stimuli will be adequate, for the parturition to start [29].

In the same direction, Vrachnis et al. investigated the contribution of progesterone and CRH in the initiation of the labor, in healthy pregnant women. The researchers mentioned the “progesterone block” hypothesis, according to which progesterone prevents contractions of the myometrium during gestation facilitating the continuation of pregnancy, while its withdrawal which is mediated by the regulated co-expression of the receptor genes PR-A and PR-B described by Tan et al., transforms the myometrium from a state of quiescence to the active state required for the initiation of the parturition [29,30].

One year later, Konopka et al investigated whether labour induction with dinoprostone is associated with changes in maternal serum progesterone, oestradiol, and estriol levels. Eighty-one women with term pregnancies were included in the study. Sixteen had vaginal birth after spontaneous labour, 12 required caesarean section after spontaneous labour and 16 underwent elective caesarean. Thirty-seven patients had labour induction with dinoprostone. Serum concentrations were measured at admission and immediately before birth in patients with and without dinoprostone induction. Progesterone levels were decreased from admission to birth in patients who underwent successful labour induction with dinoprostone [vaginal and caesarean birth after induced labour: 23% (P < 0.001) and 18% (P < 0.025) decrease, respectively], but not in those whose induction failed (6.4% decrease, P > 0.05). Oestradiol levels have shown no difference between the different groups. The researchers concluded that successful dinoprostone-induced labour was associated with reduced maternal progesterone levels from induction to birth, proposing also a potential mechanism by which the use of dinoprostone could contribute in progesterone withdrawal [31].

Recently, Pappa et al., in the same study mentioned above, found significant variations in the levels of maternal progesterone and oestradiol levels during the different modes of childbirth. The study has shown that there is a statistically significant difference at the mean of oestradiol and progesterone range during different delivery modes (p-value< .01). Patients who underwent normal delivery had higher intrapartum values of oestradiol (54,486.47 ± 19,665.84 pg/mL) compared to patients who underwent instrumental delivery (44,431.55 ± 16,712.47 pg/mL), and patients who had an operational birth had higher values of oestradiol range compared to patients who underwent Caesarean section (FTP) (24,480.10 ± 7964.98 pg/mL). Regarding progesterone levels, patients who underwent Caesarean section (FTP) had higher values of progesterone during labour (379.90 ± 91.37 ng/mL), compared to patients who delivered normally (196.64 ± 88.10 ng/mL). Women who underwent instrumental delivery, showed the lowest values of progesterone during childbirth (182.44 ± 71.42 ng/mL) [26].