Progesterone and Miscarriage

Up to 35% of repeat miscarriages are linked to low progesterone production

Up to 35% of women with repeated or habitual miscarriages have a luteal phase defect. The cause of the infertility and miscarriage is thought to be a result of an inadequate maturation and development of the endometrium. The reason for the retarded development of the endometrium is thought to be in part due to inadequate levels of progesterone production by the corpus luteum.

17.4% of women with repeat miscarriage have low progesterone

In the mid-luteal phase, low progesterone level was found in 17.4% and delayed endometrial development was noted in 27.1% of women. Although women with recurrent miscarriage women and delayed endometrium had significantly lower progesterone levels than those with normal endometrial development, only 8/24 had mid-luteal progesterone levels below 30 nmol/L (9.43 ng/ml).

91% of pregnancies with progesterone lower than 15 ng/ml will end in miscarriage

Pregnant women between 5 and 13 weeks' gestational age were included as Group I who resulted in miscarriage including missed miscarriage, incomplete miscarriage, complete miscarriage and inevitable miscarriage; Group II included normal pregnancies. When using the free beta-hCG level of <20 ng/ml as a cut off point, the sensitivity, specificity, positive predictive value and negative predictive value were 91%, 82%, 46% and 98%, when using a progesterone of <15 ng/ml as a cut off point, they were 91%, 89%, 59%, 98%. The single measurement of free beta-hCG or progesterone levels can be useful in the prediction of first trimester miscarriage, but using progesterone may be recommended since it has high availability and low cost.

Average progesterone in pregnancies that miscarry is 14 ng/ml; in healthy pregnancy: 32 ng/ml

Serum concentrations of progesterone and beta-HCG were measured between the fourth and fifth gestational weeks. The mean serum levels of progesterone and beta-HCG in patients with inevitable miscarriages (13.76 +/- 5.52 ng/ml, 3,647.00 +/- 2,123.00 mIU/ml, respectively) were significantly lower than these levels in normal intrauterine pregnancies (31.67 +/- 5.86 ng/ml, 13,437.00 +/- 6,256.00 mIU/ml, respectively) and ongoing pregnancies (25.47 +/- 6.18 ng/ml, 8,492.00 +/- 2,389.00 mIU/ml, respectively).

Progesterone lower than 12 ng/ml associated with increased miscarriage risk

In women between gestation weeks 4 and 12 in whom no apparent signs of a threatened miscarriage could be diagnosed, risk of miscarriage was significantly increased in women at higher age (>33 years), lower body mass index (< or =20 kg/ m(2)) and lower serum progesterone concentrations (< or =12 ng/ml) prior to the onset of the miscarriage. Women with subsequent miscarriage also perceived higher levels of stress/demands (supported by higher concentrations of corticotrophin-releasing hormone) and revealed reduced concentrations of progesterone-induced blocking factor. These risk factors were even more pronounced in the subcohort of women recruited between gestation weeks 4 and 7.

Progesterone over 25 ng/mL at 10 weeks associated with just a 2.15% risk of miscarriage

We determined threshold values for mean gestational sac diameters - crown-rump lengths (> or =10 mm) and progesterone (> or =25 ng/mL) to predict miscarriage at 10 weeks. For the MGSD-CRL threshold, we can predict that the pregnancy will continue with 95.78% probability, with 67% sensitivity and 89% specificity. For the progesterone threshold, the pregnancy will continue with 97.85% probability, with 80% sensitivity and 80% specificity.

Endometrial progesterone levels are 200 times higher in fertile women vs. those who habitually miscarry

Plasma progesterone was two times higher in fertile women than in habitual miscarriage. In endometrial tissue, progesterone content was 200 times higher in fertile women than in women with habitual miscarriage. Estrogen receptors and progesterone receptors were lower in the cytosol than in the nuclear fraction in fertile and obese women. Both receptors were at their lowest level in the cytosol and nuclear compartment of women with recurrent miscarriage. Fluctuations mainly in the sex hormone progesterone, in plasma and endometrium tissue, could interfere with estrogen receptor and progesterone receptor levels.

Low progesterone and low progesterone receptor found in recurrent miscarriage

Estrogen and progesterone receptors in the endometrium of eight patients with habitual miscarriage in proliferative and secretory phases were measured. The results showed that the level of serum estrogen was normal in the proliferative and secretory phases. In 5/8 patients, the serum progesterone level was below 11 ng/ml. The estrogen receptor of patients was not different from that of normal women in the proliferative and secretory phases, but the progesterone receptor was significantly lower than that of normal women in the proliferative and secretory phases. These suggest that the lower level of progesterone and progesterone receptor in the endometrium may be one of the causes of habitual miscarriage.

Progesterone induced blocking factor levels are 57% lower in cases of threatened miscarriage

Progesterone induced blocking factor concentrations in urine (19.5 ng/mL) and serum (214.4 ng/mL) of patients with threatened miscarriage were significantly lower than in healthy pregnant women (45.3 ng/mL and 357.3 ng/mL, respectively).

Progesterone is vital for maternal immuno-tolerance of the fetus

Epidemiological studies suggest the role of stress in miscarriage and exposure to stress induces miscarriage in mice via a significant reduction in progesterone levels, accompanied by reduced serum levels of progesterone induced blocking factor. These effects are corrected by progesterone supplementation. These findings indicate the significance of a progesterone-dependent immuno-modulation in maternal tolerance of the fetus.

Progesterone induced immunosuppression is vital to maintaining pregnancy

Because of the blockage of progesterone receptors and the consequent inability of the lymphocytes to produce the progesterone-induced blocking factor, miscarriage is initiated by immune factors. The fact that administration of the preformed blocking factor counteracted the effect of antiprogesterone treatment suggests that progesterone-mediated immunosuppression is needed for the maintenance of normal gestation.

Progesterone enables immunosuppression by inducing Th2 dominant cytokine production

Along with its endocrine effects, progesterone also acts as an "immunosteroid", by controlling the bias towards a pregnancy protective immune milieu. A protein called progesterone-induced blocking factor, by inducing a Th2 dominant cytokine production mediates the immunological effects of progesterone. Progesterone plays a role in uterine homing of NK cells and up-regulates HLA-G gene expression, the ligand for various NK inhibitory receptors. At high concentrations, progesterone is a potent inducer of Th2-type cytokines as well as of LIF and M-CSF production by T cells.

Women who miscarry may have an inappropriate immune response to progesterone

In a longitudinal prospective study, the wheal and flare reaction (allergic reaction) after intradermal injection of estrogen and progesterone was compared in 29 women with recurrent miscarriage to the response in 10 healthy women. Estrogen hypersensitivity was found in 23 patients, and progesterone hypersensitivity in 20 patients. No patient in the control group demonstrated sex hormone hypersensitivity. CONCLUSION: Recurrent miscarriage  may be associated with inappropriate local immune responses to sex hormones. Further research is necessary into the mechanisms of hypersensitivity to estrogen and progesterone and their interactions with other systems.

Uterine blood flow resistance is higher in recurrent miscarriage, associated with low progesterone

In the repeat miscarriage group, the uterine blood flow resistance in the uterine artery of women with antinuclear antibodies (high in autoimmune disease) was significantly higher than that of women without antinuclear antibodies. Among women without antinuclear antibodies, the mean uterine blood flow resistance in the repeat miscarriage group (2.44) was also significantly higher than in the control group (2.19). The uterine blood flow resistance was inversely correlated with serum progesterone levels. CONCLUSIONS: Elevated uterine arterial impedance is associated with repeat miscarriage.

Progesterone reduces the effect of coagulation factors and is primary marker for miscarriage risk

The relationship between coagulation factors and miscarriage was reduced after adjustment for progesterone suggesting that progesterone mediates the relationship between low levels of coagulation factors and miscarriage. Progesterone seems to be the primary marker for a miscarriage among women seeking emergent care.

See also:

Supplemental progesterone and miscarriage

Other topics covered under Progesterone:

How to increase progesterone

Effects of progesterone

Progesterone Data