In the 1930s, it was demonstrated that estrogen, even in small doses, produced abortions, and that when it is given early enough, even a very small dose will prevent implantation of the fertilized embryo. Progesterone was known, by the early 1940s, to protect against the many toxic effects of estrogen, including abortion, but it was also known as nature’s contraceptive, since it can prevent pregnancy without harmful side-effects, by different mechanisms, including prevention of sperm entry into the uterus. That is, progesterone prevents the miscarriages which result from excess estrogen (1,2), but if used before intercourse, it prevents conception, and thus is a true contraceptive, while estrogen is an abortifacient, not a contraceptive. -Ray Peat, PhD
Fertil Steril. 1986 Jan;45(1):69-74.
Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice.
Gidley-Baird AA, O’Neill C, Sinosich MJ, Porter RN, Pike IL, Saunders DM.
Daily blood samples were taken for progesterone (P) and estradiol (E2) measurements from women who showed a platelet response consistent with the presence of viable embryos after in vitro fertilization and embryo transfer procedures. A comparison of steroid levels between those women who became pregnant and those who did not revealed the following: at and after the time of transfer, women who failed to become pregnant had significantly higher E2 levels and a lower ratio of P/E2 than women who became pregnant. The P/E2 ratio was a better predictor of implantation failure than was the absolute level of either hormone. Experiments were done in mice to test the hypothesis that P could protect implantation of the embryo against the inhibitory effects of high E2. In mice, implantation was inhibited by relatively high levels of E2. This effect was overcome by concomitant administration of P. There was a significant dose-response-related interaction of P with the E2.
Fertil Steril. 1985 Aug;44(2):185-9.
Early luteal serum progesterone concentrations are higher in pregnancy cycles.
Yovich JL, McColm SC, Yovich JM, Matson PL.
In a consecutive series of 167 patients reaching the stage of embryo transfer after in vitro fertilization and embryo transfer, 19 clinical pregnancies ensued. The serum progesterone (P) levels were significantly greater on the first and second (P less than 0.01) and third (P less than 0.05) postaspiration days for those who conceived. Higher circulating levels of P were achieved on days 1, 2, and 3 (P less than 0.05) by the daily injection of P, 50 mg in oil, given for 5 consecutive days, beginning immediately after follicle aspiration. Both pregnancy and nonpregnancy cycles demonstrated high circulating P levels, but the study implies that relatively higher levels are required for conception, and such levels can be achieved by the use of intramuscular P.
arly Pregnancy. 1996 Jun;2(2):113-20.
Relationship of estradiol and progesterone levels to uterine blood flow during early pregnancy
Dickey RP, Hower JF.
The purpose of this study was to examine the relationship of uterine blood flow to serum estradiol and progesterone during early pregnancy. Recumbent uterine artery average velocity, diameter, blood flow volume and uterine and spiral artery resistance were measured using vaginal Doppler ultrasound 118 times in 43 patients during gestational (postmenstrual) weeks 5 to 16. Relationships to serum progesterone and estrogen were analyzed before and after week 10, when intervillous circulation begins, by multiple linear regression analysis and analysis of covariance (ANCOVA) to correct for the effect of gestational age. After correction for gestational age, estradiol was negatively related to uterine artery flow volume (p < 0.05), diameter (p < 0.05), pulsatility index (p < 0.05) and resistance index (p < 0.01) for weeks 5-16 and to diameter (p < 0.05) after week 9. Progesterone was positively related to volume (p < 0.05) and velocity (p < 0.01) for weeks 5-16 and to volume (p < 0.05) for weeks 5 to 9. Spiral artery indices of resistance were unrelated to hormone levels. These results indicate that before the 10th gestational week, uterine blood flow volume is related to progesterone, but not estradiol levels, and suggest that high estradiol levels during and after the 10th week may be associated with decreased uterine blood flow volume.
Proc Soc Exp Biol Med. 1958 Nov;99(2):478-82.
Anti-progestational activity of estrogens in rabbit endometrium.
MIYAKE T, PINCUS G.
1) The anti-progestational activity of 4 estrogens—estrone, estradiol, estriol, and stilbestrol—administered subcutaneously along with progesterone into Clauberg rabbits has been demonstrated by estimation of endometrial carbonic anhydrase content and simultaneous measurement of uterine G/M ratio. 2) All these estrogens inhibit the effect of progesterone on carbonic anhydrase content and G/M ratio of the endometrium. Intensity of inhibition depends upon dosage. 3) The anti-progestational activities of these estrogens are approximately the same. 4) When administered alone, these estrogens produce no significant change in either carbonic anhydrase titers or G/M ratios of the endometrium. 5) The linear relationship with negative slope which is obtained between the logarithmic dose of the estrogens and the endometrial carbonic anhydrase content of the progesterone-treated Clauberg rabbit suggests the usefulness of the carbonic anhydrase method as an assay procedure for anti-progestational activity. 6) Comparison of the log-dose-response curves of progesterone with and without estradiol indicates that estrogen may depress reactivity of the endometrium to progesterone rather than neutralize or inactivate progesterone in the body.
Fertil Steril. 1956 Jul-Aug;7(4):301-11.
Effect of various steroids on gestation and litter size in rats.
VELARDO JT, RANEY NM, SMITH BG, STURGIS SH.
The purpose of this investigation was to ascertain the action of estriol and various ratios of pregnane-3-a-20-a-diol: pregnanedione on gestation and the number of living young born in each treatment group of rats. These substances, in the doses here used, did not affect the mating response or length of gestation. Combinations of the 2 pregnanes tended to reduce the size of the litters compared with untreated controls both when given for a week before mating and also on the day of mating only. When estriol was given prior to mating, it caused a more marked reduction in live births, and when this steroid was employed after mating and daily through time of implantation, the litters decreased to 33% of the control size. In the same animals, the incidence of placental scars, abortions, and stillbirths further bears witness to the possibility that the steroids employed interfered with the optimum differentiation of progestational endometrial changes, rather than affecting any suppression of ovulatory mechanisms. It is postulated that faulty metabolism of either estrogenic or progestational hormones may play a role in certain clinical problems of miscarriage and abortion by a similar interference with the development of the maternal bed.
Domest Anim Endocrinol. 2003 Nov;25(4):329-43.
Effects of endocrine disrupting compounds on the pathology and oestrogen receptor alpha and beta distribution in the uterus and cervix of ewe lambs.
Morrison AG, Callanan JJ, Evans NP, Aldridge TC, Sweeney T.
A number of chemicals have been classed as endocrine disrupting compounds due to their ability to mimic the actions of endogenous hormones in vivo and in vitro. The objective of this experiment was to determine the pathological changes and oestrogen receptor (ER) distribution in the cervix and uterus of prepubertal ovariectomised ewe lambs following exposure to a range of compounds with a predominantly oestrogenic effect. Lambs were exposed to diethylstilbestrol (0.175 mg/kg biweekly), bisphenol-A (3.5mg/kg biweekly) or octylphenol (3.5mg/kg biweekly) for 6 weeks. Following sacrifice, uterine and cervical tissue pathology was assessed. The endometrial and myometrial areas were quantified and the distribution of ERalpha and ERbeta assessed by immunohistochemistry. No differences were observed between control and octylphenol-exposed lambs in uterine gross pathology and histopathology. Uteri from bisphenol-A- and diethylstilbestrol-exposed lambs were heavier than both control and octylphenol-exposed lambs. In the bisphenol-A-exposed lambs, endometrial oedema accounted for a significant increase in the endometrial cross-sectional area over the other groups. Uteri from animals exposed to diethylstilbestrol showed variable pathology including oedema and cellular proliferation. Keratinisation of the cervical epithelium was observed in both bisphenol-A- and diethylstilbestrol-exposed lambs. Exposure to diethylstilbestrol and bisphenol-A was associated with a diffuse intracellular distribution of ERalpha and ERbeta in the uterine endometrium. This was in addition to the strong cytoplasmic staining of uterine epithelial cells and nuclear staining of specific sub-epithelial cells observed in all groups. We conclude that a 6-week exposure of lambs to bisphenol-A and diethylstilbestrol altered the uterocervical environment and has the potential to disrupt subsequent reproductive function. Pathological changes could not be detected in the uterus or cervix of lambs exposed to octylphenol.