The incidence of recurrent miscarriage is on the rise and the causes are complex and multifaceted. I would like to discuss the role of estrogen in early pregnancy in terms of the method of maternal-fetal cycle construction.
The success of pregnancy is the process of building the maternal-fetal circulation, and the success or failure of the building process and how it is done affects the success or failure of pregnancy and the occurrence of related complications.
During maternal-fetal circulatory construction, placental vessels are recast, meconium vessels are remodeled, placenta is formed, and circulatory architecture is suggested for embryo maintenance and growth.
The human maternal-fetal vasculature is longitudinally interlaced, and among mammals, there is a rat placenta similar to humans, with the largest blood supply exchange area, and a placental interface consisting of trophoblasts and vascular endothelium forming a barrier with vertically interwoven exchange surfaces.
The placental trophoblast comes from the extra-embryonic mesoderm, and the process of trophoblast invasion is the process of maternal-fetal circulation construction, as well as the process of gestation and implantation.
The continuous invasion of trophoblast cells and the orderly apoptosis of metaphase cells are the basis for the formation of the immune tolerance mechanism of pregnancy. Trophoblast invasion is successful only if the mother does not reject the trophoblast and does not attack it, and if no thrombus is formed at the maternal-fetal interface.
The ratio of various cytokines, inflammatory factors, immune factors, vasoactive substances, endocrine hormone receptors, epithelial and mesenchymal cells and fibroblasts in the endometrium affects trophoblast invasion.
The viability of trophoblast invasion is highly dependent on the embryonic quality, and trophoblasts with normal embryonic chromosomes are highly viable and receive maternal meconium nutrients in invasion, and continuously invade successfully.
HCG is produced by trophoblast cells, i.e. originated from the extraembryonic mesoderm, also commonly known as a third party, i.e. non-maternal and non-embryonic. However, HCG is continuously produced to reflect the viability of the trophoblast and also the viability of the embryo. It is closely related to normal embryonic chromosomes. Chromosomally abnormal embryos have difficulty showing a gradient increase in trophoblast viability and HCG production.
Trophoblast infiltration is blocked and the construction of maternal-fetal circulation fails, often leading to pregnancy failure or the development of pregnancy complications such as hyperemesis.
The orderly apoptosis of meconium cells and trophoblast invasion are regulated by powerful endocrine hormones, which are the basis of strong fertility.
The placenta is formed and the trophoblast, i.e. the villi, undergoes several migrations (active period of invasion), the first active trophoblast invasion starts at the time of implantation and lasts until 7 weeks of gestation; the second from 8 to 12 weeks; and the third from 16 to 20 weeks. I did not have time to check these time points for specifics. The migration of several villi determines the success of the pregnancy and the occurrence of pregnancy complications. Insufficient trophoblast invasion and superficial placental implantation is thought to be one of the mechanisms by which hyperemesis occurs.
Endocrine hormones in early pregnancy are mainly derived from gestational corpus luteum support. The production of progesterone, androgen and estrogen, which are synthesized in the granulosa cells and epithelial cells of the gland, etc., is a process of continuous aromatization and interconnection. Progesterone, androgen, and estrogen are closely related in pregnancy and in the construction of the maternal-fetal cycle, in the continuation of pregnancy, and in the co-morbidities of pregnancy.
Estrogen is one of the most important foundations for the establishment and success of pregnancy. Estrogen is associated with many factors that influence the entire course of pregnancy, including the postpartum period. It has a major impact on the building of maternal-fetal circulation, angiogenesis, endometrial proliferation, secretion, the process of metaplasia, maternal peripheral vascular compliance, coagulation mechanisms, thrombosis and blood flow status.
Estrogen in pregnancy is mainly associated with placental vascular recasting, metaplastic vascular remodeling, and maternal-fetal circulation construction.
Estrogen in early pregnancy is mainly derived from the follicles, corpus luteum and corpus luteum of pregnancy, and the estrogen produced in the gland determines the success or failure of early pregnancy. Estrogen is derived from androgens and androgens from progesterone, a pathway that is constantly aromatized by the process.
The maintenance of estrogen in early pregnancy depends on the ability to produce estrogen in the gland, so any form of ovarian hypofunction will result in inadequate estrogen synthesis.
After pregnancy, the corpus luteum is generally maintained for 11 weeks, so the estrogen and progesterone produced by the trophoblast of the placenta are in succession with the estrogen and progesterone produced by the maternal ovary (in the gland).
Many fetal stoppages actually act on factors that occur long after implantation, or 5 weeks of gestation have been affected and cannot be maintained until 6 weeks, mainly because of insufficient estrogen, difficulties in building the maternal-fetal circulation, insufficient access to nutrients for the trophoblast, insufficient invasive viability, and blocked invasion, resulting in pregnancy failure. Therefore, hormonal monitoring in early pregnancy is very important. It should not be blind, some 8 or 9 weeks before fetal arrest is detected, but in fact the factors of action are present very early.
The 8th week of gestation is a critical point for the construction of maternal-fetal circulation and a point of success. The previous villi invasion and construction of maternal-fetal circulation are the basis for success, and the trophoblast cells produce increased progesterone and estrogen, especially estrogen, at the 8th week. Professor Zou Ying made a good point earlier that the literature suggests that at 9 weeks of gestation (a study in which removal of the ovaries did not affect pregnancy), estrogen production by trophoblast cells begins to increase, with a decrease in dependence on estrogen produced by the corpus luteum in the maternal ovarian gland.
The effect of progesterone, or progesterone, on pregnancy has not been looked at. There are few true clinical pregnancy failures due to progesterone. Progesterone is mainly responsible for endometrial transformation and metaplasia, the diastolic state of the uterus, and the prevention of peristaltic waves. In terms of hormonal physiological effects, the precise control of the ratio of progesterone, male and female during the sexual cycle, or during the whole course of pregnancy, affects the peristaltic wave of the uterus, the endometrial tolerance, the success or failure of the pregnancy, and even the failure related to the extravasation of the pregnant egg, ectopic pregnancy, etc. As well as related cytokines, inflammatory factors, and vasoactive factors all affect endometrial tolerance and peristaltic waves.
Xiangya Affiliated Reproductive Center, Prof. Yanping Li’s team has studied the peristaltic wave of the pregnant uterus with admirable results.
Progesterone is simple to supplement during pregnancy, but in estrogen deficiency related pregnancy, when estrogen is not enough due to pregnancy and female antagonism, and when progesterone is blindly supplemented, pregnancy outcome is mostly already determined and failure cannot be avoided.
Therefore, the success or failure of pregnancy with progesterone supplementation is closely related to estrogen. Progesterone supplementation alone is effective in pregnancy success or failure in the few cases where progesterone is indeed insufficient. Pregnancy failure due to inadequate progesterone is less frequent.
Estrogen supplementation, associated with ovarian function, and insufficient production of estrogen in the gland, either continuously, or with insufficient renewal capacity, leading to failure of maternal-fetal cycle construction, is associated with pregnancy failure in most normal embryos.
Estrogen measurements, and measurement points for supplementation: We consider estradiol 150 pg/ml to be the alert point for supplementation. We are in general agreement with a number of experts who have had a lot of success with this, and we have had a lot of experience with it over the years.
No less than 200pg/ml has a higher success rate for HCG levels of 5000 and below. HCG above 5000 has a higher success rate for estradiol measurements of 300pg/ml and above. 400pg/ml is generally considered safer by us when HCG is in the tens of thousands.
Estrogen test units and calibrations.
It should also be noted that the unit of estrogen testing, institutions with a scientific background, mostly use pg/ml, progesterone mostly, ng/ml; testosterone uses, ng/dl; some non-scientific institutions mostly use pmol or nmol, ng/ml units, such molar units, not good-looking, not intuitive, and inconvenient for horizontal comparison.
Testosterone unit is more confusing, in fact, in the use of reagents, the beginning of the calibration, the choice of units do not make a difference, calibration confirmation can be.
In scientific research we use a lot of enzyme standards (ELISA enzyme-linked immunoassay), putative immunoassay isotope method, etc. more accurate, less systematic error. The current chemiluminescence method is easy to operate, the reagents are inexpensive, and the determination of large samples is also better.
The safety of estrogen supplementation is safer with natural estrogens. The safety has been confirmed in many practical experiences in the clinic. However, its safety needs to be really clear in the long term (more than several decades). In reproductive ET, there is more experience with progesterone and estrogen use and larger doses.
The safety of estrogens, whether natural supplements, still needs to be confirmed by more studies, and toxicological data are still not accumulated enough in pregnancy. Therefore it is also unscientific to blindly use estrogens during pregnancy without clear judgment.
The most important thing about estrogen supplementation is that it should be clear, not blind, and not just a generalized supplement. The key point is to determine the ability of the ovaries to maintain estrogen production, i.e. the ability of the granulosa cells to produce estrogen continuously. When the estrogen and progesterone produced by the ovaries and the estrogen and progesterone produced by the placenta cannot be succeeded, only then is estrogen supplementation suitable for the population, which of course requires careful judgment, especially in cases of difficult conception and recurrent fetal stoppage. The true cause requires estrogen supplementation in order to achieve the goal.
In fact, whether it is estrogen supplementation, or progesterone, or any other method of treatment as well, it needs to be clear and not blind.
We cannot blindly recommend estrogen supplementation, and it is better not to bother with it if you are not in a position to sort out whether the ovarian estrogen and placental estrogen are not sufficiently connected.
It has always been the view that pregnancy should be natural, but in some cases of hypoplasticity, the lack of ovarian function can make it difficult to maintain a pregnancy. In a natural or normal pregnancy, estrogen should not be low, which is the necessary basis for pregnancy maintenance.
Commonly used estrogen supplements include Estradiol Valerate and Fentanyl (a combination of Estradiol and Estradiol Digestrol); Estradiol is a synthetic estrogen with valeric acid, which requires unchaining for liver inactivation, resulting in greater liver damage. Fentanyl has better estradiol and better utilization.
Estrogen usage: Oral estrogens, mostly after the first pass effect of the liver, are inactivated. Clinically, we see many oral doses with an insignificant rise related to liver inactivation. Therefore the oral dose is larger and the effect is not high.
Topical estrogens are used more often in reproductive ET and more often in manual cycles for uterine adhesions. Estradiol or combination tablets of Fentanyl, with a strong topical effect, we mostly use only 1/4 tablet topically and rarely half; estrogen would be high.
Clinical confirmation of embryo quality: The most important thing about estrogen supplementation is that it should not be done blindly and, as with progesterone supplementation, clarity is needed.
First of all, embryo quality should allow supplementation. Generally, embryo quality is directly related to trophoblast viability, which is reflected in the synthesis of HCG. Therefore, the vast majority of normal pregnancies have a gradient of rising HCG, with a regular, pronounced gradient. It generally rises 66% per day, i.e. doubles every other day. The most linear doubling is between 1000 and 10000 HCG. The measured HCG value exceeds the doubling when it is below 1000 and fails to reach it when it is above 10000. However, its curve rises showing regularity. There are also more individual differences.
The normal gradient rise of HCG measurement value, with low rate of embryo quality defects, can generally reflect the normal quality of embryo.
Progesterone supplementation is simpler and I will not write it by hand anymore. Reproductive ET is high in estrogen and progesterone supplementation and differs from conventional pregnancy requirements.
Latent thrombus status and pregnancy: Latent thrombus status is increasingly and closely related to pregnancy success or failure, with about half of all abortions or recurrent miscarriages being associated with latent thrombus. I’ll talk more about it when I have time. There is a lot of content.
Embryonic cardiovascular development is 18~25 days after fertilization, this period affects factors, such as prostaglandin synthase blockers, pathogens such as sick mother infection can lead to malformation of cardiovascular development; generally around 6 weeks of gestation, the primitive heart tube pulsation can be clearly seen on ultrasound. HCG level is generally around 40,000 and fetal heart pulsation is visible on ultrasound.
The yolk sac development shows regularity and is visible at 6 weeks of gestation and obvious at 8-10 weeks. Normal yolk sac development indicates normal embryonic cell division and development.
Ultrasound is very important in early pregnancy to confirm gestational age and gestational age. The gestational sac and embryonic development show regularity.
Many factors are involved in the success of a pregnancy and there is a lot of relevant knowledge involved.
In fact, whether estrogen supplementation, or the supplementation that is really needed, still needs to be supported by more toxicological studies. However, the clarity of the physician is more important than estrogen use. Blindness is a sign of ignorance and even more so, it is not in line with science.