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Estradiol (E2) is a common endogenous estrogen. It belongs to the class of steroids and has poor water solubility but is soluble in lipid substances. During the reproductive age of female and the first six weeks of gestation, E2 is primarily synthesized by the ovary, while during the later stages of gestation, it is synthesized by the placenta. After being synthesized, E2 enters the peripheral circulation system and binds with sex hormone-binding globulin (SHBG) and albumin reversibly. Approximately 98% of E2 in the peripheral circulation is protein-bound, among which, around 60% binds to albumin and 40% binds to SHBG. The remaining E2 exists in free forms and diffuses into target tissues to exert its biological functions.

In the ovary, E2 is secreted via the coordination of theca cells and granulosa cells in developing follicles. Under the action of enzymatic systems in theca cells, acetyl-CoA or cholesterol is converted to androgens, which then enter the granulosa cells and aromatize into estradiol and estrone (E1). After menopause, E2 is mainly derived from the peripheral conversion of estrone (E1).

In the placenta, E2 is synthesized from the hydrolysis of dehydroepiandrosterone sulfate, which is produced by the mother and the fetus during gestation, to dehydroepiandrosterone. Dehydroepiandrosterone is then converted to androstenedione and aromatized to estradiol.

Biological functions of Estradiol (E2)

Human E2 can promote the generation and development of egg cells, promote the growth and development of ovary and female reproductive system, maintain reproductive functiond and secondary sexual characteristics. E2 also plays an important role in male spermatogenesis and sperm maturation. E2 binds to the heat shock protein (Hsp) previously bound estrogen receptors (ER), causing allosteric changes of ER, releasing Hsp and activating ERs. The receptor-ligand complex monomers further diffuse into the nucleus and bind to the two half2 sites of the target DNA estrogen response element (ERE) to form homodimer or heterodimer complexes, which can stimulate transcription of target genes, thereby affecting cell proliferation and differentiation. In addition, E2 can combine with the specificly distributed ER subtypes (ER_α, ER_β) in tissues, and selectively act on target tissues.

Clinical significance of Estradiol (E2)

A. Diagnosis of Infertility

E2 is an important indicator for the diagnosis and treatment of clinical infertility, and can assist in judging whether reproductive endocrine function is abnormal. In a normal menstrual cycle, the level of E2 gradually increases with the development of follicles in the ovary. When the follicles are mature, the level of E2 rises rapidly to the peak. Due to the positive feedback of E2, the hypothalamus releases a large amount of gonadotropin-releasing hormone (GnRH), and the anterior pituitary gland releases a large amount of follicle-stimulating hormone (FSH) and a few luteinizing hormone (LH) to trigger ovulation. The hormone level of infertile women during ovulation is opposite. Due to the insufficient secretion of E2 from the ovary, the E2 in the body is lower than the normal level, and the concentration peak before ovulation cannot be formed, thus making it difficult to cause a positive feedback effect on the hypothalamus-pituitary gland, resulting in anovulation. Infertile patients are often accompanied by symptoms such as menstrual disorders and amenorrhea.

B. Monitoring early stage threatened miscarriage, hydatidiform mole and other pregnancy diseases

The level of E2 can be used to monitor pregnancy-related diseases throughout gestation. The E2 level in early pregnancy can reflect the quality of dominant follicles and the function of ovarian corpus luteum.
Although the content of E2 in the body is relatively low, it tends to rise as a whole. If E2 exceeds the threshold of ovulation, it proves that the placenta has taken over the function of the corpus luteum of the ovary and continued to carry on pregnancy, and the function of the placental unit is good. Monitoring E2 combined with human chorionic gonadotropin (HCG) and progesterone levels can predict early stage threatened miscarriage, meanwhile, E2 combined with progesterone and inhibin B levels can predict the risk of hydatidiform mole.

C. Diagnosis of menopausal syndrome and primary ovarian insufficiency

E2 is a specific indicator for the diagnosis of menopausal syndrome and primary ovarian insufficiency. Estrogen in women with normal menstruation is mainly E2, and 95% of E2 comes from the dominant follicle and corpus luteum of the ovary. Before menopause, insufficient secretion of corpus luteum causing E2 decreasing. Similarly, the ovarian function declines after menopause, and the secretion of E2 decreases significantly. Due to the lack of hormone feedback to the pituitary gland, the secretion of E2 decreases significantly, whereas FSH and LH increases significantly, which can be used as the basis for diagnosing menopausal syndrome and primary ovarian insufficiency.

D. Assisting judging the timing of artificial insemination

The clinical pregnancy rate of artificial insemination is relatively low, and one important factor affecting the success of artificial insemination is the timing. E2 level can assist in judging the best time for artificial insemination. E2 and LH levels indicate the mature situation of ovum and help to judge the timing of HCG injection. If E2 is too low, the ovum is immature or poorly developed. If E2 is too high, the ratio of estrogen and progesterone maybe out of balance, thus reducing the ability of embryo implantation, which is not conducive to gestation.

References

[1] J Guo, RI Duclos, Vk Vemuri, et al. The Conformations of 17β-Estradiol (E2) and 17α-Estradiol as Determined by Solution NMR[J]. Tetrahedron Lett 2010.51(27): 3465-3469.
[2] R William, SE Hankinson, PM Sluss, et al. Challenges to the Measurement of Estradiol: An Endocrine Society Position Statement[J]. J Clin Endocrinol Metab, 2013,98(4):1376-1387