Estrogens = Estrone E1, Estradiol E2, Estriol E3

Estrogens

Sample

1. It is done on the serum of the patient which is separated immediately.
2. Can stored at 2 to 8 °C for 2 days in a glass test tube.
3. Get the time of the sample with reference to the menstrual cycle.

Indications

1. Estrogen level is estimated to assess sexual maturity.
2. To assess menstrual problems.
3. To assess fertility problems.
4. In males to assess the gynecomastia and feminization syndrome.
5. In pregnant women to assess fetal health.
6. This can be done as a tumor marker in the hormone, estrogen-producing tumors.

Pathophysiology

Estrogen

1. There are three major estrogens:
   1. Estrone (E1).
   2. Estradiol (E2). This is predominantly ovarian estrogen.
   3. Estriol (E3).
2. Estrogen consists of C18 steroids. While progesterone is a C21 steroid.
3. All of these estrogens are derived from androgenic precursors like DHEA, and androstenedione. These are synthesized by the adrenal cortex, ovaries, and testis.
4. Estrogens are the sex hormone responsible for:
   1. The development and maintenance of female sex organs.
   2. Female secondary sex characters.
5. The most potent estrogen is estradiol E2 secreted by the ovaries. Its measurement is sufficient to evaluate ovarian function.
   1. Ovaries lake the 21-hydroxylase and 11-β-hydroxylase, so they can not produce glucocorticoids and, mineralocorticoids like the adrenal cortex.
   2. Human ovaries produce sex steroids, estrogen, progesterone, and androgens.
6. Estrogen’s main site for inactivation in the liver.
   1. The main biochemical reactions are hydroxylation, oxidation, and methylation.
7. Estrogen source:
   1. The main source of estrogen in pregnant women is the placenta and it is in mg. This is mainly the estriol.
   2. The main source in non-pregnant women is the ovary and it is in µg quantity. This is mainly estradiol.
8. Functions of the estrogen hormone:
   1. It develops and maintains the female sex organs.
   2. It develops secondary sex characters.
   3. It regulates the menstrual cycle (with the help of progesterone).
   4. Maintain breast and uterus growth.
   5. It maintains pregnancy.
   6. It also helps calcium homeostasis and has a beneficial effect on bone.
   7. It also accelerates linear bone growth and results in epiphyseal closure.
9. Depletion of estrogen for a long time leads to:
   1. Loss of bone mineral contents.
   2. There are increased stress fractures.
   3. There is postmenopausal osteoporosis.
      

      Estrogen hormone functions

7. Estrogens are secreted by:
   1. Ovarian Follicles.
   2. Corpus luteum from the ovary.
   3. Placenta during pregnancy.
   4. A minute amount is produced from:
      1. Adrenal glands.
      2. Testes.
         

         Estrogen hormone sources

8. Estradiol and progesterone are the main secretory products of the ovary.
9. More than 20 estrogens are identified but only three have clinical significance and are:
   3. Estrone (E1).
   4. Estradiol (E2).
   5. Estriol (E3).

Estradiol E2

1. It is a more potent hormone and is predominantly produced in the ovary. It exists in a reversible state with estrone.
   1. Estrone has a weaker biological function.
   2. The final product is estriol (E3), a steroid without biological activity.
      

      Components of Estrogen

   3. E2 is produced exclusively by the ovary, its measurement is often considered sufficient to evaluate ovarian function.
2. The low level of estradiol stimulates the hypothalamus to produce a gonadotropin-hormone releasing factor.
3. These hormones stimulate the pituitary to produce a Follicular stimulating hormone (FSH) and luteinizing hormone (LH).
4. These two hormones (FSH and LH) stimulate the ovary to produce E2 which will have the peak during the ovulatory phase.
5. Estradiol transport in blood:
   1. 97% of the estradiol E2 in the blood is bound to plasma proteins.
   2. It has a high affinity and is specifically mainly bound to sex hormone-binding globulins (SHBG).
   3. Nonspecifically bound to albumin.
   4. SHBG increases by the estrogens, so these are higher in the female than male.
      

      Estradiol synthesis

6. Estradiol E2 is estimated to evaluate (Estradiol significance):
   1. Menstrual and fertility problems.
   2. Menopausal status.
   3. Gynecomastia.
   4. Sexual maturity.
   5. Feminization syndrome.
   6. As tumor marker of the ovary.
7. The various estrogen types formation, and their effect in different conditions.
   

   Estrogen and its derivatives significance

   

   Estrogen derivative formation

Estrone E1

1. It is produced by the ovary in small quantities.
2. It is produced directly from androstenedione, mostly in the peripheral tissues.
3. The plasma estrone level is an indicator of estradiol production because this is an end product of the estradiol metabolism.
4. This is the major hormone after menopause.

Estriol E3

1. Estriol in nonpregnant women is formed by the metabolism of the estradiol or estrone.
2. Estriol is the major hormone in pregnant women.
   1.  Estriol has no hormonal activity.
   2. It is produced in large quantities in the last trimester of pregnancy by the placental conversion of the fetal adrenal steroids, synthesized by DHEA derived from the fetal adrenal glands.
   3. In pregnancy, it is formed by the placental tissue and is a major component.
   4. Estriol E3 is produced from the placenta from the estrogen precursors. The placenta may produce some estradiol.
3. Excretion of the Estriol E3 in pregnancy increases around the 8th week of gestation and continues to rise shortly before the delivery.
4. Significance of Estriol (E3):
5. Serial urine and blood estriol estimation provide an assessment of placental function and fetal maturity in high-risk pregnancy.
   1. The concentration of unconjugated E3 in the third pregnancy is from 5 to 40 ng/mL, while the total E3 is 40 to 500 ng/mL.
   2. This estimation on three occasions gives the idea about fetal well-being.
6. It tells fetal well-being means placenta-fetus-viability.
   1. A sudden drop in the level of estriol in the last trimester of the pregnancy is a signal for the fetal-placental abnormality.
      

      Placenta hormones

7. The measurement of secreted estriol is important for fetal well-being.
8. Decreasing values indicates fetoplacental deterioration.
9. Serial studies are started usually at 28 to 30 weeks of gestation and repeated weekly.
   1. E3 values are taken at three consecutive days at the same time if there is a decrease of more than 30%, then there is a possibility of danger to the fetus.
   2. The value of unconjugated E3 is more reliable than the total E3.
      

      Estriol E3 from the placenta

      

      Estradiol E2, and E3 source

Menstrual cycle

1. Follicular phase a rapid rise in estrogens occurs immediately before ovulation and appears to stimulate LH secretion from the anterior pituitary glands.
2. The ovarian follicle grows and produces estrogens.
3. Ovulatory phase, Just before ovulation, there is a dramatic increase in estrogen.
   1. Ovulation makes the beginning of the luteal or secretory phase.
   2. Ovarian follicle transforms into corpus luteum.
   3. LH from the anterior pituitary glands stimulates the corpus luteum to secrete progesterone, which will lead o the secretory phase.
   4. If conception occurs then nutrient-laden endometrium is ready for implantation.
4. This increased estrogen will trigger the hypothalamus and gives LH a surge.
5. LH surge is a good indicator of ovulation. This occurs 24 to 36 hours before the ovulation and peaks 10 to 12 hours before the ovulation.
6. The luteal phase is the last half of the menstrual cycle where there is increased production of progesterone and estrogen from the corpus luteum.
7. The menstrual phase without estrogen and progesterone endometrium enters the ischemic phase of the menstrual phase.
   1. This makes the beginning of another cycle.
      

      Menstrual cycle and hormonal changes

10. The menopausal phase is when the ovary cannot produce enough amount of estrogen.
11. Estradiol is the most active of endogenous estrogens.
12. This test is of value with an evaluation of other gonadotropins for in evaluating menstrual and fertility problems in adult females.
13. Measurement is also helpful in the evaluation of gynecomastia or feminization states in estrogen-producing tumors.
14. This also helps in evaluating menstrual irregularities and sexual maturity in females.

Normal values of various estrogen

Source 2

Estradiol E2 (Unconjugated)

	Serum (Blood) pg/ mL	Urine  mcg /24 hours
Adult male	10 to 50	0 to 6
Adult female
Early Follicular phase	20 to 150
Late Follicular phase	40 to 350	1 to 13
Mid-cycle phase peak	150 to 750	4 to 14
Luteal phase	30 to 450	1 to 17
Postmenopausal	≤20	0 to 4
Children under 10 years	<15	0 to 6

Another source

Estriol E 3 (Free, unconjugated)	ng/mL
Adult male	<2.0
Nonpregnant female	<2.0
34 weeks of pregnancy	5.3 to 18.3
36 weeks of pregnancy	8.2 to 28.1
38 weeks of gestation	8.6 to 38.0
39 weeks of pregnancy	7.2 to 34.3
40 weeks of pregnancy	9.6 to 28.9
Estriol E3 Total
28 to 30 weeks of pregnancy	38 to 140
34 weeks of pregnancy	45 to 260
36 weeks of pregnancy	48 to 350
38 weeks of pregnancy	59 to 570
40 weeks of pregnancy	95 to 460
Estrone E1
Adult male	1.5 to 6.5
Early follicular phase	1.5 to 15
Late follicular phase	10 to 20
Luteal phase	1.5 to 2
Postmenopausal	1.5 to 5.5
Estrogens Total	pg/mL
Adult male	20 to 80
Follicular phase	60 to 200
Luteal phase	160 to 400
Postmenopausal	<130

Urinary E3

1. 28 weeks of gestation in normal pregnancy = average 4 mg/day  (range 2 to 7 mg/day).
2. 32 weeks of gestation in normal pregnancy = 13 mg/day.
3. 36 weeks of gestation in normal pregnancy = 18 mg/day.
4. 40 weeks of gestation of normal pregnancy = 26 mg/day

Total estrogen serum = Estradiol + Estrone + Estriol.

The increased level is seen in:

1. Estrogen-producing tumors.
2. Gynecomastia.
3. Hepatic cirrhosis.
4. Liver necrosis.
5. Hyperthyroidism.
6. Ovarian tumors.
7. Precocious puberty.
8. Testicular tumor.
9. Adrenal tumors.
10. Normal pregnancy ( E3 mainly ).

The decreased level is seen in:

1. primary and secondary hypogonadism.
2. Turner’s syndrome.
3. Ovarian agenesis.
4. Hypopituitarism.
5. Primary and secondary hypogonadism.
6. Stein-Leventhal syndrome.
7. Menopause.

 

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