The measurement of H-P-O-A hormone levels in women is important for the diagnosis of the etiology of infertility, observation of the efficacy, prognosis and the study of the mechanism of reproductive physiology. The determination of hormone levels is usually performed by drawing peripheral blood, and the commonly used methods are radioimmunoassay and chemiluminescence.
I. Requirements for the determination of sex hormone 6 items
1. No sex hormone drugs have been used for at least 1 month before the serum reproductive hormone test to avoid affecting the test results (except for the re-examination after estrogen and progestin treatment or ovulation treatment). In cases of scanty menstruation or amenorrhea, if the urine pregnancy test is negative, if there are no follicles >10mm in the ovaries bilaterally on vaginal ultrasound, and if the endometrial (EM) thickness is <5mm, it can also be used as the baseline status.
2.Check according to clinical needs
(1) Basal sex hormones: The measurement of sex hormones on 2-5 days of menstrual cycle is called basal sex hormone measurement. Basal LH, FSH and E2 should be measured on days 2 to 5 of the menstrual cycle, with day 3 being the best; for cycles shorter than 28 days, the examination time should not exceed day 3, and for cycles >30 days, the examination time should not exceed day 5 at the latest. Prolactin (PRL) and testosterone (T) can be measured at any time of the menstrual cycle.
(2) Late follicular phase (D12-16): E2, LH and P are measured when the follicles are near maturity to predict ovulation and the timing and dosage of HCG injection; P value is measured to estimate endometrial tolerance.
(3) PRL measurement: can be measured at any time of the menstrual cycle, blood should be drawn at 9-11 a.m., on an empty stomach, in a quiet state. a single test can determine significantly elevated PRL, while a second test should be performed for mildly elevated cases. hyperprolactinemia (HPRL) should not be easily diagnosed and abused with bromocriptine treatment.
(4) Androgens: The commonly used tests are serum testosterone, androstenedione, and dehydroepiandrosterone sulfate. The significance of testosterone alone is small, and the biochemical indicators for evaluating hyperandrogenemia mainly rely on free testosterone.
(5) P: choose luteal phase measurement (D21-26 days) to understand ovulation or not and luteal function.
II. Clinical significance of the six sex hormone measurements
(i) Estrogen
Estrogen (E) in women of reproductive age mainly comes from the ovaries and is secreted by the follicles, the amount of secretion depends on the development of follicles and luteal function. In pregnant women, estrogen is mainly produced by the ovaries and placenta, with a small amount produced by the adrenal glands. In early pregnancy, E is mainly produced by the corpus luteum, and after 10 weeks of gestation, it is mainly synthesized by the fetal-placental unit. By the end of pregnancy, E2 is 100 times greater than in non-pregnant women.
Estrogens include estradiol (E2), estrone (E1), and estriol (E3). E2 is the most biologically active estrogen and is one of the main hormones produced by the ovaries; E3 is a degradation product of E2 and E1 and is the least active, with a relative ratio of 100:10:3.
Estradiol test value coefficient conversions.
1. Basal estrogen values and menstrual cycle changes
(1) Basal E2: E2 is at a low level in the early follicular phase, approximately 91.75 to 165.15 pmol/L (25 to 45 pg/ml).
(2) Peak E2 ovulation: E2 levels gradually increase with follicle development, with each mature follicle theoretically secreting estradiol 918-1101 pmol/L (250-300 pg/ml). The amount of E2 secreted by the follicle increases gradually from the 7th day of menstruation and rises rapidly 1 to 2 days before ovulation to reach the first peak, which is called the ovulation peak; E2 can reach 918 to 1835 pmol/L (250 to 500 pg/ml) before ovulation in the natural cycle; the pre-ovulation peak of E2 mostly occurs 1 day before the LH peak and lasts for about 48 hours before and after ovulation. It decreases rapidly after ovulation. The appearance of the ovulation peak predicts possible ovulation at about 48 hours. HCG dosage and injection time can be considered according to LH value, follicle size and cervical mucus score.
(3) E2 luteal peak: E2 level decreases after ovulation, and after luteal maturation (6-8 days after LH peak) E2 rises again to form the 2nd peak, called luteal peak, with a peak of 459-918 pmol/L (125-250 pg/ml), which is about half of the ovulation peak. If the E2 peak is maintained for a period of time without pregnancy, it decreases simultaneously with the P peak, and the E level drops sharply to the early follicular phase level when the corpus luteum atrophies.
2.The clinical significance of estradiol measurement
(1) Diagnosis of female precocious puberty: E2 is one of the hormonal indicators to determine the initiation of puberty and to diagnose precocious puberty. precocious puberty can be diagnosed when the development of secondary sex characteristics occurs before the age of 8 and blood E2 rises > 275 pmol/L (75 pg/ml).
(2) E1/E2 > 1 suggests increased peripheral conversion of E1 and is indirect evidence of increased testosterone (T), as in postmenopause and PCOS.
(3) Excessive E2 levels are seen in granulosa cell tumors, ovarian plasmacytoma cystadenoma, cirrhosis, systemic lupus erythematosus, obesity, smokers, normal pregnancies and pregnant women with diabetes mellitus.
(4) Premature ovarian failure occult stage: elevated basal E2 and normal FSH is the intermediate stage between ovarian failure and normal ovarian function, i.e., premature ovarian failure occult stage. With age and ovarian failure, high FSH and LH and low E2 status will appear.
(5) Ovarian failure: lower basal E2 and higher FSH and LH, especially when FSH ≥ 40 IU/L, suggest ovarian failure.
(6) Basal E2, FSH and LH are all low, which is hypogonadotropic (Gn) deficiency, suggesting that the lesion is in the hypothalamus-pituitary gland, such as Sheen syndrome.
(7) Polycystic ovary syndrome: maintenance of high levels of estrogen without cyclic changes is an endocrine feature of polycystic ovary syndrome (PCOS), which includes elevated levels of E2 and E1, increased secretion of T and LH, decreased secretion of FSH, and LH/FSH > 2 to 3.
(8) Early in pregnancy E is mainly produced by the corpus luteum and after 10 weeks of gestation it is mainly synthesized by the feto-placental unit. By the end of pregnancy, E2 is 100 times higher than that of non-pregnant women. e2 can be used as an observational indicator for fertility preservation treatment in patients with miscarriage.
(9) Predicting the effect of superovulation (COH) and pregnancy rate
①The pregnancy rate was significantly higher in those with basal E2 <165.2 pmol/L (45 pg/ml) than in those with E2 ≥165.2 pmol/L.
(2) Basal E2 > 293.6 pmol/L (80 pg/ml), regardless of age and FSH, indicates rapid follicular development and decreased ovarian reserve function; in IVF cycles if basal E2 > 367 pmol/L (100 pg/ml), COH is ineffective, cycle cancellation rate due to low or no ovarian response increases significantly, and clinical pregnancy rate decreases.
(10) Indicators for monitoring follicular maturation and ovarian hyperstimulation syndrome (OHSS)
①When follicles ≥ 18 mm and blood E2 ≥ 1100 pmol/L (300 pg/ml) are treated with ovulation promotion, HMG is discontinued and intramuscular injections
.
②Ovulation promotion therapy when follicles mature with E2 <3670pmol/L (1000pg/ml), OHSS will not usually occur.
(iii) A higher number of follicles developing with E2 > 9175 pmol/L (2500 pg/ml) to 11010 pmol/L (3000 pg/ml) at the time of ovulation promotion treatment is a high risk factor for OHSS.
(iv) E2 at the time of superovulation >
(4000 pg/ml) to 22,020 pmol/L (6000 pg/ml), the incidence of OHSS is nearly 100% and can rapidly develop into severe OHSS.
(ii) Progesterone
P is secreted by the ovaries, placenta and adrenal cortex, and is mainly derived from the placenta during pregnancy. P in the peripheral blood during the menstrual cycle mainly comes from the corpus luteum formed after ovulation, and its level gradually increases with the development of the corpus luteum.
During the follicular phase, P is always at a low level, averaging 0.6-1.9 nmol/L, generally <3.18 nmol/L (1ng/ml); when the LH peak occurs before ovulation, granulosa cells of mature follicles luteinize under the action of LH ovulation peak and secrete a small amount of P. Blood P concentration can reach 6.36 nmol/L (2ng/ml), and the initial rise of P is an important indication of imminent ovulation The initial rise in P is an important indication of imminent ovulation. After ovulation, the corpus luteum forms and produces a rapid rise in P concentration; when the corpus luteum matures (6-8 days after the LH peak), blood P concentration reaches a peak of 47.7-102.4 nmol/L (15-32.2 ng/ml) or higher. If the corpus luteum begins to atrophy 9-11 days after ovulation without pregnancy, the P secretion concentration decreases abruptly and drops to follicular phase level 4 days before menstruation. The blood P level changes parabolically throughout the luteal phase.
Progesterone test value coefficient conversions.
Clinical significance of P determination.
1, normal basal value P value should be maintained at <1ng/ml throughout the follicular phase, 0.9ng/ml is the minimum for changes in the endometrial secretory phase. p value starts to rise with the appearance of LH peak and increases substantially after ovulation.
2. P > 1ng/ml in the early follicular phase predicts poor ovulation promotion efficacy.
3.Determination of ovulation
Mid-luteal P>16nmol/L (5ng/ml) indicates ovulation in this cycle (except LUFS); <16nmol/L (5ng/ml) indicates no ovulation in this cycle.
4.Diagnosis of luteal insufficiency (LPD)
Mid-luteal P <32nmol/L (10ng/ml), or the sum of P measured 3 times on the 6th, 8th and 10th day after ovulation <95.4nmol/L (30ng/ml) is LPD; conversely, luteal function is normal.
5, luteal atrophy is not complete P is still higher than the physiological level on 4-5 days of menstruation, suggesting luteal atrophy is not complete.
6.Judging the prognosis of in vitro fertilization-embryo transfer (IVF-ET)
(1) P≥3.18nmol/L (1.0ng/ml) on the day of myocardial HCG injection should be regarded as elevated, which can lead to decreased endometrial tolerance, embryo implantation rate and clinical pregnancy rate. p>4.77nmol/L (1.5ng/ml) is likely to be prematurely luteinized.
(2) In IVF-ET long protocol ovulation promotion, even if there is no increase in LH concentration on the day of intramuscular HCG injection, if P (ng/ml)?1000/E2 (pg/ml) >1, it suggests possible premature follicular luteinization or ovarian dysfunction, and the clinical pregnancy rate is significantly reduced.
7.Pregnancy monitoring
(1) Changes in P during pregnancy: P is produced by the ovarian corpus luteum in early pregnancy, and placental syncytial trophoblasts are the main source of P production from 8 to 10 weeks of gestation onwards. As pregnancy progresses, the P value in maternal blood gradually increases, with blood P values of about 79.5 to 89.2 nmol/L (25 to 28.6 ng/ml) at 7 to 8 weeks of gestation, 120 nmol/L (38 ng/ml) at 9 to 12 weeks of gestation, 144.7 nmol/L (45.5 ng/ml) at 13 to 16 weeks of gestation, and 346 nmol/L at 21 to 24 weeks of gestation. The P value is about 346 nmol/L (110.9 ng/ml), and at the end of pregnancy, P can reach 312-624 nmol/L (98-196 ng/ml), and it rapidly decreases to a trace within 24 hours after delivery.
(2) Application of P in monitoring embryonic development: Measurement of serum P concentration in early pregnancy to evaluate luteal function and monitor the therapeutic effect of exogenous P can significantly improve pregnancy prognosis.
Early pregnancy P levels in the range of 79.25-92.76 nmol/L (25-30 ng/ml) suggest intrauterine pregnancy survival with a sensitivity of 97.5% and a slow increase in progesterone levels with the growth of the gestational week. Decreased P concentration in early pregnancy suggests luteal insufficiency or abnormal embryonic development, or both, but 10% of normal pregnant women have serum progesterone values below 79.25 nmol/L.
P < 47.7 nmol/L (15 ng/ml) in pregnancy suggests intrauterine gestational dysplasia or ectopic pregnancy.
P levels below 15.85nmol/L (5ng/ml) during gestation suggest a dead pregnancy, either intrauterine or ectopic.
8. Identifying ectopic pregnancy
Blood P levels in ectopic pregnancy are low, with P < 47.7 nmol/L (15ng/ml) in most patients and ≥ 79.5 nmol/L (25ng/ml) in only 1.5% of patients. Progesterone in normal intrauterine pregnancies is >79.5 nmol/L in 90% and <47.6 nmol/L in 10%. Blood P levels can be used as a reference in the differential diagnosis of intrauterine versus ectopic pregnancy.
(iii) Measurement of FSH and LH
FSH and LH are glycoprotein hormones synthesized and secreted by basophilic Gn cells of the pituitary gland and are regulated by both hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen; FSH acts on receptors on follicular granulosa cells to stimulate follicular growth and maturation and to promote estrogen secretion; the physiological role of LH is mainly to promote ovulation and luteal production and to promote luteal secretion of P and E.
In the reproductive age, the secretion of FSH and LH varies cyclically with the menstrual cycle, with the level of FSH slightly increasing in the early follicular phase, and then increasing with the development of follicles to the late follicular phase. The LH level is low in the early follicular phase, and then rises gradually to reach a peak about 24 hours before ovulation, then falls rapidly after 24 hours, and gradually decreases in the late luteal phase.
The basal values of both FSH and LH are 5-10 IU/L, reaching a peak before ovulation, and the peak LH can reach 40-200 IU/L. With the exponential increase of E2 secreted in the late follicular phase, the LH level increases 10-fold and the FSH level increases 2-fold in 2-3 days, and ovulation usually occurs 24-36 hours after the peak LH.
The measurement of FSH and LH levels in the early follicular phase allows for a preliminary determination of gonadal axis function. fsh is more valuable than LH in determining ovarian potential.
Clinical significance of FSH measurement.
1. normal basal value FSH is measured on day 1 to 3 of the menstrual cycle to understand the reserve function and basal status of the ovaries. fsh remains stable and low during the follicular phase, up to 5-10 IU/L. Basal FSH is related to the quality and quantity of eggs during ovulation promotion. with the same ovulation promotion protocol, the higher the basal FSH, the lower the number of eggs obtained and the lower the pregnancy rate of IVF-ET.
2. FSH during ovulation is about twice the basal value, not more than 30 IU/L, and drops rapidly to the follicular level after ovulation.
3, Basal FSH and LH are both <5IU/L for low Gn amenorrhea, suggesting hypothalamic or pituitary hypofunction, and the distinction between the two needs to be made with the help of GnRH excitation test. It can also be seen in hyperprolactinemia, after oral contraceptives, after pharmacological pituitary regulation, etc.
4. Basal FSH values >12-15 IU/L for two consecutive cycles suggest poor ovarian function and poor ovulation promotion efficacy. Combining CC excitation test and GnRHa excitation test can more accurately determine ovarian reserve function and predict COH effect and pregnancy rate in IVF-ET.
5. Basal FSH value >20IU/L for two consecutive cycles suggests insidious ovarian failure and predicts possible amenorrhea after 1 year.
6, Basal FSH value > 40 IU/L for two consecutive cycles and elevated LH is high Gn amenorrhea, i.e. ovarian failure; if it occurs before the age of 40, it is premature ovarian failure (POF) or ovarian insensitivity syndrome (ROS).
Clinical significance of LH measurement.
1. Normal basal value 5-10 IU/L, slightly lower than FSH, maintaining a steady low value during follicular phase.
2.Predicting ovulation
The LH peak occurs after the E2 peak and rises suddenly and rapidly, reaching 3-10 times the basal value, which lasts 16-24 hours and then falls rapidly to the early follicular phase level. Ovulation occurs 24-36 h after the blood LH peak. Since the LH peak rises and falls very quickly, sometimes the so-called peak is not the highest value of LH and needs to be detected once every 4-6 h. The urine LH peak is usually 3-6 h later than the blood LH peak, and the LH combined with ultrasound and cervical scoring is more accurate in predicting ovulation.
3, LH <10IU/L after E2 peak and follicles >18mm is the best time to inject HCG.
4, Follicular phase if E2 peak is not reached and LH>10IU/L, it predicts LUF and LUFS.
5, Basal LH <3IU/L suggests hypothalamic or pituitary hypofunction.
6, the basal LH level is elevated (>10IU/L is elevated) or maintained at normal levels, while the basal FSH is relatively low level, it forms an elevated LH to FSH ratio, LH/FSH >2 to 3, suggesting PCOS.
7, FSH/LH > 2 to 3.6 suggests inadequate ovarian reserve function and the patient may not respond well to COH.
8. Elevated LH often causes infertility and miscarriage in clinical practice. This is mainly due to high LH levels in the follicular phase (>10 IU/L) which are detrimental to both the egg embryo and the EM before implantation, especially LH induces premature maturation of oocytes, resulting in decreased fertilization and difficulty in implantation.
(iv) Prolactin
PRL is a peptide protein hormone synthesized and secreted by eosinophilic PRL cells in the pituitary gland and is regulated by both hypothalamic prolactin-inhibiting hormone and prolactin-releasing hormone.PRL has 3 forms in the blood circulation.
Monosegmental form: the relative molecular mass of
It is called small molecule prolactin and accounts for 80% to 90% of the blood circulation.
Bipartite: It is composed of two unipartite forms with relative molecular masses of
It accounts for 8-20% and is called large molecule PRL.
Multi-segmental type: There are multiple single-segmental synthesis, and the relative molecular weight can be greater than
1-5%, called large molecule PRL.
Small molecule PRL has high biological activity, while large molecule PRL has low binding ability to PRL receptors, but immunoreactivity is not affected. The clinically determined PRL is the sum of various forms of PRL, therefore, in some patients, serum PRL is elevated, but reproductive function is not affected, mainly because of the high proportion of multi-segmental PRL in the blood circulation.
Pituitary secretion of PRL is pulsatile and unstable. Emotion, exercise, nipple stimulation, sexual intercourse, surgery, chest trauma, herpes zoster, hunger and eating can affect its secretion status, and there are small fluctuations with the menstrual cycle; it has a sleep-related rhythm, with PRL secretion increasing after falling asleep and gradually decreasing after waking up in the morning, with the lowest secretion at 9-11 am. Therefore, according to this rhythmical secretion characteristic, PRL should be measured by drawing blood at 9-11 a.m. on an empty stomach and in a quiet state.
For amenorrhea, infertility and menstrual disorders, PRL should be measured regardless of the presence or absence of lactation to exclude hyperprolactinemia (HPRL), which can be determined in one test if PRL is significantly elevated, or in a second test if PRL is mildly elevated in the first test. For confirmed HPRL, thyroid function should be measured to exclude hypothyroidism.
Prolactin test value coefficient conversion.
Clinical significance of PRL determination.
1. Normal value of PRL in non-pregnancy period
~25ng/ml (222~1110nmol/ml).
2.PRL changes during pregnancy PRL begins to rise after pregnancy and gradually increases with the month of pregnancy. Early pregnancy PRL rises about 4 times as much as during non-pregnancy, up to 12 times in the middle of pregnancy, and up to 20 times in late pregnancy, about 200ng/ml or more. In non-lactating women, PRL decreases to non-pregnant levels 4-6 weeks after delivery, while in breastfeeding women, PRL secretion continues for a long time.
3.PRL elevation and pituitary tumor
PRL≥25ng/ml for HPRL.
PRL>50ng/ml, about 20% have prolactinoma.
PRL>100ng/ml, about 50% have prolactinoma, and can be done selectively with pituitary CT or MRI.
With PRL >200ng/ml, microadenomas are often present and a pituitary CT or MRI is mandatory.
In most patients, PRL levels are proportional to the presence or absence of a prolactinoma and its size. Although serum PRL level is >150-200ng/ml, it should be excluded when menstruation is regular.
4.PRL elevation and PCOS About 30% of PCOS patients have elevated PRL.
5.PRL elevation and thyroid function
In some cases of primary hypothyroidism, TSH is elevated, leading to an increase in PRL.
6.PRL elevation and endometriosis Some patients with early endometriosis have elevated PRL.
7.PRL elevation and drugs
Certain drugs such as chlorpromazine, antihistamines, methyldopa, reserpine, etc. can cause an increase in PRL level, but more than <
8.PRL elevation and amenorrhea
86.7% of menorrhagia occurs when PRL is 101-300ng/ml.
In the case of PRL >300ng/ml, 95.6% of patients had amenorrhea.
In patients with pituitary adenoma, 94% of them have amenorrhea.
In some patients with elevated PRL levels >150 to 200 ng/ml without associated clinical symptoms or whose symptoms do not explain the degree of elevation, the presence of macromolecular PRL and macromolecular PRL needs to be considered.
9.PRL decrease
Sheen syndrome, the use of anti-PRL drugs such as bromocriptine, levodopa, VitB6, etc., prolactin has been reduced to varying degrees.
(v) Testosterone
Androgens in women mainly come from the adrenal glands and a small amount from the ovaries. The main androgen products of the ovaries are androstenedione and testosterone. Androstenedione is synthesized and secreted mainly by follicular membrane cells; testosterone is synthesized and secreted mainly by ovarian interstitial cells and hilar cells. Elevated androgens in the preovulatory circulation promote atresia of nondominant follicles on the one hand and increase sexual desire on the other. There are four main androgens in the female blood circulation, namely testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). t is mainly converted from A, with 50% of A coming from the ovaries and 50% from the adrenal glands. In women, DHEA is mainly produced by the adrenal cortex. The biological activities are T, A and DHEA in descending order of strength. T has about 5 to 10 times the androgenic activity of A and 20 times that of DHEA. In premenopause, direct and indirect T from the ovaries accounts for 2/3 of the total circulating T and indirect T from the adrenal glands accounts for 1/3 of the total, thus blood T is a marker for the source of ovarian androgens. The postmenopausal adrenal glands are the main site of androgen production.
During the reproductive period, there is no significant rhythmic change in T. 98-99% of total T exists in the form of conjugates, and only 1%-2% is free and active. Therefore, the measurement of free T can reflect the androgenic activity in the body more accurately than total T.
Conversion of testosterone test value coefficients.
Clinical significance of testosterone determination.
1.Normal basal value
Total T1.04~2.1nmol/L (0.3~0.6ng/ml) in women, physiological upper limit 2.8nmol/L (0.8ng/ml); free T＜8.3nmol. T gradually decreases with age after 35 years old, but changes are not obvious or even slightly increase during menopause; T level＜1.2nmol/L after menopause.
2.Premature sexual maturity
Premature appearance of pubic and axillary hair with DHEAS >1.1umol/L (42.3ug/dl), suggesting incipient adrenal function.
A may be normal or mildly to moderately elevated, but generally <5.2 nmol/L (1.5 ng/ml). A may be elevated, and some patients have elevated DHEAS. If androgens are elevated before treatment and decrease after treatment, it can be used as one of the indicators to evaluate the efficacy.
3.Late onset 21-hydroxylase deficiency
Elevated and DHEAS elevated, while observing blood 17-hydroxyprogesterone (17-OHP) and DHEAS response of ACTH provocation test.
4.Mesenchymal follicular proliferative disorder T is elevated, but DHEAS is normal.
5.Androgen producing tumor Progressive androgen excess symptoms in short term with T level >
(1.5ng/ml), DHEAS level >18.9umol/L (726.92ug/dl) and A >21nmol/L (600ng/dl) suggest that there may be androgen-producing tumors in the ovaries or adrenal glands.
6. Hirsutism 40% to 50% of total T is elevated, and almost all free T is elevated. In female hirsutism, if the T level is normal, the hair follicles are more likely to be sensitive to androgens.
7, DHEAS is the best indicator of adrenal androgen secretion, >18.2umol/L (700ug/dl) is too much.
8, T < 0.02ng/ml, predicts low ovarian function.
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