Vagaries of beta HCG

GSD (mm)    what will be serum Beta-hCG? In 95% percentile
5               1,026 iu/l
6               1,226/l
7               1,465/l
8               1,749/l
9                                 2,085
10                               2,483
11                                2,952
12                                  3,502
13                                 4,145
14                                   4,894
15                                 5,766
16                                  6,776
17                                   7,964
18                                   9,343
19                                    10,951
20                                     12,820
21                                     15,020
22                                     17,560
23                                      20,573

ECTOPIC

B hcg class in EP ,Progesterone value < 9.4 mg/ml=ep,B hcg in serum is detectable if this is  > 5mlu/ml. But not at urine unless serum Beta HCG is >20 -25.HCG is secreted  from   Syncititotrophoblasrs  on day 5 to day -8 of implantation, & at thIs stage the doubling time- After 7 weeks  time is high i.e.3.5

Surprisingly 30% of EP can show normal rising B HCG. But in rest 70 % rise is slow and in some cases HCG may remain plateau or even   fall. Therefore abnormal B hcg is suspicious but not conclusive. Fr EP .  So only serial mean titre can help in diag of EP about the exact diag.

Therefore EP can have NORMAL /rising / or even fall of B hcg below the expected value B hcg delay in rise (show)

Falling B hcg

UPT will be (+)-13 day after

Blood (+) 9 days after

Average of 3 CRL sacs (GSD)

TVS findings –From LMP

Pertaining to Menstrual week

4^th M week =2 mm sac

5^th M week=5 mm sac

6^th m week=10 mm  sac

7^th m week=20 mm sac

8^th m week=25mm sac

Vaginally   sac can be seen if serum

B hCG  is > 1500 to 1000 but by TAS ( ABD Scan) only if > 3000

Serum level of hCG:-from LMP of a regular fertile cycle:-

16-23 days= 10-30 Iu

24-30 days= 30-100

31-38  days-10,000 to 160000

Day 35-day 45= 200-4000

2-3 m=12000-200000

12weeks=10000

Second tri= 24000-55000

3^rd tri= 6000-48000

VIABILITY SCAN :-

Blighted ovem –

Gsd >8 mm but no anembryonic pregnancy GSD >16 mm, no f.p. signs of failing IUP:- a)bradycardia in relation to CRL, MSD

b)  CRL is < 5 mm i.e. oligoamnitic sac

c)  poor sac growth profile

d)large y. sac >5.6 mm priod to 10 weeks / abnormal y. sac

e) disappearance of CL

Human chorionic Gonadotropin

This so called pregnancy hormone is a glycoprotein with biological activity similar to luteinizing hormone. Both act via the same plasma membrane LH hCG receptor.

Source of HCG synthesis in preg period:  Although hCG is produced almost exclusively in the placenta. Low levels are synthesized in the foetal kidneys . Other fetal tissues produce either the B subunit or intact hCG molecule

Various malignant tumors alao produce hCG sometimes in large amounts –especially trophoblastic neoplasms .  Not impossible either:-!!!Chorionic gonadotropin is in vey scant aount in  the anterior pituitary gland. Nonetheless the detection of hCG in blood or urine almost always indicates pregnancy.

Chemical Characteristics

Chorionic gonadotropin is a glycoprotein with a molecular weight of 36,000 to 40,000 Da. It has the highest carbohydrate content of any human hormone -30 percent. The carbohydrate component and specially the terminal sialic acid , protects the molecule from catabolism. The 36 hour plasma half life of intact hCG molecule is composed of two dissimilar subunits termed a and b subunits. These are noncovalently linked and are held together by electrostatic nd hydrophobic forces.

 Isolated subunits are unable to bind the LH-hCG receptor and thus lack biological activity.

This hormone is structurally related to three other glycoprotein hormones –LH, FSH, and TSH. All four glycoproteins share a common a subunits.

The B-subunits ,although sharing certain similarities are characterized by distinctly different amino- acid sequences. Recombination of an a and a B subunit of the four glycoprotein hormones gives a molecule with biological activity characteristic of the hormone from which the B- subunit was derived.

Biosynthesis

Syntheses of the alpha  and beta  –chains of hCG are regulated separately. A single gene located on chromosome 6 encodes the a-subunit common to hCG,LH,FSH andTSH . Seven genes on chromosome 19 encode for the B hCG and one for B-LH . Both subunits are synthesized as larger precursors which are then cleaved by endopeptidases. Intact hCG is then assembled and rapidly released by secretory granule exocytosis. There are multiple forms of hCG in maternal plasma and urine that vary enormously in bioactivity and immunoreactivity. Some result from enzymatic degradation and other from modifications during molecular synthesis and processing.

Before 5 weeks hCG is expressed in both syncytiotrophoblast and cytotrophoblast . Later in the first trimester when maternal serum levels peak hCG is produced almost solely in these syncytiotrophonlast . At this time m RNA concentrations of both a and B subunits in the syncytiotrophoblast are greater  than at term . This may be an important consideration when hCG is used as a screening procedure to identify abnormal fetuses.

Different units & subunits make Obstetricians confused as confused we are with PNDT Lc & CPA subclasses:-Circulating free B-subunit levels are low to undetectable throughout pregnancy. In part this is the result of its rate limiting synthesis. Free subunits that do not combine with the B subunit are found in placental tissue and maternal plasma. These levels increase gradually and steadily until they plateau at about 36 weeks gestation. At this time they account for 30 to 50 percent of hormone. Thus a hCG secretion of complete hCG molecules is maximal at 8 to 10 weeks.

Concentrations of hCG in serum and urine

The combined hCG molecule is plasma of pregnant women 7 to 9 days after the midcycle surge of LH that precedes ovulation. Thus hCG likely enters maternal blood at the time of blastocyst implantation. Plasma levels increase rapidly doubling every 2 days in the first trimester. Appreciable fluctuations in levels for a given patients are observed on the same day evidence that trophoblast secretion of protein hormones is episodic.

Intact hCG circulates as multiple highly related isoforms with variable cross reactivity between commercial assays. Thus there is considerable variation in calculated serum hCG levels among the more than a hundred available assays . peak maternal plasma levels reach approximately 100,000 mlU/mL between the 60^th and 80 th days after menses. At 10 to 12 weeks plasma levels begin to decline and a badir is reached by approximately16 weeks . Plasma levels are maintained at this lower level for the remainder of pregnancy .

The pattern of hCG appearance in fetal blood is similar to that in the mother. Fetal plasma levels however are only about 3 percent of those in maternal plasma . Amnionic fluid hCG concentration early in pregnancy is similar to that in maternal plasma. As pregnancy progresses hCG concentration in amnionic fluid declines and near term the levels are approximately 20 percent of those in maternal plasma.

Maternal urine contains the same variety of hCG degradation products as maternal plasma . The principal urinary form is the terminal degradation hCG product the B-core fragment. Its concentrations follow the same general pattern as that in maternal plasma peaking at about 10 weeks. It is important to recognize that the so-called B subunit antibody used in most pregnancy tests reacts with both intact hCG- the major form in the plasma and with fragments of hCG – the major forms found in urine.

Regulation of hCG synthesis and clearance

Placental gonadotropin releasing is likely involved in the regulation of hCG formation. Both GnRH and its receptor are expressed by cytotrophoblasis and syncytiotrophoblast. GnRH administration elevated circulating hCG levels and cultured trophoblast cells respond to GnRH treatment with increased hCG secretion. Pituitary GnRH production also is regulated by inhibin and Activin. In cultured placental cells Activin stimulated and inhibin inhibits GnRH and hCG production.

Renal clearance of hCG accounts for 30 percent of its metabolic clearance. The remainder is likely cleared by metabolism in the liver .Clearances of B and a- subunits are   approximately 10- fold and 30-fold respectively greater than that of intact hCG.

Biological Functions of hCG

Both hCG subunits are required for binding to the LH-hCG receptors are present in various other tissues but their role there is less defined. The best –known biological function of hCG is the so called rescue and maintenance of corpus luteum function that is continued progesterone production. Bradbury and colleagues found that the progesterone producing life span of a corpus luteum of menstruation could be prolonged perhaps for 2 weeks by hCG administration . This is only an incomplete explanation for the physiological function of hCG in pregnancy. For example maximum plasma hCG concentration are attained well after hCG stimulated corpus luteum secretion of progesterone has ceased. Specifically progesterone luteal synthesis begins to decline at about 6 weeks despite continued and increasing hCG production.