(See below for definitions of specific terms)
When NIH scientists did their research in the early 1970s on
measuring and identifying hCG, they were not sure what the role
of hCG was in normal pregnancy, what normal levels of hCG should
be, or how they would rise and fall during the course of the
Much research has been done, however, in the last 30 years,
to answer these questions. Here is what happens during the menstrual
cycle and pregnancy as it relates to hCG.
There are three phases of the menstrual cycle:
1. Follicular phase: the pituitary gland increases release
of follicle stimulating hormone (FSH) and luteinizing hormone
(LH). FSH stimulates growth of follicles in the ovary and prompts
the release of estrogen from the ovary. Estrogen, in turn, causes
the thickening of the endometrium. One follicle will mature
and release an ovum (egg). LH is secreted mid-cycle, and stimulates
the release of that ovum from the follicle in the ovary.
2. Ovulatory phase: The ovum is released from the follicle
and makes its way down the fallopian tubes toward the uterus,
perhaps to be fertilized along the way. There are increased
levels of LH during this phase. An ovulation prediction kit
will detect a surge in LH about 1-2 days before ovulation.
3. Luteal phase: this covers the time from ovulation
through the next menstrual period. Following ovulation the follicle
that released the ovum closes and becomes the corpus luteum.
LH sustains the corpus luteum until, in the event of pregnancy,
it is supported by hCG. Increased production of estrogen and
progesterone follow. Both hormones prepare the endometrium for
the implantation of a fertilized egg.
If pregnancy does not occur: the corpus luteum regresses,
the hormone levels of progesterone and estrogen go back down,
and the breakdown of the endometrium causes menstrual bleeding.
The corpus luteum will last 10 to14 days and then die.
If pregnancy does occur, the corpus luteum begins to
produce hCG. This hormone stimulates the corpus luteum, preventing
it from dying in early pregnancy. The corpus luteum produces
estrogen and progesterone in the early part of the pregnancy,
and is therefore vital for maintaining that pregnancy. Later,
these hormones will be produced by the placenta. Therefore,
if the corpus luteum does not function early on, the uterine
lining will not support a pregnancy. Menstruation will occur
and the pregnancy will miscarry. hCG is produced by the placenta
in pregnancy, specifically by what is called the trophoblast
of the chorionic villi. Levels are higher in the first trimester
and then decrease as other hormones take over the job of protecting
the embryo and, later, the fetus.
If, for any reason, the embryo does not develop normally, the
trophoblast will lose its capacity to sustain the rapid rise
in hCG necessary to maintain the corpus luteum. To force support
of the corpus luteum and sustain a pregnancy, hCG can be used
clinically as part of IVF (in-vitro fertilization) and other
Endocrinology: Endocrinology is the study of the nature
and effects of hormones. Reproductive endocrinology, then, is
the study of hormones related to reproduction.
Hormone: A hormone is a “chemical messenger”
produced in the human body by the endocrine glands. The hormone
then acts on a distant target organ.
Chorion: the outermost protective membrane around the
fetus. The life-support system for the embryo and fetus will
be the the chorion, amnionic fluid, the umbilical cord, and
Gonadotropin: any substance that stimulates the gonads
(ovary/testes). The three main human gonadotropins are: FSH
(follicle stimulating hormone), LH (luteinizing hormone), and
hCG (human chorionic gonadotropin). Their functions in female
reproduction are explained above in the description of the menstrual
cycle. TSH (thyroid stimulating hormone) also shares biological
characteristics with these hormones.
Corpus luteum: a yellow glandular mass remaining in the
ovary after a follicle has ruptured to release its ovum.
Hemagglutination: Hemagglutination tests are based on
an antigen-antibody reaction. Distilled water and urine are
added to a freeze-dried mixture of hCG antiserum from rabbits
and hCG-coated red blood cells from sheep. If there is no hCG
in the urine, the antibodies bind to the sheep cells, resulting
in clumping (or, more technically, “hemagglutination”).
If there is hCG in the urine, the antibodies will bind to it,
instead, causing the sheep cells to fall out of solution and
forming a reddish-brown ring at the bottom of the vial. This
ring is a sign of pregnancy. Hemagglutination tests were used
at doctor’s offices to diagnose pregnancy in the 1960s
Antigen, antibody, antiserum: An antigen is a substance
that can act on the immune system and cause the system to create
antibodies against it. An antibody is made by the immune system
as part of a process to destroy the antigen. An antiserum is
created by scientists. It is a blood serum that contains antibodies
to known antigens. Antiserums are often prepared from immunized
rabbits or other animals, as was the case with the antiserum
to the beta-subunit of hCG. This process is often used in the
diagnosis and treatment of disease.
Scientists in NICHD’s Reproductive Research Branch developed
a radioimmunoassay in 1972 to detect and measure hCG. This
was an improvement on previous bioassays and immunoassays
used to detect the presence of certain hormones.
Bioassay: A bioassay is a test that uses animals or
live tissue to look for a response to the hormone that is
injected or added.
Immunoassay: An immunoassay is a test that uses antibodies
directed against the hormone to “capture” the
hormone. The test involves using materials or substances that
are related to or are part of the immune system. To perform
an immunoassay, a scientist introduces cells from the immune
system with serum that may or may not have an antibody, and
observes whether or not the cells clump together.
Radioimmunoassay: A radioimmunoassay uses a radioisotope
as the label to detect and measure the amount of hormone present
in the sample.
JV: The biologic assays were too insensitive. A
couple of years before I arrived here in Bethesda, [NCI researcher]
Roy Hertz had developed a way of treating choriocarcinoma
with chemotherapy, and in order to monitor whether they had
cured the patient, they had to use bioassays, and the bioassays
were not very sensitive. They are about a thousandfold less
sensitive than radioimmunoassays.
JV: The first time we tried using I125 [the radioactive
isotope of iodine] -- it had never been used before for labeling
hormone for doing radioimmunoassay -- it worked. I just made
some guesses how to do it, and it worked. It’s nice
when that happens. It saves a lot of grief.
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Early e.p.t test kit, courtesy Pfizer,