From Cows to Hormones to Cheap Food:
It All Comes Full Circle
By: Katrina Pioli
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| A jersey cow and I at the U of I Research Dairy Farm |
Working at
the University of Illinois Research Dairy Farm has incredible upsides as an
animal science major. I started two years ago having no experience with
large animals, now dairy cows have become one of my favorite animals to be
around. I have learned and gotten so much hands on experience these past
two years. These experiences include helping give birth to a calf, seeing hooves
being trimmed, watching a surgery to untwist the abomasum (which is apart of
the cow’s stomach), and in particular feeling a super ovulated ovary. A super
ovulated ovary in basic terms is an ovary that is over stimulated by hormones
to maximize the number of eggs that it can produce in one cycle.
A couple
months ago, my boss at the dairy farm told me a veterinarian was coming to
collect ovarian eggs from two brown swiss cows we milk at the farm. This
process is called flushing. I immediately became excited because I had
never seen this process before. Skipping part of my lunch break, I
watched the veterinarian put a tube in the fallopian tube that leads to the
ovary. He then used chemically treated water to expand and contract the ovary in order
to try to irritate the follicles enough to release the eggs inside them.
The water will then carry the eggs out in the tube to a container that I was
holding at the time. After this process was done, the veterinarian
invited me to feel the ovaries of the cow. The little bumps I was feeling
were ruptured follicles. After this whole entire process, I could not
help but ponder about how these follicles on the ovaries flourish. At the
time, I knew hormones were apart of this process. But how are these hormones
made? How do they make follicles? What are these mechanisms? I was
diving headfirst into answering these questions.
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| Preview of process |
In order to
get to the final product of follicles on ovaries, I had to start from the very
beginning. I found that all the hormones that are involved in this
process are called gonadotropins or glycoproteins, but what are glycoproteins
exactly? Where do they come from? The major glycoprotein that is involved in follicular development is called follicular stimulating hormone. The hormones are produced in the anterior
pituitary. Just in case you do not know, the anterior pituitary is part
of the pituitary gland and is a very influential gland of the body. It controls different hormones to regulate organs and practically the whole body
system in general. How are these specific hormones made?
Well, I had
to go back even further in the process. Follicular stimulating hormone
consists of an alpha subunit and a specific beta subunit. The alpha
subunit is the same in other hormones, and the beta subunit is
a unique part of the follicular stimulating hormone. What is the “alpha subunit” exactly? I
found that it was not as complicated as it sounded. The alpha subunit is
basically a sequence of amino acids. Amino acids are the building blocks
for proteins. Amino acids will have a carboxylic acid group, amino group,
and unique side chain. Therefore, the alpha subunit is just a protein that
is encoded by the gene chorionic gonadotropin alpha. Recall from your
basic physiology class that genes encode for proteins so this makes
sense! The beta subunit contains a
longer amino acid sequence. To complete the structures of these hormones, n-linked glycosylation must occur, but yet another question comes up.
What exactly is glycosylation? In short, glycosylation is the process of
attaching the carbohydrate to the protein. N-linked glycosylation is
where the carbohydrate attacks the nitrogen on a specific amino acid in the
protein. In the case of FSH, a carbohydrate will attach to asparagine’s
side chain, which is an amino group (nitrogen). So now we know how FSH is
made, but what causes it to release from the anterior pituitary?
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| GnRH |
It seemed
important to know that the release of follicular stimulating hormone (FSH)
depends on the frequency and amplitude of the pulses of GnRH. GnRH will
regulate the transcription, or synthesis, of the gene that we just learned
about above (chorionic gonadotropin alpha) based on the pulses. Low
frequency of GnRH will increase the transcription of chorionic gonadotropin alpha and beta. This process then produces FSH in the anterior pituitary.
When FSH is
secreted, it will travel in the blood and attach to its receptor on the ovary
to create follicles. Before moving on to what happens when FSH binds to its
receptor on the ovary, I needed to know more about the receptor itself.
The main FSH receptor has a high affinity for FSH, which means the
hormone is very attracted to its receptor. The receptor is found on the
membrane of granulosa cells, which are the cells that make up the
follicle. The FSH receptor is part of a family called the G
protein-coupled receptors that situate themselves in the membrane; therefore
called a transmembrane receptor. In general terms, the receptor will
sense familiar molecules and then do the appropriate signaling inside the cell.
One part of the FSH receptor is hydrophobic which means it does not
dissolve in water. This is obvious since the cell membrane is made up of
a phospholipid bilayer that has a hydrophobic tails inside; therefore part of
the receptor must be hydrophobic in order for it to be a transmembrane
protein. The other part of the FSH receptor is the extracellular
domain. This domain is very important because it is where the hormone
binds.
Finally, FSH
binds to its receptor. Then what happens? The next steps are a cascade of
events. The hormone and receptor will change conformation to make
it active. The Gs alpha subunit, which is a protein on the receptor, can
now leave and signal adenylyl cyclase within the cell, or follicle.
Adenylyl cyclase will then convert ATP (which is where we get our energy!) into
cAMP. This pathway is shown below. It is done by removing two
phosphate groups and making a ring out the phosphate still attached to the rest
of the molecule. cAMP is used on an inside the cell to signal a
specific reaction. Because of the synthesis of cAMP in the follicle, protein kinase A is activated. Protein kinase A is an
enzyme. It has two regulatory and two catalytic subunits. When
there is an increase of cAMP, the enzyme is activated and breaks part the
catalytic subunits from the regulatory subunits. Transcription factors
will then be activated because of this, and mRNA transcription begins in
the cell.
That seems
like a whole bunch of mumbo jumbo, right? The activation of mRNA
transcription is essentially the end of the process in which FSH has an effect
on the ovary. What happens? What we are leading up to is the
synthesis and growth of the follicle on the ovary. FSH will cause the granulosa
cells to grow and multiply. The growth of the granulosa cells will cause
a follicle to become bigger. As you are probably fully aware, the follicle will
contain an egg. When the follicle is fully mature, it will rupture at a
particular time in the cycle where the egg will be release and have a fate of
being fertilized or not.
Coming full
circle, as I felt the brown swiss cow’s ovaries, I had no idea how complex the
mechanism of FSH was on those super ovulatory follicles I was feeling. I
could not imagine how much cooler animal science could get. All I knew
was there was one hormone that was partly responsible for the excitement I
received that day. But really it was not just that one hormone. It
was the organic chemistry in and of itself.
One thing I
wanted to end on is why should you care? The process of super ovulating
ovaries (increasing the amount of FSH to increase follicle production) is not a
new phenomenon, and it is practiced widely today. This process is so
important because we can increase the amount of good eggs, which increases
chances of pregnancy in production animals, which in turn increases efficiency.
The United States is a consumer society. We have cheap food so we
can afford to buy other things. Increasing conception rate for production
animals allows for maximum efficiency for that animal. Maximum efficiency means less input to the animal which gives us cheap food. For humans, it gives women the ability to increase their
chances of pregnancy, freeze her eggs for a later date, or donate to a woman
who has infertile eggs. These are just some ways super ovulating and the
mechanism of FSH on an ovary is important to today’s society and why it is so
exciting to me.
Resources
Bernard, Daniel, et. al. 2010. Mechanisms
of FSH synthesis: what we know, what we don’t, and why we should care.
Fertility and Sterility 93: 2465: 2485.
Simoni, Manuela, et. al. 1997. Follicle
Stimulation Hormone Receptor: Biochemistry, Molecular Biology, Physiology,
Pathophysiology. Endocrine Reviews 18: 739-773.
Bousifield, George and Diaz, James. 2011.
Synthesis and Secretion of Gonadotropins including structure function
correlates. Review Endocrine Metabolism Disorders 12: 289-302.
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