Wednesday, July 1, 2015

Thinking Asymmetrically About Hormones

Biology concepts – neuroendocrine system, bilateral asymmetry, internal asymmetry, hormones, endocrine glands

Jack Nicholson did some try asymmetric thinking
in The Shining. The fact that he was driven insane
by the ghost of a horrid past shouldn’t think less of
his accomplishments. Predicting that Shelly Duvall
would go for the radio – brilliant. Sneaking up on
Scatman Crothers – inspired. Following the boy
into the maze –oops.
Independent thinking; thinking outside the box; free thinking; lateral thinking; these are all terms for trying to come up with answers to problems through rejection of established logical methodologies. In today’s business, military and political worlds, they like to call it asymmetric thinking.

An asymmetric military engagement might be one where a traditional force is thwarted and confused by a nontraditional force of computer geeks hacking their communications and selling all their weapons on Etsy. Asymmetric thinking approaches what might be a traditional question at a creative angle, rejecting the tools and assumptions that are normally found “inside the box.”

Asymmetric thinking asks why outrageous solutions aren’t being considered. Many job interviews now include asymmetric thinking questions. A man goes into a restaurant and asks for a glass of water. The waiter points a gun at him and the man thanks the waiter and leaves. What’s your explanation for that? (see end of post)

Today we'll talk about asymmetric thinking in a different way – a lateral thinking approach to asymmetrical thinking, as it were. We have talked about the asymmetry of the brain hemispheres and how they sit asymmetrically in your skull. We have also talked about the neuroendocrine system and how it is controlled by a part of your brain that isn’t really part of your brain. Now let’s talk about the asymmetry of the neuroendocrine system as it begins in your brain and ends in the endocrine glands.

Most views show the hypothalamus from the side
(see last week’s post), so you don’t appreciate that
there are two of each nucleus. For those that dump
hormones into the pituitary gland, both sides
participate, but our story today shows that they don’t
necessarily participate equally.
The hypothalamus, as well as the paired endocrine and neuroendocrine glands (see last week's post), demonstrate significant asymmetry. I suppose that’s not so unusual - all the structures we’ve talked about in the past few weeks have structural and functional asymmetries. The weird part about it here is that we are talking about hormones being moved into the blood.

The whole purpose of the hormone system is that it can be used to bathe the entire body in functional hormones at the precise levels, so that all cells that can respond will respond. How does that jibe with an asymmetry where one gland of a pair does more than the other?

The hypothalamus is a good example. You have two halves of your hypothalamus, one in each hemisphere (sort of, see above), but they both deposit releasing hormones into the same pituitary vein complex so they can stimulate your single pituitary gland. Yet, studies show that the right hypothalamus makes more gonadotropin-releasing hormone than the left hypothalamus.

On the other hand, thyrotropin-releasing hormone (stimulates the release of thyroid stimulating hormone, TSH, from the pituitary) is higher in the left hypothalamus. Together, the results of several studies shows that the right hypothalamus plays a bigger role in controlling reproduction, while the left hypothalamus works more in metabolic rate. You have a lateralization of structure and function in your two hypothalami, just like in your two cerebral hemispheres, even though both halves work on a single pituitary gland.

How about some of the other endocrine and neuroendocrine glands?

Thyroid –  You only have one thyroid gland, which lies over the front of your windpipe in your neck. There are two lobes, one on the right side and one on the left, connected by the isthmus across the windpipe.

The thyroid receives stimulation from the anterior
pituitary release of TSH (thyroid stimulating
hormone). If for some reason you get to much
stimulation (maybe autoantibodies), or the thyroid
start making too much thyroxin on its own (tumor),
then you have Grave’s disease. In some cases, you also
get an autoantibody during Graves that attacks the
fibroblasts around the orbit of the eye. The
inflammation makes the lid retract and pushes on the
eyeball, making it bulge out of the socket. Which of these
two has thyroid eye disease?
The thyroid releases thyroxine hormones T3 and T4 into the blood that function to control your metabolic rate (see this post). Yet the right lobe of the thyroid is more vascularized and is almost always larger than the left lobe. The thyroid also has a sexual dimorphism, as it is usually bigger in women than in men, and the asymmetry of right > left is even larger in women.

The size difference may not be innocuous. Many studies have shown that thyroid diseases and cancer affect the right lobe more often than the left. And it gets weirder. A 2009 research paper from China showed that handedness may also play a role. They found that the right > left size difference was larger in right-handed people. However, the left lobe was about the same size no matter which hand the person preferred. So, does the hand you use influence the size of the thyroid, or does your thyroid predict which hand you will use? Or, is it a correlation without significance?

Parathyroid – You have four parathyroid glands – maybe. These are located on the backside of your thyroid gland (hence the name para = by). The parathyroids are important in regulating calcium levels in the body. This may seem weird, having four glands to control the levels of one element. But consider that calcium plays some major roles, from controlling muscular contraction, to neuron transmission, to at least a dozen different second messenger systems in every cell.

The parathyroids are small, only about 33 mg each, so they are easy to lose when people have surgery on their thyroid gland. A 2011 study sought to find out where they sit normally so surgeons would be able to find them and preserve them. Unfortunately, they found that position and number are quite variable. Forty-three percent of people have at least five glands instead of four. And the positions of the four common ones can be variable, they aren’t always in the same place. The extra ones can be just about anywhere! Good hunting Mr. surgeon.

If you soak bone in vinegar (acetic acid), it will remove
the calcium and leave the protein matrix. Notice that it
must be the calcium that gives bone rigidity. This isn’t
how PTH works. PTH stimulates osteoclast activity,
which removes the calcium AND the protein matrix. PTH
also decreases the amount of calcium lost in the urine,
but for some reason, we work just fine without PTH or
without its balancer hormone, calcitonin.
The thyroid and parathyroid seem to do different jobs, but they’re linked by more than just anatomy. The parathyroid hormone (PTH) made and released by the parathyroids works to increase calcium availability, by increasing bone break down (osteoclast activity, see this post) and increasing the amount of calcium recovered from the urine.

But wouldn’t you need a balancing hormone to decrease calcium levels if they get too high, so a balance could be established? This is how many hormones work; there are hormone pairs that have opposite stimulatory functions. The balancing hormone for PTH is calcitonin, made by the neuroendocrine parafollicular cells (C cells) in the thyroid gland.

But here’s the exception. Calcitonin is important in fish and birds, but it seems people and many other mammals can get along fine without it. Remove someone’s thyroid and they have to take thyroid hormone for the rest of their life. But they get along just fine without calcitonin. This is one instance where the balancing hormone isn’t necessary. It seems an asymmetry of function in calcium regulation is just fine in people.

Adrenal glands -  These glands sit on top of each kidney. You think of them as sources of epinephrine in the fight or flight syndrome, but they do much more. Adrenal (ad = of or near, renal = kidney) glands have a cortex, which is toward the outside (not the core, this always confused me), and a medulla, which is in the middle (makes more sense).

cortex of three layers and a medulla. The cells of the two
regions are of different origin, the medulla is nerve like,
while the cortex is epithelial in origin.
The medulla is neuroendocrine, the cells look like neurons and are stimulated directly by sympathetic (autonomic) nerves (see this post). The medullary chromaffin (they take up lot of stain) cells release epinephrine and norepinephrine in response to a fight or flight situation. Epinephrine and norepinephrine are neurotransmitters in many parts of the brain, and in this case they work on cells to increase heart rate, glucose availability to muscle and the like.

The adrenal cortex is made up of three layers, each produces hormones to be released into the blood. The outside most is the zona glomerulosa, which makes aldosterone to help control osmolarity and blood pressure. The zona fasiculata is the biggest, and makes cortisol that controls the metabolic rate. The zona reticularis is inner most and makes sex hormones, androgens specifically.

You have two adrenal glands – and they each do the same things in response to the same signals, either hormonal or neural. So why is the left adrenal gland almost always bigger than the right? Is it because the venous drainage of the right and left adrenals is different? In the right, the veins dump into the inferior vena cava, while the left drains into the left renal vein. I really don’t know if that would make a difference.

This is just weird. A paper from 2005 states that since
the autonomic (sympathetic and parasympathetic)
nervous system controls the neuroendocrine system,
asymmetries in the ANS can have ramifications on
endocrine function. Asymmetry in behavior can
affect ANS, which then can affect endocrines. This study
showed that feeding cows from the left side (affects right
side ANS) improved reproductive ability and lactation; so
the right ANS must have more influence on reproductive
endocrine function. Could I have some left-hand milk please?
But here’s the kicker, a group in 2002 studied the size of the adrenal glands and their functional abilities in wild animals and their domesticated counterparts; several species of foxes, minks, etc. They found that domesticated animals had a larger size difference in adrenals than did the wild versions.

What is more, when they compared aggressiveness, no matter whether the animal was wild or domesticated, the most aggressive animals had the largest size differential – always left bigger than right. This makes it sound like the medulla was involved – aggression being involved, but it wasn’t.

The increase in left adrenal size in domesticated animals was due to an oversized zona fasiculata (cortisol and other glucocorticoids), while the left adrenal asymmetry in the aggressive animals was due to a larger zona reticularis (sex hormones). Ah… now that makes some sense. Doesn’t it always come back to sex?

Next week, let’s look more into the neuroendocrine system and gender. The testes and ovaries have the most spectacular asymmetries.

(The man had the hiccups)

Ying M, & Yung DM (2009). Asymmetry of thyroid lobe volume in normal Chinese subjects: association with handedness and position of esophagus. Anatomical record (Hoboken, N.J. : 2007), 292 (2), 169-74 PMID: 19051270

Trut LN, Prasolova LA, Kharlamova AV, & Plyusnina IZ (2002). Directional left-sided asymmetry of adrenals in experimentally domesticated animals. Bulletin of experimental biology and medicine, 133 (5), 506-9 PMID: 12420075

Rizhova, L., & Kokorina, E. (2005). Behavioural asymmetry is involved in regulation of autonomic processes: Left side presentation of food improves reproduction and lactation in cows Behavioural Brain Research, 161 (1), 75-81 DOI: 10.1016/j.bbr.2005.01.007

Hojaij, F., Vanderlei, F., Plopper, C., Rodrigues, C., Jácomo, A., Cernea, C., Oliveira, L., Marchi, L., & Brandão, L. (2011). Parathyroid gland anatomical distribution and relation to anthropometric and demographic parameters: a cadaveric study Anatomical Science International, 86 (4), 204-212 DOI: 10.1007/s12565-011-0111-0

For more information or classroom activities, see:

Hypthalamus – see last week’s post

Thyroid gland–

Parathyroid glands–

Adrenal glands-