S2C4: The Endocrine & Reproductive Systems

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a) Role of hormones and integration with nervous system

We have covered a fair bit already in the first three chapters of this second series: the respiratory, circulatory, digestive, renal and musculoskeletal systems. In every one of those systems the word regulation has been used and the beginning of the previous chapter also mentioned form or semi-fixed shape as part of the purposes of our species having evolved a skeleton, so that spatial positioning of various parts of the organism could be ascertained and coordination could be achieved. This of course calls for signalling and communication media that can travel within the organism even where there is no innervation (meaning there are no nervous connections). This messaging role is carried out by biomolecules we call hormones and these were previously introduced in Series 1 Section 5.a and defined as “a signalling molecule used by complex organisms to carry information in another part of the organism from which it originates”. The example cited then was insulin but what should be made clear is that there is nothing intrinsically exceptional about a hormone from a chemical perspective, this special classification owes to the fact that it travels and this it accomplishes by being secreted and dumped into the circulatory system until its designated destination. Nor does a hormone remember or even know where to stop, it will simply bind to the relevant receptors, like the metaphoric key will find the right lock to insert itself into. My point here is not to be disparaging to hormones, it is to demystify their properties and highlight there is nothing we have not seen before from a molecular standpoint or in terms of chemical reactions. This doesn’t make the topic of the endocrine system, the internal messaging network relying on those chemical compounds, any less interesting; it simply shifts the focus on the coordination aspects and regulation effects.

Now, let’s start at the anatomical beginning before exploring the chain of command. Hormones are secreted by endocrine glands and like the “endo” in endocrine suggests, these are released within the body. Their counterparts, the glands secreting chemical substances directed towards the outside of the body, such as on the skin, are called exocrine glands. The major endocrine glands are the pineal gland which produces melatonin, the adrenal above the kidneys, the thyroid in our throat, and the pituitary at the base of our brain.

The next step in the system is the signalling to the organ where the relevant hormones for the job are being stored, which may or may not be the gland itself, so it can release some of the molecules into the bloodstream. This ties in with the command-and-control role of the nervous system and the central part played by the hypothalamus in this act – in fact it is involved in the regulation of so many metabolic processes, as well as that of the autonomous nervous system, that it would be too long to list but if you wish to read more about it I have included a link to the Wikipedia entry for Hypothalamus at the end of this chapter.

The hypothalamus is located at the base of our brain and is highly connected to the rest of the central nervous system; when it receives instructions it effectively translates these into chemical language by secreting hormones that are either stored in or trigger the release of other hormones by the pituitary gland located immediately below it. We will dive deeper into the hypothalamus-pituitary connection and the type of hormones they release when we examine the HPA and HPG axes in the subsequent sections of this chapter.

Once a hormone has made its way in the circulatory system and bound to a matching receptor protein, the instruction is transmitted through a chemical chain, this is called signal transduction and ultimately will result in the alteration intended by the central nervous system. To be sure, the chemical reaction is the information, there is no extra message somehow riding on top of it.

Nevertheless, that can’t be all because regulation requires a continuous assessment of a situation, which includes measuring the impact of the alteration. If you have a heater in your house, you also want a thermostat to measure and maintain the temperature within the desired range. So it is with the endocrine systems, and our organism has several ways to downregulate or upregulate so as to maintain homeostasis. It can increase or decrease the number of active chemical receptors, it can activate antagonist receptors that will offset the signal of another receptor, and it can also rely on the integration of sensory signals originating from within our body by the hypothalamus and subsequent transfer of information to the central nervous system to close the feedback loop. Indeed, most nervous fibres between the hypothalamus and the rest of the brain are bi-directional.

b) Key endocrine subsystems

We won’t be able to go through an extensive description of all the endocrine sub-systems so, instead, I thought I would provide a mid-length description of a major one in order to know more about it and better convey an idea of the complexity embedded in those subsystems. Then I will provide a shorter overview of two more sub-systems and, in the next section, focus on a fourth one which will provide the transition to the human reproductive system.

First in the list, and this reflects no specific order of importance, is the HPA axis where H is for hypothalamus, P for the pituitary gland and A is for the adrenal. There will be two more axes mentioned in this section with the initials H and P carrying the same references. The name adrenal is somewhat of a giveaway, implying it will have some effect on the renal system (refer to S2 Section 2.d) and in particular the kidneys above which they are located. Thus, unsurprisingly, the HPA axis regulates the digestive process but it does much more than that and also plays a pivotal homeostatic role in conjunction with the circulatory system, the immune system and in our organism’s adaptation to stress factors. This stress can be physical, such as fatigue or illness, or psychological, as we know only too well in our modern-day environment with deadlines and unrelenting expectations from all quarters.

In a high stress react-or-die type of situation, the limbic system in our brain will instruct the hypothalamus to produce CRH (corticotropin-releasing hormone), this hormone then reaches and stimulates the pituitary so it produces ACTH (adrenocorticotropic hormone) that travels to the adrenal where, in turn, it signals for the production of glucocorticoid hormones, and in particular cortisol, sometimes dubbed the “stress hormone”. Finally, cortisol will make its way to the liver to upregulate the synthesis of glucose and to our skeletal muscles to break down some of the glycogen stored there, thus providing the energy boost required to face the stress factor in whatever manner is most appropriate, including running away from it as fast as possible. This fight-or-flight response is further boosted by epinephrine (also known as adrenaline), also mostly produced in the adrenals, which promotes higher cardiac output and blood sugar level. Importantly, some of the cortisol in the bloodstream will make its way back up to the hypothalamus where it will downregulate the production of CRH and epinephrine will do likewise at the pituitary level in relation with ACTH production, thus completing a negative feedback loop.

Besides CRH, the other main hormone produced by the hypothalamus as part of the HPA axis is the vasopressin, also named AVP or ADH, which stands for antidiuretic hormone. Like CRH it travels to the pituitary and then flows into the circulatory system where its main roles are to raise blood pressure by constricting arterioles, and to promote the reabsorption of water from the nephrons. You may want to revisit S2 Section 2.e for details on the filtration and reabsorption processes taking place within the kidneys.

The second endocrine sub-system we’ll take a look at now is the HPT axis involving the hypothalamus, the pituitary gland and the thyroid gland situated below our Adam’s apple (and yes, both human sexes have it though the protrusion is on average more pronounced in men). At the neuroendocrine level, the hypothalamus will upregulate the level of thyroid hormones by producing TRH hormone that will then stimulate the pituitary to synthesize TSH hormones, those will in turn bind onto receptors in the thyroid, which will increase production of thyroid hormones. The feedback loop closes when the hypothalamus and pituitary sense the level of thyroid hormones has become too elevated and accordingly will downregulate TRH and TSH production.
The thyroid produces three different hormones, one is called calcitonin and helps manage Ca²⁺ concentration, a chemical compound that is key in mechanisms such as muscle contraction, as we have seen previously. The other two hormones are called thyroid hormones, there is triiodothyronine and thyroxine who go by the more convenient names of T3 and T4, respectively.
The main effect of thyroid hormones is a rise in our base metabolic rate, which is the rate at which we cycle through energy when we are at rest. This is a consequence of increased glucose synthesis and then breakdown for ATP production, higher nutrient absorption during the digestive processes, and other such upticks in various metabolic processes. Not coincidentally, these hormones also accelerate various aspects of our development, especially that of the nervous system in infancy.

The third sub-system we will look at is the renin-angiotensin-aldosterone system or “RAAS”. Renin is an enzyme secreted by the kidneys that catalyses proteolysis, the cleaving of proteins into smaller chains or single units of amino acids. The precursor to the angiotensin is angiotensinogen, it is synthesized in the liver and hydrolysed by renin to form angiotensin I. A further chemical reaction produces angiotensin II which stimulates the central nervous system to bump up vasopressin production, and as we have seen in our account of the HPA axis, this results in blood vessels constriction and an increase in blood pressure. But that’s not all, it also signals the adrenal gland to lift its production of aldosterone hormones which bind to the nephrons, in the kidneys, and influence the reabsorption of sodium (Na⁺) and the excretion of potassium (K⁺). Altogether, this translates into an increase in water retention within the circulatory system, as opposed to be flushed out of the organism by way of the urine, and consequently increases blood volume and pressure. Actually, there is more to it since angiotensin II degrades into angiotensin III and there is a v4 of the molecule, angiotensin IV, which is mostly expressed in the hippocampus within our brain. However, I think we get the gist so I’ll stop there and take this opportunity to remark as I did in S1 Section 1.b on property emergence, so right at the outset of the very first chapter in the first series, that even though in theory we could predict some of those behaviours since they all obey the fundamental laws of physics shaping our universe, in reality complexity brings in so many variables that practically it is impossible to anticipate many of those properties and behaviours, if not most of them.

And finally, the fourth major sub-system is termed the HPG axis where G stands for gonadal glands and is the topic of the next section.

c) The HPG axis and sex hormones

The gonads are known as the reproductive glands, this is where the reproductive female and male cells called gametes are produced. The chemical chain of the HPG axis unsurprisingly starts in the hypothalamus from which gonadotropin-releasing hormone (“GnRH”) is secreted. After binding to the appropriate receptors of the pituitary, it stimulates the production of two different hormones: luteinizing (LH) and the follicle-stimulating hormone (FSH). Both will act on the gonads and those, besides producing the gametes, also synthesize the sex hormones and inhibin which closes the negative feedback loop of the HPG axis by downregulating the production of GnRH and FSH.

Sex hormones fall into three categories and each have different functions though, if we are to paint them with a broad brush, these would centre on the development and function of the sex organs, the various stages of pregnancy all the way to lactation, as well as the gene regulation and ensuing expression giving rise to secondary sex characteristics.

Androgens are mostly synthesized in the testes, the male gonad, and as their Greek etymology suggests (“andr” means “man”) their principal business relates to the development of the male genitalia. The main androgen is the testosterone, during puberty its presence is key in the growth of the sex organs and other bodily appearances such as facial hair, and it remains involved in the subsequent decades by regulating sperm production and maintaining libido, the desire for sexual intercourse. Testosterone is also produced to a lesser degree in the adrenals and the female gonad, the ovaries, since it has other roles including the promotion of protein creation, something we can witness in the increase of muscle mass. There are several other androgen hormones that are relatively less important than testosterone, and those include DHEA, the precursor molecule to both testosterone and oestrogen (also spelled estrogen).

If androgens are principally about male sex characteristics and development, the role of oestrogens is mainly centred around those same aspects but for females. These include the genitalia as well as the breasts and oestrogens are also heavily involved in the regulation of the entire pregnancy process, from the menstruation cycle (pre-pregnancy) all the way through to lactation (post-pregnancy) and eventually menopause when they cease to be produced in the ovaries. Oestradiol (or estradiol) is to oestrogens what testosterone is to androgens, it is mainly produced in the follicles of the ovaries but is also synthesized in much smaller quantities in various organs, including the testes in males where it performs various functions in relation with the reproductive system. Non-sexual functions of oestradiol are varied and include an increase in bone density, metabolic rate regulation, and even coagulation (the clotting of blood).

The third and last category of sex hormones is the progestogens with progesterone as the main representative. Once again, the name is a bit of a giveaway since these hormones are mostly called upon during pregnancy, which they facilitate – not in the sense of improving the odds of fertilization but of delivering a viable offspring at the end of the gestation period. Ahead of pregnancy, progesterone is involved in downregulating the production of oestrogen post-ovulation by inhibiting the secretion and release of GnRH and LH at the level of the hypothalamus and pituitary, respectively. In case of conception, i.e. successful fertilization and implantation, secretion of progesterone will continue (though that role is then primarily devolved to the placenta) and ovulation is suspended.

d) The human reproductive system

This discussion of sex hormones and naming of various male and female sex organs seamlessly brings us to the subject of the human reproductive system. It is characterized by a marked differentiation between both sexes and is explained by the fact that our species does reproduce sexually, not a systematic occurrence among living organisms but one that can be explained in terms of the evolutionary fitness advantage it provides, including at the level of the prime replicators, the genes. I will not cover the same ground as I did in S1 Section 1.d on reproduction and inheritance, nonetheless I will reiterate the conclusion that the genetic variability ensuing from the genetic recombination taking place during the sexual reproduction translates, statistically, in useful mutations becoming the norm within a species and, incrementally, developing into fully fledged new functions and phenotypic traits or possibly internal organs.

Specialization need not be symmetrical and given the luxury of having two different individuals involved in the performance of sexual reproduction, we should fully expect the evolution of organs and processes of fertilization and pregnancy that are highly complementary rather than duplicating the same forms and functions.

The female reproductive apparatus is shaped by its role as recipient and incubator: there is an opening between the outside environment to allow for the penetration of a male sex organ and ensuing fertilization through ejaculation of semen containing male gametes, and that same opening is used, not without substantial dilation and much pain, as the way out for the offspring. The opening leads to the vagina which serves both as the birth canal and the area of copulation, where sperm is released. The vagina is attached to the uterus by way of the cervix, this is the home of the embryo and foetus development but not the final destination of the male gametes who must make their way into the fallopian tubes where fertilization will occur. The female gametes on the other hand will have made their way there after ovulation from the ovaries where they have been produced. I have included a link to the Wikipedia entry on oogenesis at the end of the chapter if you wish to read more about female gametes.

Likewise, I have included a link to the entry on spermatogenesis if you wish to know more about the synthesis of human male gametes. As mentioned earlier in this chapter, these are created in the testicles and the fluid that makes up the sperm, indispensable to ensure the survival of the sperm in the acidic environment of the uterus, is synthesized in various glands such as the prostrate and the seminal vesicles. During copulation and upon ejaculation, the sperm will flow through the urethra located within the penis.

e) Fertilization and pregnancy

Fertilization will occur when the male and female gamete fuse but this can only happen when the egg cell arrives or is already present following ovulation. And so, rather than dive headlong into embryogenesis and prenatal development, it is worth describing what is called the menstrual cycle, especially since it completely ties in with the HPG axis described in section c).

The menstrual cycle lasts on average 28 days and is regulated by the release and inhibition via negative feedback loops of the oestradiol and progesterone, with the level of the latter varying by a factor of more than 10 over the cycle. At the level of the ovaries, there are two phases of about equal duration, i.e. 14 days each: the luteal and the follicular phases. Each follicle has the potential to release one egg cell and at the end of the follicle phase one of them will release an immature egg cell called oocyte in the jargon, this is the ovulation. Fertilization must occur within 24 hours or the oocyte will degrade. During the luteal phase, the follicle releasing the oocyte is stimulated by FSH and LH hormones to produce progesterone before a negative loop picks up and results in the atrophy of the follicle.

Within the uterus, as the follicular phase of the ovaries progresses and they release estradiol, an inner layer will form called the endometrium. Subsequent to this, in conjunction with the luteal phase of the ovaries and an increase in progesterone levels, the endometrium is optimized to favour the implantation of the fertilized egg called blastocyst. Don’t worry, that is not the name of the baby. If there has not been fertilization, the levels of oestradiol and progesterone will taper off and trigger the release of hormone-like molecules called prostaglandins. These will, through a chemical and mechanical sequence of events, cause the endometrium to be deprived of oxygen and then to be shed, a process during which connective blood vessels are ruptured and heavy bleeding ensues. This is the menstruation and it marks the beginning of a new cycle.

In the case where the egg cell has been fertilized, a single diploid cell (meaning with pairs of homologous chromosomes) call zygote will have formed after which mitotic division will kick start with each one taking anywhere from 12 to 24 hours. Mitosis was described in S1 Section 5.c on cellular cycle and differentiation so you may want to have a look at it if you have not read Series 1 previously. At some point, some of those cells differentiate to form an outer layer, thus forming the blastocyst that will end up attaching itself to the endometrium layer of the uterus. In short order, the placenta will start to develop with a view to ensure the provision of nutrients and gas to the embryo, thus separating the maternal and foetal circulatory systems; it also facilitates waste filtration and removal, and it performs several regulatory functions by producing its own hormones. The next steps involve continuous cell differentiation resulting in the establishment of front-to-back and vertical differentiation (head to soon-to-be-feet) while maintaining bilateral symmetry. The nervous system then starts to grow followed by other organs, including the lungs though the blood-air barrier will not be tested until birth, nevertheless it is pretty much fully formed by end of month seven, which makes the survival of premature babies after this point much more likely.

And finally, around week 37-38 after fertilization, or 39-40 from the start of the menstrual cycle, pregnancy comes to an end when the offspring exits the maternal environment via the vagina, in the case of natural delivery. In the preceding days and hours, the foetus will have pivoted and engaged its head in the pelvis area and labour will be marked by contractions helping to push the offspring out through the dilated but still very much narrow cervix, generating sustained heavy pain in the mother since some innervated areas are put under heavy pressure, stretched and occasionally even ruptured is some areas.

f) Trivia – Serotonin & Dopamine

In this section we will learn about two key neurotransmitters also acting as hormones in our organism: serotonin and dopamine. In the process, this additional knowledge will further confirm an observation we ought to have made earlier on, which is that some techniques and mechanisms are being put to different uses by nature to perform non-similar functions and achieve non-identical results. Case in points are the two biomolecules we are about to spend some time on, they are able to bind on different receptors, though the receptors may not be able to be activated by any other molecule (think of a key which can open several locks but the locks can only be opened by one key), and thus have effects on different pathways within our body. If you ever wondered why some medication can have side effects, this is the principal reason.

Most of the serotonin in our body is synthesized in the gastrointestinal tract where it acts as a hormone to help regulate the constriction and dilation of the gut and therefore the motility of the substance being digested. It is also stored in the platelets of our circulatory system where it stimulates vasoconstriction or vasodilation. In the central nervous system, serotonin is produced in the brainstem and is involved in regulating several processes or behaviours, the main ones being mood, sleep and appetite. With respect to appetite, its effect is one of suppression by inhibiting the release of dopamine, which happens to be an appetite-inducing hormone, among other roles. Sleep is a multilayered process and serotonin is one of the key hormones involved in its regulation, however to date the entire biochemical reactions are not fully understood and serotonin seems to have a propensity to promote wakefulness as well as a somewhat opposite role in building up sleep pressure throughout the day. As for mood, the term itself lacks precision or rather is not well delineated in time; maybe we could say that mood is to emotions what climate is to weather, with the proviso that moods can change much faster than climate does. Low levels of serotonin contribute to heightened levels of anxiety and to depression. Hence, it falls into the group of what some call “feel good hormones”, alongside oxytocin, endorphins and dopamine.

This is a lay-up to discuss dopamine, arguably the best known of all non-sex hormones in popular science. Outside of the central nervous system it is involved in the regulation of various systems including the renal and immune ones. In our brain, dopamine is principally involved in promoting movement and in the build-up of reward expectation. This isn’t quite the same as pleasure, even though it is often described as the molecule of pleasure – indeed, pleasure is a sensation and, like pain, it hinges on our mind’s interpretation of data, including the context surrounding such data (well, context is part of the data). Actually there seems to be an obvious relationship between promoting movement and incentivizing actions and behaviours that will bring physical or emotional reward. Dopamine is always secreted but with varying levels; when we experience high reward with a specific substance repeatedly, this level will tend to fall back below baseline after each experience, thus causing pain and a strong bias towards repeating the experience not so much in a quest for pleasure as to avoid the pain or discomfort associated with the lack or withdrawal of said substance or experience. Prolonged low levels of dopamine also translate into a lack of motivation, which is a key contributing factor that may lead to depression.