Pituitary and hypothalamic hormones

This chapter is related to Section U1(iv) from the 2017 CICM Primary Syllabus, which asks the exam candidate to  "describe the control, secretions and functions of the pituitary and the hypothalamus". This niche topic has been popular in previous exams, and has been plumbed to a depth that most people might consider unreasonable in an exam designed to produce safe competent Intensive Care doctors. For instance, one of the SAQs asked about the cell types in the anterior pituitary, and the examiners tsked with disappointment because "few candidates described cell types as chromophils and chromophobes". Given that few of us intensivists ever need to stain pituitary gland slices to make a histological diagnosis, this seems like an assessment item that came from opening a physiology textbook on a random page. In this case, it was probably page 330 of Principles of Physiology for the Anaesthetist by Kam, as this is the only textbook in the "recommended reading" section of the syllabus that contains any reference to pituitary cells. This is typical  of all the pituitary questions from the CICM Part One, which are characterised by a disregard for assessment blueprinting. 

• Question 13 from the first paper of 2021 (list the cell types)
• Question 20 from the first paper of 2018 (structure of hypothalamus)
• Question 9(p.2) from the second paper of 2009 (list the hormones)

In summary:

Structure of the hypothalamus

The CICM examiner comments for Question 20 from the first paper of 2018 included weird remarks about how "many candidates had only a vague idea of the structure of the hypothalamus, while the best candidates were able to relate function to structure quite accurately". As already mentioned above, exactly how this made the candidates "best" is unclear, as it only demonstrated their ability to retain and recite irrelevant information. Still, irrelevant is what we do here at Φ, and the regular visitor will surely be well prepared for a pointless digression. Following from this, if "best" and "irrelevant detail" are conflated until they are basically the same concept, then Lechan & Toni from Endotext (2018) is by far the "best" reference for this topic, and is left for the interested reader to digest over many happy hours of satisfied curiosity. On the other hand, for the trainees who have no time for minutae, the following summary of hypothalamic anatomy can be offered:

Anatomy of the Hypothalamus

Landmarks: viewed from below, the optic chiasm forms the rostral boundary, and the mamillary bodies form the caudal boundaries.  Basic structural anatomy: small (4cm3) wallanut-shaped grey matter structure Relations:  Separated from the thalamus by the the hypothalamic sulcus of Monro Anterior limits: Lamina terminalis Superior limits: inferolateral wall of the 3rd ventricle Posteriorly,limited by the periaqueductal gray substance and tegmentum of the brainstem Inferiorly, connected to the pituitary by the infundibulum (hypophyseal stalk) Laterally, surrounded by the basal ganglia Blood supply:  Anteromedial branches of the ACA, Superior hypophyseal branch from the ACA Thalamoperforating branches of the PCA ​​​​​Posteromedial branches of Pcomm Venous drainage: Into the cavernous sinus via inferior hypophyseal veins Into the hypothalamo-hypophysial portal system Innervation:  Numerous connections to other CNS structures via multiple white matter tracts. According to Pop et al (2018), it connects to the midbrain, thalamus, hippocampus, amygdala, olfactory bulb, retina and to the frontal and prefrontal cortex. Efferent fibres to the pituitary via the infundibulum Function: Homeostatic control of numerous hormonal metabolic and autonomic functions

To describe the hypothalamus in a single sentence, one could do no better than Harvey Cushing, who in 1932 wrote:

“Here in this well-concealed spot, almost to be covered with a thumbnail, lies the very main spring of primitive existence – vegetative, emotional, reproductive – on which with more or less success, man has come to superimpose a cortex of inhibitions.”

As the name might suggest, this thumbnail-sized spot is found under the thalamus, and is generally described as a member of the diencephalon (i.e the bit that connects the midbrain to the rest of the brain, a centrally positioned group of structures that includes the hypothalamus, thalamus, epithalamus, pineal gland and the third ventricle). Its anatomy is difficult to comprehend because it is a small irregularly shaped group of neurone bodies crammed into a small space full of similar irregularly shaped bodies. The only space where it comes to the surface of the brain is near the optic chiasm, where hypothalamic structures extend into the infundibulum, the stalk from which the berry-like pituitary gland then hangs. Of the various artistic and artless representations of this region, the best would have to come from the Handbook of Clinical Neurology series (79, 3rd series, Vol. 1, 2003), where this work can be found on p.11:

The grey matter masses which  comprise the hypothalamus are organised into nuclei, and the relentless demands of pathological completionism beckon a writer to list them all in a table:

Hypothalamic Nuclei

Nucleus	Functions
Paraventricular	Fluid balance, milk let-down, parturition, autonomic & anterior pituitary control
Preoptic	Thermoregulation, sexual behaviour
Anterior	Thermoregulation, sexual behaviour
Suprachiasmatic	Biological rhythms
Supraoptic	Fluid balance, milk let-down, parturition
Dorsomedial	Emotion (rage)
Ventromedial	Appetite, body weight, insulin regulation
Arcuate	Control of anterior pituitary, feeding
Posterior	Thermoregulation
Mammillary	Emotion and short-term memory
Lateral Complex	Appetite and body weight control

It is hard to know whether listing these in exactly this fashion would have satisfied the demands of the CICM examiners, nor whether the list is especially accurate (though it does come from a reputable resource). More dangerously, it opens numerous fascinating rabbit holes to swallow the time of the careless reader. For example, one feels positively compelled to discover what amazing unethical experiments must have led the original author of this list to attribute "Emotion (rage)" to the dorsomedial nucleus. More importantly, seeing this list of functions, each of which seems to have some fundamental importance, one might ask - how exactly did this little chunk of tissue become so important? Well: the hypothalamus in fact predates the development of the vertebrate brain, and appears to have arisen as a neurosecretory structure integrating sensory input (mainly visual) into some level of photoperiodism for the early protochordate species (one can imagine a jawless ancestor rolling around the bottom of a shallow Cambrian sea, vaguely sensing the seasonal change in sunlight with some kind of photosensitive pits). From being able to sense the length of days come all sorts of regulatory benefits, for example being able to time the activity of your reproductive system and your metabolism to the seasonal flux in the abundance of prey. It would therefore make sense that this small neuroendocrine structure would gradually infiltrate all the uppermost tiers of nervous system bureaucracy, to gain control of these intimate functions. It is therefore not surprising that modern chordates all seem to have some version of a hypothalamus and a pituitary gland which is divided into a neurohypophysis and adenohypophysis portions (Norris & Carr, 2013); and all it does on its way up the evolutionary tree is grow more nuclei and move further and further from the third ventricle. 

Functions of the hypothalamus

The most rapidly accessible list of these comes from Pop et al (2018). This little lump of grey matter has a lot of critically important functions, and therefore most of these topics are explored elsewhere under different titles. Apart from trying to avoid another 8,000 word monograph, there is a purely pragmatic reason for not including more details about these functions in this section.  Exam questions which would ask you about the structure and function of the hypothalamus are unlikely to also expect a detailed breakdown of the mechanisms that regulate the tonicity of the body fluids, and questions about body fluid tonicity are unlikely to expect a lot of detail about the structure and function of the hypothalamus. It seemed reasonable to separate the topics as far as possible. Thus, the functions of the hypothalamus are listed here in the briefest possible form, in the form of links to other pages on this site.

• Thermoregulation
• Homeostasis of body fluid tonicity
• Autonomic regulation
• Arousal and emotions
• Regulation of satiety
• Circadian rhythm
• Control of pituitary endocrine function

The latter function is exercised by the secretion of hypothalamic hormones which stimulate or inhibit the secretion of pituitary hormones, and which are the subject of the next section.

Endocrine regulatory function of the hypothalamus

The hypothalamus secretes the following six hormones:

• Thyrotropin-releasing hormone (TRH)
• Gonadotropin-releasing hormone (GnRH)
• Growth hormone-releasing hormone (GHRH)
• Corticotropin-releasing hormone (CRH)
• Somatostatin
• Dopamine

The most basic representation of this control system would have to be this:

• Hypothalamic cells release a hypothalamic hormone into the local portal circulation
• This hypothalamic hormone stimulates the release of a pituitary hormone
• The pituitary hormone is released into the systemic circulation and it does stuff
• The concentration of the pituitary hormone itself, or the stuff it does, is detected by the hypothalamus, where it affects the rate of release of the hypothalamic hormone in a negative feedback loop

Or, in the stylistic fashion expected by CICM examiners:

• Stimulus: circulating endocrine hormone level, eg. thyroid hormone
• Sensor: chemosensors in the hypothalamus
• Afferent: connections between hypothalamic nuclei
• Efferent: secretion of hypothalamic hormone (eg. TRH) into the hypothalamo-hypophysial portal system
• Effector: Pituitary secretory cells release the next regulatory hormone, in this case TSH
• Effect: Stimulation of endocrine gland activity, eg. thyroid hormone release by TSH

Considering the secretion of hormones into the systemic circulation is the main objective at the end,  one might ask: why do we even have the pituitary gland as the middle man?  Surely the duplication of hormonal secretory organs here is a pointless redundancy; why can't the hypothalamus just directly influence the effector organs?

Reader, what appears as an inefficiency is in fact a clever method to minimise the neurosecretory work of the central nervous system. The entire endocrine regulatory pathway can be described as a "cascading amplifier" (Hall & Gomez-Pan, 1976), and this design is necessary. By creating a hormonal cascade like this, a handful of well-connected neurons in the CNS can influence the secretion of whole buckets of hormonal products without themselves having to be the centre for their synthesis and storage. Consider the total bulk of the endocrine pancreas, thyroid, adrenal glands and various other scattered endocrine tissues throughout the body - their mass is rather substantial, and to keep all this secretory machinery in the central nervous system would be an inefficient use of premium space (and already the human female pelvis would patiently point out that human heads are as big as they could possibly get, and should never grow any larger). 

So, owing to the singular arrangement between the hypothalamus and pituitary,  hypothalamic hormones can afford to be small fragile peptides, unaffiliated with any chaperone protein, and largely defenceless against degradation in the bloodstream - because they only need to exist in the circulation for the seconds it takes for blood to flow along the short portal system. From this, one might guess that their concentration in the peripheral circulation is miniscule, making it almost impossible to detect them (for example, much of Roger Guileimin's 2005 retrospective is spent in discussing the practical difficulties he and his team faced in identifying and characterising these substances in the 1970s).  Out of respect for these early pioneers, sweating thanklessly over a liquid chromatograph, let us discuss these hypothalamic hormones, albeit briefly. 

Hypothalamic hormones

What follows mainly came out of the Hypothalamic Hormones chapter by Stratakis & Chrousos from Endocronology (2005):

• Thyrotropin-releasing hormone (TRH)
  • Tripeptide (just pGlu-His-Pro-NH₂)
  • Secreted in a pulsatile fashion, cycle time of about 2-4 hours
  • Secretion responds mainly to T4 levels
  • Deficiency results in hypothyroidism
• Gonadotropin-releasing hormone (GnRH)
  • Decapeptide (highly preserved: all vertebrates basically have the same GnRH)
  • Secreted in a pulsatile fashion, cycle time of about 90 minutes
  • Secretion responds to emotional stress, circadian rhythm, and sexual stimuli
  • Deficiency (Kallman syndrome) results in hypogonadism and anosmia
• Growth hormone-releasing hormone (GHRH)
  • Three isoforms, all large (37 40 and 44-amino-acid peptides)
  • Secreted in a circadian fashion, mostly during sleep
  • Secretion responds to physiological stress (eg. critical illness), and is inhibited by somatostatin
• Corticotropin-releasing hormone (CRH)
  • 41-amino-acid peptide
  • Glucocorticoid concentrations are the main regulatory factor over release
  • Secretion has numerous other regulatory factors (eg. stress) and is often linked to the secretion of vasopressin (i.e. the same stimuli result in the release of both)
• Somatostatin
  • Tetradecapeptide (14 amino acids)
  • Six receptor classes in the family, the pituitary one is SSTR-2
  • Secretion is regulated by GH levels, but also by many other factors
  • Unlike the other hypothalamic hormones, this one is not a "releasing hormone", as it suppresses secretion
• Dopamine
  • Catecholamine, monoamine
  • Specifically for the hypothalamus and pituitary, it suppresses prolactin secretion 

Apart from all being peptides (apart from dopamine, which is a monamine), there are a lot of other shared characteristics among all these hormones:

• They all bind to G-protein coupled receptors in the pituitary
• They are all without a transport protein
• They all get degraded very rapidly in the blood
• Their potency is low, which means they can really only be active in the hypothalamo-pituitary portal circulation, and they would be completely useless in the peripheral blood unless administered in titanic concentrations
• Virtually all of them are not unique to the hypothalamus, and can be secreted by other CNS structures, with some (eg. TRH, dopamine ) routinely used as neurotransmitters and neuromodulators

Structure and function of the pituitary

This section would not be necessary if not for Question 13 from the first paper of 2021, which asked the trainees to "list the cell types in the anterior pituitary gland". This was the question that required the trainees to correctly remember a nineteenth-century classification system for pituitary cell types.

To get this out of the way:

• Chromophil cells:
  • Acidophils cells:
    • Somatotrophs (secrete GH)
    • Mammotrophs (secrete prolactin)
  • Basophil cells:
    • Corticotrophs (secrete ACTH and MSH)
    • Thyrotrophs (secrete TSH)
    • Gonadotrophs (secrete LH and FSH)
    • Posterior pituitary cells (secrete oxytocin and vasopressin)
• Chromophobe cells:
  • Amphophils: epithelial cells
  • Melanotrophs: secrete MSH

This whole thing is based on the tendency of cells which produce peptide hormones to store these hormones in granules, and specifically on the tendency of these granules to collect the kind of pigment that the aforementioned nineteenth-century histologists were using. Specifically, we owe this to Adolf Schönemann (1892), who initially demonstrated that they stained differently with eosin and haematoxylin, and later realised that any basic or acidic dye will do. Though CICM examiners confidently state that "chromophil cells stain by absorbing chromium salts", this is in fact entirely incorrect - the name refers to their uptake of colour in general (hence chroma, χρῶμα), of which the secretory cells are broadly fond, as they will stain with a large selection of different dyes. It does not help that the staining methods are also often referred to as "trichrome" or "tetrachrome", to indicate that they produce three or four different colours among the cell populations. The confusion of the CICM examiners may be traced to a consistent error made by the exam candidates who referred to chromaffin cells in their answers - these are the catecholamine-secreting endocrine cell type in the adrenal medulla, which do in fact stain when exposed to chromium salts, as their granules oxidise and turn brown. To be fair, other reputable authors have also been similarly confused. Even back in 1929, R.A  Young, writing on "diseases of the pituitary body", remarked:

"One author, in a book on the ductless glands, states that "the cells of the
anterior lobe are divided into 'chromophil ' and 'chromophobe,' according to whether
they stain with chrome salts or not"; chrome here means chrome, not colour, and
chromophil ijs the same as chromaffin. I have looked at some sections that had
been mordanted in Müller's solution [chrome salts] for three days; I could see no granules in any of the cells and I feel sure that this confusing statement is wrong."

Blaming CICM for this digression, we can now move on to properly characterise the pituitary gland. Musumeci et al (2015) was probably the best resource for this part of the chapter, and is manageable at only eleven pages, but the harried trainee is redirected to something shorter and more skimmable, as they are generally warned against trying to revise using any resource which has the words "A journey" in the title, or which begins with "it is virtually impossible to address the subject without a brief overview of the scholars and discoveries that have marked its history". One could certainly argue that it is possible to address the subject without that, pointing to works by more prosaic authors (eg. Amar & Weiss, 2003).

Anatomy of the pituitary gland

This thing is a small 500-600mg scrotum-shaped object, about 10 × 15 × 5 mm in the adult, and the only exciting factoid about these dimensions is that it basically doubles in size during pregnancy. The trainee asked to describe its anatomy (unlikely as this is) would have to fall back on some sort of answer structure, such as the following:

Anatomy of the Hypothalamus

Landmarks: viewed from below, the optich chiasm forms the rostral boundary, and the mamillary bodies form the caudal boundaries.  Basic structural anatomy: small gland, consisting of three lobes, and suspended from the hypothalamus on a stalk (infundibulum) Relations:  Anterior, posterior, inferior limits: the bony walls of the sella turcica.  Anterior wall: tuberculum sellae Posterior wall: dorsum sellae Floor of the sella turcica is the roof of the sphenoid sinus Superior limits: roof of the sella turcia, the diaphragma sellae (above which lays the optic chiasm) The infundibulum extends through a central aperture in this roof Lateral limits: folds of the diaphragma sellae which become continuous with the dura of the base of skull Blood supply:  Individual blood supply: Superior hypophyseal artery supplies the anterior pituitary via the portal hypophyseal vessels Inferior hypophyseal artery supplies the posterior pituitary Venous drainage: Into the cavernous sinus via anterior and posterior hypophyseal veins Innervation:  Innervated via fibres from the hypothalamus, via the infundibulum Function: Homeostatic control of hormonal functions (the second stage of the hormonal regulatory amplification cascade)

Some functional differences must be noted between the lobes of the pituitary:

• The anterior lobe is the larger, more busy from a secretory standpoint, and highly vascular (full of highly permeable sinusoidal capillaries extending from the portal network). The cell population here is mainly somatotrophs (50%), mammotrophs (10-25%) and ACTH-secreting corticotrophs (15-20%). Gonadotrophs are fewer (5-10%) and thyrotrophs are the rarest (3-5%).
• The posterior lobe is basically the terminal nerve endings of a hundred thousand hypothalamic neurons. The material of the posterior lobe is mostly axons, coddled by the attentions of some chromophobic neuroglia; the cell bodies are mainly in the supraoptic and paraventricular nuclei of the hypothalamus.
• The intermediate lobe is a thin sliver of poorly vascularised material, less than 1% of the total mass of the pituitary, and is mainly composed of agranular cells which do not stain with anything and which do not secrete anything of any great interest. Scrutinised closely, most of these cells seem to be a lost tribe of astrocytes. Various attempts have been made to attribute some physiological importance to this lobe, and various hormonal products have been identified which seem to be synthesised there (pro-opiomelanocortin, for example, and its product the melanocyte-stimulating hormone MSH), but in humans it seems to be underdeveloped and pointless. Weirdly, even though most vertebrates have this lobe, a lot of hairless mammals  (besides humans, also whales, dolphins and elephants) have a sorry-looking neglected version, whereas hairier animals (sheep, horses) and animals which enjoy a certain pizzazz in their pigmentation (amphibians) seem to have a vigorously developed one. A deep rabbit hole awaits the misplaced attention of an easily distracted reader in Howe, 1973, and Jenks et al (2018).

Pituitary hormones

The critical care trainee will at some stage potentially be asked to list these, and to attribute them to gross anatomical regions within the pituitary:

• Anterior pituitary hormones:
  • Thyroid stimulating hormone (TSH)
  • Corticotropin (ACTH)
  • Pro-opiomelanocortin
  • Growth hormone (GH)
  • Follicle-stimulating hormone (FSH)
  • Luteinising hormone (LH)
  • Prolactin
• Posterior pituitary hormones:
  • Oxytocin
  • Vasopressin

Alternatively, a sadistic exam question may ask the candidates to classify them chemically. They are rather different on a molecular level:

• ACTH, prolactin and growth hormone are (rather large) polypeptides
• LH, FSH and TSH are heterodimer glycoproteins
• Oxytocin and vasopressin are small cyclic peptides (specifically nonapeptides)
• Pro-opiomelanocortin is a 241–amino acid glycoprotein which really doesn't do much on its own, but acts as a precursor for more interesting things produced in peripheral organs

More detail than this would be an unexpected level of wickedness from even the famously evil CICM First Part examiners, but it would probably not hurt to know a little bit about these hormones, even only to randomly recall a fact years later at some pub trivia contest. 

• Thyroid stimulating hormone (TSH) is a 211-amino-acid glycoprotein. The cycle for TSH pulses is about 2-3 hours, and nocturnal levels are double in comparison to daytime levels. Its receptor at the thyroid gland (specifically, at the membrane of thyroid follicular cells) is a Gs-protein-coupled receptor. An element of its molecular weirdness is the dimeric glycoprotein structure: the 92-amino-acid α-subunit is the same in TSH, LH, FSH and β-hCG, whereas the β subunit varies for all of these hormones, and is the main reason for all their different physiological effects. 

• Luteinising hormone (LH) is a 212-amino-acid glycoprotein with a half-life of about 20 minutes. The receptors which bind it are Gs-protein-coupled and are expressed mainly by the ovaries and testes.
• Follicle-stimulating hormone (FSH) is a 213-amino-acid glycoprotein with a half-life of about 3-4 hours, which also binds to a G protein-coupled receptor. The target tissues are male gonadal germ cells, where it stimulates spermatogenesis, and the ovary, where it stimulates the recruitment of immature ovarian follicles.
• Pro-opiomelanocortin is a peptide precursor from which multiple other molecules are made, including:
  • ACTH
  • α-melanocyte-stimulating hormone (MSH) which regulates pigmentation
  • β-lipotropin, which is itself cleaved into smaller fragments
  • β-endorphin
  • corticotropin-like intermediate lobe peptide (CLIP)
  • All of these daughter molecules can be processed in the cells of the pituitary itself, or at distal sites
• Corticotropin (ACTH) is a 39-amino-acid peptide that is secreted with a circadian rhythmicity, and which binds to Gs protein coupled receptors on the surface of adrenocortical cells, where it stimulates steroid synthesis
• Growth hormone (GH) is actually two large (191-amino-acid polypeptides which bind to a transmembrane receptor with intracellular tyrosine kinase signalling (mainly mediated by JAK2). Some of it circulates bound to a dedicated chaperone molecule (unimaginatively named GHBP, where BP is Binding Protein), which - unlike the vast majority of chaperone molecules - is not a globulin produced by the liver, but is actually a soluble fragment of the extracellular portion of the GH membrane receptor. Only half of the circulating GH is bound in this way, and the rest is free, which is bizarre (if you have a dedicated chaperone protein, surely you'd want to tour the circulation in its close company, otherwise why have one at all?). The half-life of this hormone is about 20-40 minutes, which is probably much shorter than the duration of its physiological effects.
• Prolactin is a 199-amino-acid peptide with a half-life of 20-40 minutes. Its release is stimulated by oestrogen, and inhibited by dopamine binding to D2 receptors. The latter inhibitory effect is why dopamine antagonists (antipsychotics, antiemetics) can have galactorrhoea as a side effect. An exciting effect of pregnancy is the massive proliferation of these cells, going from 15% to 70% of the total pituitary volume.
• Oxytocin is a nonapeptide that binds to a Gq-coupled receptor, ostensibly mainly on myometrial cells but also elsewhere - most notably in the CNS. Its non-uterine effects are numerous and fascinating (for example implicated in the origins of social group interaction, sexual arousal, maternal behaviours, and mood regulation).
• Vasopressin is also a nonapeptide, with a half-life of perhaps 5-10 minutes in the healthy individual. It binds to three main families of receptors: the V1a and V1b receptors (Gq-coupled) and  V2 receptors (Gs-coupled). The effects of vasopressin are described in more detail elsewhere, and here it will suffice to say that the main destinations for it are the vascular smooth muscle and the distal nephron